| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Treatment of chronic hepatitis C virus (HCV) infection
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of chronic hepatitis C virus (HCV) infection |
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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 |
-To evaluate the efficacy of co-administered MK-3682 (450 mg) + Ruzasvir (180 mg) as assessed by the proportion of subjects achieving sustained virologic response (SVR) at 12 weeks post-treatment (SVR12) (defined as HCV ribonucleic acid [RNA] <lower limit of quantification [LLOQ] 12 weeks after the end of all study therapy).
-To evaluate the safety and tolerability of co-administered MK-3682 (450 mg) + Ruzasvir (180 mg). |
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| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of co-administered MK-3682 (450 mg) + Ruzasvir (180 mg) as assessed by the proportion of subjects achieving SVR at 24 weeks post-treatment (SVR24) (defined as HCV RNA <LLOQ 24 weeks after the end of all study therapy).
-To evaluate the efficacy of co-administered MK-3682 (450 mg) + Ruzasvir (180 mg), as assessed by the proportion of subjects experiencing virologic failure (either on-treatment failure or relapse post-treatment) at Follow-up Week (FW) 12 among subjects who do not discontinue study for non–treatmentrelated (e.g., administrative) reasons.
-To evaluate the effect of baseline resistance-associated variants (RAVs) in nonstructural protein (NS) 5A and/or NS5B on the efficacy of co-administered MK-3682 (450 mg) + Ruzasvir (180 mg), as assessed by the proportion of subjects with baseline RAVs 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 |
The Sponsor will conduct Future Biomedical Research on specimens consented for future biomedical research during this clinical trial. This research may include genetic analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes, depending on which specimens are consented for future biomedical research.
The objective of collecting/retaining 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/vaccines, and/or to ensure that subjects receive the correct dose of the correct drug/vaccine 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 data of this substudy will be used to validate the existing viral dynamics model for MK-3682 and Ruzasvir. These subjects will have HCV RNA samples collected during Week 1 as described in the Study Flow Chart (Section 6.0) and in Table 11 (Intensive Viral Kinetic Week 1 Sampling Timepoints) of the protocol.
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| E.3 | Principal 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 (with no evidence of non-typeable or mixed GT) infection as follows:
a. positive for anti-HCV antibody, HCV RNA, or HCV GT1, GT2, GT3, GT4, GT5, or GT6 at least 6 months before Day 1, or
b. positive for anti-HCV antibody or HCV RNA with a liver biopsy consistent with chronic HCV infection (suc as the presence of fibrosis) before Day 1
4. have liver disease staging assessment as follows:
a. Absence of cirrhosis (F0 to F3) defined as per protocol
b. Compensated cirrhosis (F4) defined as per protocol
5. have an HCV treatment status that is one of the following:
a. HCV treatment naïve (defined as no prior exposure to any IFN-containing regimen, RBV, or other approved or experimental HCV-specific DAA agent)
b. HCV treatment experienced (defined as prior virologic failure after treatment with an IFN-containing regimen, with or without RBV, or intolerance to an IFN-containing regimen). Subjects cannot have previously received treatment with HCV-specific DAA agent
6. 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 (whether due to having had a vasectomy or due to an underlying medical condition).
b. The subject is a female who is not of reproductive potential, defined as a female who either: (1) is postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age); (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) 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, and for 6 months after taking the last dose of study drug or longer if dictated by local regulations by complying with one of the following: (1) practice abstinence from heterosexual activity, OR (2) use (or have their partner use) 2 forms of acceptable contraception during heterosexual activity.
If male, subjects must agree to use a condom with spermicide or abstain from sexual intercourse during the trial until 6 months after taking the last dose of study drug (or longer if dictated by local regulations).
Spermicides alone are not an acceptable method of contraception.
Subjects must be completely informed of the unknown risks of pregnancy and agree not to become pregnant during the time they are participating in this trial.
If there is any question that a subject will not be reliable in the use of appropriate contraceptive methods, they should not be entered into the trial.
NOTE: Subjects whose study medication regimen includes only MK-3682 + RZR (and are not treated at any time with RBV) should avoid becoming pregnant or impregnating a partner for at least 14 days after taking the last dose of study drug.
7. understand the study procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent. The subject may also provide consent for FBR. However, the subject may participate in the main trial without participating in FBR
For HIV co-infected subjects, these additional 2 criteria must also be met:
8. have HIV-1/HIV-2 infection documented at any time prior to study entry (Day 1) by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit 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 VL
9. meet 1 of the following criteria:
a. not currently on antiretroviral therapy (ART) and has no plans to initiate ART treatment while participating in this study, must have CD4+ T-cell count >500 cells/mm3 at time of screening, or
b. have well controlled HIV on ART, defined as the following:
i. must have CD4+ T-cell count >200 cells/mm3 at time of screening
ii. must have achieved and maintained virologic suppression (defined as confirmed HIV RNA level <LLOQ of available assay) for at least 8 weeks prior to screening
iii. must have been on a stable regimen (without changes in drugs or
dose modification) for at least 4 weeks prior to study entry (Day 1) |
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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, 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. is cirrhotic AND has a Child-Turcotte-Pugh (CTP) score >6,corresponding to a Child Class B or C.
4. is hepatitis B surface antigen (HBsAg) positive at screening
5. is coinfected with HIV AND has a history of opportunistic infection in the preceding 6 months prior to screening
6. 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
7. has cirrhosis AND liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC
8. is taking or plans to take any of the prohibited medications listed in the protocol (Section 5.5) 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 study treatment period
9. 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 through 24 weeks after the study treatment period (FW 24)
10. is a female subject who is pregnant or breastfeeding, or expecting to conceive or donate eggs from Day 1 through 6 months after the last dose of study drug or longer if dictated by local regulations, OR a male subject who is expecting to donate sperm from Day 1 through 6 months after the last dose of study drug or longer if dictated by local regulations
11. is a male whose female partner(s) is/are pregnant (this is a contraindication for RBV use)
12. 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. has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with subject treatment, assessment, or compliance with the protocol.
e. Any clinically significant cardiac abnormalities/dysfunction that may interfere with subject treatment, assessment, or compliance with the protocol, including but not limited to: unstable angina, unstable congestive heart failure, unstable arrhythmia; subjects currently under evaluation for a potentially clinically significant cardiac abnormality/dysfunction are also excluded
f. Any major medical condition, clinically-significant illness (other than HCV), pre-study laboratory or ECG abnormality, or history of any illness, which, in the opinion of the investigator, might interfere with subject treatment, assessment, compliance with the protocol, or confound the results of the study or pose additional risk in administering the study drug to the subject
g. History of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment, other than for minor elective procedures
h. Medical/surgical conditions that may result in a need for hospitalization during the period of the study
i. Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, tumor necrosis factor (TNF) antagonists, or other immunosuppressant drugs during the course of the trial through FW24
j. Life-threatening SAE during the screening period
k. Evidence of history of chronic hepatitis not caused by HCV, including but not limited to drug-induced hepatitis, hemochromatosis, Wilson’s disease, α1-antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis (see exclusion criterion #4 regarding evidence of history of Hepatitis B).
13. has exclusionary laboratory values at the screening visit as listed in Table 6 of protocol
14. 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) |
| Proportion of subjects achieving SVR12 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Proportion of subjects achieving SVR24;
Proportion of subjects experiencing virologic failure at FW12 among all subjects who do not discontinue study for non–treatment-related reasons. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Follow-Up Week 12 and Follow-Up Week 24 |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.2 | Open | No |
| 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.8.3 |
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 | 30 |
| 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 |
| Israel |
| New Zealand |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| 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 | 14 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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