official title: a multiple-center, multiple-dose and ...position: company: name statistical...

Official Title:

A MULTIPLE-CENTER, MULTIPLE-DOSE AND REGIMEN, RANDOMIZED, ACTIVE COMPARATOR CONTROLLED, DOUBLE-MASKED, PARALLEL GROUP, 36 WEEK STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF RO6867461 ADMINISTERED INTRAVITREALLY IN PATIENTS WITH CHOROIDAL NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION

NCT Number: NCT02484690

Document:

Version & Date:

STATISTICAL ANALYSIS PLAN

Version 1: 13-Feb-2017

STATISTICAL ANALYSIS PLAN SIGNATURE PAGE

Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing that the content is acceptable for the reporting of this study.

Statistical Analysis Plan V1.0 for Protocol BP29647.

Author:

Position:

Company:

Approved By:

Position:

Company:

Name

Statistical Scientist

F. Hoffmann-La Roche Ltd.

Name

F. Hoffmann-La Roche Ltd.

Signature

Signature

Date

14FEB2017

Date

FEB2017

TITLE:

STATISTICAL ANALYSIS PLAN

A MULTIPLE-CENTER, MULTIPLE-DOSE AND REGIMEN, RANDOMIZED, ACTIVE COMPARATOR CONTROLLED, DOUBLE-MASKED, PARALLEL GROUP, 36 WEEK STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF R06867461 ADMINISTERED INTRAVITREALLY IN PATIENTS WITH CHOROIDAL NEOVASCULARIZATION SECONDARY TO AGERELATED MACULAR DEGENERATION

PROTOCOL NUMBER: BP29647

STUDY DRUG: R0687461

VERSION NUMBER: 1.0

IND NUMBER: 119225

EUDRACT NUMBER: N/A

SPONSOR: F. Hoffmann-La Roche Ltd

PLAN PREPARED BY:

DATE FINAL: 13 February 2017

R0687461-F. Hoffmann-La Roche Ltd Statistical Analysis Plan BP29647 1

STATISTICAL ANALYSIS PLAN SIGNATURE PAGE

Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing that the content is acceptable for the reporting of this study.

Statistical Analysis Plan V1.0 for Protocol BP29647.

Author:

Position:

Company:

Approved By:

Position:

Company:

Name

Statistical Scientist

Signature Date

14FEB2017

F. Hoffmann-La Roche Ltd.

Name Date

A'f FEB2017

F. Hoffmann-La Roche Ltd.

TABLE OF CONTENTS

Statistical Analysis Plan Signature Page ....................................................... 2

1. BACKGROUND ............................................................................................. 5

2. STUDY DESIGN ............................................................................................ 5 2.1 Protocol Synopsis .................................................................... 6 2.2

2.2.1 2.2.2 2.2.3 2.2.4

Outcome Measures .................................................................. 6 Primary Efficacy Outcome Measures ....................................... 6 Secondary Efficacy Outcome Measures .................................. 6 Exploratory Efficacy Outcome Measures ................................. 6 Pharmacokinetic Efficacy Outcome Measures ......................... 8

2.2.5 Pharmacodynamic Biomarker Outcome Measures 8 2.2.6 Safety Outcome Measures ....................................................... B

2.3 Determination of Sample Size .................................................. 8 2.3.1 Sample Size and Power for Treatment-Naive Population Evaluation ................................................................................. 8 2.3.2 Sample Size and Power for anti-VEGF-Incomplete-Responder Population Evaluation ........................................... 9

2.4 Analysis Timing ........................................................................ 9

3. STUDY CONDUCT ....................................................................................... 9 3.1 Randomization ......................................................................... 9 3.2 Internal Review Committee .................................................... 1 0 3.3 Data Monitoring ...................................................................... 1 0

4. STATISTICAL METHODS ........................................................................... 1 0 4.1 Analysis Populations .............................................................. 1 0

4.1.1 Efficacy, Pharmacokinetic, and Pharmacodynamic Population .................................................................. 1 0

4.1.1.1 Population A: All Patient Randomized to Arms A, B, C, and D ..................................................................................... 10 4.1 .1.2 Population B: All Patients Randomized to Arms A and E 10 4.1.1.3 Population C: Anti-VEGF-Incomplete Responder Population ........................................................................................... 11

R06867461-F. Hoffmann-La Roche Ltd Statistical Analysis Plan BP29647

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4.1.2 4.2

4.3 4.4

4.4.1 4.4.2

4.5 4.5.1

Safety Population ................................................................... 11 Analysis of Study Conduct ..................................................... 11 Analysis of Treatment Group Comparability ........................... 11 General Considerations ......................................................... 11 Visit Windows ......................................................................... 11 Baseline ................................................................................. 12 Efficacy Analysis .................................................................... 12 Primary Efficacy Endpoint ...................................................... 12

4.5.1.1 Evaluation in the Treatment-Naive Population ...................... 12 4.5.1.2 Evaluation in the anti-VEGF Incomplete Responder Population C ..................................................................... 13

4.5.2 Secondary Efficacy Endpoints ............................................... 13 4.5.3 Exploratory Efficacy Endpoints .............................................. 14 4.5.4

4.5.5 4.6

4.6.1

Sensitivity Analyses ............................................................... 14 Subgroup Analyses ................................................................ 14 Safety Analyses ..................................................................... 15 Adverse Events ...................................................................... 15

4.6.2 Clinical Laboratory Test Results ............................................ 15 4.6.2.1 Standard Reference Ranges and Transformation of Data ....................................................................... 15 4.6.2.2 Definition of Laboratory Abnormalities .................................. 16

4.6.3 Vital Signs .............................................................................. 16 4.6.4 ECG Data Analysis ................................................................ 16

4.6.5 4.6.6

4.6.7 4.6.8

4.7 4.8

Figure 1

Anti-Drug Antibody Data Analysis .......................................... 16 Ocular Assessments .............................................................. 16

Concomitant Medications ....................................................... 17 Exposure to Study Medication ............................................... 17

Missing Data .......................................................................... 17 Interim Analyses .................................................................... 17

LIST OF TABLES

Study Design ................................................................................. 5

R06867461-F. Hoffmann-La Roche Ltd Statistical Analysis Plan BP2964 7

4

1. BACKGROUND

This Statistical Analysis Plan (SAP) documents the statistical methods for summarizing and analyzing the efficacy and safety data from study BP29647. The main purpose of this SAP is to describe the data handling rules, derivation rules, and statistical analysis methods.

2. STUDY DESIGN

This is a multiple-center, multiple-dose and regimen, randomized, active comparator controlled, double-masked, five parallel groups, 36-week study in patients with subfoveal CNV secondary to AMD. The study design is shown in Figure 1 Study Design.

The five groups of this study are as follows.

• Arm A: 0.5 mg ranibizumab IVT every 4 weeks for 32 weeks (9 injections)

• Arm B: 1.5 mg R068674611VT every 4 weeks for 32 weeks (9 injections)

• Arm C: 6 mg R06867461 IVT every 4 weeks for 32 weeks (9 injections)

• Arm 0: 6 mg R06867461 IVT every 4 weeks up to Week 12 (4 injections), followed by 6 mg R06867461 IVT every 8 weeks (i.e., on Weeks 20 and 28; 2 injections)

• Arm E: 0.5 mg ranibizumab lVT every 4 weeks up to Week 8 (3 injections), followed by 6 mg R06867461 IVT every 4 weeks (6 injections)

Figure 1 Study Design

Screening & Baseline

Study Treatment Administration

[ Active comparator (0 5 mg ranibizumab04W)

I 1.5 mg R06867461 04W

~=~~ [ BmgR06867461 04W

( 8 mg R06867481 04W ( 6 mg R06867481 OBW

Active comparator 0.5 ranibizumab04W B mg R068674B1 0 4W

Day1

04W =every 4 weeks; OBW =every a weeks

Final safety period

WHk l2 WHk38

These treatment arms have been chosen to compare the treatments in a treatment-na"ive population and in an anti-VEGF- incomplete-responder population. For the treatment-na"ive population the arms Band C will be compared with the reference arm A. For the anti-VEGF incomplete responder population, a subgroup of arm E will be compared to a similar subgroup of arm A.

R0687461-F. Hoffmann-La Roche Ltd Statistical Analysis Plan BP29647 5