| 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 subjects in each group 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. Objective: To evaluate the effectiveness of the combination regimens of MK-5172 and MK-3682 (300 mg (Part A) or 450 mg (Parts A & B)) 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 subjects in each arm achieving SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy), 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 be evaluated for the HIV co-infected population.
2. Objective: Among HIV-1 co-infected patients, to evaluate the proportion of subjects who develop HIV-1 virologic failure (HIV-1 RNA 200 copies/mL, confirmed on two consecutive tests at least 2 weeks apart,in subjects compliant with their HIV antiretrov |
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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 |
Patient will be invited to consent to take part in the optional Future Biomedical Research (FBR). If patients decline to take part in FBR they may still participate in the main study. Merck will conduct Future Biomedical Research on leftover DNA, leftover plasma from HCV RNA analysis and leftover plasma from viral resistance and biomarker analysis collected during this clinical trial. Such research will be used to study various causes for how subjects may respond to a drug. FBR specimens will be stored to provide a resource for future trials conducted by Merck focused on the study of biomarkers responsible for how a drug enters and is removed by the body, how the drug works, other pathways a drug may interact with, or other aspects of disease. The specimens may be used for future assay development and or drug development.
The protocol includes an Intensive Viral Kinetic Sub-study. In addition, patients participating in this Intensive Viral Kinetic Sub-study will also have additional PK samples taken. The UK will not be participating in the Viral Kinetic Sub-study and subjects will have sparce PK samples collected as outlined in Table 13, column: Part B, Non-Intensive Viral Kinetic Subjects. |
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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
2. HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening
3. have documented chronic HCV GT1a, GTb or GT2 (with no evidence of non-typeable or mixed genotype) infection:
•Positive for anti-HCV antibody, HCV RNA, or any of the above HCV genotypes 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.be HCV treatment naïve
7.meet one of the following categories:
-not of reproductive potential
-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 barrier contraception during heterosexual activity. Acceptable methods of contraception are:
• oral contraceptive (Part B and C only)
• intrauterine device (IUD) with or without local hormone release
• diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
• cervical cap with spermicide (only for women who have not previously given birth)
• contraceptive sponge with spermicide (only for women who have not previously given birth)
• male condom with spermicide or female condom with spermicide (cannot be used together)
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.
8. understand the study procedures, alternative treatments available, risks involved, and voluntarily agrees to participate.
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 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:
- not currently be on antiretroviral therapy (ART) and have no plans to initiate ART treatment.
-subjects not on ART must have CD4+ T-cell count >500 cells/mm3 at screening
-have well controlled HIV on ART, defined as:
• must have achieved virologic suppression (defined as confirmed HIV RNA level below the LLOQ of available assay) on HIV 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
•have HIV RNA <LLOQ at screening
•have not experienced virologic failure (defined as confirmed HIV RNA ≥200 copies/mL after virologic suppression) 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 Parts A who relapse following completion of therapy:
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| E.4 | Principal exclusion criteria |
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 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.co-infected with hepatitis B virus
5.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.
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 drug treatment period.
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 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 at least 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 haematopoietic 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 or subject with a history of malabsorption disorders.
d.Current or history of any clinically significant cardiac abnormalities/dysfunction.
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: Haemoglobinopathy, including, but not limited to. thalassaemia major
g. 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 haemorrhage 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 hospitalisation within the 3 months prior to enrollment, other than for minor elective procedures.
k.Medical/surgical conditions that may result in a need for hospitalisation 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 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
15. has exclusionary laboratory values at the screening visit as listed in Table 5
For Part C only:
16. Subjects are excluded if:
a) they experience virologic rebound,
b) they experience virologic breakthrough,
c) they are withdrawn from the study due to reasons other than virologic failure
d) they meet the other criteria for exclusion as outlined above. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoints will be the proportion of subjects achieving SVR12 in each treatment arm. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 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 |
| 24 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Taiwan |
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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