worldwide development retention category: grs019 ... · 1.2. multiple sclerosis relapsing remitting...

2012N133918_00 CONFIDENTIAL GlaxoSmithKline group of companies H3M116477

1

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Protocol

Title: Proof of Mechanism Study to Assess the Potential of GSK239512 to Remyelinate Lesions in Subjects with Relapsing Remitting Multiple Sclerosis

Compound Number: GSK239512

Development Phase Phase IIA

Effective Date: 26-JUL-2012

Subject:

Relapsing Remitting Multiple Sclerosis (RRMS), GSK239512, Histamine 3 Receptor (H3R) Antagonist, magnetic resonance imaging (MRI), magnetization transfer ratio (MTR), remyelination

Author(s):

Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

2012N133918_00 CONFIDENTIAL H3M116477

3

SPONSOR INFORMATION PAGE

Clinical Study Identifier: H3M116477

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited Five Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone:

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.

Sponsor Medical Monitor Contact Information:

RTP, North Carolina USA Phone: Mobile Phone: FAX: 1 Work e-mail:

Regulatory Agency Identifying Number(s): EUDRA CT: 2012-003627-38


4

INVESTIGATOR PROTOCOL AGREEMENT PAGE

• I confirm agreement to conduct the study in compliance with the protocol.

• I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

• I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name: _____________________________

Investigator Signature Date


5

TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS ............................................................................................... 8

PROTOCOL SUMMARY ................................................................................................. 12

1. INTRODUCTION ..................................................................................................... 13 1.1. Background .................................................................................................. 13 1.2. Multiple Sclerosis ......................................................................................... 13 1.3. H3 Receptor, GSK239512 and MS Preclinical Background .......................... 14 1.4. GSK239512 Clinical Experience .................................................................. 14 1.5. Rationale ...................................................................................................... 16

1.5.1. Study Rationale ............................................................................. 16 1.5.2. Dose Rationale ............................................................................. 16

1.6. Summary of Risk Management .................................................................... 17

2. OBJECTIVE(S) AND ENDPOINTS .......................................................................... 20

3. INVESTIGATIONAL PLAN ...................................................................................... 22 3.1. Study Design ................................................................................................ 22 3.2. Study Design Schematic .............................................................................. 24 3.3. Discussion of Design .................................................................................... 24

3.3.1. Primary Endpoint Rationale .......................................................... 25

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 26 4.1. Number of Subjects ...................................................................................... 26 4.2. Eligibility Criteria ........................................................................................... 26

4.2.1. Inclusion Criteria ........................................................................... 26 4.2.2. Exclusion Criteria .......................................................................... 28 4.2.3. Randomization Criteria ................................................................. 31

4.3. Screening/Run-in Failures and Rescreen .................................................... 32 4.4. Withdrawal Criteria ....................................................................................... 32

5. STUDY TREATMENTS ........................................................................................... 33 5.1. Investigational Product and Other Study Treatment .................................... 33 5.2. Treatment Assignment ................................................................................. 34 5.3. Dosing Guidance .......................................................................................... 34 5.4. Dose Titration Guidance............................................................................... 34

5.4.1. Up-Titrate Dose Level (Well-Tolerated): ....................................... 36 5.4.2. Maintain Dose Level (Tolerated with Some Issues): ..................... 36 5.4.3. Down-Titrate Dose Level (Tolerability Issues): ............................. 37

5.5. Treatment Dispensing and Subject Treatment Instructions ......................... 37 5.5.1. Baseline Visit Dispensing and Dosing .......................................... 37 5.5.2. Titration Visits Dispensing and Dosing ......................................... 38 5.5.3. Maintenance Visits Dispensing and Dosing .................................. 38

5.6. Treatment Blinding ....................................................................................... 39 5.7. Product Accountability .................................................................................. 39 5.8. Treatment Compliance ................................................................................. 39 5.9. Dietary Requirements and Restrictions ........................................................ 40 5.10. Concomitant Medications and Non-Drug Therapies .................................... 40


6

5.10.1. Permitted Medications and Non-Drug Therapies .......................... 40 5.10.2. Prohibited Medications and Non-Drug Therapies ......................... 41

5.11. Treatment after the End of the Study ........................................................... 44 5.12. Treatment of Study Treatment Overdose ..................................................... 44

6. STUDY ASSESSMENTS AND PROCEDURES ...................................................... 44 6.1. Time and Events .......................................................................................... 44 6.2. Critical Screening Assessments ................................................................... 49 6.3. Efficacy ......................................................................................................... 49

6.3.1. Primary Efficacy Assessment (MRI) ............................................. 49 6.3.1.1. Reference MRI ............................................................ 49 6.3.1.2. Timing and Scheduling of MRI Assessments .............. 49

6.3.2. Secondary Efficacy Assessments ................................................. 50 6.3.2.1. MRI Assessment ......................................................... 50 6.3.2.2. Relapse Assessment and Management ...................... 51

6.3.2.2.1. Relapse Criteria ...................................... 52 6.3.2.2.2. Relapse Management ............................. 52

6.3.2.3. Disability Assessment ................................................. 53 6.3.2.4. Cognitive Assessment ................................................. 53

6.4. Safety ........................................................................................................... 53 6.4.1. Liver chemistry stopping and follow up criteria ............................. 54 6.4.2. Adverse Events ............................................................................. 57

6.4.2.1. Definition of an AE ....................................................... 57 6.4.2.2. Definition of a SAE ...................................................... 58

6.4.3. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs .......................................................... 59

6.4.4. Assessments of Suicidality ........................................................... 59 6.4.5. Disease-Related Events and/or Disease-Related

Outcomes Not Qualifying as SAEs ............................................... 60 6.4.6. Pregnancy ..................................................................................... 60 6.4.7. Time Period and Frequency of Detecting AEs and SAEs ............. 61 6.4.8. Prompt Reporting of Serious Adverse Events and Other

Events to GSK .............................................................................. 61 6.4.8.1. Regulatory reporting requirements for SAEs ............... 62

6.4.9. Internal Safety Review Committee (iSRC) .................................... 62 6.5. Health Outcomes.......................................................................................... 63 6.6. Pharmacokinetics ......................................................................................... 63

6.6.1. Plasma Sample Analysis .............................................................. 64 6.7. Pharmacogenetic Research ......................................................................... 64 6.8. Early Withdrawal and Follow-up ................................................................... 64

7. DATA MANAGEMENT ............................................................................................. 65

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 65 8.1. Hypotheses .................................................................................................. 65 8.2. Study Design Considerations ....................................................................... 66

8.2.1. Sample Size Assumptions ............................................................ 66 8.2.2. Sample Size Sensitivity ................................................................. 68 8.2.3. Sample Size Re-estimation ........................................................... 70

8.3. Data Analysis Considerations ...................................................................... 70 8.3.1. Analysis Populations ..................................................................... 70 8.3.2. Analysis Data Sets ........................................................................ 70


7

8.3.3. Treatment Comparisons ............................................................... 70 8.3.3.1. Primary Comparisons of Interest ................................. 70 8.3.3.2. Other Comparisons of Interest .................................... 71

8.3.4. Interim Analysis ............................................................................. 71 8.3.5. Key Elements of Analysis Plan ..................................................... 72

8.3.5.1. Efficacy Analyses ........................................................ 72 8.3.5.2. Safety Analyses ........................................................... 72 8.3.5.3. Health Outcomes Analyses ......................................... 72 8.3.5.4. Pharmacokinetic Analyses .......................................... 73 8.3.5.5. Pharmacokinetic/Pharmacodynamic Analyses ........... 73 8.3.5.6. Pharmacogenetic Analyses ......................................... 73

9. STUDY CONDUCT CONSIDERATIONS ................................................................. 73 9.1. Posting of Information on Publicly Available Clinical Trial Registers ............ 73 9.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process .......................................................................................... 73 9.2.1. Subject Reconsent ........................................................................ 74 9.2.2. Pharmacogenetic Research Consent ........................................... 74

9.3. Quality Control (Study Monitoring) ............................................................... 74 9.4. Quality Assurance ........................................................................................ 75 9.5. Study and Site Closure................................................................................. 75 9.6. Records Retention........................................................................................ 75 9.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers and Publication .................... 76

10. REFERENCES ........................................................................................................ 77

11. APPENDICES .......................................................................................................... 79 11.1. Appendix 1: Pharmacogenetic Research ..................................................... 79 11.2. Appendix 2: Country Specific Requirements ................................................ 84 11.3. Appendix 3: Liver Chemistry Stopping and Follow-up Criteria ..................... 85 11.4. Appendix 4: Protocol Summary .................................................................... 86


8

LIST OF ABBREVIATIONS

AD Alzheimer's Disease ADME Absorption, Distribution, Metabolism and Excretion ADR Adverse Drug Reaction AE Adverse Event AESI Adverse Events of Special Interest ALP Alkaline Phosphatase ALT Alanine Aminotransferase AST Aspartate Aminotransferase AUC0-24 24 hour Area under the Curve BID Twice Daily Dosing Cmax Maximum Concentration CBD Cannabidiol CHF Congestive heart failure CIAS Cognitive Impairment Associated with Schizophrenia CNS Central Nervous System CPK Creatine Phosphokinase CRF Case Report Form C-SSRS Columbia-Suicide Severity Rating Scale CYP3A4 Cytochrome P450 3A4 DMPK Drug Metabolism and Pharmacokinetics DMT Disease Modifying Therapy DNA Deoxyribonucleic Acid DNRI Dopamine-Norepinephrine Reuptake Inhibitor DRE Disease Related Event EAE Experimental Autoimmune Encephalomyelitis ECG Electrocardiogram eCRF Electronic Case Report Form EDSS Expanded Disability Status Scale EDTA Ethylenediaminetetraacetic Acid EEG Electroencephalography ERP Event related potential EW Early Withdrawal eC-SSRS electronic Columbia Suicide Severity Rating Scale FDA Food and Drug Administration FSH Follicle Stimulating Hormone GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilance Gd Gadolinium GdE Gadolinium Enhanced GLP Good Laboratory Practice GM Gray Matter GSK GlaxoSmithKline H3R Histamine 3 Receptor or H3 Receptor HB Hepatitis B


9

HBc Hepatitis B core protein HBs Hepatitis B surface protein HBsAg Hepatitis B Surface Antigen HCV Hepatitis C virus HDPE High-density polyethylene Hep C Hepatitis C HIV Human Immunodeficiency Virus Hx History IB Investigator’s Brochure ICF Informed Consent Form ICH International Conference on Harmonization IEC Independent Ethics Committees IFN Interferon IgG Immunoglobulin G IgM Immunoglobulin M IL Interleukin INR International Normalized Ratio IP Investigational Product IRB Independent Review Board iSRC internal Safety Review Committee IUD Intrauterine Device IUS Intrauterine System IVR Interactive Voice Response IVRS Interactive Voice Response System IWR Interactive Web Response K2-EDTA Dipotassium EDTA LDH Lactate Dehydrogenase LFT Liver Function Tests LSLV Last Subject Last Visit MMRM Mixed Model Repeated Measures MRI Magnetic Resonance Imaging MS Multiple Sclerosis MSQoL Multiple Sclerosis Quality of Life MTR Magnetization Transfer Ratio NERI Norepinephrine reuptake inhibitor OPC Oligodendrocyte Precursor Cell(s) PCC Potential Clinical Concern PD Pharmacodynamics PET Positron Emission Test PGx Pharmacogenetics Pgp Phosphoglycoprotein or P-Glycoprotein PK Pharmacokinetics PP Posterior Probability PSRAE Possible Suicidality Related Adverse Event PT Preferred Term QOL Quality of Life


10

QTc Corrected QT interval QTcB Bazett’s Corrected QT interval QTcF Fridericia’s Corrected QT interval RAP Reporting and Analysis Plan RNA Ribonucleic Acid RO Receptor Occupancy RRMS Relapsing Remitting Multiple Sclerosis S1P Sphingosine 1 phosphate SAE Serious Adverse Event SD Standard Deviation siRNA Small Interfering Ribonucleic Acid SNRI Serotonin-norepinephrine reuptake inhibitors SOC System Organ Class SPM Study Procedures Manual SPMS Secondary Progressive Multiple Sclerosis SRT Safety Review Team SSRI Selective serotonin reuptake inhibitors TCA Tricyclic Antidepressants THC Tetrahydrocannabinol ULN Upper Limit of Normal WBC White Blood Cell Wk Week WM White Matter


11

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NONE ACTHAR AMPYRA ARAVA AVONEX BETASERONE CAMPATH CellCept CogState COPAXONE DECADRON FLO-PRED GILENYA IMURAN LEUSTATIN MedDRA MEDROL NOVANTRONE ORAPRED PRELONE PROVIGIL REBIF RITUXAN SAS SATIVEX SYMMETREL TYSABRI ZENAPAX


12

PROTOCOL SUMMARY

A summary of the protocol, including the rationale, objectives and endpoints, and an overview of the study design is included in Appendix 4: Protocol Summary.


13

1. INTRODUCTION

1.1. Background

GSK239512 is a potent, selective, orally bioavailable and brain penetrant histamine 3 (H3) receptor antagonist. H3 receptors (H3R) are predominantly expressed in the mammalian central nervous system (CNS) including areas relevant to cognitive processing such as the cerebral cortex, hippocampus and hypothalamus. In contrast, minimal expression of H3 receptors is observed in peripheral tissues except on some sympathetic nerves. Blockage of H3 receptors by selective antagonists results in the release of neurotransmitters from a variety of different nerve populations, including histaminergic, cholinergic and other monoaminergic neurons. Consequently, GSK239512 was originally under development for the symptomatic treatment of cognitive impairment in conditions including mild-to-moderate Alzheimer’s disease (AD) and Cognitive impairment Associated with Schizophrenia (CIAS). Recent data (Section 1.3) demonstrating H3R expression and activity on oligodendrocyte precursor cells (OPCs) has indicated the potential for development of GSK239512 in Multiple Sclerosis (MS). Details on the compound, disease target and preclinical experiments are included in the Investigator's Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012). A high level summary is provided in the following sections.

1.2. Multiple Sclerosis

Relapsing Remitting Multiple Sclerosis (RRMS) is a chronic progressive neurologic disorder characterized pathologically by multiple lesions in the central nervous system (CNS: brain, brainstem, optic nerve, and spinal cord) with varying degrees of demyelination and axonal injury followed by subsequent remyelination. Chronic or severe demyelination can lead to subsequent axonal degeneration and accumulation of irreversible disability (Dutta 2011), including demyelination of grey matter with resulting brain volume loss and potential cognitive impairment, which is a common core symptom of Multiple Sclerosis (MS) (Julian 2011).

Remyelination of axons is a naturally occurring process and, together with adaptations in ion channel distributions, is thought to maintain low levels of disability in patients in the early stages of MS (Franklin 2008). However, remyelination is rarely complete and although heterogeneity of remyelination capacity exists within the MS population (Patrikios 2006), as disease duration lengthens, remyelination failure becomes more extensive (Hagemeier 2012). In MS, most evidence supports a failure of OPC differentiation as the root cause of remyelination failure (Kuhlmann 2008). Therefore, promotion of remyelination through increased OPC differentiation may ultimately provide functional recovery and prevention of irreversible disability accumulation which is not possible with current MS therapies which target decreasing the occurrence of inflammatory events.


14

1.3. H3 Receptor, GSK239512 and MS Preclinical Background

Rat oligodendrocyte precursor cells express the Histamine 3 receptor (H3R) and receptor antagonists, including GSK239512, promote OPC differentiation. GSK239512 promoted OPC differentiation in vitro in a concentration-dependent manner with an EC50 value of 159 ± 57nM (n=5 independent experiments) (Clinical Investigator Brochure GlaxoSmithKline Document Number HM2008/00498/06 2012). This observation is supported by small interfering RNA (siRNA) knockdown experiments, in which reduction of H3R levels resulted in enhanced OPC differentiation. GSK239512 has been tested in two MS relevant preclinical models (experimental autoimmune encephalitis [EAE] and the cuprizone myelination model). Doses of GSK239512 up to 10mg/kg twice daily (BID) provided no protection from clinical disease in the EAE model. However, GSK239512 enhanced remyelination in cuprizone treated animals, at the maximum tested dose of 10mg/kg BID which provided moderate and consistent reductions in the corpus callosum demyelination area and increases in myelin intensity as described in the Investigator's Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012). Treatment with GSK239512 promoted myelin repair but had no apparent efficacy on autoimmune neuroinflammation. Therefore H3receptor antagonists could be effective in promoting OPC differentiation and increased remyelination in MS patients.

1.4. GSK239512 Clinical Experience

Six clinical trials with GSK239512 have been completed to date (summaries of the results from these studies are included in the Clinical Investigator Brochure GlaxoSmithKline Document Number HM2008/00498/06 2012) in which 229 subjects have been exposed to GSK239512. Studies have included young and elderly healthy volunteers, subjects with mild-to-moderate AD and subjects with Schizophrenia

From Phase I studies, the tmax of approximately 3 hours and the apparent t½ of approximately 15 hours was consistent with repeat and single dose administration. The PK of GSK239512 was approximately dose proportional between 20 µg and 50 µg, but for the 3-fold increase in dose between 50 µg and 150 µg, there was an approximately 2-fold increase in systemic exposure. Overall, systemic exposure to GSK239512 increased upon once daily oral administration (up to, on average, 60%) and steady state was achieved by Day 5. Between subject variability in Cmax and AUC0-24 values ranged from approximately 30-40%. Similar variability (27-43%) in plasma concentrations was observed during the AD Phase II efficacy study (H3B110651).

A full description of GSK239512 safety and tolerability data is provided in the Investigators Brochure (Clinical Investigator Brochure Section 5.3; GlaxoSmithKline Document Number HM2008/00498/06 2012). Key aspects of GSK239512 safety and tolerability to date are:

• Although a clear relationship between the observed adverse events (AEs) and study drug is difficult to establish given the limited data available, evaluation of the overall safety profile to date suggests that a number of AEs may be considered to be potentially associated with the administration of GSK239512. These AEs, grouped by System Organ Class, are: Nervous system disorders


15

(Headache, Dizziness, Somnolence), Psychiatric disorders (Sleep disorder, Insomnia, Nightmare), and Gastrointestinal disorders (Nausea).

• AEs of special interest (AESIs) were identified as areas of potential risk for clinically relevant AEs for the AD and/or CIAS populations involved in the Phase II studies. The AESIs identified by the blinded GSK Safety Review team were insomnia/sleep disorders, mood symptoms, perceptual abnormalities, abnormal dreams, and feeding and body weight change. Incidence of AESIs were 18% on GSK239512 and 7% on placebo in the AD study (H3B110651), and 48% on GSK239512 and 40% on placebo in the schizophrenia study (H3B113147). The incidence of AEs and AESIs were similar across treatment groups in the follow-up period.

• Dose-limiting AEs and serious AEs (SAEs) were predominantly associated with CNS activity predominantly occurring around the introduction of dosing. GSK239512 tolerability was improved during Phase II studies compared with Phase I through use of a four-week titration scheme (10µg/20µg/40µg/80µg) of GSK239512. The majority of subjects in both trials treated with GSK239512 (73% in H3B110651 and 70% in H3B113147) were able to achieve the highest dose level of 80 µg GSK239512.The AE profile during the maintenance period was similar to placebo

• In H3B110651, 6 subjects (3 GSK239512; 3 placebo) had AEs leading to withdrawal. In H3B113147, 3 subjects (2 GSK239512; 1 placebo) had AEs leading to withdrawal.

• A single persistent liver function test (LFT) elevation in the GSK239512 treatment group was observed in study H3B113147 (CIAS), deemed as possibly related to study drug. Values decreased back to baseline values until the subject’s final follow up visit.

Efficacy of GSK239512 in promoting cognitive function has been assessed in randomized, placebo-controlled, double blind Phase II efficacy studies of AD (H3B110651) and CIAS (H3B113147). Trial sizes were small and of short duration (H3B110651 - n=196, 16 weeks treatment) and (H3B113147 - n=50; 7 weeks treatment). Cognitive testing was conducted using CogState batteries compiled specifically to reflect domains of interest in each indication.

• In H3B110651, one of the co-primary efficacy objectives was met; there was a statistically significant difference between GSK239512 and placebo for the change in Episodic Memory Composite score from baseline to Week 16 for the intent to treat population. An effect size of 0.35 on Episodic Memory was also statistically significant (p=0.0495) and considered clinically relevant. In the analysis of the Executive Function/Working Memory Composite (co-primary endpoint), while results showed an improvement for GSK239512 relative to placebo (effect size 0.16), they were neither statistically significant nor considered clinically relevant.

• In H3B110147, the CogState Schizophrenia Battery showed mild/moderate improvement for GSK239512 versus placebo with an effect size of 0.29.


16

1.5. Rationale

1.5.1. Study Rationale

GSK239512 is being developed as an adjunct therapy that by promoting remyelination may halt disability progression or reverse disability in patients with RRMS. In addition, it is possible that GSK239512 may enhance cognitive function in patients with RRMS.

A critical first step for GSK239512 development in MS is to determine whether GSK239512 can promote remyelination. Areas of recent and longer-term demyelination are frequent in the CNS of RRMS patients. These areas are potential sites in which to visualize an increase in organized myelin content. Amongst few methods to assess CNS myelin content, magnetization transfer imaging is supported as the best candidate endpoint for myelination by histopathology/MRI correlation data and use of a simplified analysis form (magnetization transfer ratio [MTR]) which allows for standardized implementation in multicentre clinical trials (Section 3.3.1).

Therefore, this study is designed to assess whether GSK239512 can enhance remyelination in patients with RRMS, using brain MRI assessments of MTR to detect lesion remyelination. As GSK239512 is not anticipated to reduce the number of relapses, RRMS patients participating in this study will remain on background disease modifying therapy (Avonex [interferon-beta1a] or Copaxone [glatiramer acetate]).

The timecourse of CNS remyelination in vivo in MS patients is unclear and assessments of direct pharmacological promotion of lesion myelination are unprecedented. Observational studies using MTR, and other related imaging modalities (T1 hypointensity), suggest the natural timecourse of new lesion remyelination to be between starting at 3 months and up to 5 months or possibly longer (Chen 2007, Chen 2008). A timecourse for remyelination of chronic demyelinated areas is unknown. However, the frequency of new gadolinium enhanced (GdE) lesions in the recruited patient population is estimated to be 40-60% over a 6 month period (Cohen 2010, Comi 2001, Rovaris 2007) allowing for lesion signal detection in this study. The occurrence of delta MTR lesions is anticipated to be higher with potentially 100% of subjects having lesions detected (unpublished communication with Douglas Arnold). A treatment duration of 48 weeks is expected to permit completed remyelination assessment of at least one new delta MTR lesion per subject. The target effect size for this study is 0.5. Sample size adjustment may take place after instream review of lesion counts.

1.5.2. Dose Rationale

Preclinical data demonstrates H3 receptor occupancy (RO) of at least 70% by GSK239512 was associated with improvement in performance on cognitive tasks (GlaxoSmithKline Document Number HM2008/00498/06 2012). Modulation of cognitive electroencephalography (EEG) and event related potential (ERP) were observed at a 20µg/day dose in healthy elderly subjects and in AD subjects and there was preliminary evidence of cognitive improvement at doses of 20-80µg/day. Cognitive performance in study H3B109689 in AD subjects who titrated up to 40µg or higher showed a numerical improvement over placebo in memory and attention tasks. A dose of 20-40µg/day may therefore be on the threshold of producing some clinically-evident cognitive benefit, at least for part of the dosing interval.


17

Based on data from a healthy volunteer PET study (H3B106026), to achieve a RO of at least 80% over 24 hours in over 95% of subjects a dose of approximately 80µg is required (Table 1).

Table 1 Predicted steady-state RO values for each dose titration regimen from study H3B106026 (using the PK-RO model* with correction for tracer mass dose) for once daily dosing

75%

85%

92%

97%

RO at CminMedian

89%

92%

97%

99%

RO at CmaxMedian

40%75%20ug assuming PK linearity




RO at Cmin5% percentiles

RO at Cmax5% percentiles

75%

85%

92%

97%

RO at CminMedian

89%

92%

97%

99%

RO at CmaxMedian





RO at Cmin5% percentiles

RO at Cmax5% percentiles

95% of the population haveRO at ss above these values

50% of the population havethese RO values

* PK-RO model was built using repeat dose data from study H3B105321 and RO values from study H3B106026 assuming a direct effect model.

Exposures in the mouse cuprizone model exceeded the levels required for >90% RO and the maximum tested dose of 10mg/kg BID demonstrated a significant effect on remyelination (GlaxoSmithKline Document Number HM2008/00498/06 2012).

The target maximum dose of 80µg/day is selected for this study, as it is anticipated that the receptor occupancy required is >80% for promotion of remyelination. Furthermore it is expected that this dose level will provide a tolerability profile comparable to those observed in previous repeat dose clinical studies.

1.6. Summary of Risk Management

In the design of this study with GSK239512, some of the key potential risks involved in the study design and related to the study medication are identified in the following table (Table 2) along with the methods to be employed in the study to mitigate or manage the risks.


18

Table 2 Study Risks and Management/Mitigation Strategy

Risk Management/Mitigation MS Trial Risks Subjects may not tolerate MRI assessments Subjects are excluded based on common

contraindications to MRI, and use of Gd-contrast agents, as described in Section 4.2.2.

Subjects may consider burden of assessments to be prohibitive to continuation in the study

The protocol has been designed to minimize, as much as possible, the burden to sites and subjects while maintaining the integrity of the design to support the primary and secondary endpoints, such as minimizing the number of procedures at clinic visits and conducting the MRI visits at 6 week intervals.

Subjects may experience relapses/disease exacerbations/disease worsening during the study

To ensure subjects are managed appropriately, guidance on how to manage the occurrence of a relapse, relapse management, and considerations on subject withdrawal based on worsening disease is provided in Section 6.3.2 and Section 4.4. To minimize risk to the study objectives, guidance on MRI scheduling accommodations is also provided in Section 6.3.1.2 to enable all enrolled subjects to continue to participate as much as appropriate.

GSK239512 Risks Based on data from prior clinical trials of healthy volunteers and subjects (with either AD or schizophrenia), the following were identified as AESIs:

• Insomnia/sleep disorders • Abnormal dreams/nightmares • Mood symptoms (e.g. depressed

mood, anxiety) • Feeding and body weight change

(transient fluctuation in food consumption and body weight)

• Perceptual Abnormalities Section 5.3.2.2 of the Investigator's Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012) includes further details on AESIs and other events described in this section.

Subjects are excluded from participation in the study, if they are at a known safety risk related to the possible occurrence of these AEs (Section 4.2). In addition, routine monitoring of ALL safety assessments including Liver Function tests, Suicidality and Body Weight changes will be performed during weekly visits in the up-titration period and monthly visits during the maintenance period. Data will be reviewed at the study level by the Safety Review Team (SRT) and an internal Safety Review Committee (iSRC) for signals/patterns regularly throughout the study (Section 3.1 and Section 6.4.9)


19

Risk Management/Mitigation Furthermore, mood disorders and fatigue are commonly reported symptoms in MS patients, leading to a risk of symptom exacerbation through GSK239512 activity. In addition to the above safety areas, in the CIAS study (H3B113147) there was one possible suicidality related adverse event reported due to an increase in ideation, this subject presented with suicidal ideation at screen. In study H3B113147 (schizophrenia), one subject in the GSK239512 treatment group experienced persistent liver function test (LFT) elevations meeting predefined criteria for Potential Clinical Concern (PCC). Furthermore, ins study H3B111343 (healthy volunteers), a subject experienced transient AST and ALT elevation approximately seven days after starting GSK239512 at 20 µg. Total bilirubin remained within normal range.

The 4-week titration period used to achieve the target dose of 80 µg/day in the preceding clinical trials minimizes the occurrence of AESIs (which occurred more predominantly at the introduction of treatment) and has been incorporated into this protocol. In addition, subjects are permitted to down-titrate, if necessary during the maintenance period if they are experiencing tolerability issues. The safety review will also include a review of the efficacy assessments for indicators of disease worsening.

There is a low risk that an interaction may occur between GSK239512 and permitted disease modifying therapies for MS (Avonex and Copaxone)

No potential interactions are anticipated between GSK239512 and beta-interferons or glatiramer acetate based on current PK and PD information. During concomitant administration of GSK239512 and beta-interferon or glatiramer acetate, any possible risk of interaction on AEs, such as depression/insomnia (included on the Summary of Product Characteristics for Avonex as common Adverse Drug Reaction [ADR]) and depression/anxiety (Copaxone – very common ADR), are mitigated through exclusion criteria, suicidality assessments and safety monitoring at the individual subject and regular monitoring at the study level.

Due to the early phase of this study, there is limited information available to support co-administration with medications from several classes of commonly used medications (e.g. potent P-glycoprotein inhibitors, potent Cyp3A4 inhibitors/inducers and known CNS-penetrant medications).

The eligibility criteria and prohibited medications sections (Section 4.2 and Section 5.10) provide details of the medications and appropriate washout periods.


20

Risk Management/Mitigation H3M116477 Study Risks Variable levels of disease activity on background treatment with Avonex or Copaxone, may result in differences in the ability of subjects to contribute to the assessment of remyelination.

Copaxone and Avonex are two of the most common first line treatments for MS and have a similar immunosuppressant/ immunomodulatory efficacy profile. The study will stratify randomization by background treatment to allow for assessment of background treatment differences. The rationale for limiting background treatments to only two is to minimize the impact on study complexity (e.g. safety differences, efficacy differences, stratification, etc...). In addition, in order to increase the likelihood that the population enrolled has sufficient lesion activity, the protocol requires subjects to have demonstrated disease activity (either via MRI lesion detection or relapse) during the year preceding enrolment while on background treatment.

2. OBJECTIVE(S) AND ENDPOINTS

The study objectives and endpoints are detailed in Table 3.


21

Table 3 Objectives and Endpoints

Primary Objectives Endpoints Estimation of the effects of GSK239512 on lesion remyelination in subjects with Relapsing Remitting Multiple Sclerosis on stable treatment with Avonex [interferon-beta1a] or Copaxone [glatiramer acetate].

Changes in lesion myelination using two exploratory magnetization transfer ratio (MTR) endpoints comparing placebo to GSK239512 treated subjects in: 1) Mean change in gadolinium (Gd) enhanced (GdE) lesion MTR differences (calibrated to reference scan [Section 6.3.1.1]) from before enhancement to stable recovery (≥3 months post new GdE lesion), and 2) Mean change in Delta MTR lesion MTR differences (calibrated to reference scan) from before lesion appearance to stable recovery (≥3 months post lesion appearance).

Secondary Objectives Endpoints Evaluate the effects of GSK239512 on alternate potential marker of remyelination of lesions.

Change from baseline in T2 lesion MTR at Week 48.

Evaluate the effects of GSK239512 on brain MRI lesion counts.

Cumulative new and enlarging Gd enhancing, T2 and Combined Unique Active lesions comparing placebo to GSK239512 treated subjects.

Evaluate the effects of GSK239512 on overall neurodegeneration by assessing brain volumes (Total, white matter and grey matter)

Change from baseline at Week 48 in total brain volume, white matter volume and grey matter volume comparing placebo to GSK239512 treated subjects.

Evaluate the effects of GSK239512 on T1 hypointense lesion development associated with MS

Cumulative number of persistent black holes and new, unenhancing T1 lesion counts comparing placebo to GSK239512 treated subjects over treatment duration up to Week 48.

Proportion of new GdE lesions evolving into chronic (unenhancing) T1 lesions (black holes) comparing placebo to GSK239512 treated subjects over treatment duration up to Week 48.

Evaluate the effect of GSK239512 on Cognitive ability

Mean change from baseline in overall Cognitive impairment and cognitive domains comparing placebo to GSK239512 treated subjects.

Evaluate the effect of GSK239512 on relapses

Comparison of Relapse Rates between placebo and GSK239512 treated subjects.

Comparison of Time to First Relapse between placebo and GSK239512 treated subjects.

Comparison of the proportion of subjects Relapse Free between placebo and GSK239512 treated subjects


22

Evaluate the effect of GSK239512 on Disability and Functionality

Proportion of subjects with sustained worsening of Expanded Disability Severity Scale (EDSS) over 3 months comparing placebo to GSK239512 treated subjects.

Mean change from baseline in the EDSS functional systems and a subset of component assessments comparing placebo to GSK239512 treated subjects.

Safety Objectives Endpoints Evaluate the safety and tolerability of GSK239512

Frequency and severity of AEs and SAEs.

Percentage of subjects withdrawing due to AEs. Summary of suicide behavior and ideation risk as

assessed by the eC-SSRS and PSRAE. Change from baseline in clinical chemistry, hematology,

and urinalysis parameters. Frequency of clinical chemistry, hematology, and

urinalysis parameters of potential clinical concern. Change from baseline in vital signs and ECG

parameters. Frequency of vital signs and ECG parameters of

potential clinical concern. Pharmacokinetic Objectives Endpoints Evaluate pharmacokinetics of GSK239512 in MS subjects

Pre-dose trough concentration at Wk 4, Wk 24, Wk 36 and Wk 48 with sparse sampling (1 pre-dose and 3 post-dose) at Wk 8.

Exploratory Objectives Endpoints Evaluate the effect of GSK239512 on MS symptoms and quality of life

Mean change from baseline in the Multiple Sclerosis Quality of Life (MSQoL) 54 comparing GSK239512 and placebo treated subjects

3. INVESTIGATIONAL PLAN

3.1. Study Design

This study is randomized, parallel group, and placebo-controlled. Subjects with RRMS on stable background treatment with either Avonex (Interferon-beta1a) or Copaxone (Glatiramer Acetate) are eligible to participate.

Subjects will be randomized in a 1:1 ratio between placebo and GSK239512. Randomization will be stratified by background disease modifying therapy (DMT) of either Avonex or Copaxone.


23

The total treatment period is 48 weeks, including a standard 4 week titration period and 44 week maintenance treatment period (which could be adapted to a 5-week titration and 43 week maintenance period, if needed [Section 3.3]). Titration doses start at 10µg and increase up to 80µg (10µg first week, 20µg second week, 40µg third week, 80µg fourth week). Subjects will be titrated to the maximum tolerated dose with the objective of titrating to the highest dose (80µg GSK239512), whenever possible, based on investigator judgement of tolerability, as described in Section 5.3. Subjects unable to titrate to 80µg will be allowed to remain in the study, at the highest dose that they were able to tolerate. The post-treatment follow-up period will be a minimum of 2 weeks in duration following the end of treatment at Week 48 or early withdrawal, as appropriate. Safety data including all safety assessments will be reviewed throughout the study by the Safety Review Team (SRT) for GSK239512. Trends in clinical endpoint data (e.g. relapse, EDSS, etc...) to assess signals of disease worsening that could be indicative of a safety signal, will be reviewed and may include, as appropriate, the engagement of external expert consultation. At a minimum, these reviews will include efficacy data approximately every 3 months following randomization of the first subject. An internal Safety Review Committee (iSRC) consisting of GSK personnel who are not involved in the conduct of this study will be assembled and chartered to answer specific questions on behalf of the study team (Section 6.4.9). The study will be conducted as a 'single-blind' study. Only, a subset of individuals defined in the iSRC Charter will be unblinded. ALL subjects and non-GSK personnel (including the principal investigator, sub-investigators, and study site personnel) involved in measuring, monitoring and obtaining data in the study will be blinded to subject treatment assignment. In addition all GSK and vendor personnel involved in the on-site monitoring and direct management of the data and study sites will also remain blinded to individual subject data. The study will be conducted as a 'single-blind' study due to the exploratory nature of the study and use of the endpoints. The instream reviews of the MRI data will be conducted at intervals throughout the study with available subject data as defined in Section 8 and the iSRC Charter, including involvement of external MS and/or imaging expert(s), as appropriate. The SRT will review study data as part of the standard SRT monitoring and review process for GSK239512. Measures will be taken to ensure that unblinded information is not provided to the site personnel, subjects or any GSK and vendor staff involved in the management of the study sites and subject data. In addition, a formal Interim Analysis will be conducted, in accordance with Section 8 and the iSRC charter, to assess the characteristics of the remyelination signal that may be detectable at the end of the study. This will include an assessment of the probability of achieving the primary study objective and allows for the possibility of stopping the study for futility. Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct. Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.


24

3.2. Study Design Schematic

Figure 1 Study Design with Titration

3.3. Discussion of Design

Subjects will continue to be managed with their current standard of care therapy (Copaxone or Avonex) while being provided study medication [placebo or active (GSK239512)]. (NOTE: Standard of care therapy is not provided as part of this study, only study medication will be provided.) The current standard treatments for RRMS decrease the number of demyelination events that occur. Placebo is used in this study to enable an appropriate assessment of the effect of GSK239512 on remyelination. Therefore, there is no additional risk to subjects randomized to and receiving placebo in this trial as they will be maintaining their current background DMT.

The objective of the titration is to titrate to the highest dose (80µg GSK239512), whenever possible. Therefore, there is an option for a subject that has had a tolerability issue during the 4 week up-titration period to have an additional optional titration week to attempt progression to the next dose level, if based on investigator judgement, the tolerability issues have been resolved and their current treatment is well-tolerated at the Week 4 visit. All subjects will be able to continue into the Maintenance period on the dose level they achieve at the end of titration, regardless of the dose level that was achieved. Tolerability criteria guidelines are provided for both the titration and maintenance periods in Section 5.3. Unless tolerability in RRMS subjects is significantly different from tolerability in previously studied indications, there is a low risk that the majority of subjects will not be able to achieve the 80µg dose of GSK239512.


25

3.3.1. Primary Endpoint Rationale

All current disease modifying treatment modalities for MS target the reduction of demyelinating events (by decreasing the inflammation that triggers the demyelination). Therefore, traditional MRI endpoints demonstrate areas of demyelination by evaluating counts of Gd enhanced lesions as well as non-enhanced images. By evaluating both enhanced and unenhanced images, the appearance of demyelination events can be viewed and used to generally assess activity in the brain associated with MS. However, to date there are limited methods for specifically evaluating remyelination.

There is increasing data to support that MRI magnetization transfer ratio (MTR) imaging methodology can be correlated to brain myelin content and can detect not only demyelination but also remyelination and potentially the extent of remyelination (Schmierer 2004, Chen 2007, Chen 2008, van den Elskamp 2010). Schmierer (2004) demonstrated that changes in the MTR of cerebral white matter are correlated to changes in myelin content. And it has been identified that MTR imaging is sensitive to changes in myelin density and detectable changes occur during the demyelination and remyelination processes (van den Elskamp 2010) with a corresponding decrease in MTR associated with demyelination and an increase with remyelination (Chen 2007). However, there is limited data to support the selection of the optimal MTR MRI methodology in a clinical trial assessing remyelination treatment effectiveness. The most promising of these methods includes the use of MTR MRI (Chen 2007, Chen 2008) Utilizing MTR methodology, the analysis of the evolution over time of MTR in Gd enhancing lesions and the recovery of MTR in newly formed MTR lesions (Delta MTR lesions) will enable the assessment of remyelination following a demyelination event. As the research in this area has been exploratory, to date, it is unclear whether the analysis of Gd enhanced lesion MTR or the Delta MTR lesions will be better able to provide a clear signal with the approximate one year treatment period and proposed sample size. It is not known if there will be differences in the outcomes from the two endpoints in this population with this study design. However, based on the information available, at this time, it is reasonable to anticipate that they should result in demonstrating a consistent signal in the event that remyelination is occurring. Ultimately, the MTR approach is considered to be the most likely to detect a remyelination signal though it may be influenced by the level and type of lesion activity in the study population.

Therefore, two MTR endpoints serve as co-primary endpoints in this study. MTR using a voxel-threshold approach will be used for the analysis of the progression (increase, decrease, stable) of Gd-enhanced MTR lesion images. In addition, MTR changes in both MTR lesions (focal area changes detected in paired images [delta MTR lesions]) will also be used to detect the extent of remyelination.


26

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects

Assuming a 20% screen failure rate and 12% drop-out rate, based on those observed with other RRMS clinical trials, this study will screen approximately 144 subjects and randomize approximately 114 subjects to result in approximately 100 subjects with at least one post-baseline MRI.

4.2. Eligibility Criteria

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Investigator's Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012).

4.2.1. Inclusion Criteria

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects eligible for enrolment in the study must meet all of the following criteria:

1. Age: 18 to 50 years of age, inclusive

2. RRMS Diagnosis and Treatment:

• Diagnosed with a relapsing-remitting course of multiple sclerosis as defined by the appropriate McDonald criteria at the time of diagnosis, most recently updated by Polman (2011) and:

• Diagnosis made within approximately 10 years prior to the screening visit (as documented by year of diagnosis or duration of disease), and

• No physical manifestations of other forms of MS including signs of progression to secondary progressive MS (SPMS).

• Currently compliant with a stable dose regimen of Avonex [Interferon Beta1a] or Copaxone [Glatiramer Acetate] for management of MS for ≥ 1 year prior to the screening visit.

• The occurrence of at least one of the following (within the year preceding the screen visit AND after ≥2 months of stable treatment with Avonex OR Copaxone):

• 1 reported and/or documented relapse, OR

• 1 Gadolinium Enhanced (GdE) lesion on MRI,

Example: If treatment with Avonex initiated at 12 months prior to screen the earliest a lesion or relapse could occur to qualify for the study would be 10 months prior to screen..


27

• Currently neurologically stable, in the investigator’s judgment, and not actively experiencing or recovering from a recent relapse at the screening visit.

3. MS Disability: A Kurtzke Expanded Disability Status Scale (EDSS) (Kurtzke 1983) score of 1 – 4.5 (inclusive) at the screening visit.

4. Clinical Trial Commitment: Must agree not to participate in a clinical study involving another investigational drug or device throughout their participation in this study. Non-interventional study participation is allowed if the time involvement and scheduling will not interfere with compliance in this study in the opinion of the investigator.

5. Female Reproduction and lactation: A female subject is eligible to enter the study if she is

a. Not pregnant or nursing

b. Of non-childbearing potential (i.e. women who have had a hysterectomy, are postmeznopausal, which is defined as >2 years without menses (female subjects who have been post-menopausal for <2 years must be confirmed with Follicle Stimulating Hormone (FSH) and estradiol levels), have both ovaries surgically removed or have current documented tubal ligation); or,

c. Of childbearing potential (i.e. women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhea [even severe], women who are perimenopausal or have just begun to menstruate. Subject has a negative serum pregnancy test at screening and agrees to one of the following:

1. Complete abstinence from intercourse for one month prior to administration of the first dose of investigational product until 1 month after the last dose of investigational product; or,

2. Consistent and correct use of one of the following acceptable methods of birth control for one month prior to the start of investigational product to 1 month after the last dose of investigational product

• Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of <1% per year

• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject’s entry into the study, and this male is the sole partner for the subject

• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

• Consistent and correct use of one of the following acceptable methods of birth control WITH a single barrier method (condom, occlusive cap, or vaginal spermicidal agent) for one month prior to the start of investigational product to 1 month after the last dose of investigational product:


28

• Oral contraceptives (either combined or progesterone only)

• Injectable progesterone

• Implants of levonorgestrel

• Estrogenic vaginal ring

• Percutaneous contraceptive patches

6. Informed Consent: Must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures.

4.2.2. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects meeting any of the following criteria must not be enrolled in the study:

1. MRI:

• Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media).

• Lacks adequate venous access for administration of Gd-enhancing agent.

• Findings on brain MRI scan indicating any clinically significant brain abnormality other than MS (e.g. damage associated with prior traumatic brain injury).

2. Past and Concurrent Medical Conditions:

• History of severe and clinically significant CNS trauma with current sequelae (e.g. traumatic brain injury, spinal cord compression)

• Significant concurrent, uncontrolled medical condition or disease which in the opinion of the investigator could (e.g. significant psychiatric disorder, etc...):

• affect the subjects’ safety,

• impair the subject’s reliable participation in the trial,

• impair the evaluation of the endpoints

OR

• necessitate the use of medication not allowed by this protocol.

• History or presence of myelopathy due to spinal cord compression by disk or vertebral disease or chronic progressive myelopathy

• Diagnosis of any type epilepsy.

• At risk of suicide, as indicated by:


29

• A documented history of attempted suicide or significant suicidal ideation during the 6 months preceding the screening visit, OR

• If in the investigator’s judgment the subject is at risk of a suicide attempt based on the screen visit assessment, including the eC-SSRS

• Presence of significant and routine sleep disturbance that has a negative impact on quality of life that, in the judgement of the investigator, may increase the risk of tolerability issues during dose escalation.

Examples of significant sleep disturbances may be: severe insomnia, nocturnal wandering, confusion, disorientation, agitation, or vivid dreams.

• Presence or history of hallucinations that, in the judgement of the investigator, may increase the safety risk to the subject.

• Known diagnosis or history consistent with positive human immunodeficiency virus (HIV).

3. Past and Current Medications and Therapies:

• Have had treatment with the following to manage their MS within 1 or 2 years prior to the Screen Visit:

• One year:

• fingolimod [e.g. Gilenya],

• Rebif (interferon beta1a),

• interferon beta1b [e.g. Betaseron],

• mycophenolate mofetil [e.g. CellCept], or

• Recently approved medication or formulation indicated for the management of MS. Consult with GSK Medical Monitor if there are specific questions regarding eligible treatments.

• Two years:

• natalizumab [e.g. Tysabri]

• alemtuzumab [e.g. Campath].

• daclizumab [e.g. Zenapax],

• rituximab [e.g. Rituxan].

• mitoxantrone [e.g. Novantrone],

• cladribine [e.g. Leustatin], or

• azathioprine [e.g. Imuran].

• Have used corticotropin to manage a relapse within 6 months prior to Screen Visit.


30

• Have had treatment with the following and were unable to discontinue and refrain from treatment for the specified time period and are not able to discontinue use throughout participation in the clinical trial (see Section 5.10.2 for information regarding reason for exclusion):

• dalfampridine /fampridine [e.g. Ampyra] - 1 month prior to Screen Visit,

• nabiximols [e.g. Sativex] - 1 month prior to Screen Visit,

• amantadine [e.g. Symmetrel] - 3 months prior to Screen Visit, or

• leflunomide [e.g. Arava] - 1 year prior to Screen Visit.

• Have used the following medications within the last 30 days or 5 half-lives (whichever is longer) prior to screening and are not able to discontinue use throughout participation in the clinical trial:

• Any CNS stimulants (e.g., modafinil, dexamphetamine, methylphenidate).

• Known potent P-glycoprotein inhibitors (e.g. itraconazole, ketoconazole, cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine, carvedilol).

• Known potent inhibitors or inducers of the CYP3A4 enzyme (e.g., verapamil, ketoconazole, cimetidine, rifampin, modafinil).

• CNS-penetrant antihistamines (e.g. bromopheniramine, chlorpheniramine, clemastine, diphenhydramine, hyrdoxyzine)

• History of medically significant adverse effects (including allergic reactions and hypersensitivities) following treatment with:

• Histamine H3 receptor antagonist or inverse agonist,

• Gadolinium enhancing agent,

• Relapse medication: glucocorticoids (e.g., methylprednisolone)

OR

• A known hypersensitivity to components of the investigational product [Clinical Investigator Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012), relapse medication, or Gadolinium enhancing agent.

4. Cardiovascular Status at Screening: Electrocardiogram (ECG) showing a clinically significant abnormality at screening. Including a QTcB or QTcF interval of ≥450 msec or ≥480 msec for patients with a Bundle Branch Block.

5. Infections Disease Status at Screening:

• Subjects with no documented record of vaccination against Hepatitis B (primary and secondary immunization and booster) AND a positive test for hepatitis B surface antigen (HBsAg and Hepatitis B Core Antibody (IgM anti-HBc).


31

• Subjects with serologic evidence of active Hepatitis C, as indicated by a positive HCV RNA test and anti-HCV antibody test.

6. Laboratory Values at Screening:

• Hematology values of:

• Total white cell count < 2.0 x 109/L

• Neutrophils < 1.0 x 109/L

• Platelets < 75 x 109/L (If out of range, platelet count can be repeated to exclude platelet clumping)

• Haemaglobin < 80 g/L

• Clinical chemistry liver function test values of:

• Alanine aminotransferase (ALT) >2.0 x ULN

• Aspartate aminotransferase (AST) >2.0 x ULN

• Alkaline phosphatise (ALP) >1.5 x ULN

• Bilirubin >1.5 x ULN

• Documented renal insufficiency or laboratory results indicative of renal insufficiency (due to risks associated with administration of Gadolinium based contrast agents to subjects with moderate to severe kidney disease):

• Estimated Creatinine Clearance (Cockroft-Gault) <60 mL/minute

7. Protocol Compliance: If known, or according to investigator judgement, subject is suspected of not being able to comply with the study protocol requirements. Contributing factors to this assessment by the investigator could be, but not limited to: job demands, substance abuse, alcoholism, drug dependency or psychological disorder.

8. Prior Clinical Trial Experimental Therapy Experience: Prior participation in a clinical trial or use of an investigational product for a non-approved intervention:

• Prior use of an investigational drug for a condition other than MS within 4 weeks or 5 half-lives (whichever is longer) prior to screening.

• Prior use of an investigational drug for MS within 4 weeks or 5 half-lives (whichever is longer) prior to screening. The GSK Medical Monitor should be consulted to confirm eligibility.

4.2.3. Randomization Criteria

Subjects may be randomized only if all of the following criteria apply at the time of the Baseline visit:

1. Met Inclusion/Exclusion Criteria at Screen Visit, including screen laboratory and MRI criteria and compliant with procedures between Screen and Baseline Visits.

2. Neurologically stable subjects with no evidence of relapse at the Baseline visit. Subjects who relapse during the screening/baseline phase can re-enter the screening


32

period at a later date, once the relapse has resolved and they meet the eligibility criteria. NOTE: If more than one relapse occurs, the GSK Medical Monitor should be consulted to ensure subject is appropriate for study participation.

3. MS Therapies should be the same as at the Screen Visit (including no change in dose or route of administration).

4. Subjects have not received corticosteroid treatment within 1 week prior to randomization at the Baseline visit. Subjects who are receiving corticosteroid treatment just prior to or at the time of the Baseline (randomization) visit can re-enter the screening period at a later date, once they have completed corticosteroid treatment and meet the inclusion criteria.

4.3. Screening/Run-in Failures and Rescreen

If a subject (who has not yet completed the screen/baseline MRI) is unable to meet the randomization criteria following the initial screening visit due to occurrence of relapse, requirement to use a prohibited medication or inability to complete the screen/baseline MRI, they will be eligible for an opportunity to rescreen. If more than one rescreen is considered, the GSK Medical Monitor should be consulted to ensure the subject is appropriate for study participation.

The subject number will remain the same as the initial subject number for a rescreen. And the site will follow the optional visit schedule for a rescreen visit. Any subject who is interested in participating, but unable to meet the randomization criteria following completion of the screen/baseline MRI, will be a screen failure. The subject would need to enrol in the study for screening as a new subject and they would receive a new subject number at the new screen visit.

4.4. Withdrawal Criteria

Subjects who have been randomized to study treatment and withdraw are NOT eligible to re-enter the study or resume treatment. When a subject withdraws from the study, the withdrawal and reason(s) for withdrawal must be documented in the subject's medical record and the eCRF. When a subject withdraws from the study, the follow-up visit should be scheduled approximately 2 weeks following discontinuation of treatment (Section 6.8).

Subject withdrawal from the study, at any time, may be due to, but not limited to, the following reasons:

• At the discretion of the Investigator, it would be in the best interest of the subject to withdraw from participation. Investigator discretion may apply to but is not limited to discontinuations associated with adverse events (AE), tolerability for GSK239512, abnormal changes in MS disease activity, abnormal findings on MRI unrelated to MS, etc...(When an AE or SAE leads to subject discontinuation, this should be captured on the AE or SAE page of the eCRF, as appropriate. In addition, the Withdrawal Page of the eCRF should indicate that the subject withdrew due to an AE.)


33

• Subject deviates from or is unable to comply with study procedures and requirements and in the opinion of the investigator and consultation with the GSK Medical Monitor; it is in the best interest of the subject to withdraw from the study. (NOTE: This may include changes in background dose and/or regimen of disease modifying therapy (Avonex [interferon-beta1a] or Copaxone [glatiramer acetate]).

• Subject meets GSK Liver Stopping Criteria (Section 6.4.1).

• Subject exhibits Tolerability Concerns on Dose Level 1 (Section 5.4.3)

• Subject voluntarily discontinues participation from this study at any time (consent withdrawn) or is lost to follow-up during the study.

• Study termination by sponsor

• Post-randomization QTc interval >500msec or uncorrected QT interval >600msec; for subjects with Bundle Branch Block QTc>530msec based on average QTc value of triplicate ECGs.

• The subject develops renal insufficiency (defined as Creatinine Clearance <60 mL/minute on 2 consecutive tests). Such subjects must not have any additional Gd- enhanced MRI scans performed and withdrawal from the study should be evaluated as they may be unable to contribute to the primary endpoint analysis.

• Subject becomes pregnant.

5. STUDY TREATMENTS

5.1. Investigational Product and Other Study Treatment

Product name: GSK239512 Placebo Dosage form: Tablet Tablet Unit dose strength(s)/Dosage level(s):

10µg, 20µg, 40µg 80µg -

Route/ Administration/ Duration:

Oral Oral

Dosing instructions: once daily dose once daily dose Physical description: White to almost white,

round tablets White to almost white, round tablets

Manufacturer/ source of procurement:

GSK GSK

GSK239512 is a bicyclic nitrogen containing heterocycle also possessing pyridyl, alkyl and amide functions and is a white to almost white crystalline, non-hygroscopic solid.

Additional information about the investigational product is provided in the Clinical Investigator Brochure [GlaxoSmithKline Document Number HM2008/00498/06 2012].

GSK239512 tablets are packed in opaque HDPE bottles with child-resistance closures. There is provision for the use of oxygen absorption canisters when packing the tablets for subject use. The recommended storage conditions, and expiry date where required, are stated on the product label.


34

The contents of the label will be in accordance with all applicable regulatory requirements.

Investigational product must be stored in a secure area (at the investigative site), prior to dispensing to the subject, and under the appropriate physical conditions for the product (including refrigeration). Access to and administration of the investigational product will be limited to the investigator and authorized site staff. Clinical Trial Material should be stored in a secure refrigerated location at temperatures between 2°C and 8°C, protected from light. Subjects do not need to store under refrigeration, but should be instructed to keep Clinical Trial Material in a safe location and minimize exposure to extreme temperatures and light.

At the end of the study, all unused study medication will either be packaged and returned to GSK for destruction or will be destroyed in accordance with local standards with certificates of destruction provided to the GSK local operating company.

Only IP will be provided as randomized study medication. All other medications including Avonex [Interferon Beta1a] or Copaxone [Glatiramer Acetate] will not be supplied by GSK.

5.2. Treatment Assignment

Randomization information will be provided to sites via a central interactive voice or web response (IVR or IWR) system at the Baseline Visit. The study will have a central randomization via a computer-generated central randomization schedule created by the study statistician. Subjects who qualify following the screening assessments will be assigned to study treatment at a 1:1 ratio (placebo:GSK239512) at the baseline visit. Subject randomization will be stratified according to background DMT of either Avonex or Copaxone. Once a subject number and randomization number has been assigned, it must not be re-assigned.

Further details on the allocation of a randomization number can be found in the Study Procedures Manual (SPM).

5.3. Dosing Guidance

It is recommended that regular dosing occur in the mornings to potentially minimize sleep disturbance effects. However, subjects should avoid, as much as practical, consumption of food (other than clear beverages) within approximately 2 hours prior to and following dosing.

5.4. Dose Titration Guidance

Subjects will be randomized to GSK239512 or placebo and will enter Dose Level 1 of the Titration period as demonstrated in the Study Design Schematic in Section 3.2. The subject should progress to the next Dose Level, unless the subject demonstrates tolerability issues (as judged by the investigator). If a subject demonstrates tolerability issues they will be allowed to remain in the study on the highest tolerated Dose Level.


35

Subjects will be permitted to continue in the study even if unable to titrate up beyond Dose Level 1.

A phone call will be made to the subject the day following each Clinic Visit during the titration period to assess for the occurrence of any adverse events or abnormal occurrences since the subject was in clinic and received the first dose of Study Medication from the new bottle. The investigator should assess the tolerability of the Dose Level and determine if it is in the subject's best interest to continue treatment at that Dose Level.

As summarized in Section 1.6 and in the Investigator's Brochure (GlaxoSmithKline Document Number HM2008/00498/06 2012), tolerability issues that have been observed in healthy volunteers and prior populations include, but are not limited to the following:

• Insomnia of moderate intensity which interferes with function/activities of daily living

• Sleep disturbance in excess of normal fluctuations for the subject that are of moderate intensity, that result in sleep impairment or sufficiently distressing to cause the subject to wake or perceive as distressing upon recollection the following day. The disturbances can be:

• Disturbing or vivid dreams (e.g.nightmares)

• Waking episodes

• Behavioural disturbances (e.g. wandering)

• Gastrointestinal disturbances (e.g. nausea, vomiting, diarrhoea, abdominal pain) of moderate intensity and in excess of normal daily fluctuations for the subject,

During the Titration Period of the study, the titration will occur in accordance with the investigator assessment of tolerability using the guidance in this section and the following paradigm.

Table 4 Titration Period Guidance for Dose Level Adjustment

Status Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4 Well Tolerated Progress to Level 2 Progress to Level 3 Progress to Level 4 Continue on Level 4

Tolerated with Some Concerns

Continue on Level 1 Continue on Level 2 Continue on Level 3 Continue on Level 4

Tolerability Issues* Withdraw Change to Level 1 Change to Level 2 Change to Level 3 * If a subject has tolerability issues following the first night of dosing at a new Dose Level, they should have their

dose adjusted in accordance with this paradigm, as soon as possible. If a subject does not tolerate more than one Dose Level, an assessment should be made to determine if the subject should be withdrawn.

During maintenance treatment, a subject may down-titrate once due to Tolerability Issues identified in the judgment of the investigator and using the guidance below (Section 5.4.3). The following paradigm will apply for assessing down-titration associated with tolerability issues:


36

Table 5 Maintenance Period Guidance for Dose Level Adjustment

Status Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4 Well Tolerated Maintain on Level 1 Maintain on Level 2 Maintain on Level 3 Maintain on Level 4

Tolerated with Some Concerns

Maintain on Level 1 Maintain on Level 2 Maintain on Level 3 Maintain on Level 4

Tolerability Issues* Withdraw Change to Level 1 or Withdraw

Change to Level 2 or Withdraw

Change to Level 3 or Withdraw

Meets Withdrawal Criteria

Withdraw Withdraw Withdraw Withdraw

* If a subject does not tolerate more than one Dose Level, an assessment should be made to determine if the subject should be withdrawn.

Guidance for assessing tolerability and categorizing as "Well Tolerated", "Tolerated with Some Concerns" and "Tolerability Issues" are provided in the following sections (Section 5.4.1, Section 5.4.2, and Section 5.4.3).

The investigator should exercise clinical judgement in their assessment of Dose Level tolerability and use the information provided in Section 5.4.1, Section 5.4.2 and Section 5.4.3 as guidance for assessing the subject's tolerability and readiness to progress to the next dose level. In addition to the Dose Level guidance provided, the investigator may seek consultation with the GSK Medical Monitor if tolerability issues arise that are not addressed explicitly in the protocol.

5.4.1. Up-Titrate Dose Level (Well-Tolerated):

All of the following should be met prior to titrating to the next Dose Level.

1. Adverse event reports indicate that Dose Level is well-tolerated.

2. During the Visit, subject reports minimal or no impairment of normal daily functions or impact on activities in excess of expected normal fluctuations for the subject.

3. No emergence of new hallucinations, mood disturbance, abnormal thoughts, aggression, agitation and other behavioural disturbances, and no worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject.

4. No worsening of pre-existing symptoms in excess of expected normal fluctuations for the subject.

5.4.2. Maintain Dose Level (Tolerated with Some Issues):

If one of the following are met, the subject may be experiencing some tolerability concerns. The investigator should consider maintaining the subject at either their current Dose Level or evaluate whether Down-Titration of the Dose Level is more appropriate by reviewing the guidance in Section 5.4.3.

1. During the Visit, subject reports some impairment of normal daily functions or impact on activities in excess of expected normal fluctuations for the subject.

2. The emergence of hallucinations or mood disturbances that are mild, transient, infrequent and not distressing.


37

5.4.3. Down-Titrate Dose Level (Tolerability Issues):

If one of the following are met the subject may be experiencing tolerability issues that may improve with a dose adjustment to the previous Dose Level (down-titrated). If experienced at Dose Level 1, then the subject should be withdrawn from the study.

1. Overall effect of adverse events that are thought to be possibly associated with study medication lead to significant impairment of normal daily functions or curtailment of normal daily activities of the subject in excess of expected normal fluctuations for the subject.

2. Emergence of hallucinations, mood disturbance, abnormal thoughts, aggression, agitation and other behavioural disturbances, OR worsening of such pre-existing symptoms in excess of expected normal fluctuations for the subject. (The investigator may, in his/her clinical judgement, consider that this does not apply to hallucinations or mood changes which are mild/not distressing, transient and infrequent.)

3. No evidence that tolerability is improving over the course of treatment at the current Dose Level.

5.5. Treatment Dispensing and Subject Treatment Instructions

Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol (e.g. meet eligibility criteria). Accountability requirements for study medication are described in Section 5.7. Subjects will start treatment with a titration period, at the randomization visit they will receive a unique bottle of study medication (corresponding to the appropriate treatment assignment and Dose Level) and at each weekly clinic visit, they will return the previous bottle and receive a unique bottle of study medication corresponding to the appropriate Dose Level for that week. After the titration period, subsequent clinic visits during the maintenance period will be approximately 1 month apart and subjects will receive a single bottle of study medication at the appropriate Dose Level at each visit.

Study medication should NOT be taken prior to the clinic visit for ANY visit.

5.5.1. Baseline Visit Dispensing and Dosing

At the Baseline Visit (Day 0), all subjects meeting the randomization criteria (Section 4.2.3) will receive Dose Level 1 treatment and progress through the titration period. Each subject will be dispensed one bottle and instructed to avoid exposing the medications to extreme temperatures and light. They will take one tablet daily, at approximately the same time each day. The first dose will be administered at the study site and the general timing for subsequent dosing will be discussed. It is recommended that regular dosing occur in the mornings to potentially minimize sleep disturbance effects.


38

5.5.2. Titration Visits Dispensing and Dosing

On the morning of the Week 1 Titration Visit, subjects will NOT take their dose of Study Medication prior to their scheduled clinic visit. At the Week 1 visit, subjects will receive a new bottle of study medication and the first dose of medication from the new bottle will be administered at the study site and the general timing for subsequent dosing will be discussed.

The process will be the same for each of the Titration Visits, including the Week 4 Visit (and the Optional Week 5 Visit, if that is needed).

Further details on drug dispensing can be found in the Study Procedures Manual (SPM).

During the titration period, in addition to the Site Phone Call on the day following each Clinic Visit, subjects should be reminded to contact the site if they are experiencing tolerability issues. If down-titration is required during the titration period, the subject should NOT take the medication from the current bottle prior to returning to the clinic. They should return the bottle to the clinic. If the return to the clinic is not at a regularly scheduled Clinic Visit, then the site should follow the Unscheduled Visit procedures in Table 11 [NOTE: If it is determined that the subject meets withdrawal criteria, then the Early Withdrawal Visit procedures should be followed]. When the subject has returned to the clinic, they will be dispensed a new bottle of Study Medication corresponding to the new Dose Level. The first dose of medication from the new bottle will be administered at the study site and the general timing for subsequent dosing will be discussed.

5.5.3. Maintenance Visits Dispensing and Dosing

On the morning of ANY Clinic Visit, subjects will NOT take their morning dose of Study Medication prior to coming to the clinic. At the clinic visit, they will receive a new bottle of Study Medication and be instructed when to take the first dose from that bottle. The general time for subsequent dosing will be discussed.

During the maintenance period, subjects should be reminded to contact the site if they are experiencing tolerability issues. If down-titration is required during the maintenance period, the subject should NOT take the medication from the current bottle prior to returning to the clinic. They should return the bottle to the clinic. If the return to the clinic is not at a regularly scheduled Clinic Visit, then the site should follow the Unscheduled Visit procedures in Table 11 [NOTE: If it is determined that the subject meets withdrawal criteria, then the Early Withdrawal Visit procedures should be followed].. When the subject has returned to the clinic, they will be dispensed a new bottle of Study Medication corresponding to the Dose Level administered prior to the Dose Level being returned to the clinic. The first dose of medication from the new bottle will be administered at the study site and the general timing for subsequent dosing will be discussed.

If a subject does not tolerate more than one Dose Level during the Maintenance Period, an assessment should be made to determine if the subject should be withdrawn.


39

5.6. Treatment Blinding

This study is a 'single-blind' study, where the subject, investigator and all site and vendor personnel involved in the assessment of subjects and primary interpretation of subject data (e.g. MRI reading, laboratory assessments) will remain blinded to treatment assignment. This includes all site staff, MRI facility personnel, vendor personnel, and GSK personnel who are or could be involved with the day to day management of the site interactions and data at the sites (including monitoring staff and Data Management).

The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. Whenever possible, the investigator must first discuss options with the GSK Medical Monitor or appropriate GSK study personnel before unblinding the subject’s treatment assignment. If this is impractical, the investigator must notify GSK as soon as possible, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be recorded in the subject's medical records and captured in the appropriate data collection tool.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to clinical investigators in accordance with local regulations and/or GSK policy.

Subjects will be withdrawn if the treatment code is unblinded by the investigator or treating physician (if different). The primary reason for discontinuation (the event or condition which led to the unblinding) will be recorded in the eCRF.

5.7. Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.

5.8. Treatment Compliance

Subject compliance will be assessed at each study visit, by conducting a pill count for the medication returned to the site. If one or more dose is missed, the subject will be re-educated and overall protocol compliance will be assessed to ensure that subject safety is not compromised. If a subsequent dose or dosing time is missed and the time following the last dose, is 72 hours or less, the subject should take the next dose. The subject should be instructed to contact the site/investigator immediately, if 4 or more consecutive doses are missed and the investigator should consider whether early withdrawal procedures should be followed.


40

Chronic non-compliance should be considered for > 10 missed doses in a 1 month period. The investigator should consider chronic non-compliance with dosing to be a protocol violation, and withdrawal of the subject should be considered.

The GSK Medical Monitor may be consulted to assess subject appropriateness for continuation in the study in the event of dosing non-compliance.

5.9. Dietary Requirements and Restrictions

Subjects should avoid, as much as practical, food consumption within approximately 2 hours prior to and following dosing.

Consumption of Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication and during the course of the study until the follow-up visit is prohibited due to potential CYP3A4 interactions.

There are no other dietary or fluid restrictions in the study.

5.10. Concomitant Medications and Non-Drug Therapies

All subjects should remain on a stable dose and regimen of either Avonex [Interferon-beta1a] or Copaxone [glatiramer acetate] for the duration of the study. Any changes in treatment required while the subject is participating in the study may require withdrawal from the study and should be discussed with the GSK Medical Monitor.

All concomitant medications taken during the study will be recorded in the eCRF. The minimum requirement is that drug name and the dates of administration are recorded.

5.10.1. Permitted Medications and Non-Drug Therapies

This section describes categories of medications and non-drug therapies which are permitted, although some have restrictions. If there are any questions during the study, the GSK Medical Monitor may be able to provide further clarification.

The following medications and dietary supplements are permitted. And subjects should remain on a stable dose regimen for the duration of the study. If a change in dose regimen or use is required, this should be recorded in the eCRF:

• Paracetamol at doses of ≤ 2 g/day (higher doses, up 4g in 24 hour period, may be administered for prophylactic management of flu like symptoms associated with administration of Avonex or Copaxone).

• Vitamin E.

• Dietary supplements which may have benefits on cognitive impairment (e.g., fish oils, β-hydroxybutyrate, non-medicinal herbal dietary supplements).

• Statins.

• Thyroid hormones.

• Anti-diabetic medications.


41

• Anti-hypertensive medications.

• Tricyclic anti-depressants (TCA) which do not have anti-cholinergic effects.

• Monoamine reuptake inhibitors (SSRI, SNRI, DNRI, NERI).

• Sedatives (e.g. barbiturates, benzodiazepines)

If not prohibited in Section 5.10.2, other concomitant medications are generally permitted if they do not interfere with the integrity of the imaging assessments, efficacy assessments, safety assessments, or pharmacokinetic assessments and if they do not increase the risk to subject safety.

5.10.2. Prohibited Medications and Non-Drug Therapies

This section describes categories of medications and non-drug therapies which are prohibited for use during the study. If there are any questions during the study, the GSK Medical Monitor may be able to provide further clarification.

As the study is assessing the remyelination effects of GSK239512 in subjects treated with specific disease modifying therapies as background treatment (Avonex [interferon-beta1a] or Copaxone [glatiramer acetate]) treatment with the disease modifying therapies listed in Table 6 is NOT permitted:

Table 6 Prohibited Disease Modifying Therapies

Class Treatments Washout Minimum prior to Screen Visit

Rationale

Interferons interferon beta1b [e.g. Betaseron] 1 year Could interfere with assessment of disease activity

Rebif: (interferon beta1a) 1 year Could interfere with assessment of disease activity

S1P receptor modulator

fingolimod [e.g. Gilenya] 1 year Could interfere with assessment of disease activity

Immuno-suppressive (off-label)

mycophenolate mofetil [e.g. CellCept]

1 year Off-label for MS and could interfere with assessment of disease activity

IL-2 alpha subunit Monoclonal Antibody

daclizumab [e.g. Zenapax] 2 years Could interfere with assessment of disease activity

Monoclonal antibodies

alemtuzumab [e.g. Campath] 2 years Could interfere with assessment of disease activity

natalizumab [e.g. Tysabri] 2 years Prolonged immunosuppression (e.g.24 weeks post-treatment to steady state) could interfere with assessment of disease activity

Anti-CD20 Monocloncal antibody

rituximab [e.g. Rituxan] 2 years Prolonged immunosuppression (e.g.24 weeks post-treatment to steady state) could interfere with assessment of disease activity


42

Relapse management with corticotropin is not permitted while participating in this study (Table 7). However, use of glucocorticoids is permitted with a 1 week washout prior to any MRI assessments (Section 6.3.2.2.2).

Table 7 Prohibited Medications for Relapse Management

Treatment Class Washout Minimum Prior to Screen Visit

Rationale

corticotropin

[e.g. Acthar]

Anti-inflammatory (hormonal)

6 months

Excluded in this study due to increased risk of infection AND potential for adrenal insufficiency. There are also multiple drug interactions that could lead to significant adverse effects during the study.

Management of MS symptoms with treatments that have a safety risk that could confound the assessment of safety of GSK239512 are not permitted. The classes of medication and examples of specific products are provided in Table 8.

Table 8 Prohibited Medications for MS Symptom Management (other than glucocorticoids)

Class Treatments (examples)

Indication Washout Minimum prior to

Screen Visit

Rationale

Adamantine: antivirals; dopaminergic anti-parkinsonism

amantadine [e.g. Symmetrel]

Antiviral prophylaxis of Influenza A (to manage increased risk associated with DMT). Off-label use for MS related fatigue.

3 months Increased CNS and cardiovascular safety risks

Potassium channel blocker

dalfampridine [e.g. Ampyra]

Walking Improvement

3 months Dose-related seizure risk and elevated risk of urinary tract infection.

Cannabinoid Nabiximols [e.g. Sativex]

Anti-spasticity 1 month THC and CBD may store in fatty tissues and may have effects that interfere with safety and efficacy assessments

CNS stimulants methylphenidate fatigue symptoms (off-label for MS)

1 month May have effects that interfere with the assessment of efficacy

dexamphetamine fatigue symptoms (off-label for MS)

1 month May have effects that interfere with the assessment of efficacy

modafinil [e.g. Provigil]

fatigue symptoms (off-label for MS)

6 months May have effects that interfere with the assessment of efficacy and safety and could interfere with effectiveness of contraceptive

Isoxazole immune-modulatory agent

leflunomide [e.g. Arava]

Immuno-modulation (off-label for MS)

1 year Increased risk of infection and latent liver toxicity


43

Class Treatments (examples)

Indication Washout Minimum prior to

Screen Visit

Rationale

Antineoplastic anthracenedione

mitoxantrone [e.g. Novantrone]

Intended for reducing neurologic disability associated with worsening relapsing-remitting MS.

2 years Latent cardiovascular toxicity. Cardiovascular toxicity and CHF warning not temporally associated with treatment

Antimetabolite cladribine [e.g. Leustatin]

Immune suppression (off-label for MS and no data available supporting a safe interval)

2 years Increased risk of infection due to prolonged immune suppression post-treatment

Antirheumatics, immune-suppressives

azathioprine [e.g. Imuran]

Immuno-suppression (off-label for MS)

2 years Increased risk of infection and known mutagenic potential that is not associated with drug administration temporally

Based on the absorption, distribution, metabolism profile of GSK239512, as described in the Investigator's Brochure, subjects will not be permitted to take strong P-glycoprotein (Pgp) inhibitors or strong cytochrome P450 (CYP) 3A4 inhibitors or inducers. Examples of these treatments are provided in Table 9.

Table 9 Prohibited Medications associated with Pharmacokinetics

Inhibitor or Inducer Category

Treatments (examples)

Washout Minimum prior to Baseline Visit

Rationale

P-glycoprotein inhibitor (potent)

Itraconazole, ketoconazole, cyclosporine, loperamide, diltiazem, verapamil, spironolactone, quinidine, Bepridil, quinine, carvedilol

Agree to discontinue use (at Screen Visit) for duration of study participation.

GSK239512 is a substrate of the Pgp transporter. There is a potential for Pgp blockade to increase exposures (including increased brain concentrations). To minimize the risk to subjects, potent Pgp inhibitors are not permitted.

CYP3A4 Inducer/Inhibitor (potent)

Amiodarone, conivaptan, diethyl-dithiocarbamate, diltiazem, erythromycin, fluconazole, fluvoxamine, gestodene, itraconazole, ketokonazole, mifepristone, nefazodone, verapamil, voriconazole, norflxacin, morfluoxetine

Agree to discontinue use (at Screen Visit) for duration of study participation.

GSK239512 is primarily metabolized by CYP3A4. Therefore, inducers or inhibitors of CYP3A4 may lead to significant variations in exposure. To minimize the risk to subjects, potent CYP3A4 inducers or inhibitors are not permitted.


44

5.11. Treatment after the End of the Study

There are currently no plans for an extension study for subjects following completion of this study. However, if an extension study is available for subjects completing participation in this study, they will be eligible for enrolment, as appropriate.

There is no specified medical care or treatment provided by GSK upon completion of the treatment and follow-up periods.

The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition whether or not GSK is providing specific post study treatment.

5.12. Treatment of Study Treatment Overdose

There is no specific antidote for overdose with GSK239512. In the event of a suspected overdose, it is recommended that the appropriate supportive clinical care should be instituted, as dictated by the subject’s clinical status. The event should be reported in accordance with Section 6.4.2.1.

6. STUDY ASSESSMENTS AND PROCEDURES

6.1. Time and Events

The Time and Events for all standard protocol visits are presented in Table 10. Time and Events for all optional protocol visits are presented in Table 11.


45

Table 10 Time and Events for All Standard Visits

Protocol Activity Screen Treatment Follow Up

Titration Maintenance

≤5 wks Baseline Wk1 Wk 2 Wk 3 Wk4 Wk 8 Wk12 Wk16 Wk20 Wk24 Wk28 Wk32 WK36 Wk40 Wk 44 Wk48 2 Wks

after Wk 48 or EW

Target Study Day1 ≤ -35 0 7 14 21 28 56 84 112 140 168 196 224 252 280 308 336 350 Standard Procedures Informed Consent Process2 X Demographic Information X Medical / Disease / Therapy Hx X Review Concomitant Meds X X X X X X X X X X X X X X X X X X Initial Physical Exam3 X Brief Physical Exam3 X X X X X X X X X X X X X X X X Complete Follow-Up Exam3 X Inclusion/Exclusion Criteria X Randomization X Efficacy Assessments

Brain MRI With Contrast X A total of 8 MRIs will be conducted at approximate 6 week intervals: Wk 6, Wk 12, Wk 18, Wk 24, Wk 30, Wk 36, Wk 42, Wk 48

Relapse Assessment2 X X X X X X X X X X X X X X X X X Extended Disability Status Scale2,4 X X X X X Other Efficacy Assessment Cognitive Battery X5 X X X X Multiple Sclerosis QoL X X Safety Assessments Suicidality (including eC-SSRS) X X X X X X X X X X X X X X X X X X ECG, Tracing only X X X X X X X AEs, SAEs and PSRAEs X X X X X X X X X X X X X X X X X Titration Assessment X X X X Post Up-Titration Day Phone Call X X X X X6 Laboratory Assessments


46

Protocol Activity Screen Treatment Follow Up

Titration Maintenance

≤5 wks Baseline Wk1 Wk 2 Wk 3 Wk4 Wk 8 Wk12 Wk16 Wk20 Wk24 Wk28 Wk32 WK36 Wk40 Wk 44 Wk48 2 Wks

after Wk 48 or EW

Target Study Day1 ≤ -35 0 7 14 21 28 56 84 112 140 168 196 224 252 280 308 336 350 Hematology X X X X X X X X X X X X X Chemistry X X X X X X X X X X X X X X X X X X Urinalysis X X X X X X X X X X X X X Serum Pregnancy, Quantitative X X Urine Pregnancy Test, Qualitative X X X X X X X X X X X X X X X Hepatitis C Antibody (HCVAb) X Hepatitis B Surface Antigen (HBsAg) X

Pharmacogenetic Sample (PGx) X Therapy-specific laboratory Assessment(s) PK Blood draw7 X X7 X X X Investigational product Assess IP Compliance X X X X X X X X X X X X X X X Dispense Invest. Product. X X X X X X X X X X X X X X X IVRS Registration X X X X X X X X X X X X X X X X X X 1. Every effort should be made to schedule visits as close as possible to the study visit day. Due to drug supply limitations, titration visits should be within 3 days of the Target Study

Day and Maintenance visits should be within 6 days of the Target Study Day. 2. Reconsent of a subject should be done when, according to the judgement of the principle investigator, the benefit risk ratio changes for the subject (e.g. increase in relapse activity

and/or disability score) AND/OR in accordance with local clinical trial practice standards (e.g. disease progression). 3. All physical exam visits will include, but are not limited to the assessment of body weight, blood pressure, heart rate, and temperature. Height is only required at the screen visit. 4. If a subject is experiencing a relapse at a regular clinic visit that does not include a scheduled EDSS, an unscheduled EDSS should be performed and the information captured in

the subject's medical record and reported in the eCRF. 5. The Cognitive Battery is a computerized battery, which will be executed twice during the screen visit to familiarize the subject with the use of the tool. 6. If Titration period is extended an additional week, then a Phone Call should be made to the subject the day after the Week 4 Visit. This DOES NOT need to be done, if the subject

does not change Dose Level at the Week 4 Visit. 7. Four trough PK samples will be drawn at Weeks 4, 24, 36, 48 and one Sparse Sampling Day with 4 PK samples will occur at Week 8 in accordance with Table 14 in Section 6.6.


47

Table 11 Time and Events for All Optional Visits

Protocol Activity Re-screen

Optional Titration

Unscheduled Tolerability1 Relapse Early Withdrawal

Unscheduled Relapse Visit Unscheduled Relapse Phone Call RS Wk 5 Tol Relapse2 Relapse PC Study Day ≤ -35 35 EW Standard Procedures Informed Consent Process2 X X2 Medical / Disease / Therapy Hx X Review Concomitant Meds X X X X X Comp. Follow-Up Exam3 X Brief Exam3 X X Inclusion/Exclusion Criteria X Titration Assessment X X Efficacy Assessments Relapse Assessment2 X X X X Extended Disability Status Scale1 X X X Brain MRI With Contrast X4 Other Efficacy Assessment Cognitive Battery Multiple Sclerosis QoL X Safety Assessments Suicidality (incl eC-SSRS) X X X X X ECG, Tracing Only X X AEs, SAEs and PSRAEs X X X X X Laboratory Assessments Hematology X X Chemistry X X Urinalysis X X Urine Pregnancy Test, Qualitative X X


48

Protocol Activity Re-screen

Optional Titration

Unscheduled Tolerability1 Relapse Early Withdrawal

Unscheduled Relapse Visit Unscheduled Relapse Phone Call RS Wk 5 Tol Relapse2 Relapse PC Study Day ≤ -35 35 EW Investigational Product (IP) Assess IP Compliance X X X Dispense Invest. Product. X X IVRS Registration X X X X X X 1. An Unscheduled Tolerability visit may occur to assess tolerability issues raised by a subject during either the Titration or Maintenance periods. If the investigator determines that

the Dose Level for a subject should be changed, then this will be registered through the IVR system and new study medication will be provided. 2. OPTIONAL: Reconsent of a subject should be done when, according to the judgement of the principle investigator, the benefit risk ratio changes for the subject (e.g. increase in

relapse activity and/or disability score) AND/OR in accordance with local clinical trial practice standards. 3. All physical exam visits will include, but are not limited to the assessment of body weight, blood pressure, heart rate, and temperature. 4. If a subject is withdrawn during the maintenance period and has not had an MRI conducted in the 4 weeks preceding their withdrawal from the study, assuming their consent and

appropriateness with respect to the reason for withdrawal, it is desirable to obtain a final MRI.


49

6.2. Critical Screening Assessments

Screening assessments with respect to disease and treatment history are designed to ensure that the population enrolled in this study, has a strong potential to demonstrate GSK239512's effect on remyelination with the MRI methodology being employed. Enrolled subjects are required to be at a relatively early phase of RRMS, but to have demonstrated sufficient disease activity to require treatment with either Avonex or Copaxone for at least the 1 year preceding enrolment in the study. In addition, while on these background treatment, subjects are continuing to demonstrate a level of activity (lesion and/or relapse) that is indicative of relatively active disease.

Cardiovascular medical history/risk factors will be assessed at baseline as part of the screening visit. These assessments along with laboratory tests, including pregnancy tests, are conducted to ensure that subjects meet the minimal criteria to support their safe participation in the study, as well as to support the safety evaluation of GSK239512.

6.3. Efficacy

6.3.1. Primary Efficacy Assessment (MRI)

The primary efficacy assessment is the MRI using the MTR sequence. This assessment will support both the GdE lesion MTR and delta MTR lesion co-primary endpoint analyses and key secondary endpoints. The MRI will be conducted at a local MRI facility. The images will be transmitted to a central MRI vendor, where they will be read and analyzed. Prior to enrolling subjects into the study, the local MRI facility will run a dummy scan according to a standard protocol as part of the study start-up process. This scan will serve as the calibration scan for all subjects enrolled in the study with MRI images conducted on that scanner. The central MRI vendor will oversee and manage the process for calibration throughout the study. The ability of the facility to utilize the same equipment for each subject throughout the duration of the study will also be a part of the facility assessment to ensure that the data is of an appropriate quality to contribute to the analyses.

6.3.1.1. Reference MRI

In order to accommodate variations in MTR images acquired using different scanners, the images must be normalized to eliminate intensity shifts and contrast variations. To accomplish this, the normalization scheme proposed in Brown (2011) will be used. For each scanner, images from a normal subject will be obtained and processed to serve as a calibration for each scanner prior to initiating scanning for subjects participating in the study.

6.3.1.2. Timing and Scheduling of MRI Assessments

MRI scans will be performed at a frequency that permits the establishment of pre-lesion signal, detection of an MTR lesion and the subsequent detection of stable recovery (remyelination) of demyelinated lesions. The pre-lesion MTR signal will require at least 2 MRIs over a 3 to 4 month period, but immediately preceding the formation of a lesion. The stable recovery period occurs, at least 3 months following lesion formation and


50

requires at least 2 post-lesion MRIs to confirm. It is estimated, that a 6 week spacing of MRIs, will allow approximately 4 opportunities to detect a lesion signal from each subject and should provide appropriately evaluable pre-lesion and stable recovery data.

Completing the MRI assessments in accordance with the Time and Events schedule (Table 10) is critical. This study does not restrict the use of rescue medications (e.g. glucocorticoids) to manage the occurrence of a relapse. However, glucocorticoids can impact brain volumes due to changes in fluid levels and would interfere with imaging assessment. Therefore, if a relapse requiring management with glucocorticoids occurs around the time of a scheduled MRI, the MRI should be rescheduled to ensure that the subject has a minimum of a 1 week washout period following completion of treatment with glucocorticoids.

Due to the use of Gadolinium enhancing agent in the MRI procedure, most local protocols require that MRIs should be scheduled approximately ≥1 month apart. If an MRI needs to be rescheduled, but the change in timing would decrease the time between MRIs to less than 1 month, an MRI may need to be substituted with an unenhanced MRI (or possibly skipped) to ensure that the images are obtained as close as possible to the target timeframe specified in the Time and Events (Table 10). Missing an MRI should be avoided, if at all possible.

If an MRI assessment is 'missed' either because there is a problem with the scheduling or execution of the MRI OR in the event that it is unevaluable by the MRI reader, then as above, the MRI should be rescheduled if it will not interfere with the subsequent schedule of MRIs in accordance with the Time and Events table. If more than 2 consecutive MRIs are not conducted, the investigator should consult with the GSK Medical Monitor to assess the appropriateness of the subject continuing to participate in the study.

6.3.2. Secondary Efficacy Assessments

6.3.2.1. MRI Assessment

The secondary MRI assessments include the standard MRI assessment of lesions with and without contrast (Gd). As with the primary assessment, the MRI will be conducted at the same time as the MTR scan at a locally qualified MRI facility. The image will be transmitted and read by a central MRI vendor. Assessments of the scanned image will include, but may not be limited to:

• T2 lesion MTR

• Cumulative new GdE lesions

• Cumulative new or enlarging GdE lesions

• Cumulative new or enlarging T2 lesions

• Combined unique active lesions

• Brain Volumes (Total, WM, GM)

• Number of new, unenhancing T1 hypointense lesions

• Number of GdE lesions evolving to chronic, unenhancing black holes


51

Due to the exploratory nature of evaluating remyelination of MS lesions, the MRI scans may be reread post-hoc, utilizing other methods or measures, in order to confirm or enhance the interpretation of the effects of GSK239512. Any post-hoc assessment may be documented and reported separately from the pre-defined study outcomes.

6.3.2.2. Relapse Assessment and Management

At each visit, a subject will be evaluated for the occurrence of relapse (including both current symptoms and those which may have occurred since the preceding study visit) according to the criteria in Section 6.3.2.2.1. If a relapse occurs, the relapse will be assessed as completely as possible and details (e.g. onset, symptoms, duration, etc...) will be captured, as appropriate, at each visit during the study and in the situation where the subject returns to or calls the site with an unscheduled visit or telephone report during the study. All suspected relapses should be recorded in the subject’s medical record and on the “Relapse Form” in the eCRF.

As relapses are expected events for the RRMS population, reporting of relapses and associated hospitalization as an AE or SAE is only required in this study if they meet the definitions as specified in Section 6.4.2.1, Section 6.4.2.2 and Section 6.4.5. Information reported on the Relapse Form in the eCRF will be part of the ongoing safety review of this study.

When a subject in the study experiences a relapse (as defined in Section 6.3.2.2.1), it is preferable for the subject to return to the clinic for a full evaluation of their relapse. The Unscheduled Relapse Visit procedures will be followed, documented in the subject's medical record and captured in the eCRF (Table 11). If a subject does not return to the clinic, subjects should contact the site to report the relapse and will be advised that they should be managed according to their local standard of care. Site personnel should follow the Unscheduled Relapse Phone Call Visit procedures, whenever possible for a contact from a subject reporting a relapse. This should be documented in the subject's medical record and captured in the eCRF (Table 11). Information about permitted and prohibited medications for relapse and symptom management while participating in this study is provided in Section 6.3.2.2.2.

If the subject waits until their next scheduled visit to return to the site either to report the relapse or for confirmation and management, the site should follow the corresponding visit schedule, as specified in Table 10. In the event that the visit to the clinic for the confirmation and management of the relapse coincides with a regular Clinic Visit and the Clinic Visit DOES NOT include an EDSS, the appropriately certified study team personnel at the site should conduct an unscheduled EDSS. The information necessary to confirm the diagnosis should be captured in the subject's medical record and used to complete the relapse eCRF page as completely as possible.

If a relapse is diagnosed and managed by a non-study physician, if possible, it is recommended that the site attempt to obtain copies of the medical records for inclusion in the subject’s study medical records and description in the relapse eCRF (including EDSS scoring, if available).


52

6.3.2.2.1. Relapse Criteria

A relapse in this protocol is defined according to the criteria in Polman 2011. Where it is defined as: "patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, current or historical". It must occur in the absence of fever or infection and should:

• follow improvement from a previous relapse,

• occur at least 30 days following the onset of a previous relapse, and

• be persistent for at least 24 hours.

All suspected relapses, per the above definition, whether evaluated by a study or other physician should be entered in the eCRF.

When relapse data are further evaluated for analysis the neurological changes, as determined by the formal EDSS evaluation, will meet at least one of the following criteria:

• an increase of at least 0.5 in the EDSS score, as compared to previous evaluation,

• a score increase of one in at least two of the seven Functional System Scores, as compared to previous evaluation, and/or

• a score increase of two in one system, either the pyramidal, or cerebellar, brain stem, sensory, bowel and bladder, visual, or cerebral, as compared to previous evaluation.

Note: Changes in bowel and bladder or cerebral functions will not solely be responsible for the changes in EDSS or Functional Scale scores upon documentation of a relapse.

6.3.2.2.2. Relapse Management

Treatment of relapse is permitted and must be in accordance with local standard of care, including use of corticosteroids, as appropriate. However, due to the inflammation associated with glucocorticoid treatment subjects should wait to have an MRI conducted until at least 1 week following completion of glucocorticoid therapy (Table 12).

Table 12 Relapse Treatment Washout Information

Class Treatments Washout Minimum prior to any MRI

Rationale

Glucocorticoids prednisolone [e.g. Orapred, Prelone, Flo-Pred, etc…] prednisone methylprednisolone [e.g. Medrol] dexamethasone [e.g. Decadron]

1 week While there is no known increased risk to the subject, treatment with glucocorticoids within 1 week of an MRI could alter the MRI due to the inflammation associated with glucocorticoids.


53

For relapse management during the study, subjects may receive up to 1 gram per day of IV methylprednisolone for 3-5 days (without oral taper). However, any treatment for relapse must be in accordance with local standard of care. In addition, Table 13 includes the standard glucocorticoids and general treatment guidelines for relapse management, as supportive information. However, treatment for relapse must be in accordance with local standard of care.

Table 13 Potential Relapse Treatment Information

Treatment Class General Treatment Guideline for Relapse

Duration of Treatment Completion prior to MRI

prednisolone [e.g. Orapred, Prelone, Flo-Pred, etc…]

Glucocorticoids Daily doses of 200mg for 1 week followed by 80mg every other day for 1 month

1 week

prednisone Glucocorticoids Daily doses of 200mg for 1 week followed by 80mg every other day for 1 month

1 week

methylprednisolone [e.g. Medrol]

Glucocorticoid Daily doses of 160mg for 1 week followed by 64mg every other day for 1 month

1 week

dexamethasone [e.g. Decadron]

Glucocorticoid Daily doses of 30mg for 1 week followed by 4-12mg every other day for 1 month

1 week

6.3.2.3. Disability Assessment

The EDSS is an assessment of disability specifically associated with Multiple Sclerosis. The EDSS will be conducted by an appropriately certified clinician (rater) at the investigative site. Whenever possible, each subject should be evaluated by the same rater throughout the study. The assessment will be captured in the medical records including the detailed assessment and scoring for each functional system and domain. Both the detailed assessment scoring and the total score for each of the domains will be captured in the eCRF.

6.3.2.4. Cognitive Assessment

A cognitive battery is included in this study to assess the impact, if any, on several cognitive functional domains. A central vendor will provide the methodology, training and support for the set-up and execution of the assessment, including equipment provisioning and certification of site personnel responsible for administering the cognitive battery. Site personnel responsible for administration of the cognitive battery will be appropriately certified to ensure consistency in execution across the study. The tool is electronically administered and the data will be transmitted to the vendor for data management before being transmitted to GSK.

6.4. Safety

Details of how to assess all study safety assessments will be provided in the Study Procedures Manual. Safety and tolerability assessments included in this study will include:


54

• Adverse Events, including:

All adverse events (AEs)

Serious adverse events (SAEs)

Possible suicidality-related AEs (PSRAEs) (Section 6.4.4)

• Potential suicidality risk (eC-SSRS) (Section 6.4.4)

• Clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis), including liver function tests

• Vital signs (blood pressure and heart rate)

• ECG measurements

• Physical examination

• Body weight

• Pregnancy testing

All laboratory analyses will be performed in association with the visits, as specified in the Time and Events tables (Table 10 and Table 11). Samples will be processed by a central laboratory vendor with the exception of the urine pregnancy test which will be done locally.

ECGs will be conducted locally and managed and read by a central ECG vendor.

6.4.1. Liver chemistry stopping and follow up criteria

Phase II liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).

Phase II liver chemistry stopping criteria 1-5 are defined below and in Appendix 3: Liver Chemistry Stopping and Follow-up Criteria:

1. ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR>1.5, if INR measured).

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

2. ALT ≥ 5xULN.

3. ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).

4. ALT ≥ 3xULN persists for ≥4 weeks

5. ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks


55

When any of the liver chemistry stopping criteria 1-5 is met, do the following:

• Immediately withdraw investigational product for that subject

• Report the event to GSK within 24 hours of learning its occurrence

• Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR>1.5, if INR measured; INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

• Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

• Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below.

• Withdraw the subject from the study (unless further safety follow up is required) after completion of the liver chemistry monitoring as described below.

• Do not re-challenge with investigational product.

In addition, for criterion 1:

• Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

• A specialist or hepatology consultation is recommended

• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values

For criteria 2, 3, 4 and 5:

• Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.


56

Subjects with ALT ≥3xULN but <5xULN and bilirubin <2xULN, without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks

• Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety.

• Can continue investigational product

• Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline

• If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.

For criteria 1-5, make every attempt to carry out the liver event follow up assessments described below:

• Viral hepatitis serology including:

• Hepatitis A IgM antibody;

• Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

• Hepatitis C RNA;

• Cytomegalovirus IgM antibody;

• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);

• Hepatitis E IgM antibody

• Blood sample for pharmacokinetic (PK) analysis, obtained within 48 hours or 3 half-lives of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SPM.

• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

• Fractionate bilirubin, if total bilirubin≥2xULN

• Obtain complete blood count with differential to assess eosinophilia

• Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report form


57

• Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form.

• Record alcohol use on the liver event alcohol intake case report form

The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) but are optional for other abnormal liver chemistries:

• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma globulins).

• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week (James 2009).

• Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody.

• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

6.4.2. Adverse Events

The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

6.4.2.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Events meeting the definition of an AE include:

• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition

• New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study

• Signs, symptoms, or the clinical sequelae of a suspected interaction

• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.


58

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events that do not meet the definition of an AE include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital)

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition

6.4.2.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death

b. Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c. Requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d. Results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect


59

f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants).

NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin ≥ 2xULN, then the event is still reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.

6.4.3. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.

However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs.

6.4.4. Assessments of Suicidality

GSK239512 is considered to be a CNS-active drug. There has been some concern across the industry and among regulators that some CNS-active drugs may be associated with an increased risk of suicidal thinking or behaviour when given to some patients with certain conditions. Although this drug or other similar drugs in this class have not been shown to be associated with an increased risk of suicidal thinking or behaviour when given to healthy volunteers, as well as Alzheimer's and schizophrenia patients, GSK considers it important to monitor for such events before and during clinical studies with compounds such as this.

In addition, there is a risk that patients with MS that are being treated with interferon beta may occasionally experience symptoms of depression and/or suicidality (suicidal ideation or behaviour) (Fragoso 2010). Therefore, GSK also considers it appropriate to monitor subjects for suicidality before and during treatment.


60

Subjects being treated with GSK239512 should be assessed appropriately for suicidality and unusual changes in behaviour. Consideration should be given to discontinuing GSK239512 in subjects who experience signs of suicidal ideation or behaviour that increases the safety risk to the subject. It is recommended that the Investigator consider mental health consultation or referral for subjects who experience signs of suicidal ideation or behaviour.

The eC-SSRS assessment of suicidal risk will be conducted via an IVRS system. This will be accompanied by a review of the report by the principal investigator or appropriately qualified designee along with the review and assessment of any possible suicidality related adverse events (PSRAEs). The principal investigator and designated site personnel involved in the assessment of suicidality should be appropriately trained and certified. In the event that the IVR is not accessible, the C-SSRS guided interview will be used and appropriately documented in the eCRF.

6.4.5. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs

This study does NOT include any defined Disease-Related Events and/or Disease-Related Outcomes not qualifying as SAEs.

All relapses of MS will be captured in the subject source documents and on the “Relapse Form(s)” in the eCRF. As they are expected events for the RRMS population, reporting of relapses and associated hospitalization as an AE and/or SAE is only required in this study if they meet the definitions as specified in Section 6.4.2.1 and Section 6.4.2.2. Information reported on the Relapse Form(s) in the eCRF will be part of the ongoing safety review by the Safety Review Team (SRT).

6.4.6. Pregnancy

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. If the study is actively participating in the study (e.g. taking study mediction) the subject should be withdrawn in accordance with Section 4.4. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.

Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK.


61

6.4.7. Time Period and Frequency of Detecting AEs and SAEs

The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

AEs will be collected from the start of study treatment and until the follow up contact.

SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 6.4.8.

6.4.8. Prompt Reporting of Serious Adverse Events and Other Events to GSK

SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours “SAE” data

collection tool 24 hours Updated “SAE”

data collection tool Device Incident 24 hours “Medical Device

Incident Report Form”

24 hours Updated “Medical Device Incident Report Form”

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Liver chemistry abnormalities for Phase I to IV: ALT≥3xULN and Bilirubin≥2xULN (>35% direct) (or ALT≥3xULN and INR>1.5, if INR

measured)1

24 hours2 “SAE” data collection tool.

“Liver Event CRF” and “Liver

Imaging” and/or “Liver Biopsy”

CRFs, if applicable3

24 hours Updated “SAE” data collection

tool/“Liver Event” Documents3

Remaining liver chemistry abnormalities for Phase II: ALT≥5xULN;

ALT≥3xULN with hepatitis or rash or 3xULN ≥4 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3


62

Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents ALT≥3xULN and

<5xULN and bilirubin <2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

if applicable3

1. INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants.

2. GSK must be contacted at onset of liver chemistry elevations to discuss subject safety 3. Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as

applicable) should be completed as soon as possible.

The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.

6.4.8.1. Regulatory reporting requirements for SAEs

Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

6.4.9. Internal Safety Review Committee (iSRC)

An internal Safety Review Committee (iSRC), consisting of GSK personnel who are not involved in the conduct of this study, will be assembled to answer specific questions on behalf of the study team. External experts, who are not involved in the conduct of the study, may be included on the iSRC to provide review and input on data, as appropriate.


63

The iSRC will provide instream unblinded review of study data including MS disease activity, specific central nervous system (CNS) AEs and potential other events of interest in the study participants. The iSRC will operate according to the iSRC charter. The iSRC will be empowered to recommend the protocol be amended or the study terminated if any safety concerns or changes in the risk to benefit ratio are identified, in accordance with the charter. A copy of the iSRC charter can be provided by GSK upon request.

6.5. Health Outcomes

The primary objective in this study is to estimate the effects of GSK239512 in the remyelination of lesions in subjects with RRMS. In support of the clinical development plans for this compound, it is important to initiate the evaluation of disabilities that are problematic in a way that is meaningful for MS patients and which are most likely to be positively impacted by the remyelination. The exploratory assessment that is being included is the Multiple Sclerosis Quality of Life (MSQoL) 54 assessment (Vickrey 1995). A paper version of the form will be provided to each subject to complete independently at the Baseline visit and the last Treatment visit. This assessment will be included in the medical record and the responses will be recorded in the eCRF.

6.6. Pharmacokinetics

Pharmacokinetic sampling will occur according to the following schedule:

Table 14 Pharmacokinetic Sampling Schedule

Titration Maintenance Wk 4 Wk 8 Wk 24 Wk 36 Wk 48 Sparse X Trough X X X X

The Sparse PK samples are to be collected from subjects at 'pre-dose', and 3 times post-dose. No samples should be collected within 30 minutes of the previous sample. The target time along with the allowable range for collecting the 3 post-dose samples are:

• 30 minutes post-dose (15 min to 1 hour post-dose),

• 2 hours post-dose (1-4 hours post-dose), and

• 6 hours post-dose (4-8 hours post-dose).

Subjects should avoid, as much as practical, food consumption within approximately 2 hours prior to and following dosing. The time of dose and the time of each sample collection will be captured on the eCRF and the sample processing form. Additionally, information about missing doses will be captured on the eCRF.

The Trough PK samples are to be collected at the visits designated in Table 14, prior to the subject taking their daily dose of medication.


64

Patient dosing instructions are provided in Section 5.5.2 for the Titration visits and Section 5.5.3 for the Maintenance visits.

At each time point, blood (3 mL) will be collected into a K2-EDTA vacutainer, gently mixed by inversion (do not shake), placed on ice and centrifuged at 1500 g for 10 minutes at 4°C. Samples should be processed within 1 hour. The harvested plasma for each sample should be transferred into an appropriately labeled 1.4mL Matrix tube and immediately frozen at -20°C or lower. All samples will be stored at least -20°C.

Details of shipping procedures are provided in the Study Procedures Manual (SPM).

6.6.1. Plasma Sample Analysis

Plasma analysis will be performed under the management of Worldwide Bioanalysis, Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline. Concentrations of GSK239512 will be determined in plasma samples using the currently approved analytical methodology. Raw data will be stored in the GLP Archives, GlaxoSmithKline. Once the plasma has been analyzed for GSK239512, any remaining plasma may be analyzed qualitatively for other circulating compound-related material and the results reported under a separate DMPK protocol.

6.7. Pharmacogenetic Research

A sample will be collected from each subject providing consent for pharmacogenetic (PGx) sampling in this study.

Information regarding PGx research is included in Appendix 1: Pharmacogenetic Research.

6.8. Early Withdrawal and Follow-up

In the event that a subject withdraws from the study, the Early Withdrawal Visit procedures should be followed according to the Time and Events table for Optional Visits (Table 11). This visit includes the procedures that should be followed, whenever possible, to ensure that there is appropriate completion of the subjects participation in the study. There are several long-term assessments in the study, which are collected at different timepoints but not included at every Clinic Visit. Therefore, completion of the Early Withdrawal Visit will include these assessments and optimize the ability to include data previously provided by the subject in the analyses.

If the decision to withdraw a subject occurs at either a regularly scheduled Clinic Visit or at an Optional Clinical Visit (e.g. relapse, titration, etc...), the visit should ONLY be treated and recorded as an Early Withdrawal Visit (Table 11) and the corresponding procedures should be completed.

A Follow-up Visit should be completed at least 2 weeks following last dose of study medication. This occurs after completion of the Week 48 visit or Early Withdrawal. The Follow-Up Visit is a complete assessment of the subject, including critical safety assessments.


65

7. DATA MANAGEMENT

For this study subject data will be entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using MedDRA and an internal validated medication dictionary, GSKDrug. An appropriate medical dictionary that covers all approved drugs in studies where Japan is participating will be referenced]. eCRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy. In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1. Hypotheses

There are no statistical hypotheses to be tested in this study. As stated in Section 2, the primary objectives of this study are around estimation of the effects of remyelination of GSK239512 versus placebo. These objectives will be assessed by the generation of predictive probabilities that the remyelination of new lesions is of an effect size greater than zero and considered of potential clinical relevance. The target effect size for this study is 0.5. To this extent, inference will be carried out to estimate the posterior probability that the difference between the mean of the test treatment and the mean of the reference treatment µ(GSK239512) - µ(Placebo), is greater than 0 for each co-primary endpoint using effect sizes. An effect size is defined as the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. The posterior probability that the true effect size is greater than zero will be referred to as PP(∆>0).

In addition in this study it is also of interest to estimate the changes in the co-primary endpoints that are of potential clinical relevance, define their statistical distributions, estimate their relationship and explore the most appropriate statistical methodology to analyses these endpoints.


66

8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

The following assumptions have been made in the design of this study:

• The treatment effect for both co-primary endpoints will be expressed as effect sizes and are therefore assumed to have distributions of mean 0 and standard deviation 1. The target effect size for this study is 0.5. Based on unpublished data in post-mortem brains for SPMS subjects, it is believed that an effect size of 0.5 is approximately equivalent to a 50% increase in remyelination compared to the natural remyelination process that would be expected in the placebo group.

• The correlation between the two co-primary endpoints is 0.5. The distribution of the co-primary endpoints is described by a Bivariate Normal Distribution.

• Analysis will be performed at the subject level with the estimation of remyelination within each lesion averaged for each subject. It is assumed that each subject will have at least 1 lesion that contributes to the analysis for both endpoints.

• An interim analysis will be performed when approximately half the subjects have Week 42 MRI data available. The study will be considered as potentially futile if both co-primary endpoints have a PP(∆>0)<30% at the time of the interim analysis (Section 8.3.4 includes full details).

• A signal of efficacy will be declared if the posterior probability the true effect size (GSK239512-placebo) is greater than zero is more than 80% (PP(∆>0)>80%) for both co-primary endpoints. An efficacy signal will also be considered observed if one co-primary endpoint has a PP(∆>0)>80% and the other co-primary endpoint has a PP(∆>0)>70%. A negative study will be declared if the posterior probability that the true effect size (GSK239512-placebo) is greater than zero is less than 70% (PP(∆>0)<70%). A negative study will also be considered to have been observed if one co-primary endpoint has a PP(∆>0)<70% and the other co-primary endpoint has a PP(∆>0)<80%. Otherwise there is a grey area. Table 15 provides a summary of the potential outcomes using a color-coded approach.

• Given the exploratory nature of the study, no formal Type I and Type II Error rates are defined and no adjustments for multiplicity are required.

Based on the above assumptions, a simulation approach has been employed to investigate the chance of stopping for futility, and correctly or incorrectly detecting a signal of efficacy on the co-primary endpoints, based on 10,000 simulations. Based on the outcome of these simulations 114 subjects will be randomized to achieve 100 subjects with at least one post-baseline MRI. Figure 2 shows the chance of stopping for futility or declaring a positive "Go" or negative "Stop" study with 50 evaluable subjects/arm for a range of unknown true effect sizes and Table 15 shows the chances of each making each potential decision in the study based on each co-primary endpoint for true unknown effect sizes of 0 and 0.5 for the study sample size.


67

Figure 2 Chance of Stopping for Futility at the Interim Analysis (PP(∆>0)<30%), Positive "Go" Result at Study End (PP(∆>0)>80%) and Negative "Stop" Result at Study End (PP(∆>0)<70%)

Table 15 Chance of Stopping for Futility at the Interim Analysis

(PP(∆>0)<30%), Positive "Go" Result at Study End (PP(∆>0)>80%) and Negative "Stop" Result at Study End (PP(∆>0)<70%)

Treatment Difference for both Co-Primary Endpoints

Percentage of Trials in this scenario (%)

Decision for Co-Primary Endpoint 2 Futile Go Grey Stop

0 Decision for Co-Primary Endpoint 1

Futile 15.39% 0.00% 0.00% 0.00% Go 0.00% 8.01% 2.75% 8.21% Grey 0.00% 2.64% 1.40% 5.66% Stop 0.00% 8.44% 5.63% 41.87%

0.5 Decision for Co-Primary Endpoint 1


In this study with 100 subjects, the selected criterion for efficacy detection is the posterior probability the true effect size (GSK239512-placebo) is greater than zero is more than 80%. From Figure 2 and Table 15 we can see that for this efficacy detection (i.e. PP(∆>0)>80%) with 50 subjects per arm, if the true effect is 0.5 for both co-primary endpoints we will detect a signal of efficacy in approximately 94% of trials, and declare a negative "Stop" signal in ~41% of trials. Less than 1% of studies would be stopped for futility at the interim analysis. If the true effect is 0 for both co-primary endpoints (i.e. GSK239512 is no better than placebo) then the studies would incorrectly detect a signal in ~13% of trials. If the true effect for both co-primary endpoints was 0 the study would be considered futile for its primary objective in ~16% of trials; and if the true effect for both co-primary endpoints was 0 the study would be considered negative for its primary objective at the study end in ~53% of trials.


68

8.2.2. Sample Size Sensitivity

As discussed in Section 1.5.1, it is possible that not all subjects will have an analyzable GdE lesion while participating in the study. It is estimated that 40-60% of subjects will have a GdE lesion that can be assessed for remyelination. It is believed that based on non-published data [personal communication, Douglas Arnold] the prevalence of delta-MTR lesions will be higher than the prevalence of GdE lesions.

Therefore, it is possible that not all subjects will be able to contribute to the analyses for either co-primary endpoint. Figure 3 demonstrates the chance of stopping for futility, or declaring a positive or negative study, with 30 evaluable subjects/arm for a range of unknown true effect sizes.

Figure 3 Chance of Stopping for Futility or Declaring a Positive or Negative study with 30 evaluable subjects/arm

It can be seen that with fewer subjects being evaluable for the GdE lesion co-primary endpoint reduces the probability of declaring a positive study and slightly increases the chances of stopping the study at the interim analysis or declaring a negative study for the target effect size of 0.5. For this efficacy detection (i.e. PP(∆>0)>80%) with 30 subjects per arm, if the true effect is 0.5 for both co-primary endpoints we will detect a signal of efficacy in approximately 84% of trials, and declare a negative signal in ~4% of trials. Less than 1% of studies would be stopped for futility at the interim analysis. If the true effect is 0 for both co-primary endpoints (i.e. GSK239512 is no better than placebo) then with 30 subjects per arm the outcomes are similar in that studies would incorrectly detect a signal in ~13% of trials. If the true effect for both co-primary endpoints was 0 the study would be considered futile for its primary objective in ~15% of trials; and if the true effect for both co-primary endpoints was 0 the study would be considered negative for its primary objective at the study end in ~53% of trials.


69

Table 16 shows the probability of each study outcome varying the correlation coefficient between the two co-primary endpoints for the sample size of 50 subjects per group. It can be seen that when the true treatment effect size is 0, the stronger the correlation between the two co-primary endpoints the more likely the study would either stop for futility at the interim analysis or declare a negative study. For a true effect size of 0.5 there is little impact on the outcomes of the study with changing correlation coefficients. As the correlation increases, there is a slight increase in the probability of a positive signal being observed.

Table 16 Assessment of Impact of Correlation Coefficients on Study Outcomes

Treatment Difference for both Co-Primary Endpoints

Percentage of Trials in this scenario (%)

Decision for Co-Primary Endpoint 2 Futile Go Grey Stop

Correlation Coefficient: 0.2 0 Decision for

Co-Primary Endpoint 1















70

8.2.3. Sample Size Re-estimation

During the instream reviews (Section 8.3.4), an assessment of the GdE lesion rate and the ability of the study to detect effects of GSK239512 where PP(∆>0)>80% will be performed. If the GdE lesion occurrence rate is lower than expected an increase in sample size or changes in the inclusion/exclusion criteria will be considered to increase the likelihood that subjects recruited will contribute lesions to the primary analysis (Section 8.3.4).

8.3. Data Analysis Considerations

8.3.1. Analysis Populations

The primary population of interest in this study is the intent-to-treat population which is defined as all subjects receiving at least one dose of investigational product post randomisation. This population will be used for all assessments of efficacy, pharmacokinetic and safety data.

Due to the exploratory nature of this study, no per protocol population will be defined.

8.3.2. Analysis Data Sets

The primary dataset of interest for all MRI endpoints and all other efficacy endpoints is the Observed Cases (dataset). Sensitivity analyses may be performed on datasets using imputed data; all details will be specified in the RAP.

GdE or delta-MTR lesions that have not reached a stable recovery (consistent MTR value for a minimum of 2 MTR readings post-lesion) value indicating that the remyelination process has not completed will not be included in the primary analysis dataset. It is believed that the dataset that will provide the best balance between lesions being available to include in the analysis and the clearest signal in changes in demyelination/remyelination is where a lesion has at least 2 MRI assessments in the 12 weeks prior to the lesion being identified and 2 assessments at least 12 weeks after the lesion has been identified (i.e. at stable recovery). This is expected to include all lesions identified at MRI scans at Weeks 12, 18, 24 and 30, and will be the primary data of interest. Additional sensitivity analyses using all lesions identified in the study and alternative observation windows around the lesion appearance will be specified in the study RAP. For all other endpoints, the primary time point of interest is the Week 48 assessment at the end of the treatment phase.

8.3.3. Treatment Comparisons

8.3.3.1. Primary Comparisons of Interest

The primary comparisons of interest in this study are the estimation of the effects of GSK239512 relative to placebo, taken adjunctively to IFN-b1a or glatiramer acetate in the remyelination of acute lesions as identified by the co-primary endpoints. A nominal Type I error rate is defined on the basis that 90% confidence intervals for the treatment difference and effect size will be presented alongside the predictive probabilities from the posterior distribution that remyelination of lesions is >0. No hypothesis testing will be performed.


71

8.3.3.2. Other Comparisons of Interest

Given the exploratory nature of the study and the novelty of the indication under study, the effects of GSK239512 relative to placebo will be estimates using 90% confidence intervals for the treatment difference and effect size will be presented alongside the predictive probabilities from the posterior distribution that the treatment difference is >0 for all statistical analyses of secondary endpoints.

8.3.4. Interim Analysis

Unblinded instream reviews will be conducted by the iSRC approximately every 3 months following the first review conducted when approximately 10 subjects have completed the Week 12 assessment and their MRI data is available for review. These instream reviews will be used to monitor safety and key efficacy data in this patient population and to understand the statistical distributions that underlie the novel co-primary endpoints in this study. During these instream reviews the iSRC will review study progress and may request that the GSK Study Team institute a protocol amendment to try to increase the overall lesion activity in the study by either increasing the subject numbers or increasing the lesion activity required of the subjects included in the study if the observed lesion rates are considered potentially too low to allow an assessment of the remyelination potential of GSK239512 to be assessed. A formal interim analysis will be conducted to assess the MRI efficacy of GSK239512 with respect to the co-primary endpoints when Week 42 MTR data from approximately 50% of subjects is available. The study may be considered futile with respect to its primary objective if the posterior probability that the Effect Size is greater than zero is less than 30% for both co-primary endpoints. If the futility criteria are met the study and all subject participation could be discontinued before the full complement of subjects have completed. However, this futility rule is not binding in the study design and if secondary endpoints are indicating potentially clinically meaningful benefit such that the benefit:risk ratio for subjects is still considered favourable the study may continue to completion. In this situation, GSK will provide a rationale for the decision to complete the study in the Clinical Study Report. The study will not be declared a success and terminated early based on positive MTR data for the co-primary endpoints at the interim analysis due to the exploratory nature of the study and the limited understanding of the endpoints and their relationship to clinical benefit. As such, the study would continue to completion to allow a full assessment of the data collected.

The timing of the interim analysis will be specified in the iSRC Charter but is anticipated to be conducted alongside the instream review that corresponds most closely to when MRI data is available from the Week 42 visit for approximately 50 subjects.

Circulation of the instream review and interim analysis data will be restricted to unblinded study team members, the iSRC and external experts, as appropriate (details to be included in iSRC Charter, but in particular, unblinded data will not be shared with GSK staff involved in the conduct of the study on a day-to-day basis or anyone who may be involved in data query resolution) to protect the integrity of the study.


72

8.3.5. Key Elements of Analysis Plan

8.3.5.1. Efficacy Analyses

The co-primary endpoints will be analysed using Mixed Model Repeated Measures (MMRM) analysis with restricted maximum likelihood estimation and an unstructured covariance matrix. The proposed MMRM model will include the effects of treatment, gender, age at baseline, time relative to lesion identification, MS-disease modifying treatment, baseline brain volume as covariates and treatment by time relative to lesion identification, MS-disease modifying treatment by time relative to lesion identification and baseline by time relative to lesion identification interactions. Time relative to lesion identification will be fitted as a repeated effect within subject. It is possible that this model may not be able to converge due to the large number of terms proposed and the small number of subjects. The RAP will detail how the number of terms may be reduced in the situation of non-convergence. Effects of other covariates that may also be included in the model and potential weighting approaches will be defined in the RAP.

Effect sizes (i.e. estimate of treatment difference / standard deviation) using the between-subject standard deviation from the MMRM model will be provided.

8.3.5.2. Safety Analyses

Adverse events will be coded using MedDRA and summarized by system organ class and preferred term. A summary of the number and percentage of subjects with any adverse event, any serious adverse event, adverse events leading to permanent discontinuation of study drug, and study drug-related adverse events in each treatment group will be provided.

Summary statistics will be presented for laboratory values and their change from baseline. Each laboratory value will also be flagged to show if it is a value within, below or above the normal range or if it is of clinical concern. The number and percentage of subjects in each of these categories at each assessment will be summarized by laboratory parameter.

Summary statistics will be presented for vital signs and ECGS, and their change from baseline. In addition number and percentage of subjects with values within, below or above values of clinical concern will be presented.

8.3.5.3. Health Outcomes Analyses

Data from the MSQOL-54 will be scored according to the scoring algorithm suggested by the authors of the questionnaire (Vickrey 1995). Scale scores will be generated by averaging the items within scales and transforming the mean scores linearly from 0 to 100 possible scores, with higher scores indicating a better QOL. Physical and mental health composite scores will be generated by weighting the sum of selected scales to generate a simplified two-factor solution to the MSQOL-54. For exploratory reasons, we will use both the individual QOL scales and the composite scores of the MSQOL-54. Data from the MSQOL-54 will be considered exploratory and will not be interpreted inferentially.


73

8.3.5.4. Pharmacokinetic Analyses

Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics Modeling and Simulation Department, QSci, GlaxoSmithKline. Pre-dose trough concentrations of GSK239512 will be summarized descriptively by week and dose level. Concentrations of GSK239512 at week 8 will be summarized descriptively by nominal sampling time and dose level.

Population PK analysis may be conducted to provide estimates of population PK parameters and individual Bayes parameter, based on the pooled PK data of this study, Study H3B105321 (GlaxoSmithKline Document Number: HM2007/00235/00) and Study H3B106026 (GlaxoSmithKline Document Number: HM2008/00274/00).

8.3.5.5. Pharmacokinetic/Pharmacodynamic Analyses

The relationship between the primary study endpoints and the average GSK239512 trough concentration at maintenance stage or steady state GSK239512, Cave at maintenance stage, if derived from individual Bayes estimate of population PK analysis, will be graphically explored. In the presence of a signal of correlation, alternative models will be used to explore quantitative exposure with primary study endpoints. Secondary endpoints may be treated in a similar manner.

8.3.5.6. Pharmacogenetic Analyses

See Appendix 1: Pharmacogenetic Research for details about the Pharmacogenetics Analysis Plan.

9. STUDY CONDUCT CONSIDERATIONS

9.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.

9.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:


74

• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments.

• Subject informed consent.

• Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or both.

Written informed consent must be obtained from each subject prior to participation in the study.

9.2.1. Subject Reconsent

Due to the progressive nature of RRMS, it is possible that at a subject level, the potential risk to benefit ratio may change and it is important to ensure that a subject is fully informed of the voluntary nature of their participation in this study. Therefore, reconsent of a subject should be done when, according to the judgement of the principle investigator, the benefit risk ratio changes for the subject (e.g. increase in relapse activity and/or disability score) AND/OR in accordance with local clinical trial practice standards.

9.2.2. Pharmacogenetic Research Consent

In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory agency are also approving the optional assessments e.g., PGx assessments described in Appendix 1: Pharmacogenetic Research unless otherwise indicated. Where permitted by regulatory authorities, approval of the optional assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the optional assessments is being deferred and the study, except for the optional assessments, can be initiated. When the optional assessments are not approved, then the approval for the rest of the study will clearly indicate this and therefore, the optional assessments will not be conducted.

9.3. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK will monitor the study to ensure that the:

• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.


75

9.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

9.5. Study and Site Closure

A subject will complete the study when they have completed their last study visit. And the study will be closed, after the last subject has completed their last study visit (LSLV).

Upon completion or termination of the study, the GSK monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe non-compliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.

If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.

9.6. Records Retention

Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.


76

GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis.

GSK aims to post a results summary to the GSK Clinical Study Register and other publicly available registers no later than 8 months after the last subject’s last visit (LSLV) [this applies to each data analysis phase for studies with multiple phases, e.g., primary analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-reviewed journal for publication within 18 months of LSLV. GSK also aims to publish the full study protocol on the GSK Clinical Study Register at the time the results of the study are published as a manuscript in the scientific literature.

When manuscript publication in a peer-reviewed journal is not feasible, further study information will be posted to the GSK Clinical Study Register to supplement the results summary.


77

10. REFERENCES

Brown RA, Narayanan S, Freedman M, Atkins HL, Arnold DL. Normalization of Magnetization Transfer Ratio MRI for Multicentre Clinical Trials. International Society for Magnetic Resonance in Medicine Annual Conference and Exhibition. 2011; 4082.

Chen JT, Collins DL, Atkins HL, Freedman MS and Arnold DL. Magnetization transfer evolution with demyelination and remyelination in multiple sclerosis lesions. Ann Neuro. 2008;63: 254-262.

Chen JT, Kuhlmann T, Jansen GH, Collins DL, Atkins HL, Freedman MS, O’Connor PW and Arnold DL. Voxel-based analysis of the evolution of magnetization transfer ratio to quantify remyelination and demyelination with histopathological validation in a multiple sclerosis lesion. Neuroimage. 2007; 36: 1152-1158.

Cohen JA, Barkhof F, Comi G, Hartung, HP, Khatri BO, Montalban X, Peeletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med. 2010; 362: 402-415.

Comi G, Filippi M, Wolinsky JS. Glatiramer Acetate Study Group Study of the Effects of Glatiramer Acetate on Magnetic Resonance Imaging–Measured Disease Activity and Burden in Patients with Relapsing Multiple Sclerosis. Ann Neuro. 2001; 49: 290–297.

Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011; 93(1): 1-12.

Fragoso YD, Comini Frota ER, Lopes JS, Noal JS, Gacomo MC, Gomes S, et al. Severe Depression, Suicide Attempts, and Ideation During the Use of Interferon Beta by Patients with Multiple Sclerosis. Clin Neuropharm. 2010; 33: 312-316.

Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008; 9(11): 839-855.

GlaxoSmithKline Clinical Pharmacology Study Report Document Number HM2007/00235/00; H3B105321. Effective Date: 10 June 2008

GlaxoSmithKline Clinical Pharmacology Study Report Document Number HM2008/00274/00; H3B106026. Effective Date: 7 November 2008

GlaxoSmithKline Document Number HM2008/00498/06; Clinical Investigator Brochure. Effective Date: 25 July 2012

Hagemeier K, Brück W, Kuhlmann T. Multiple sclerosis: remyelination failure as a cause of disease progression. Histology and Histopathology. 2012; 27(3): 277-287.


78

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos. 2009; 37: 1779-1784.

Julian LJ. Cognitive functioning in multiple sclerosis. Neurol Clin. 2011; 29(2): 507-525.

Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Brück W. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain. 2008; 131(7): 1749-1758.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurol. 1983; 33: 1444-1452.

Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Lauresen H, Sorensen PS, Brück W, Lucchinetti C, Lassmann H. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006; 129(12): 3165-3172.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Ann Neurol. 2011; 69: 292–302.

Rovaris M, Comi G, Rocca MA, Valsasina P, Ladkani D, Pieri E, Weiss S, Shifroni G, Wolinsky JS, Filippi M. Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial. Multiple Sclerosis. 2007; 13: 502-508

Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization Transfer Ratio and Myelin in Postmortem Multiple Sclerosis Brain. Ann Neurol. 2004; 56: 407-415.

van den Elskamp IJ, Knol DL, Vrenken H, Karas G, Meijerman A, Filippi M, Kappos L, Fazekas F, Wagner K, Pohl C, Sandbrink R, Polman CH, Uitdehaag BMJ, Barkhof F. Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis. Multiple Sclerosis. 2010; 16(6): 660-669.

Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995; 4(3): 187-206.


79

11. APPENDICES

11.1. Appendix 1: Pharmacogenetic Research

Pharmacogenetics - Background

Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in populations. There is increasing evidence that an individual's genetic background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx associations with safety/adverse events include:

Drug Disease Gene Variant Outcome Abacavir HIV

[Hetherington, 2002; Mallal, 2002; Mallal, 2008]

HLA-B* 5701 Carriage of the HLA-B*5701 variant has been shown to increase a patient's risk for experiencing hypersensitivity to abacavir. Prospective HLA-B*5701 screening and exclusion of HLA-B*5701 positive patients from abacavir treatment significantly decreased the incidence of abacavir hypersensitivity. Treatment guidelines and abacavir product labeling in the United States and Europe now recommend (US) or require (EU) prospective HLA-B*5701 screening prior to initiation of abacavir to reduce the incidence of abacavir hypersensitivity. HLA-B*5701 screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity.

Carbamazepine

Seizure, Bipolar disorders & Analgesia Chung, 2010; Ferrell, 2008

HLA-B*1502 Independent studies indicated that patients carrying HLA-B*1502 are at higher risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis and that this marker is prevalent in some populations, particularly with Asian ancestry. Regulators, including the US FDA and the Taiwanese TFDA, have updated the carbamazepine drug label to indicate that patients with ancestry in genetically at risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with carbamazepine.


80

Drug Disease Gene Variant Outcome Irinotecan Cancer

[Innocenti, 2004; Liu, 2008; Schulz, 2009]

UGT1A1*28 Variations in the UGT1A1 gene can influence a patient’s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects, that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have two copies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene.

A key component to successful PGx research is the collection of samples during the conduct of clinical studies.

Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in response to GSK239512.

Pharmacogenetic Research Objectives

The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a relationship between genetic factors and response to GSK239512. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with GSK239512, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:

• Pharmacokinetics and/or pharmacodynamics of study treatment

• Safety and/or tolerability

• Efficacy]

Study Population

Any subject who is enrolled in the clinical study, can participate in PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research.

Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study or result in any penalty or loss of benefits to which the subject would otherwise be entitled.


81

Study Assessments and Procedures

Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in PGx assessments.

If taking blood samples: in addition to any blood samples taken for the clinical study, a whole blood sample (~6ml) will be collected for the PGx research using a tube containing EDTA. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study,. It is recommended that the sample be collected at the Baseline Visit.

• The PGx sample is labelled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample is taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample.

The DNA extracted from the blood sample may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

The need to conduct PGx analysis may be identified after a study (or a set of studies) of GSK239512 has been completed and the clinical study data reviewed. In some cases, the samples may not be studied. e.g., no questions are raised about how people respond to GSK239512.

Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form.

Subjects can request their sample to be destroyed at any time.

Subject Withdrawal from Study

If a subject who has consented to participate in PGx research and has had a sample taken for PGx research withdraws from the clinical study for any reason other than lost to follow-up, the subject will be given the following options:

• Retain the sample for PGx research

• Destroy the PGx sample

If a subject withdraws consent for PGx research or requests sample destruction for any reason, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records.


82

Screen and Baseline Failures

If a blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator should instruct the participant that their PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files.

Pharmacogenetics Analyses

Pharmacogenetics Analyses

1. Specific genes may be studied that encode the drug targets, or drug mechanism of action pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse events, disease risk or drug response. These candidate genes may include a common set of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to determine the relationship between gene variants or treatment response and/or tolerance.

In addition, continuing research may identify other enzymes, transporters, proteins or receptors that may be involved in response to [insert the name of the study treatment]. The genes that may code for these proteins may also be studied.

2. Genome-wide scans involving a large number of polymorphic markers (e.g., single nucleotide polymorphisms) at defined locations in the genome, often correlated with a candidate gene, may be studied to determine the relationship between genetic variants and treatment response or tolerance. This approach is often employed when a definitive candidate gene(s) does not exist and/or the potential genetic effects are not well understood.

If applicable and PGx research is conducted, appropriate statistical analysis methods will be used to evaluate pharmacogenetic data in the context of the other clinical data. Results of PGx investigations will be reported either as part of the main clinical study report or as a separate report. Endpoints of interest from all comparisons will be descriptively and/or graphically summarized as appropriate to the data. A detailed description of the analysis to be performed will be documented in the study reporting and analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.

Informed Consent

Subjects who do not wish to participate in the PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any blood being taken for PGx research.

Provision of Study Results and Confidentiality of Subject's PGx Data

GSK may summarize the PGx research results in the clinical study report, or separately, or may publish the results in scientific journals.


83

GSK does not inform the investigator, subject, or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of individual genotyping results that are not known to be relevant to the subject’s medical care at the time of the study, unless required by law. This is due to the fact that the information generated from PGx studies is generally preliminary in nature, and therefore the significance and scientific validity of the results are undetermined.

References

Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.

Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008; 9: 1543-46.

Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2.

Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382-1388.

Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer. 2008; 112: 1932-40.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32.

Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78

Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J. Gastroenterol. 2009; 15: 5058-66.


84

11.2. Appendix 2: Country Specific Requirements

No country-specific requirements exist.


85

11.3. Appendix 3: Liver Chemistry Stopping and Follow-up Criteria

Phase II Liver Safety Algorithms

ALT > 3xULN

plus Bilirubin > 2xULN or plus INR>1.5, if measured)* No

Yes

Yes • Instruct subject to stop investigational product (IP) • Notify GSK + arrange clinical followup within 24 - 72h • Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) • Complete liver event CRF, SAE data collection tool if appropriate, + liver imaging +/or biopsy CRFs if these tests performed. • Obtain weekly liver chemistries [**as far as possible] until resolved, stabilised or returned to baseline • Withdraw subject from study after liver chemistry monitoring complete (unless protocol has option to restart drug

-

• Instruct subject to stop investigational product (IP) • N otify GSK + arrange clinical followup within 24h • Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) • Report as an SAE (excl. hepatic impairment or cirrhosis studies)+ and complete li ver event CRF, SAE data collection tool, + liver imaging +/or biopsy CRFs if testsperformed. • Obtain twice weekly liver chemistries until resolved, stabilised or returned to baseline values • Consultation with hepatologist /specialist re commended • Withdraw subject from study after monitoring complete unless protocol has option to restart drug

-

ALT > 5xULN Hepatitis symptoms or rash?

No Able to monitor weekly

for 4 wks? No

Notify GSK within 24h to discuss subject safety Continue IP Check liver chemistry weekly for 4 weeks

No

No**

Yes

Yes

Continue IPObtain twice monthly liver chemistries until normalisedor back to baseline values

Yes

Yes

ALT > 3xULN or bilrubin > 2xULN? Yes

*INR value not applicable to patients on anticoagulants


86

11.4. Appendix 4: Protocol Summary

Rationale

GSK239512 is being developed as an adjunct therapy that by promoting remyelination may halt disability progression or reverse disability in patients with RRMS. In addition, it is possible that GSK239512 may enhance cognitive function in patients with RRMS.

A critical first step for GSK239512 development in MS is to determine whether GSK239512 can promote remyelination. Areas of recent and longer-term demyelination are frequent in the CNS of RRMS patients. These areas are potential sites in which to visualize an increase in organized myelin content. Amongst few methods to assess CNS myelin content, magnetization transfer imaging is supported as the best candidate endpoint for myelination by histopathology/MRI correlation data and use of a simplified analysis form (magnetization transfer ratio [MTR]) which allows for standardized implementation in multicentre clinical trials.

Therefore, this study is designed to assess whether GSK239512 can enhance remyelination in patients with RRMS, using brain MRI assessments of MTR to detect lesion remyelination. As GSK239512 is not anticipated to reduce the number of relapses, RRMS patients participating in this study will remain on background disease modifying therapy (Avonex [interferon-beta1a] or Copaxone [glatiramer acetate]).

The timecourse of CNS remyelination in vivo in MS patients is unclear and assessments of direct pharmacological promotion of lesion myelination are unprecedented. Observational studies using MTR, and other related imaging modalities (T1 hypointensity), suggest the natural timecourse of new lesion remyelination to be between starting at 3 months and up to 5 months or possibly longer (Chen 2007, Chen 2008). A timecourse for remyelination of chronic demyelinated areas is unknown. However, the frequency of new gadolinium enhanced (GdE) lesions in the recruited patient population is estimated to be 40-60% over a 6 month period (Cohen 2010, Comi 2001, Rovaris 2007) allowing for lesion signal detection in this study. The occurrence of delta MTR lesions is anticipated to be higher with potentially 100% of subjects having lesions detected (unpublished communication with Douglas Arnold). A treatment duration of 48 weeks is expected to permit completed remyelination assessment of at least one new delta MTR lesion per subject. The target effect size for this study is 0.5. Sample size adjustment may take place after instream review of lesion counts.


87

Objectives and Endpoints

Primary

Objectives Endpoints Estimation of the effects of GSK239512 on lesion remyelination in subjects with Relapsing Remitting Multiple Sclerosis on stable treatment with Avonex [interferon-beta1a] or Copaxone [glatiramer acetate].





















88



Percentage of subjects withdrawing due to AEs. Summary of suicide behavior and ideation risk as assessed

by the eC-SSRS and PSRAE. Change from baseline in clinical chemistry, hematology, and

urinalysis parameters. Frequency of clinical chemistry, hematology, and urinalysis

parameters of potential clinical concern. Change from baseline in vital signs and ECG parameters.

Frequency of vital signs and ECG parameters of potential clinical concern.

Pharmacokinetic Objectives Endpoints Evaluate pharmacokinetics of GSK239512 in MS subjects

Pre-dose trough concentration at Wk 4 and 8, 3M, 6M, 9M and 12M.



Primary

Objectives Endpoints Estimation of the effects of GSK239512 on lesion remyelination in subjects with Relapsing Remitting Multiple Sclerosis on stable treatment with Avonex [interferon-beta1a] or Copaxone [glatiramer acetate].









89















Percentage of subjects withdrawing due to AEs. Summary of suicide behavior and ideation risk as assessed

by the eC-SSRS and PSRAE. Change from baseline in clinical chemistry, hematology, and

urinalysis parameters. Frequency of clinical chemistry, hematology, and urinalysis

parameters of potential clinical concern. Change from baseline in vital signs and ECG parameters.

Frequency of vital signs and ECG parameters of potential clinical concern.

Pharmacokinetic Objectives Endpoints Evaluate pharmacokinetics of GSK239512 in MS subjects

Pre-dose trough concentration at Wk 4, Wk 24, Wk 36 and Wk 48 with sparse sampling (1 pre-dose and 3 post-dose) at Wk 8.




90

Study Design

This study is randomized, parallel group, and placebo-controlled. Subjects with RRMS on stable background treatment with either Avonex (Interferon-beta1a) or Copaxone (Glatiramer Acetate) are eligible to participate.

Subjects will be randomized in a 1:1 ratio between placebo and GSK239512. Randomization will be stratified by background disease modifying therapy (DMT) of either Avonex or Copaxone.

Assuming a 20% screen failure rate and 12% drop-out rate, based on those observed with other RRMS clinical trials, this study will screen approximately 144 subjects and randomize approximately 114 subjects to result in approximately 100 subjects with at least one post-baseline MRI.

The total treatment period is 48 weeks, including a standard 4 week titration period and 44 week maintenance treatment period (which could be adapted to a 5-week titration and 43 week maintenance period, if needed. Titration doses start at 10µg and increase up to 80µg (10µg first week, 20µg second week, 40µg third week, 80µg fourth week). Subjects will be titrated to the maximum tolerated dose with the objective of titrating to the highest dose (80µg GSK239512), whenever possible, based on investigator judgement of tolerability. Subjects unable to titrate to 80µg will be allowed to remain in the study, at the highest dose that they were able to tolerate. The post-treatment follow-up period will be a minimum of 2 weeks in duration following the end of treatment at Week 48 or early withdrawal, as appropriate.

Safety data including all safety assessments will be reviewed throughout the study by the Safety Review Team (SRT) for GSK239512. Trends in clinical endpoint data (e.g. relapse, EDSS, etc...) to assess signals of disease worsening that could be indicative of a safety signal, will be reviewed and may include, as appropriate, the engagement of external expert consultation. At a minimum, these reviews will include efficacy data approximately every 3 months following randomization of the first subject. An internal Safety Review Committee (iSRC), consisting of GSK personnel who are not involved in the conduct of this study, will be assembled and chartered to answer specific questions on behalf of the study team.

The study will be conducted as a 'single-blind' study. Only, a subset of individuals defined in the iSRC Charter will be unblinded. ALL subjects and non-GSK personnel (including the principal investigator, sub-investigators, and study site personnel) involved in measuring, monitoring and obtaining data in the study will be blinded to subject treatment assignment. In addition all GSK and vendor personnel involved in the on-site monitoring and direct management of the data and study sites will also remain blinded to individual subject data.

The study will be conducted as a 'single-blind' study due to the exploratory nature of the study and use of the endpoints. The instream reviews of the MRI data will be conducted at intervals throughout the study with available subject data as defined in the iSRC Charter, including involvement of external MS and/or imaging expert(s), as appropriate.


91

The Safety Review Team (SRT) will review study data as part of the standard SRT review process for GSK239512. Measures will be taken to ensure that unblinded information is not provided to the site personnel, subjects or any GSK and vendor staff involved in the management of the study sites and subject data. In addition, a formal Interim Analysis will be conducted, in accordance with the protocol and the iSRC charter to assess the characteristics of the remyelination signal that may be detectable at the end of the study. This will include an assessment of the probability of achieving the primary study objective and allows for the possibility of stopping the study for futility.