Clinical Trial Results:
A Phase 3, Open-Label Study to Evaluate the Safety and Efficacy of TMC435 plus Pegylated Interferon alfa-2a and Ribavirin Administered for 12 Weeks in Treatment-Naïve Subjects with Chronic Genotype 1 or Genotype 4 HCV Infection
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Summary
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EudraCT number |
2012-004905-29 |
Trial protocol |
BE GB AT IT ES DE |
Global end of trial date |
31 Aug 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Sep 2016
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First version publication date |
08 Sep 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TMC435HPC3014
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01846832 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Janssen Cilag International NV
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Sponsor organisation address |
Antwerpseweg 15-17, Beerse, Belgium, B-2340
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Public contact |
Clinical Registry Group, Janssen Cilag International NV, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen Cilag International NV, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Aug 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective was to determine the efficacy of simeprevir (SMV) plus pegylated interferon alpha-2a(PegIFNα-2a) and ribavirin (RBV) when administered for 12 weeks in treatment-naïve subjects with chronic genotype 1 hepatitis C virus (HCV) infection, as measured by the proportion of subjects with sustained virologic response 12 (SVR12) and to assess the safety and tolerability of SMV plus PegIFNα-2a and RBV when administered for 12 weeks in treatment-naïve subjects with chronic genotype 1 HCV infection.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory
requirements. Safety evaluations were based upon the type, incidence, and severity of AEs reported throughout the study, changes in clinical laboratory tests (hematology, biochemistry and urinalysis), vital sign measurements, 12-lead electrocardiograms (ECGs) and physical examination (including weight, height, and temperature).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Sep 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 30
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Country: Number of subjects enrolled |
Belgium: 24
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Country: Number of subjects enrolled |
Germany: 28
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Country: Number of subjects enrolled |
Spain: 43
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Country: Number of subjects enrolled |
France: 50
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Country: Number of subjects enrolled |
United Kingdom: 11
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Country: Number of subjects enrolled |
Italy: 27
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Country: Number of subjects enrolled |
Saudi Arabia: 17
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Worldwide total number of subjects |
230
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EEA total number of subjects |
213
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
226
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 31 sites in 8 countries. | ||||||||||||||||||
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Pre-assignment
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Screening details |
In total, 277 subjects were screened, of whom 230 were enrolled and treated. Two subjects were enrolled but not treated. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Simeprevir 150 milligram 12 Weeks PR12/24 | ||||||||||||||||||
Arm description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Simeprevir
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Simeprevir (TMC435) 150 milligram capsule orally once daily up to week 12.
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Investigational medicinal product name |
Pegylated Interferon-2a
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received pegylated interferon-2a 180 microgram (mcg) administered subcutaneous injection of 0.5 mL once weekly up to week 12.
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Investigational medicinal product name |
Ribavirin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received ribavirin 1000 mg or 1200 mg tablets administered orally twice daily as per subjects weight up to week 12.
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Baseline characteristics reporting groups
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Reporting group title |
Simeprevir 150 milligram 12 Weeks PR12/24
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Reporting group description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8. | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Simeprevir 150 milligram 12 Weeks PR12/24
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Reporting group description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8. | ||
Subject analysis set title |
Simeprevir 12Wks 150 mg PR12/24: Genotype 1
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus
pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at
Week 2, Week 4, and Week 8.
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Subject analysis set title |
Simeprevir 12Wks 150 mg PR12/24: Genotype 4
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus
pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.
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End point title |
Percentage Of Subjects Infected With Genotype 1 hepatitis C virus (HCV) With A Sustained Virologic Response 12 Weeks (SVR12) [1] | ||||||||
End point description |
Sustained Virologic Response (SVR) 12 is defined as the percentage of subjects (ITT analysis set)
genotype 1 hepatitis C virus (HCV) ribonucleic acid (RNA) levels less than (<) 25 International unit per milliliter (IU/mL) detectable or undetectable at 12 weeks. The Intent to treat (ITT) population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistical analysis has been reported for this endpoint based on the comparison of the response rate in the genotype 1-infected subjects who received a 12-week treatment with the minimally acceptable response rate of 80%. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Subjects Infected With Genotype 4 HCV With A Sustained Virologic Response 12 Weeks (SVR12) | ||||||||
End point description |
SVR 12 is defined as the percentage of subjects (ITT analysis set) genopype 4 HCV RNA levels < 25 IU/mL detectable or undetectable at 12 weeks. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Subjects Achieved Rapid Virologic Response (RVR) | ||||||||||||||||||
End point description |
Rapid virologic response (RVR) defined as HCV RNA < 25 IU/mL undetectable measured 4 weeks after start of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 4
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| Notes [2] - Subjects enrolled are 123 up to week 12 and 39 for more than (>)12 (24/48) Weeks. [3] - Subjects enrolled are 34 up to week 12 and 32 for more than (>)12 (24/48) Weeks. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage Of Subjects Achieved Virologic Response At Week 2 (W2VR) | ||||||||||||||||||||||||
End point description |
Virologic response at Week 2 (W2VR) defined as HCV RNA < 25 IU/mL (detectable or undetectable) measured 2 weeks after start of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 2
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage Of Subjects With Sustained Virologic Response 24 Weeks After Planned End Of Treatment (SVR24) | ||||||||||||||||||
End point description |
SVR 24 is defined as the percentage of subjects (ITT analysis set) HCV RNA levels less than < 25 IU/mL detectable or undetectable at 24 weeks after the end of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| Notes [4] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks. [5] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Hepatitis C Virus (HCV) RNA At Each Time Point | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir). n is defined as number of subjects analysed for this endpoint at specific timepoint. EOT is defined as the end of treatment at week 48.
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage Of Subjects With Viral Breakthrough | ||||||||||||||||||
End point description |
Viral breakthrough is a confirmed increase of more than (>) 1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of > 100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (< 25 IU/mL detectable or undetectable) while on study treatment. The Viral Breakthrough during triple therapy or PR phase includes ITT Population with randomized subjects received at least 1 dose of study drug (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| Notes [6] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks. [7] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage Of Subjects With Viral Relapse | ||||||||||||||||||
End point description |
Subjects considered to have a viral relapse if at actual end of treatment HCV RNA levels < 25 IU/mL undetectable, and during the follow-up period HCV RNA levels > or = 25 IU/mL. The ITT population included all randomized subjects who received at least 1 dose of study drud (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| Notes [8] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks. [9] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline In The Hepatitis C Treatment Symptom and Impact Questionnaire (HCV SIQ) Symptom And Impact Scores | ||||||||||||||||||||||||||||||||||||
End point description |
The HCV SIQ asks subjects to rate 26 symptoms associated with HCV or its treatment and how symptoms impacted the subjects life during the prior week. Total Symptom Score [symptom items 1-26 were rescaled from 0 (none) to 100 (maximum severity/frequency) with a total score calculated from the mean of all symptoms] and Body System Scores [symptom items 1-26 were rescaled from 0 (none) to 100 (maximum severity/frequency) with domain scores calculated for each body system based on mean items scores within each domain. The overall body system score is then calculated as mean of the domain scores] were calculated and analyzed for HCV SIQ. The ITT population included all randomized subjects who received at least 1 dose of study drug (SMV) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The value 99999 indicates standard deviation cannot be determined as only one subject analyzed at this time point.
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End point type |
Secondary
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End point timeframe |
Day 1 and at each study visit up to Week 72
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline In The Fatigue Severity Scale (FSS) Total Score | ||||||||||||||||||||||||||||||
End point description |
The FSS was used to document fatigue severity and impact of fatigue on subjects daily lives. Fatigue severity was measured using the FSS score, created as the mean of patient ratings for 9 items in the Fatigue Severity Scale. FSS scores have a range from 1 to 7 where higher scores indicate more severe fatigue. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is number of subjects analysed at specific timepoint.
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End point type |
Secondary
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End point timeframe |
Day 1 and at each study visit up to Week 72
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline In The Center For Epidemiologic Studies Depression Scale (CES-D) Score | ||||||||||||||||||||||||||||||
End point description |
The Center For Epidemiologic Studies Depression Scale (CES-D) is the scores (0-3) for each of the 20 individual items are summed up to yield a total score (0 -60) with higher scores indicating more and/or more frequent experience of depressive symptoms during the past week. The scores of 16 to 22 indicate mild to moderate depressive illness and CES-D scores more than or equal to (≥) 23 indicate probable major depressive illness (sensitivity: 0.95, specificity: 0.29). The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is 'number of subjects' analysed in this endpoint at specific timepoint.
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End point type |
Secondary
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End point timeframe |
Day 1 and at each study visit up to Week 72
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline In The Work Productivity And Activity Index (WPAI) For Hepatitis C Missed Work Time, Daily Activity Impairment And Productivity Scores | ||||||||||||||||||||||||||||||
End point description |
The Work Productivity And Activity Index (WPAI) was used to measure the impact of HCV on time missed from work (absenteeism), reduced performance while at work (productivity impairment), and impairment in daily activities without regard to employment status. The WPAI Productivity score has a possible range from 0% to 100% with higher scores indicating greater impairment in productivity. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is 'number of subjects' analysed for this endpoint at specific timepoints.
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End point type |
Secondary
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End point timeframe |
Day 1 and at each study visit up to Week 72
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline In The EuroQol 5 Dimension (EQ5D) Visual Analog Scale (VAS) Valuation Index And Descriptive System Scores | ||||||||||||||||||||||||||||||
End point description |
The EQ-5D questionnaire is an instrument designed to assess overall health status using 5 health dimension scores (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a "thermometer" visual analog scale (VAS) ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is'number of subjects' analysed for this endpoint at specific timepoint.
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End point type |
Secondary
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End point timeframe |
Day 1 and at each study visit up to Week 72
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
The Percentage Of Subjects With Normalized Alanine Aminotransferase (ALT) Levels | ||||||||
End point description |
The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Subjects With Sustained Virologic Response 12 Weeks After Planned End Of Treatment (SVR12) | ||||||||||||||||||||||||
End point description |
SVR 12 is defined as the percentage of subjects (ITT analysis set) HCV RNA levels less than < 25 IU/mL
detectable or undetectable at 12 weeks after the end of treatment. Subjects with HCV RNA <25 detectable or undetectable at 2 Weeks and <25 undetectable at 4 Weeks and <25 undetectable at 8 Weeks meet the Response Guided Treatment (RGT) criteria. Subjects that meet the RGT criteria have a planned treatment duration of 12 Weeks, whereas subjects who do not meet this rule have a planned treatment duration of 24 (or 48) weeks The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir). The value 000 or 999 indicates that no data evaluated at this timepoint.
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End point type |
Secondary
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End point timeframe |
Week 36
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| Notes [10] - N includes number of subjects analysed to evaluate RGT Criteria. [11] - N includes number of subjects analysed to evaluate RGT Criteria. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
The Number Of Subjects Reporting Adverse Events | ||||||||||
End point description |
All subjects will be monitored throughout the study for the occurrence of adverse events including psychiatric symptoms, anemia, hyperglycemia (elevated glucose levels), disturbances in serum creatinine levels (a measure of renal [kidney] safety), decreased White Blood Cell (WBC) Count, decreased Platelet Count (ability of the blood to clot), and thyroid abnormalities. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
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End point type |
Secondary
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End point timeframe |
Up to Week 48
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| No statistical analyses for this end point | |||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 48 weeks
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
Simeprevir 150 milligram 12 Weeks PR12/24
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Reporting group description |
Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Sep 2013 |
The overall reason for the amendment was to implement comments received from ethics committees (EC) and Health authorities (HA) and to update the benefit-risk assessment with Phase 3 data that had become available. |
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28 Oct 2013 |
The overall reason for the amendment was to introduce precautionary language on photosensitivity. |
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02 Dec 2013 |
The overall reason for the amendment was to include subjects with genotype 4 hepatitis C virus (HCV) infection in the trial population. |
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16 Jun 2014 |
This amendment was created as an urgent safety measure because, in the ongoing study, a higher than expected relapse rate was observed in subjects infected with HCV genotype 1 and with a host interleukin-28B (IL28B) genotype CT or TT, who had detectable HCV Ribonucleic acid (RNA) at week 2. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
