| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 100000004848 |
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| 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 in Parts A and B 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 17 (Intensive Viral Kinetic Week 1 Sampling Timepoints) of the protocol. In addition, PK samples will be collected as described in Table 15 (Pharmacokinetic Sampling Timepoints for Parts A and B) and in Table 16 (Pharmacokinetic Sampling Timepoints for Part C). These samples will be used to evaluate the PK/PD relationships of MK-5172, MK-3682 (and metabolites), MK-8742, MK-8408, and ribavirin, as appropriate.
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| E.3 | Principal inclusion criteria |
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 or GT6
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. Have a prior treatment history of:
• 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)
• Prior virologic failure after treatment with a Peg-IFN/RBV regimen (Part B only):
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 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.
8. provide written informed consent for the trial.
For Part B only:
For HIV coinfected subjects :
1. Have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay at any time prior to study entry
2. 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 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 for at least 8 weeks prior to screening
iv. subjects on ART must have a CD4+ T-cell count >200 cells/mm3 at screening
3. 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.
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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.
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; 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 from 2 weeks prior to Day 1 through 2 weeks after the study treatment period.
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 through at least 6 months after the last dose of study drug, or longer if dictated by local regulations OR is a male subject who is expecting to donate sperm or planning to impregnate female partner(s) from at least 2 weeks prior to Day 1 through 6 months after the last dose of study drug or longer if dictated by local regulations.
13. Parts B and C only: is a male whose female partner(s) is/are pregnant (this is a contraindication for ribavirin use).
14. has any of the following conditions:
a. Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair.
b. Poor venous access that precludes routine peripheral blood sampling required for this trial.
c. Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease).
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 agents for cardiac conditions, prolonged ECG QTc interval (>470 ms for males or >480 ms for females by the Fridericia formula) at the screening visit, 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, or 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 (whether adequately repaired or not).
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, or likely to require, chronic systemic administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the course of the trial.
m. has any condition, prestudy 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.
14. has exclusionary laboratory values at screening visit as in Table 8 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 secondary efficacy endpoint will be the proportion of subjects in each treatment arm achieving SVR24 (defined as HCV RNA <LLOQ (either TD[u] or TND) 24 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 | 5 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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