| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Infected Patient |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis C Infected Patient |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019183 |
| E.1.2 | Term | HCV |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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 |
MK-3682B (MK-3682 [225 mg] + GZR [50 mg] + MK-8408 [30 mg]) administered as two fixed-dose combination (FDC) tablets given once daily; Objectives will be evaluated separately for each HCV Genotype (GT)
1. To evaluate the efficacy of MK-3682B following 12 weeks of treatment as assessed by the proportion of subjects achieving SVR12 (defined as HCV RNA <Lower Limit Of Quantification (LLOQ) 12 weeks after the end of all study therapy)
2. To evaluate the safety and tolerability of MK-3682B
|
|
| E.2.2 | Secondary objectives of the trial |
Objectives will be evaluated for each HCV GT
1. To evaluate the efficacy of MK-3682B following 8 weeks of treatment as assessed by the proportion of subjects achieving SVR12 (HCV RNA <LLOQ 12 weeks after the end of study therapy)
2. To evaluate the efficacy of 12 or 8 weeks of treatment with MK-3682B, respectively, as assessed by the proportion of subjects achieving SVR24 (HCV RNA <LLOQ 24 weeks after the end of study therapy)
3. To evaluate the efficacy of 12 or 8 weeks of treatment with MK-3682B, respectively, as assessed by the proportion of subjects experiencing virologic failure (either on-treatment failure or relapse post-treatment) at FW12 among subjects who do not discontinue the study for non-treatment-related reasons
4. To evaluate the effect of baseline resistance-associated polymorphisms in NS3, NS5A, and/or NS5B on the efficacy of 12 or 8 weeks of treatment with MK-3682B, respectively, as assessed by the proportion of subjects with baseline RAPs achieving SVR12 |
|
| 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 theprotocol (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. |
|
| E.3 | Principal inclusion criteria |
1. be >or=18 years of age and >or= age of consent per local regulations on day of signing informed consent
2. HCV RNA (>or= 10,000 IU/mL in peripheral blood) at the time of screening
3. have documented chronic HCV GT5 or GT6 (with no evidence of non-typeable or mixed GT) infection and meet the definition below:
- Positive for anti-HCV antibody, HCV RNA, or HCV GT5 or GT6 at least 6 months before Day 1, or
- Positive for anti-HCV antibody or HCV RNA with a liver biopsy consistent with chronic HCV infection (such as the presence of fibrosis) before Day 1
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:
- 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 <or=12.5 kPa
- A Fibrosure® (Fibrotest®) score of <or=0.48 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) of <or=1 during Screening
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 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 × 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 the above criteria, a liver biopsy or Fibroscan is required. Liver biopsy results supersede the results obtained by Fibroscan® or Fibrosure®
6. be HCV treatment naïve (defined as no prior exposure to any interferon, RBV, or other approved or experimental HCV-specific direct-acting antiviral agent) OR prior virologic failure after treatment with an interferon-containing regimen (comprised of interferon or pegylated interferon, with or without ribavirin) only. Subjects who were intolerant to an interferon-containing regimen will be allowed to enroll. Subjects may not have previously received treatment with HCV direct-acting antiviral agents
7. meet one of the following criteria:
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 >or=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. The 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 through 14 days 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) acceptable contraception during heterosexual activity. Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
- intrauterine device (IUD)
- vasectomy of a female subject’s male partner
- contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
- diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
- cervical cap with spermicide (nulliparous women only)
- contraceptive sponge (nulliparous women only)
- male condom or female condom (cannot be used together)
- hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.
Refer to protocol for complete list. |
|
| 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. For cirrhotics:
a. subjects that are Child-Pugh Class B or C, or who have a Pugh-Turcotte score >6, must be excluded
NOTE To calculate the Child-Pugh score, refer to the following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality
4. is coinfected with hepatitis B virus (eg. HBsAg positive)
5. 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
6. has a history of malignancy <or=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 or is under evaluation for HCC
NOTE If liver imaging within 6 months prior to Day 1 is not available, imaging is required during screening
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), 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
10. Has, in the opinion of the investigator, 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 14 days 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 14 days after the last dose of study drug, or longer if dictated by local regulations
NOTE After randomization, female subjects should avoid conceiving or donating eggs and male subjects should avoid impregnating a partner or donating sperm for at least 14 days after taking the last dose of study drug
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 (eg. stapling, bypass) or subject with a history of malabsorption disorders (eg. celiac sprue disease)
d. 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, significant arrhythmia; subjects currently under evaluation for a potentially clinically-significant cardiac abnormality/dysfunction are also excluded
e. 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
f. History of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment, other than for minor elective procedures
g. Medical/surgical conditions that may result in a need for hospitalization during the period of the study
h. 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
i. Life-threatening SAE during the screening period
j. 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
NOTE Subjects with history of acute non-HCV-related hepatitis, which resolved >6 months before study entry, can be enrolled
Refer to protocol for complete list |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects achieving SVR12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy). The subject has HCV RNA <LLOQ 12 weeks after the end of all study therapy |
|
| E.5.2 | Secondary end point(s) |
Proportion of subjects achieving SVR24
Proportion of subjects experiencing virologic failure at Follow-up Week 12 among subjects who do not discontinue study for non-treatment-related reasons |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy). The subject has HCV RNA <LLOQ 24 weeks after the end of all study therapy
Virologic failure rate among subjects who do not discontinue the study for non-treatment-related reasons at FW12 |
|
| 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) | Yes |
| 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
| 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 | 2 |
| 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 |
| Belgium |
| Canada |
| France |
| Hong Kong |
| South Africa |
| Thailand |
| United States |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 6 |
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