| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatitis C Virus Genotype 2/4/5/6 |
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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 | 17.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047457 |
| E.1.2 | Term | Viral hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
As this is a hypotheses-generating study, there are no formal hypotheses for this study.
Pt A:
In treatment naïve (TN) non-cirrhotic subjects with chronic GT2, HCV with pre-treatment HCV RNA levels of at least 10,000 IU/ml
(1)Evaluate efficacy of MK5172 with MK8742 and RBV for 12wks 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 <25 IU/mL 12wks after the end of all study therapy.
(2)Evaluate safety/tolerability of MK5172 in combination with MK8742 and RBV.
Pt B:
In TN non-cirrhotic subjects with chronic HCV with GT2, 4, 5 or 6:
(1)Evaluate efficacy of MK5172 in combination with or without MK8742 and/or RBV for 12wks as assessed by the proportion of subjects achieving SVR12, defined as HCV RNA <25 IU/mL 12wks after the end of all study therapy.
(2)Evaluate safety/tolerability of each treatment arm of MK5172 in combination with or without MK8742 and/or RBV.
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|
| E.2.2 | Secondary objectives of the trial |
For Pt A and Pt B:
In TN subjects with chronic GT2, GT4, GT5 and GT6 HCV:
(1) Evaluate the efficacy in each treatment arm of MK5172 with/without MK-8742 and/or RBV as assessed by the time to achieve undetectable HCV RNA levels.
(2) Evaluate the efficacy in each treatment arm of MK-5172 in combination with/without MK-8742 and/or RBV as assessed by the proportion of subjects achieving undetectable (TND) HCV RNA levels and HCV RNA levels <25 IU/mL at Wk2, Wk4, and Wk12.
(3) Evaluate efficacy in each treatment arm of MK-5172 in combination with/without MK-8742 and/or RBV as assessed by the proportion of subjects achieving:
•SVR4, defined as HCV RNA <25 IU/mL 4 wks after the end of
all study therapy.
•SVR24, defined as HCV RNA <25 IU/mL 24 wks after
the end of all study therapy.
(4) Evaluate the emergence of antiviral resistance to MK-5172 and MK-8742 in each treatment arm when administered as part of a combination regimen with RBV.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
The following applies to both Part A and Part B (unless specified otherwise)
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. For Part A only: have chronic HCV GT2 infection. The amino acid variant at position 31 in the NS5A region must be documented prior to enrollment in the trial
For Part B only: have chronic HCV GT2, or GT4, or GT5 or GT6 infection
Note: For Part B of the trial, the amino acid variant at position 31 does not need to be determined prior to enrolling GT2 subjects in treatment arm 2.
• Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 months before screening, and positive for HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening
• 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 absence of cirrhosis, which is defined as any one of the following:
• Liver biopsy performed within 2 years of Day 1 of this study showing absence of cirrhosis
• Fibroscan (in countries where locally approved) performed within 12 months of Day 1 of this study with a result of ≤12.5 kPa
• A FibroTest (FibroSure®) score of ≤0.48 and aspartate aminotransferase (AST) platelet ratio index (APRI) of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. Liver biopsy results supersede the results obtained by Fibroscan or FibroTest (FibroSure®).
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).
If acceptable by local regulatory agencies, methods of birth control allowed in the study are: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, female condom, male condom with spermicide, vasectomy, and hormonal contraceptives (e.g. birth control pills, transdermal patch, or injectables) as well as true abstinence, if abstinence is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., abstinence only on certain calendar days, abstinence only during ovulation period, use of symptothermal method, use of post-ovulation methods) and withdrawal are not acceptable methods of contraception].
For the purposes of this protocol, a woman of non-childbearing potential is defined as one who has either (1) reached natural menopause (defined as 12 months with no menses without an alternative medical cause), (2) 6 weeks post-surgical bilateral oopherectomy with or without hysterectomy, or (3) bilateral tubal ligation.
For the purposes of this protocol, a male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as: one who has undergone a successful vasectomy. A successful vasectomy is defined as: (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
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 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. |
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| E.4 | Principal exclusion criteria |
The subject must be excluded from the trial if the subject:
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 stuy or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures
2.For Pt A: has non GT2 HCV, including a mixed GT infection or infection with a non-typeable GT.
For Pt B: has HCV with a GT other than GT2, GT4, GT5 or GT6, including a mixed GT infection or infection with a non-typeable GT.
3. is NOT treatment naïve,
4. is coinfected with hepatitis B virus or HIV.
5. has evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
6. is taking or plans to take any of the prohibited medications listed in Sec. 5.5 of this protocol within 2 weeks prior to day 1.
7. 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 study. Collection of additional blood, urine, or tissue samples or additional data, beyond that specified in this protocol, is prohibited (other than that related to subject’s medical care).
8. has a clinical diagnosis of substance abuse of the following specified drugs within specified timeframes:
a. Alcohol, intravenous drugs, inhalational (not including marijuana), psychotropics, narcotics, cocaine use, prescription or over-the-counter drugs: within 1 year of the screening visit, or if shorter, is judged by investigator to be capable of complying with study procedures OR
b. receiving opiate agonist substitution therapy within 1 year of screening visit, or if shorter, is judged by investigator to be capable of complying with study procedures
c. history of marijuana use if deemed excessive by a physician investigator or interferes with the subject's daily function. If subject's marijuana use is not deemed excessive and does not interfere with daily function, subject must agree to discontinue any current use of recreational marijuana prior to entry into trial and throughout the trial period.
9. has evidence of active or suspected malignancy, or a history of malignancy, within the last 5yrs (except adequately treated carcinoma in situ, squamous cell carcinoma, and basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible.
10. is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing potential and unwilling to commit to 2 methods of birth control throughout treatment and after the completion of all treatment; or male subject is planning to impregnate or provide sperm donation or has a female sexual partner of childbearing potential and is unwilling to commit to using 2 methods of birth control throughout treatment and after the completion of all treatment.
11. is a male whose female partner is pregnant.
12. has any other condition which, in the opinion of the principal investigator or study physician, would make the subject unsuitable for enrollment or could interfere with the subject participating in and completing the study , including but not limited to:
a. Organ transplants other than cornea and hair
b. Hemoglobinopathy
c. Poor venous access that precludes routine peripheral blood sampling required for this trial.
d. Subject with indwelling venous catheters.
e. Subject with a history of gastric surgery or subject with a history of malabsorption disorders.
f. Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial.
13. had a life-threatening SAE during the screening period.
14. is a member or a family member of the investigational study staff or sponsor staff directly involved with this study.
15. has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis.
NOTE: Subjects with history of acute non-HCV-related hepatitis, which resolved > 6 months before study entry, may be enrolled.
16. For subjects diagnosed with diabetes mellitus, documented HbA1c >8.5%
17. has exclusionary laboratory values as listed below:
Note: If any of the laboratory exclusion criteria below are met, the site may have the abnormal value retested one time.
Lab Assessment
hemoglobin < LLN of laboratory reference range
neutrophils <1.5 x 103/μL (<1.2 x 103/μL for Blacks)
platelets <125 x 103/μL
direct bilirubin >1.5 x ULN
Total Bilirubin >1.6 mg/dL unless history of Gilbert's disease. (If Gilbert’s disease is the proposed etiology, this must be documented in the subject’s chart)
Serum Albumin < 3.5 g/dL LLN of laboratory reference range
creatinine clearance <50 mL/min
INR >1.5
ALT/AST >350 |
|
| 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. |
|
| 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) |
| The key secondary objective will be evaluated using summary statistics to characterize the time to first achievement of undetectable HCV RNA in each of the treatment arms. |
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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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| France |
| Israel |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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