| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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 each treatment arm of GZR/EBR (MK-5172A) in combination with Sofosbuvir (SOF) +/- Ribavirin (RBV) as assessed by the proportion of subjects 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 GZR/EBR (MK-5172A) in combination with SOF +/- RBV.
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| E.2.2 | Secondary objectives of the trial |
(1) Objective: To evaluate the efficacy of each treatment arm of GZR/EBR in combination with SOF +/- RBV as assessed by the proportion of subjects 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.
(2) Objective: To evaluate the emergence of viral resistance-associated variants (RAVs) resistant to GZR, EBR, or SOF when administered as part of a combination regimen +/- RBV.
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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. |
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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 (with no evidence of non-typeable or mixed genotype) infection:
• Positive for anti-HCV antibody, HCV RNA, or HCV genotype 3 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, electrocardiogram (ECG), and clinical laboratory measurements performed at the time of screening.
5. have liver cirrhosis assessment as follows:
Compensated cirrhosis is defined as any one of the following:
• 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 FibroTest® (FibroSure®) 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.)
NOTE: In the absence of a definitive diagnosis of presence or absence of cirrhosis by a FibroTest®, a FibroScan® or liver biopsy is required. Liver biopsy results supersede the results obtained by FibroTest® or FibroScan®.
6. has liver imaging within 6 months of Day 1 with no evidence of hepatocellular carcinoma (HCC).
NOTE: If liver imaging within 6 months of Day 1 is not available, imaging is required during screening.
7. Have a prior treatment history of either:
a. HCV treatment-naïve (defined as no prior exposure to any interferon, ribavirin, or other approved or experimental HCV-specific direct-acting antiviral agent)
b. Documented prior virologic failure or intolerance to a PR regimen to allow for categorization of prior response:
i. PR Null Responder: <2 log10 IU/mL reduction in HCV RNA after at least 12 weeks of a PR regimen OR <1 log10 IU/mL reduction in HCV RNA after 4 weeks and discontinued therapy prior to treatment-week 12.
ii. PR Partial Responder: ≥2 log10 IU/mL reduction in HCV RNA after at least 12 weeks of treatment, but not achieving HCV RNA target not detected at end-of-treatment, with a PR regimen.
iii. PR Relapser: HCV RNA target not detected at end-of-treatment with a PR regimen, but HCV RNA quantifiable (≥ LLOQ) during follow-up.
iv. Intolerant to peg-IFN: ≥ 4 weeks of peg-IFN treatment and no more than 80% of treatment duration:
1. ≤ 20 weeks for a 24 week treatment regimen
2. ≤ 40 weeks for a 48 week treatment duration
NOTE: Documentation of prior PR treatment history must include clinic notes or referral letter documenting regimen administered, approximate dates of treatment, approximate date of virologic failure, and a history of laboratory confirmed prior virologic failure or documented intolerance to allow for categorization of prior response. If the subject was treated with a PR regimen more than once, the categorization must be based on the most recent round of treatment.
Refer to protocol for complete list
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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. had prior treatment (defined as 1 dose or more) with direct acting antiviral (DAA) therapy.
3. 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.
4. is classified as Child-Pugh B or C or has a Child Pugh-Turcotte score (CPT) >6:
NOTE: To calculate the Child-Pugh score, refer to the following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality.
5. is co-infected with hepatitis B virus (e.g., HBsAg positive).
6. For subjects with HIV, has a history of opportunistic infection in the preceding 6 months prior to screening. A list of these events may be found in Appendix B of the following document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm
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 hepatocellular carcinoma or other active or suspected malignancy.
8. 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) within 2 weeks of Day 1, during treatment, and for at least 2 weeks following the last dose of study drug.
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.
10. has clinically-relevant drug or alcohol abuse within 12 months of screening.
11. 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 medication 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 medication or longer if dictated by local regulations.
12. is a male whose female partner(s) is/are pregnant (this is a contraindication for ribavirin use)
13. 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 or anti-arrhythmic 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, sarcoidosis.
f. Hemoglobinopathy, including but not limited to, thalassemia major.
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, TNF antagonists, or other immunosuppressant drugs during the course of the trial.
j. 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.
k. had a life-threatening SAE during the screening period.
l. 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.
Refer to protocol for complete list. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects achieving SVR12 (Sustained Virologic Response 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 completing therapy. |
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| E.5.2 | Secondary end point(s) |
| Proportion of subjects achieving SVR24 (Sustained Virologic Response 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 completing 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 | 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 | 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 |
| Evaluate the combination regimen of Elbasvir/Grazoprevir and Sofosbuvir with and without Ribavirin |
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| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 21 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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