| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatitis C Virus Genotype 1 (HCV GT 1) |
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| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C Virus Infection |
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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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
In treatment naïve (TN) subjects with chronic HCV GT 1 infection with pre-treatment HCV RNA of at least 10,000 IU/mL:
(1)To evaluate the efficacy of each treatment arm of MK-5172 in combination with MK-8742 +/- RBV as assessed by the proportion of subjects achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy).
For Part B, each treatment arm will be assessed for efficacy, safety, and tolerability (as defined above) within each subject population
(2)To evaluate the relative safety and tolerability of MK-5172 in combination with MK-8742 +/- RBV.
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| E.2.2 | Secondary objectives of the trial |
In Part B, the secondary objectives above will be evaluated within each subject population separately. In addition, the following objectives will also be evaluated for the HIV co-infected population:
(5) Objective: To evaluate the proportion of subjects who develop detectable plasma HIV-1 RNA during therapy (only applicable for co-infected sub-population in part B of the study)
(6) Objective: To evaluate the effect of the study regimen on CD4+ T-cell counts
(only applicable for co-infected sub-population in part B of the study)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. be ≥18 years of age on day of signing informed consent.
2. have a body weight ≥50 kg (111 lbs) and ≤ 125 kg (275 lbs).
3. have chronic, compensated HCV GT 1a or GT 1b infection:
• Positive serology for HCV with HCV RNA levels ≥ 10,000 IU/mL in peripheral blood at screening, and
• Absence (no medical history or physical findings) of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs or symptoms of advanced liver disease, or cirrhosis.
4. have had a liver biopsy without evidence of advanced fibrosis, cirrhosis and/or hepatocellular carcinoma. A liver biopsy done prior to screening is acceptable if it is performed:
• Within 2 years of screening and the result was METAVIR (or equivalent) Stage 0 (F0) to 2 (F2).
If the prior liver biopsy was obtained outside the acceptable windows, a repeat biopsy may be performed, and the results must show no evidence of advanced fibrosis, cirrhosis and/or hepatocellular carcinoma in order for the subject to be randomized in the study.
For countries where liver biopsy is not performed prior to treatment and where noninvasive tests (for e.g. FibroScan and/or FibroTest) are used for staging of liver disease, these results may be used to assess eligibility. Subjects with a documented FibroScan score of ≤9.5 kPa, or FibroTest score of ≤0.58, are allowed to be enrolled in the study. These non-invasive tests done prior to screening are acceptable if they were performed within 1 year of screening and meet the indicated cut-offs. If the prior non-invasive tests were not performed within 1 year of screening, results from one of these non-invasive tests are required before study drug dosing. If a subject has both liver biopsy and one of these non-invasive tests, whichever test demonstrates the presence of advanced fibrosis or cirrhosis would be used to determine eligibility. In other words, if the liver biopsy shows advanced fibrosis or cirrhosis, the subject is excluded, regardless of results of the non-invasive assay. If the liver biopsy does not show advanced fibrosis or cirrhosis, but the non-invasive assay does, then the subject is excluded as well.
5. agree to use two acceptable methods of birth control from at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations (for female subject who is of childbearing potential or male subject with female sexual partner who is of childbearing potential).
6. understand the study procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
7. Provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
PART B
4. have liver disease staging assessment as follows:
Cirrhosis is defined as any one of the following [53,54]:
A liver biopsy performed within 24 calendar months of Day 1 of this study showing cirrhoisis (F4)
Fibroscan performed within 12 calendar months of Day 1 of this study showing cirrhosis with result >12.5 kPa [54]*
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.)
5. Have prior Peg-IFN treatment status as follows:
Treatment naïve: Naive to all anti-HCV treatment
PegIFN/Ribavirin (P/R) Null Responders: Patients in this category can be further defined as: P/R Null responder: <2 log10 IU/mL reduction in HCV RNA at Week 12 of a Peg-IFN/RBV regimen
OR <1 log10 IU/mL decline from baseline at Week 4 futility rule and
discontinued therapy prior to Week 12 of a Peg-IFN/RBV regimen
6. For HIV coinfected patients these additional criteria must also be met: Be HIV-1 infected, 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.
Be on stable HIV Antiretroviral Therapy (ART) for at least 8 weeks prior to study entry using a dual NRTI backbone of tenofovir or abacavir and either emtricitabine or lamivudine PLUS raltegravir. CD4+ T-cell count > 200 cells/mm3 at screening. Have undetectable plasma HIV-1 RNA at screening and history of
undetectable plasma HIV-1 RNA for at least 3 months prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification or its equivalent
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| E.4 | Principal exclusion criteria |
1) has a non-GT 1 HCV infection, including a mixed GT infection (with a non-GT 1) or a non-typeable genotype.
2) is NOT treatment naïve, i.e. subject has had previous treatment with any interferon, ribavirin, approved or experimental direct acting antiviral(s), or other investigational therapies for HCV.
3) As determined by documented records, subject is HIV positive or known to be coinfected with hepatitis B virus (HBsAg positive).
4) has evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
5) has pre-existing psychiatric condition(s)
6) has any known medical condition that could interfere with the subject's participation in and completion of the trial
7) has evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years
8) (female) is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing potential and unwilling to commit to two methods of birth control throughout treatment and after the completion of all treatment
9) is a male whose female partner(s) are pregnant
10) has exclusionary laboratory values as listed in the protocol
i) Hemoglobin <12 g/dL for females and <13 g/dL for males.
ii) Neutrophils <1.5 x 10^3/μL (<1.2 x 10^3/μL for Blacks).
iii) Platelets <150 x 10^3/μL
iv) Direct bilirubin >1.5 x ULN (upper limit of normal) of the laboratory reference range
v) PT/PTT values > 10% above laboratory reference range
vi) Anti-nuclear antibodies (ANA) > 1:320
vii) ALT > 350IU/L
viii) AST > 350 IU/L
PART B
has a non-GT1 HCV infection, including mixed GT infection (with a non-GT 1) or a nontypeable genotype.
Has previously received any HCV direct-acting antivirals.
Evidence of decompensated liver disease manifested by the presence of or history of ascites, variceal bleeding, or hepatic encephalopathy. If hepatic cirrhosis is determined by
liver biopsy (Stage 4 Metavir or Stage 5, 6 Ishak) or by imaging, then participants must
be no more than Child-Pugh Class A and have a Child-Pugh-Turcotte (CPT) score of 6 or less.
has evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
is taking or plans to take any of the prohibited medications listed in Section 5 of this 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 SVR12 in each of the treatment arms. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 Weeks after the end of all study therapy |
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| E.5.2 | Secondary end point(s) |
1) the time to first achievement of undetectable (TND) HCV RNA
2) the proportion of subjects achieving undetectable (TND) HCV RNA and HCV RNA < 25 IU/mL at Week 2, Week 4, and Week 12 (end of treatment visit)
3) the proportion of subjects achieving SVR4 and SVR24
4) the emergence of antiviral resistance to MK-5172 and MK-8742 when administered as a combination regimen +/- RBV
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| time to first achievement of undetectable HCV RNA. Weeks 2, 4, 12, and 24 Weeks following end of treatment, respectively. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 12 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Denmark |
| Norway |
| Sweden |
| Germany |
| Spain |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
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