| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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) To evaluate the efficacy of the combination regimen of MK-5172, MK- 3682 and MK-8408 with or without ribavirin as assessed by the proportion of subjects in each arm achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy), defined as HCV RNA <Lower Limit of quantification (LLOQ), either target detected but unquantifiable (TD-u or Target not detected (TND) 12 weeks after the end of all study therapy.
(2) Objective: To evaluate the safety and tolerability of the combination regimen of MK-5172, MK-3682 and MK-8408 with or without ribavirin to subjects in each arm.
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| E.2.2 | Secondary objectives of the trial |
(1) To evaluate the efficacy of the combination regimen of MK-5172, MK- 3682 and MK-8408 with or without ribavirin as assessed by the proportion of subjects in each arm achieving SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy)
(2) Objective: To evaluate the efficacy of the combination regimen of MK-5172, MK-3682 and MK-8408 with or without ribavirin as assessed by the proportion of subjects in each arm experiencing virologic failure (either on treatment failure or relapse post-treatment) through FW12 among subjects who do not discontinue the trial for nontreatment- related reasons.
(3) Objective: To evaluate the effect of baseline resistance-associated substitutions (RASs) in nonstructural protein 3 (NS3), NS5A, and/or NS5B on the efficacy of GZR, RZR, and UPR with or without RBV, as assessed by the proportion of subjects with baseline RAS achieving SVR12
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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 |
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| E.3 | Principal inclusion criteria |
Enrollment into Part A is complete; therefore, the criteria are applicable to Part B. Refer to MK-3682-021-01 for the Part A inclusion criteria.
1. Be ≥18 years of age on day of signing informed consent.
2. Have HCV RNA (≥10,000 IU/mL in peripheral blood) at the time of screening.
3. Have documented chronic HCV GT1, GT2, GT3, GT4, GT5, or GT6 infection (with no evidence of nontypeable or mixed GT):
• Positive for anti-HCV antibody, HCV RNA, or HCV GT1, GT2, GT3, GT4, GT5, or GT6 at least 6 months before screening (HCV RNA and HCV GT must be confirmed by screening laboratory results), 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 chronic hepatitis C disease, such as the presence of fibrosis), before Day 1.
4. Have documented VF, defined as having quantifiable HCV RNA at any time after completion of HCV therapy with a DAA regimen, as prescribed by approved dosage and duration or by completion of a clinical trial that was not attributed to re infection. Documentation of prior DAA treatment history must include clinic notes or referral letter documenting regimen administered, approximate dates of treatment, approximate date of VF, and a history of laboratory-confirmed failure.
•DGT1, GT2, GT4, GT5, or GT6: any prior all-oral DAA regimens
•DGT3: any prior all-oral DAA regimen or SOF/PR
5. Have liver disease staging assessment for Absence of cirrhosis or Compensated cirrhosis as defined in the protocol
6. Meet one of the following criteria:
a. The subject is a male
b. The subject is a female who is not of reproductive potential
c. The subject is a female who is of reproductive potential and agrees to avoid becoming pregnant beginning at least 14 days prior to administration of the initial dose of trial drug through 14 days after the last dose of trial drug or longer if dictated by local regulationsby complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have their partner use) two forms of acceptable contraception during heterosexual activity. Acceptable methods of contraception are outlined in the protocol
7. Can be HIV co-infected as documented as requested by protocol
7. HIV co-infected subjects must either not be on antiretroviral therapy(ART); or have well controlled HIV on ART
Refer to protocol for a complete list |
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| E.4 | Principal exclusion criteria |
Enrollment into Part A is complete; therefore, the criteria are applicable to Part B. Refer to MK-3682-021-01 for the Part A exclusion criteria.
1. The subject has significant emotional problems or a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.
2. Did not complete their prior DAA therapy due to intolerance to the DAA regimen or who failed the DAA regimen for reasons other than VF.
3. 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.
4. Is cirrhotic AND has a Child-Turscotte-Pugh score >6, corresponding to a Child Class B or C.
5. Is hepatitis B surface antigen (HBsAg) positive at screening.
6. Is co-infected with HIV AND has a history of opportunistic infection in the preceding 6 months prior to screening.
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) from 2 weeks prior to Day 1 through 2 weeks after the trial treatment period.
10. Is currently participating or has participated in a trial with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another such trial through 24 weeks after the trial treatment period (FW24). (Subjects participating in MK-5172 Protocol 017 may be enrolled in this trial, MK- 3682 Protocol 021).
11. Has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with subject treatment, assessment, or compliance with the protocol.
12. Is a female subject and is pregnant or breastfeeding, or expecting to conceive or donate eggs from at least 2 weeks prior to Day 1 through at least 14 days after the last dose of trial drug, or longer if dictated by local regulations. .
13. Has any of the condition as defined in the protocol
14. Has an exclusionary laboratory value at the screening visit as as defined in table 5 of the protocol.
15. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Proportion of subjects achieving SVR12. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the end of treatment |
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| E.5.2 | Secondary end point(s) |
1) The proportion of subjects achieving SVR24.
2) Proportion of subjects experiencing VF through FW12 among subjects who do not discontinue the trial for nontreatment-related reasons.
3)Proportion of subjects with baseline RASs achieving SVR12
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 24 weeks after the end of treatment
2 and 3) 12 weeks after the end of Treatment
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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 | No |
| 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 | 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 | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| France |
| Germany |
| New Zealand |
| Spain |
| Sweden |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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