| 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 |
| Hep C virus infected patient |
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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) or MK-8408 (Parts A and B), with or without ribavirin (Part B), 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 <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 (Part A) or 450 mg (Parts A and B)) with either MK-8742 (Part A only) or MK-8408 (Parts A and B), with or without ribavirin (Part B) 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 regimens of MK-5172 & MK-3682 (300 mg (Part A) or 450 mg (Parts A & B)) with either MK-8742 (Part A) or MK-8408 (Parts A and B), +/- ribavirin (Part B), as assessed by the proportion of 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, the secondary objectives above will be evaluated within each subject population (HIV/HCV co-infected vs. mono-infected, and cirrhotic vs. non-cirrhotic) separately. In addition, the following objectives will also be evaluated for the HIV co-infected population:
2 Among HIV-1 co-infected patients, to evaluate proportion of subjects who develop HIV-1 virologic failure (HIV-1 RNA 200 copies/mL, confirmed on 2 consecutive tests at least 2 weeks apart, in subjects compliant with their HIV antiretroviral therapy).
3 Among HIV-1 co-infected patients, to 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 |
FBR “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. (Intensive Viral Kinetic Week 1 Sampling Timepoints). In addition, PK samples will be collected. (Pharmacokinetic Sampling Time points for Part A and B) and Table 15 (Pharmakokinetic Sampling Time points for Part C). These samples will be used to evaluate the PK/PD relationships of MK-5172, MK-3682 (and metabolites), MK-8742(part A), and MK-8408, and MK-3682B 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 GT1a, GT1b, or GT2
4. Be otherwise healthy 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
• Fibroscan performed within 12 months of Day 1 a result of ≤12.5 kPa
• A Fibrosure® (Fibrotest®) score of ≤0.48 and APRI Index 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 showing cirrhosis (F4)
• Fibroscan performed within 12 calendar months of Day 1 with a result >12.5 kPa
• A FibroSure® (Fibrotest®) performed during Screening with a score of >0.75 and an (APRI) of >2.
6. be HCV treatment naïve (both Part A and Part B)
7. meet one of the following categories:
a. The subject is a male who is not of reproductive potential, defined as a male who has azoospermia
b. The subject is a female who is not of reproductive potential, defined as a female who either: (1) is postmenopausal and have a documented follicle stimulating hormone (FSH) level in the postmenopausal range at pretrial (screening); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR (3) has a congenital or acquired condition that prevents childbearing.
c. The subject is a female or a male who is of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner beginning at least 2 weeks prior to administration of the initial dose of study drug, for 6 months after taking the last dose of study drug , by 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‡:
• oral contraceptives (Part B and C only)
• Intrauterine device (IUD) with or without local hormone release
• diaphragm with spermicide
• cervical cap with spermicide
• contraceptive sponge with spermicide
• male condom with spermicide or female condom with spermicide
If male, subjects must agree to use a condom with spermicide or abstain from sexual intercourse during the trial until 6 months after the last dose of trial drug
Spermicides alone are not an acceptable method of contraception.
Note: In Part A, Oral contraceptives are not allowed as a method of birth control.
8. understand the study procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
9. provide written informed consent for the trial.
For Part B only:
For HIV co-infected 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 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:
1. not currently be on antiretroviral therapy (ART) and have no plans to initiate ART while participating in this study.
2. have well controlled HIV on ART, defined as:
• must have achieved virologic suppression on HIV Antiretroviral Therapy at least 8 weeks prior to 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
• have HIV RNA <LLOQ at screening
• have not experienced virologic failure for at least 8 weeks prior to screening
• 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:
NOTE: Subjects will be eligible to start retreatment in Part C after Follow-up Week 12 in Part A.
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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
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
4. Co-infected with hepatitis B virus
5. Co-infected with HIV (Part A only)
6. For subjects with HIV, 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;
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)
12. a female and is pregnant or breastfeeding or expecting to conceive or donate eggs OR is a male subject who is expecting to donate sperm or planning to impregnate female partner(s) from at least two weeks prior to Day 1 through at least 6 months after last dose of study drug,
13. Parts B and C only: is a male whose female partner(s) is/are pregnant
14. has any of the following conditions:
a. Organ transplants other than cornea and hair.
b. Poor venous access that precludes routine peripheral blood sampling.
c. Subject with a history of gastric surgery or subject with a history of malabsorption disorders
d. Current or history of any clinically significant cardiac abnormalities/dysfunction, including but not limited to: angina, congestive heart failure, myocardial infarction, pulmonary hypertension, complex congenital heart disease, cardiomyopathy, significant arrhythmia, uncontrolled hypertension, a history of use of antianginal or anti-arrhythmic agents for cardiac conditions, prolonged ECG QTc interval (>470 ms for males or >480 ms for females), personal or family history of Torsade de pointes.
e. Chronic pulmonary disease, including but not limited to: clinically significant chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sarcoidosis.
f. Part B and C only: Hemoglobinopathy, including, but not limited to, thalassemia major
g. Central nervous system (CNS) trauma requiring intubation, intracranial pressure monitoring, brain meningeal or skull surgery, or resulting in seizure, coma, permanent neurologic deficits, abnormal brain imaging, or cerebral spinal fluid (CSF) leak. Prior brain hemorrhage and/or intracranial aneurysms
h. Current or history of seizure disorder unless seizure was >10 years ago, a single isolated event, no history of or current use of anti-seizure medications, and a normal neurological examination is documented in trial files within 6 months of Day 1.
i. History of stroke or transient ischemic attack.
j. History of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment, other than for minor elective procedures.
k. Medical/surgical conditions that may result in a need for hospitalization during the period of the study.
l. Any medical condition requiring chronic systemic administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the course of the trial.
m. has any condition, pre-study laboratory or ECG abnormality or history of any illness, which, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering the study drugs to the subject.
n. had a life-threatening SAE during the screening period.
o. has evidence of history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, hemochromatosis, Wilson’s disease, α1-antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis.
15. has exclusionary laboratory values at the screening visit as listed in Table 7 of the 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 achieving SVR 12 in each treatment arm.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| (24 weeks after completion of therapy) |
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| E.5.2 | Secondary end point(s) |
| The secondary objective of this study is to estimate the SVR24 rates for each of the treatment arms. A two-sided 95% confidence interval will be constructed for SVR24 for each arm separately. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| ( 4 weeks after completion of 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| MK-3682, MK-5172 plus MK-8742 versus MK-3682 , MK-5172 plus MK-8408 (Part A only) |
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| E.8.2.4 | Number of treatment arms in the trial | 16 |
| 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 | 41 |
| 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 |
| Austria |
| Canada |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Lithuania |
| New Zealand |
| Poland |
| Puerto Rico |
| Spain |
| Sweden |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 15 |
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