| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C infected patient |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| 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 |
1.Objective: To evaluate the efficacy of the combination regimens of MK-5172 and MK-3682 (300 mg or 450 mg) with either MK-8742 (Part A only) or MK-8408 (Parts A and B), with or without ribavirin (Part B), as assessed by the proportion of GT3-infected subjects in each arm 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.
2.Objective: To evaluate the safety and tolerability of the combination regimens of MK-5172 and MK-3682 (300 mg or 450 mg) with either MK-8742 (Part A only) or MK-8408 (Parts A and B), with or without ribavirin, in GT3-infected subjects in each arm.
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| E.2.2 | Secondary objectives of the trial |
1.Evaluate the efficacy of the combination regimens of MK5172 & MK3682 with MK8742 (Part A only) or MK8408 (Parts A and B), +/-ribavirin (Part B), as assessed by the proportion of GT3-infected subjects in each arm achieving SVR24, defined as HCV RNA <LLOQ (either TD(u) or TND) 24 weeks after the end of all study therapy.
In Part B, this secondary objective will be evaluated within each GT3-infected subject population (treatment-naïve vs. treatment-experienced, HIV/HCV co-infected vs. mono-infected, and cirrhotic vs. non-cirrhotic) separately.
In addition, the following objectives will be evaluated for the GT3-infected HIV co-infected population:
2.Among GT3-infected HIV-1 co-infected patients, evaluate the proportion of subjects who develop HIV-1 virologic failure (HIV-1 RNA 200 copies/mL, in subjects compliant with their HIV antiretroviral therapy).
3.Among GT3-infected HIV-1 co-infected patients, evaluate the effect of the study regimens on CD4+ T-cell counts.
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| 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.
Intensive Viral Kinetic Sub-study:
A subgroup of the study population will be included in an intensive viral kinetic sub-study. The purpose of this sub-study is to determine whether early viral kinetics can aid in developing a PK/PD model that can predict combinations which may be efficacious with shorter treatment durations.
These subjects will have HCV RNA samples collected during Week 1 as described in the Study Flow Chart (Section 6.0) and in Table 10 (Intensive Viral Kinetic Week 1 Sampling Timepoints). In addition, PK samples will be collected as described in Table 12 (Pharmacokinetic Sampling Timepoints). These samples will be used to evaluate the PK/PD relationships of MK-5172, MK-3682 (and metabolites), MK-8742, and MK-8408, as appropriate.
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| E.3 | Principal inclusion criteria |
The following applies to Part A and Part B (unless otherwise specified):
1.be ≥18 years of age on day of signing informed consent.
2.HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening.
3.have documented chronic HCV GT3, GT4, GT5, GT6 (with no evidence of non-typeable or mixed genotype) infection.
•Positive for anti-HCV antibody, HCV RNA, or HCV genotype 3 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 the presence of fibrosis)
4.Be otherwise healthy as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at the time of screening.
5.have liver disease staging assessment as follows:
Absence of cirrhosis is defined as any one of the following (both Part A and Part B):
•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
•A Fibrosure® (Fibrotest®) score of ≤0.48 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) of ≤1 during Screening
Compensated cirrhosis is defined as any one of the following (Part B only):
•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 with a result >12.5 kPa
•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.)
6.Have a prior treatment history of:
a.HCV treatment-naïve (defined as no prior exposure to any interferon, ribavirin, or other approved or experimental HCV-specific direct-acting antiviral agent) (both Part A and Part B)
b.Prior virologic failure after treatment with a Peg-IFN/RBV regimen (the subject’s medical records must include sufficient detail of prior virologic failure to allow for categorization of prior response) (Part B only):
i.P/R Null Responder: <2 log10 IU/mL reduction in HCV RNA after at least 12 weeks of a Peg-IFN/RBV regimen.
ii.P/R Partial Responder: ≥2 log10 IU/mL reduction in HCV RNA after at least 12 weeks of treatment, but not achieving HCV RNA target not detected at end-of-treatment, with a Peg-IFN/RBV regimen.
iii.P/R Relapser: HCV RNA target not detected at end-of-treatment with a Peg-IFN/RBV regimen, but HCV RNA quantifiable (≥LLOQ) during follow-up.
See protocol for exclusion criteria 7 to 9.
For Part B only:
For HIV coinfected subjects these additional criteria must also be met.
10. Have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1) and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA viral load.
11.meet one of the following criteria:
a.not currently be on antiretroviral therapy (ART) and have no plans to initiate ART treatment while participating in this study.
i.subjects not on ART must have CD4+ T-cell count >500 cells/mm3 at screening
b.have well controlled HIV on ART, defined as:
i.must have achieved virologic suppression (defined as confirmed HIV RNA level below the LLOQ of available assay) on HIV Antiretroviral Therapy (ART) at least 8 weeks prior to study entry (Day 1).
1.the ART regimen must contain only the following antiretroviral medications: tenofovir, abacavir, lamivudine, emtricitabine, raltegravir, dolutegravir and rilpivirine
2.dose modifications or changes in drugs during the 4 weeks prior to study entry (Day 1) are not permitted
ii.have HIV RNA <LLOQ at screening
iii.have not experienced virologic failure (defined as confirmed HIV RNA ≥200 copies/mL after virologic suppression) for at least 8 weeks prior to screening
iv.subjects on ART must have a CD4+ T-cell count >200 cells/mm3 at screening
12.have at least one viable antiretroviral regimen alternative beyond their current regimen in the event of HIV virologic failure and the development of anti-retroviral drug resistance.
For Part C only:
13.Enrollment in Part C will be open only to subjects in Part A who relapse following completion of therapy. |
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| E.4 | Principal exclusion criteria |
The following applies to Parts A, B and C (unless otherwise specified):
1.is under the age of legal consent, is mentally or legally incapacitated, has significant emotional problems at the time of pre-study screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.
2.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.
3.For cirrhotics (Part B only):
a.subjects that are Child-Pugh Class B or C, or who have a Pugh-Turcotte (CPT) score >5, must be excluded.
4.is coinfected with hepatitis B virus (e.g. HBsAg positive).
5.is coinfected with HIV (Part A only).
6.For subjects with HIV, has a history of opportunistic infection in the preceding 6 months prior to screening. A list of these events may be found in Appendix B of the following document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm
7.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.
8.has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
9.is taking or plans to take any of the prohibited medications listed in the protocol or is taking herbal supplements, including but not limited to St. John’s Wort (Hypericum perforatum) within 2 weeks of Day 1.
10.is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another such study during the course of this study.
11.has clinically-relevant drug abuse within 12 months of screening.
12.is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs from at least 2 weeks prior to Day 1 and 90 days after the last dose of study medication, or longer if dictated by local regulations OR a male subject who is expecting to donate sperm from at least 2 weeks prior to Day 1 until 90 days after the last dose of study medication or longer if dictated by local regulations.
13. Part C only: is a male whose female partner(s) is/are pregnant (this is a contraindication for ribavirin use).
see protocol for exclusion criterion 14.
15. has exclusionary laboratory values at the screening visit as listed in Table 6 of protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the proportion of subjects in each
treatment arm achieving SVR12 (defined as HCV RNA <LLOQ (either
TD[u] or TND) 12 weeks after the end of all study therapy). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after completion of study therapy |
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| E.5.2 | Secondary end point(s) |
The primary efficacy endpoint will be the proportion of subjects in each
treatment arm achieving SVR12 (defined as HCV RNA <LLOQ (either
TD[u] or TND) 12 weeks after the end of all study therapy). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after completion of study therapy |
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| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 22 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Australia |
| Canada |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| New Zealand |
| Switzerland |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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