trial synopsis 1241.25 dr - boehringer ingelheim...plasma hcv rna ≥100000 iu/ml at screening 5....

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of company:

Boehringer IngelheimTabulated

Trial Report ABCD

Synopsis No.:

Name of finished product:

Not applicable

Name of active ingredient:

Deleobuvir (BI 207127), Faldaprevir (BI 201335)

Page:

2 of 11

Module: Volume:

Report date:

02 APR 2014

Trial No. / Doc. No.:

1241.25 / c02155491-02 / / U13-2589-01

Dates of trial:

16 FEB 2012 – 23 AUG 2013

Date of revision (if applicable):

Not applicable

Proprietary confidential information 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Diagnosis and maincriteria for inclusion:

1. Chronic hepatitis C, diagnosed by positive anti-HCV antibodies and detected HCV ribonucleic acid (RNA) at screening in addition to:

a positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening; or

b liver biopsy consistent with chronic HCV infection

2. HCV infection of genotype 1 confirmed by genotypic testing at screening

3. Therapy-naïve to interferon, pegylated interferon, ribavirin, or any antiviral/immunomodulatory drug for acute or chronic HCV infection

4. Plasma HCV RNA ≥100 000 IU/mL at screening

5. Liver biopsy within 3 years or fibroscan within 6 months prior to study treatment, and confirmed without cirrhosis

6. Age 20 to 70 years

7. Female patients who are infertile or who are of childbearing potential with a negative pregnancy test and agreeing to use one accepted method of birth control in addition to the use of a condom by their male partners,orMale patients who are infertile, who are without pregnant female partners or who consistently and correctly use condoms

8. Signed informed consent form prior to trial participation

Test product 1: Deleobuvir tablet

dose: 600 mg twice daily (b.i.d.)

mode of admin.: Oral

batch no.: B113000201

Boehringer Ingelheim BI Trial No.:

Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

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Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



Page:

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Module: Volume:

Report date:

02 APR 2014


1241.25 / c02155491-02 / / U13-2589-01

Dates of trial:

16 FEB 2012 – 23 AUG 2013


Not applicable



Test product 2: Faldaprevir capsule

dose: Group 1: 80 mg once daily (q.d.), Group 2: 120 mg q.d.

A loading dose of 160 mg (Group 1) or 240 mg (Group 2) was given on the first day of administration.


batch no.: B113000210 (40 mg capsules); B113000199, B123000017 (120 mg capsules)

Test product 3: Ribavirin

dose: 600 mg/day (body weight ≤60 kg), b.i.d.800 mg/day (body weight >60 kg and ≤80 kg), b.i.d.1000 mg/day (body weight ≤80 kg), b.i.d.


batch no.: B113000202

Duration of treatment: A 8-week treatment with deleobuvir and faldaprevir in combination with RBVfollowed by a 24-week treatment with faldaprevir in combination with pegylated interferon alfa-2a (PegIFN) and RBV.Patients were followed up for 24 weeks after completion of all therapy or in the event of early discontinuation.

Criteria for evaluation:

Efficacy: Primary efficacy endpoint: not applicable (no primary endpoint was set in this study)

Secondary efficacy endpoints:

• Virological response at Week 4: Plasma HCV RNA level <25 IU/mL (undetected or detected) at Week 4

• Virological response at Week 8: Plasma HCV RNA level <25 IU/mL (undetected or detected) at Week 8



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Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



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Report date:

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1241.25 / c02155491-02 / / U13-2589-01

Dates of trial:

16 FEB 2012 – 23 AUG 2013


Not applicable



Efficacy (continued): Further efficacy endpoints:

• Plasma HCV RNA at each visits up to Week 8, both absolute and change from baseline

• Virological response at Week 4, Week 8: Proportion of plasma HCV RNA level <25 IU/mL (undetected) responders

• Virological response at Week 4 and Week 8: Proportion of plasma HCV RNA level <25 IU/mL (undetected or detected) responders at Week 4 and plasma HCV RNA level <25 IU/mL (undetected) responders at Week 8

• Time to virological response: Time to the first measurement of undetectable plasma HCV RNA level.

• End of treatment response (ETR): Proportion of plasma HCV RNA level <25 IU/mL (undetected) responders at the end of all treatment.

• Sustained virological response at 12 weeks after completion of all therapy (SVR12): Proportion of plasma HCV RNA level <25 IU/mL (undetected) responders at 12 weeks after completion of all therapy

• Sustained virological response (SVR): Proportion of plasma HCV RNA <25 IU/mL (undetected) responders at 24 weeks after completion of all therapy

• Rate of breakthrough and relapse



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Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



Page:

5 of 11

Module: Volume:

Report date:

02 APR 2014


1241.25 / c02155491-02 / / U13-2589-01

Dates of trial:

16 FEB 2012 – 23 AUG 2013


Not applicable



Clinical pharmacology: Pharmacokinetic (PK) parameters:

Deleobuvir and its metabolites (BI 208333, CD 6168, CD 6168 acylglucuronide[CD 6168-AG])

On Day 1: Cmax,1, tmax,1, AUCτ,1

On Day 11: Cmax,11, tmax,11, AUCτ,11, RA,Cmax,11, RA,AUC,11

On Day 57: Cmax,ss, tmax,ss, AUCτ,ss, MRTpo,ss, CL/F,ss (deleobuvir only), RA,Cmax,57 RA,AUC,57, RCmax,Met,ss, RAUC,τ,Met,ss

Trough PK: Cpre,N, Cpre,ss

RBV:


On Day 57: Cmax,ss, tmax,ss, AUCτ,ss, MRTpo,ss, RA,Cmax,57, RA,AUC,57


Faldaprevir:


On Day 11: Cmax,11, tmax,11, AUCτ,11, RA,Cmax,11, RA,AUC,11

On Day 57: Cmax,ss, tmax,ss, AUCτ,ss, MRTpo,ss, CL/F,ss, RA,Cmax,57, RA,AUC,57


Safety: Adverse events (AEs), discontinuations due to AEs, laboratory tests, vital signs, and 12-lead electrocardiogram (ECG)

The primary endpoint was defined post hoc as number (%) of patients with drug-related AEs.

Statistical methods: All the analyses were descriptive in nature and no hypothesis was tested.

SUMMARY – CONCLUSIONS:

Efficacy / clinical pharmacology results:

Patient disposition and baseline characteristics

A total of 12 patients were entered in Group 1 and a total of 13 patients wereentered in Group 2. Of those, 11 (91.7%) patients in Group 1 and 12 (92.3%) patients in Group 2 completed the 8-week



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Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



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16 FEB 2012 – 23 AUG 2013


Not applicable



Efficacy / clinical pharmacology results

(continued):

faldaprevir/deleobuvir/RBV treatment. One premature withdrawal in Group 1 was due to AE (asthma) on Day 8 and one premature withdrawal in Group 2 was due to AE (hepatic function abnormal) on Day 56.

The 2 prematurely withdrawn patients (one in each group) did not enter the faldaprevir/PegIFN/RBV treatment phase. All other patients (Group 1: 11 patients, Group 2: 12 patients) started the interferon-based treatment. Of those, 1 patient in Group 1 was withdrawn 3 days after the start of the interferon-based treatment because of the patient’s refusal of trial continuation. In addition, there was 1 patient in Group 2 who was treated with only PegIFN/RBV during the interferon-based treatment phase, because faldaprevirwas discontinued due to AEs (vomiting and decreased appetite) after the last dose in the interferon-free treatment phase.

The trial population (N=25) contained more female patients (64.0%) than male patients (36.0%); the mean age was 56.5 years and the mean body mass index (BMI) was 23.4 kg/m2. All the patients had HCV genotype 1b. The mean baseline HCV viral load was 6.5 log10 IU/mL in Group 1 and 6.1 log10 IU/mL in Group 2. The majority of patients (64.0%) had IL28B (rs12979860) genotype CC. Overall, no apparent difference in baseline characteristics was observed between the 2 dose groups.

Secondary efficacy endpoints

The secondary endpoint (plasma HCV RNA <25 IU/mL, undetected or detected) was reached in more than 90% of patients. The proportion of responders was similar in the 2 dose groups both at Week 4 (Group 1: 91.7%[11 of 12 patients], Group 2: 92.3% [12 of 13 patients]) and at Week 8 (Group 1: 91.7% [11 of 12 patients], Group 2: 100% [13 of 13 patients]). The only patient who did not achieve the endpoint at Week 8 in Group 1 had been withdrawn from all treatment on Day 8 because of worsening of pre-existing asthma.

Further efficacy endpoints

The mean log10 viral load dropped rapidly with initiation of treatment on Day 1. The mean reduction was 2.6-2.7 log10 within 12 hours and 3.3-3.4 log10



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Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



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Module: Volume:

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1241.25 / c02155491-02 / / U13-2589-01

Dates of trial:

16 FEB 2012 – 23 AUG 2013


Not applicable




(continued):

within 24 hours after the first treatment. The mean absolute viral load (log10) reached less than 2 on Day 8 for both groups. The overall viral load reduction profiles were similar in the 2 groups.

Undetected plasma HCV RNA (below lower limit of detection [BLD]) was achieved by approximately 80% of patients in both groups at Week 4 (Group 1: 83.3% [10 of 12 patients], Group 2: 76.9% [10 of 13 patients]) and further by 3 additional patients in Group 2 at Week 8 (Group 1: 83.3% [10 of 12 patients], Group 2: 100% [13 of 13 patients]).

Proportion of patients with plasma HCV RNA level <25 IU/mL (undetected or detected) at Week 4 and with undetected plasma HCV RNA level (BLD) at Week 8 was 83.3% [10 of 12 patients] in Group 1 and 92.3% [11 of 13 patients] in Group 2.

Time to the first measurement of undetectable plasma HCV RNA level (BLD) was similar in the 2 groups. The first BLD was achieved as early as on Day 15 in Group 1 and on Day 4 in Group 2. All patients except one early withdrawal achieved BLD by Day 64 in Group 1 and by Day 57 in Group 2.

End of treatment response (ETR) was achieved by 91.7% [11 of 12 patients] in Group 1 and 100% [13 of 13 patients] in Group 2.

Sustained virological response at Week 12 (SVR 12) and at Week 24 (SVR) was achieved by all patients who achieved ETR (Group 1: 91.7% [11 of 12 patients], Group 2: 100% [13 of 13 patients]).

No patients experienced virological breakthrough during the interferon-free treatment period. No relapse occurred in this trial.

Pharmacokinetics

Deleobuvir and its metabolites

The gMean trough plasma concentrations of deleobuvir after multiple administrations of deleobuvir 600 mg b.i.d. with faldaprevir 80 mg q.d. and RBV increased and reached the maximum at Day 4, declined gradually after Day 11 to Week 4, and subsequently remained relatively stable up to Week 8.



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Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



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Module: Volume:

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16 FEB 2012 – 23 AUG 2013


Not applicable




(continued):

On the other hand, gMean trough plasma concentrations of deleobuvir after multiple administrations of deleobuvir 600 mg b.i.d. with faldaprevir 120 mg q.d. and RBV reached the highest level at around Week 3, then declined to Week 6, and subsequently remained relatively stable up to Week 8. The increase of faldaprevir dose by 40 mg drastically increased the deleobuvir trough concentrations and changed the time to maximum trough concentration. The trends of increasing concentration with increase of faldaprevir dose and decreasing trough plasma concentration after the peak trough plasma concentration were also observed with the metabolites (BI 208333, CD 6168, and CD 6168-AG).

The median tmax of deleobuvir was around 4-5 hours post dose on Days 1, 11, and 57 in both dose groups. The tmax of metabolites on Days 11 and 57 (4-6 hours) appeared to be equal to or slightly later than the tmax of deleobuvir. As the co-administered faldaprevir dose was increased from 80 mg to 120 mg q.d., the exposure to deleobuvir and its metabolites was increased and the elimination half-life of deleobuvir was prolonged from 2.9-4.9 hours to 5.0-7.6 hours. The metabolic ratios of BI 208333, CD 6168, and CD 6168-AG based on AUC on Day 11 in the faldaprevir 80 mg dose group were 0.437, 0.516, and 0.0300, respectively. Those on Day 57 were comparable to those on Day 11, although the concentration levels of deleobuvir and its metabolites were decreased from Day 11 to Day 57.

Faldaprevir

The gMean trough plasma concentrations of faldaprevir in the faldaprevir 80 mg dose group reached the peak on Day 11, then declined gradually, and reached an almost steady state on Week 8. On the other hand, the trough plasma concentrations of faldaprevir in the faldaprevir 120 mg dose groupreached the peak at around Week 3, and decreased gradually to Week 8. The time to reach peak trough plasma concentration was delayed drastically by an increase of faldaprevir dose.

The median tmax of faldaprevir was around 4 to 6 hours post dose on Days 1, 11, and 57 in both dose groups. It is suggested that exposure to faldaprevir increased more than proportionally to the dose when faldaprevir was co-



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Name of company:


Trial Report ABCD

Synopsis No.:


Not applicable



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Not applicable



administered with deleobuvir, and this trend was prominent on Day 57.

Ribavirin (RBV)

Trough plasma concentrations of RBV in the faldaprevir 80 mg group and faldaprevir 120 mg group showed a similar exposure level, and reached an almost steady state by Week 8 in both groups. The median tmax of RBV was at 2 to 4 hours post dose on Days 1 and 57 in both dose groups. Exposure to RBV is comparable regardless of faldaprevir dose for on both Days 1 and 57.

Safety results: Safety profile of deleobuvir in combination with faldaprevir and RBV was evaluated in a total of 25 Japanese patients with chronic genotype-1 HCV infection. During the 8-week interferon-free treatment phase, all patients in both groups (100%) experienced at least 1 AE and 1 drug-related AE. The majority of the reported AEs were of mild or moderate intensity; only 1 AE of severe intensity (weight decreased) was reported for 1 (7.7%) patient in Group 2. No serious AE was reported during the interferon-free treatment phase. One patient in each of the 2 groups discontinued all trial medications because of AEs; one in Group 1 had worsening of pre-existing asthma on Day 8 and the other in Group 2 had hepatic function abnormal (reported as ‘function liver decreased’) on Day 56. Another patient in Group 2 was discontinued from faldaprevir on Day 57 after taking the last dose in the interferon-free treatment phase because of decreased appetite and vomiting. The frequency of AEs was generally higher in Group 2 than in Group 1.

The most frequently reported AEs during the interferon-free treatment phase were ‘gastrointestinal disorders,’ reported for 11 (91.7%) patients in Group 1 and 12 (92.3%) patients in Group 2. Nausea, vomiting, and diarrhoea were most common on a preferred term level. The frequency of each event was generally similar in the 2 groups, but vomiting was more frequently reported in Group 2 than in Group 1 (33.3% vs. 61.5%). The intensity of these gastrointestinal events was mild, except for 2 events of moderate intensity (constipation in Group 1 and diarrhoea in Group 2). In the majority of patients, gastrointestinal events began within the first week of treatment.

The second most common system organ class was ‘skin and subcutaneous



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Not applicable



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Not applicable



Safety results(continued):

disorders,’ reported for 5 (41.7%) patients in Group 1 and 8 (61.5%) patients in Group 2. Rash was the most common on a preferred term level and uniquely reported in Group 2 (0% vs. 53.8%). Other common events occurred at a similar frequency in the 2 groups: pruritus (16.7% vs. 23.1%), erythema (16.7% vs. 7.7%), and photosensitivity reaction (8.3% vs. 15.4%). The intensity of these ‘skin and subcutaneous disorders’ were mild, except for 3 events of moderate intensity (photosensitivity reaction in Group 1, rash and pigmentation disorder in Group 2). All these events were manageable and did not require discontinuation of trial medication(s). The first incidence of rash was observed within the first week of treatment in the majority of patients.

Mean haemoglobin decreased in both groups (-2.1 g/dL, -2.8 g/dL). Similar changes were also observed for red blood cell count and haematocrit. In terms of AEs related to haemoglobin, anaemia (Group 1: 25.0%, Group 2: 0%), iron deficiency anaemia (Group 1: 0%, Group 2: 7.7%), and haemoglobin decreased (Group 1: 0%, Group 2: 15.4%) were reported. These events were manageable by dose reduction of RBV according to the protocol.

Mean white blood cell count (WBC) and neutrophils count remained stable during the treatment, while mean platelets count increased from baseline in both groups.

Liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) decreased during treatment in both groups, indicating an improved liver metabolism. In the majority of patients who had elevated values above the upper limit of normal (ULN) at baseline, ALT and AST values shifted to within normal range after treatment. Increase in lipase was observed in 3 (23.1%) patients in Group 2; this was transient and mostly not accompanied by increase in amylase.

Mean total bilirubin increased in both groups; the extent of increase was more pronounced in Group 2 than in Group 1. Correspondingly, increases in Division of Acquired Immunodeficiency Syndrome (DAIDS) grades were more frequent and more severe in Group 2. In terms of AEs related to bilirubin, hyperbilirubinaemia was reported only in Group 2 (0% vs. 30.8%). Jaundice was also reported only in Group 2 (0% vs. 15.4%). The changes in total



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Trial Report ABCD

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Not applicable



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Not applicable



Safety results(continued):

bilirubin values were mainly driven by an increase in indirect bilirubin.

No substantial changes were observed in coagulation, electrolytes, plasma proteins, hormones, inflammatory parameter, or urinalysis. There were no relevant changes in the vital signs of the patients. Mean body weight tended to decrease by approximately 3 kg during the treatment (Group 1: -2.5 kg, Group 2: -3.0 kg).

Evaluation of the ECGs indicated an increase in the mean QTcF of 10 to 20 ms from baseline. However, no patients had abnormal QTcF interval defined according to current standards as >450 ms for males and >470 ms for females.

Overall, the combination treatment with faldaprevir, deleobuvir, and RBV was tolerated in Japanese patients with chronic genotype-1 HCV infection. Common AEs such as rash, vomiting, and hyperbilirubinaemia were more frequently reported in the regimen with faldaprevir 120 mg q.d. (Group 2) than in the regimen with faldaprevir 80 mg q.d. (Group 1).

Conclusions: The results of this trial indicate that the dosing regimen of deleobuvir 600 mg b.i.d. with faldaprevir 80 mg q.d. and RBV provides sufficient exposure to obtain a potent early viral load reduction in treatment-naïve Japanese patients with chronic genotype 1 HCV infection. The 8-week treatment with deleobuvirin combination with faldaprevir (80 mg or 120 mg q.d.) and RBV was tolerable with either dose of faldaprevir and similar in terms of efficacy; however, the regimen with faldaprevir 80 mg q.d. was favourable in terms of safety profile. It is therefore recommended to use the regimen with faldaprevir 80 mg q.d. for future investigation of the combination therapy in Japanese patients with chronic genotype-1 HCV infection.



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Synopsis

trial synopsis 1241.25 dr - boehringer ingelheim...plasma hcv rna ≥100000 iu/ml at screening 5....

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