E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
A viral infection affecting the liver |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047457 |
E.1.2 | Term | Viral hepatitis C |
E.1.2 | System Organ Class | 100000004862 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In subjects with chronic HCV GT 1 infection who have failed prior DAA + PR treatment, with pre-treatment HCV RNA of at least 10,000 IU/mL:
•To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the proportion of subjects achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy), defined as HCV RNA <LLoQ (either TD[u] or TND) 12 weeks after the end of all study therapy.
•To evaluate the safety and tolerability of MK-5172 in combination with MK-8742 + R.
|
|
E.2.2 | Secondary objectives of the trial |
•Evaluate efficacy of MK-5172 in combination with MK-8742 + R as
assessed by proportion of subjects achieving SVR12 by prior DAA and prior DAA class, defined as HCV RNA <LLoQ (either TD[u] or TND) 12 weeks after end of study therapy
•Evaluate emergence of RAVs to MK-5172 and MK-8742 when
administered as part of a combination regimen + R by population
sequencing and deep sequencing as applicable
•Evaluate efficacy of MK-5172 in combination with MK-8742 + R as
assessed by proportion of subjects achieving SVR24, defined as HCV RNA
<LLoQ (either TD[u] or TND) 24 weeks after end of study therapy
•Evaluate efficacy of MK-5172 in combination with MK-8742 + R as
assessed by time to first achievement of undetectable (TND) HCV RNA
•Evaluate efficacy of MK-5172 in combination with MK-8742 + R as
assessed by proportion of subjects achieving undetectable (TND) HCV
RNA and HCV RNA <LLoQ at Week 2, 4, 12, and Follow-up Week 4 (SVR
4) |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood)
specimens collected during this clinical trial. Such research is for
biomarker testing to address emergent questions not described
elsewhere in the protocol (as part of the main trial) and will only be
conducted on specimens from appropriately consented subjects. The
objective of collecting specimens for Future Biomedical Research is to
explore and identify biomarkers that inform the scientific understanding
of diseases and/or their therapeutic treatments. The overarching goal is
to use such information to develop safer, more effective drugs, and/or to
ensure that subjects receive the correct dose of the correct drug at the
correct time. |
|
E.3 | Principal inclusion criteria |
•be ≥18 years of age on day of signing informed consent.
•HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening
•have documented chronic HCV GT1 (with no evidence of non-typable or mixed genotype) infection:
-Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 months before screening or
-Positive for anti-HCV antibody or HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of CHC disease, such as presence of fibrosis)
•have liver disease staging assessment as follows
Cirrhosis is defined as any one of the following:
- A liver biopsy performed prior to Day 1 of this study showing cirrhosis (F4)
- Fibroscan performed within 12 calendar months of Day 1 of this study showing cirrhosis with result >12.5 kPa [17]*
- A FibroSure® (Fibrotest®) performed during Screening with a score of >0.75 and an aspartate aminotransferase (AST):platelet ratio index (APRI) of >2. APRI formula: AST÷lab upper limit of normal (ULN) for AST x 100 ÷ {platelet count ÷ 100} (APRI calculation to be provided by the central laboratory.
Absence of cirrhosis is defined as any one of the following:
- Liver biopsy performed within 24 months of Day 1 of this study showing absence of cirrhosis
- Fibroscan performed within 12 months of Day 1 of this study with a result of ≤12.5 kPa[17]*
*Fibroscan cut-off of 12.5 kPa has a positive predictive value of 90% and a sensitivity of 95% for ≥F3. Based on box and whisker plot of interquartile distribution >12.5 kPa will exclude the majority of subjects with metavir F3 fibrosis
- A FibroSure® (Fibrotest®) score of ≤0.48 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. Liver biopsy results supersede the results obtained by Fibroscan or FibroSure®.
•have received a prior regimen containing an approved DAA (boceprevir, telaprevir, simeprevir, or sofosbuvir) co-administered for at least 4 weeks with PR (note: due to the 4 week PR lead-in for boceprevir, a subject would meet this criterion after 8 weeks on this regimen). If prior to the approved DAA + PR containing regimen, the subject received a regimen only containing ribavirin and/or interferon (i.e., PR or interferon alone; unaccompanied by a DAA), this is also permitted.
Subject’s HCV treatment history (i.e., type of therapy and duration of therapy) and reason for discontinuation of prior treatment (i.e., virologic failure, safety/tolerability, or administrative reasons) should be available.
Subjects that discontinued prior therapy due to virologic failure must have met one of the following definitions:
- PR+DAA Nonresponder: HCV RNA detected at end of treatment with a regimen that included one HCV DAA dosed in combination with PR. Subject must not have had undetectable HCV RNA during treatment. Can include subjects who met protocol-defined virologic futility rule (except for breakthrough, which is captured elsewhere).
- PR+DAA Breakthrough: Confirmed increase in HCV RNA ≥LLoQ after HCV RNA previously declined to < LLOQ. Occurred during the DAA dosing period with a regimen that included one DAA dosed in combination with PR.
- PR+DAA Tail Breakthrough: Confirmed increase in HCV RNA ≥LLoQ after HCV RNA previously declined to <LLoQ. Occurred during the PR ‘tail’ dosing period that followed a PR + DAA dosing period.
- PR+DAA Relapser: HCV RNA undetectable (TND) at end of treatment with a regimen that included one DAA dosed in combination with PR, but HCV RNA quantifiable (≥LLoQ) during follow-up |
|
E.4 | Principal exclusion criteria |
•has received any HCV regimen containing a DAA with the exception of boceprevir, telaprevir, simeprevir, or sofosbuvir in combination with PR. Subjects who have been treated with one of these regimens more than once are excluded. Patients who have taken any DAAs in an interferon-free regimen are excluded.
•Has evidence of decompensated liver disease manifested by the presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver disease. For cirrhotics, subjects that are Child-Pugh Class B or C or who have a Child-Pugh-Turcotte (CPT) score >6, must be excluded.
NOTE: To calculate the Child-Pugh score, refer to the following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality.
•is coinfected with hepatitis B virus (e.g., HBsAg positive) or HIV.
•has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy.
•Cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
NOTE: If liver imaging within 6 months of Day 1 is not available, imaging is required during screening
•has clinically-relevant drug or alcohol abuse within 12 months of screening
•has any of the following conditions:
- Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair.
- Poor venous access that precludes routine peripheral blood sampling required for this trial.
- Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease).
-Hemoglobinopathy, including, but not limited to, thalassemia major
- Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial.
•has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis.
NOTE: Subjects with history of acute non-HCV-related hepatitis, which resolved > 6 months before study entry, can be enrolled.
•has exclusionary laboratory values as listed below:
NOTE: If any of the laboratory exclusion criteria below are met, the site may have the abnormal value retested one time.
Noncirrhotic/Cirrhotic Subjects
creatinine clearance <50 mL/min
haemoglobin < 12 g/dL for male, <11 g/dL for female subjects
platelets <50 x 103/μL
Serum Albumin < 3.0 g/dL (lower limit of normal) of laboratory reference range
INR >1.7
HbA1c >10%
ALT >10xULN
AST >10xULN
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects achieving SVR12. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• the proportion of subjects achieving SVR12 by prior DAA (i.e. boceprevir, telaprevir, simeprevir, sofosbuvir) and by prior DAA class
• the emergence of antiviral resistance to MK-5172 and MK-8742 when administered as a combination regimen with R
• the proportion of subjects achieving SVR24 and SVR4
• the time to first achievement of undetectable (TND) HCV RNA
• the proportion of subjects achieving undetectable (TND) HCV RNA and HCV RNA < LLoQ at Week 2, Week 4, and Week 12
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 2, 4, 12; SVR4, SVR12, SVR24 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Israel |
Italy |
Spain |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |