Clinical Trial Results:
A Phase III Double Blind Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-8742 in Subjects With Chronic HCV GT1, GT4 and GT6 Infection With Inherited Blood Disorders With and Without HIV Co-Infection
Summary
|
|
EudraCT number |
2014-002356-27 |
Trial protocol |
DE IT GB GR |
Global end of trial date |
14 Jun 2016
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
15 Jun 2017
|
First version publication date |
15 Jun 2017
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
5172-065
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02252016 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
Merck Sharp & Dohme Corp.
|
||
Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
|
||
Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
|
||
Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
14 Jun 2016
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
14 Jun 2016
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
This is a randomized, multi-site, placebo-controlled trial of a fixed dose combination (FDC) of grazoprevir (MK-5172) 100 mg + elbasvir (MK-8742) 50 mg in participants with chronic Hepatitis C Virus (HCV) genotype (GT) 1, GT4 or GT6 with inherited blood disorders. The primary hypothesis is that the proportion of participants treated with grazoprevir+elbasvir achieving Sustained Virologic Response (SVR) 12 weeks after the end of all study therapy (SVR12) will be greater than the reference rate of 40%.
|
||
Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Oct 2014
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Australia: 13
|
||
Country: Number of subjects enrolled |
Canada: 2
|
||
Country: Number of subjects enrolled |
France: 23
|
||
Country: Number of subjects enrolled |
Germany: 10
|
||
Country: Number of subjects enrolled |
Greece: 10
|
||
Country: Number of subjects enrolled |
Israel: 15
|
||
Country: Number of subjects enrolled |
Italy: 34
|
||
Country: Number of subjects enrolled |
Thailand: 4
|
||
Country: Number of subjects enrolled |
United Kingdom: 13
|
||
Country: Number of subjects enrolled |
United States: 35
|
||
Worldwide total number of subjects |
159
|
||
EEA total number of subjects |
90
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
154
|
||
From 65 to 84 years |
5
|
||
85 years and over |
0
|
|
||||||||||||||||||||||
Recruitment
|
||||||||||||||||||||||
Recruitment details |
Adult participants with hepatitis C virus (HCV) genotypes (GT)1, GT4, and GT6 with inherited blood disorders and with or without human immunodeficiency virus (HIV) co-infection were recruited at study centers around the world. | |||||||||||||||||||||
Pre-assignment
|
||||||||||||||||||||||
Screening details |
The screening period lasted up to 45 days. | |||||||||||||||||||||
Period 1
|
||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
|||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Subject | |||||||||||||||||||||
Arms
|
||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||
Arm title
|
Immediate Treatment | |||||||||||||||||||||
Arm description |
Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Grazoprevir 100 mg + Elbasvir 50 mg
|
|||||||||||||||||||||
Investigational medicinal product code |
MK-5172A; MK-5172 + MK-8742
|
|||||||||||||||||||||
Other name |
ZEPATIER
|
|||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||
Dosage and administration details |
A single FDC tablet containing grazoprevir 100 mg + Elbasvir 50 mg taken once daily by mouth.
|
|||||||||||||||||||||
Arm title
|
Deferred Treatment | |||||||||||||||||||||
Arm description |
Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Grazoprevir 100 mg + Elbasvir 50 mg
|
|||||||||||||||||||||
Investigational medicinal product code |
MK-5172A; MK-5172 + MK-8742
|
|||||||||||||||||||||
Other name |
ZEPATIER
|
|||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||
Dosage and administration details |
A single FDC tablet containing grazoprevir 100 mg + Elbasvir 50 mg taken once daily by mouth.
|
|||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||
Other name |
||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||
Dosage and administration details |
Placebo tablet matched to MK-5172A taken once daily by mouth.
|
|||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Immediate Treatment
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Deferred Treatment
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Immediate Treatment
|
||
Reporting group description |
Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period. | ||
Reporting group title |
Deferred Treatment
|
||
Reporting group description |
Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period. |
|
|||||||||||||
End point title |
Percentage of participants achieving sustained virologic response 12 weeks after completing study therapy (SVR12) [1] | ||||||||||||
End point description |
The percentage of participants in the both arms achieving SVR12 (i.e., HCV riboncleic acid [RNA] level below the lower limit of quantification [LLoQ] 12 weeks after completing study therapy) was determined. HCV RNA levels were measured using the Roche COBAS™ Taqman™ HCV Test v2.0 (High Pure System), which has a LLoQ of <15 IU/mL. All randomized participants who received at least one dose of study treatment and had available data were analyzed. Data for the Deferred Treatment Arm was reported after participants received open-label active treatment.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
12 weeks after completing study therapy (Week 24)
|
||||||||||||
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: No statistical comparisons between experimental arms were performed for this endpoint. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percentage of participants experiencing an adverse event (AE) | ||||||||||||
End point description |
An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. All participants receiving ≥1 dose(s) of study drug were analyzed. For the Deferred Treatment arm, data indicate results obtained during the initial 12-week placebo treatment period.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Week 14
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Percentage | ||||||||||||
Statistical analysis description |
The estimated difference (95% confidence interval [CI]) in percentage of participants experiencing an AE in the Immediate versus Deferred arms was determined.
|
||||||||||||
Comparison groups |
Immediate Treatment v Deferred Treatment
|
||||||||||||
Number of subjects included in analysis |
159
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
7.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7.3 | ||||||||||||
upper limit |
23.3 |
|
|||||||||||||
End point title |
Percentage of participants discontinuing from study treatment due to an AE(s) | ||||||||||||
End point description |
An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. All participants receiving ≥1 dose(s) of study drug were analyzed. For the Deferred Treatment arm, data indicate results obtained during the initial 12-week placebo treatment period.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Week 12
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Percentage | ||||||||||||
Statistical analysis description |
The estimated difference (95% confidence interval [CI]) in percentage of participants discontinuing due to an AE(s) in the Immediate versus Deferred arms was determined.
|
||||||||||||
Comparison groups |
Immediate Treatment v Deferred Treatment
|
||||||||||||
Number of subjects included in analysis |
159
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.155 | ||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-10.2 | ||||||||||||
upper limit |
1.6 |
|
|||||||||||||
End point title |
Percentage of participants achieving sustained virologic response 24 weeks after completing study therapy (SVR24) | ||||||||||||
End point description |
The percentage of participants in both arms achieving SVR24 (i.e., HCV RNA level below the LLoQ 24 weeks after completing study therapy) was determined. HCV RNA levels were measured using the Roche COBAS™ Taqman™ HCV Test v2.0 (High Pure System), which has a LLoQ of <15 IU/mL. All randomized participants who received at least one dose of study treatment and had available data were analyzed. Data for the Deferred Treatment Arm was reported after participants received open-label active treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
24 weeks after completing study therapy (Week 36)
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 52 weeks.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. AEs were reported for all participants receiving ≥1 dose of study treatment.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Deferred Treatment Group
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Immediate Treatment Group
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Feb 2015 |
AM2: The primary purposes of AM2 were to reduce target enrollment of participants with sickle cell anaemia and thalassemia, and to increase the pretreatment period to 12 weeks to more accurately collect safety events. |
||
09 Nov 2015 |
AM3: The primary purposes of AM3 were to change the statistical methodology for efficacy analyses and to change the efficacy population of interest. |
||
14 Mar 2016 |
AM4: The primary purpose of AM4 was to change the efficacy analysis population. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |