| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A viral infection affecting the liver |
|
| 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 MK-5172 + MK-8742 in HCV GT1 subjects
with chronic kidney disease (CKD) within the immediate treatment and the intensive PK groups.
• To evaluate the safety and tolerability of MK-5172 in combination with MK-8742 in the immediate treatment group relative to the placebo treatment of the deferred treatment group. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of MK-5172 in combination with MK-8742 as assessed by the proportion of subjects achieving:
-SVR24 within the immediate treatment and the intensive PK groups, defined as HCV RNA <25 IU/mL (either TD(u) or TND) 24 weeks after the end of all study therapy.
- SVR4, defined as HCV RNA <25 IU/mL (either TD(u) or TND) 4 weeks after the end of all study therapy.
-SVR12, defined as HCV RNA <25 IU/mL (either TD(u) or TND) 12 weeks after the end of all study therapy on active period of deferred treatment arm,
- SVR12, defined as HCV RNA <25 IU/mL (either TD(u) or TND) 12 weeks after the end of all study therapy for all active treatment arms combined.
• To evaluate the safety and tolerability of MK-5172 in combination with MK-8742 for all treatment arms.
• To evaluate the emergence of viral RAVs resistant to MK-5172 and MK-8742 when administered as part of a combination regimen. |
|
| 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 trials. Such research is for biomarker testing to adress 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 drugd, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
• Be ≥18 years of age on day of signing informed consent.
• Have documented chronic (at least 6 months) HCV GT1 infection (with no evidence of non typable or mixed genotypes) :
- Positive for anti-HCV antibody, HCV RNA, or an HCV genotype
- HCV RNA (≥ 10,000 IU/mL in peripheral blood)
• Have no evidence of cirrhosis based on 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 ≤12.5 kPa
- A FibroSure® (Fibrotest®) score of ≤0.48 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above critieria, a liver biopsy is required. Liver biopsy results supersede the results obtained by Fibroscan or FibroSure®.
• Have an HCV treatment status that is one of the following:
Treatment naïve: Naive to all anti-HCV treatment
Prior Treatment Relapse: Subjects relapsed after completing a prior course of HCV therapy that included IFN or PEG-IFN + Ribavirin but that did not include any direct acting antivirals.
• Have Chronic Kidney Disease defined as:
Subjects with GFR ≤29 who are non-dialysis dependent (NDD) or have been on hemodialysis (HD) for at least 3 months (including subjects awaiting kidney transplant and subjects with failed kidney transplants no longer on immunosuppressant therapy). |
|
| E.4 | Principal exclusion criteria |
• 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.
• Evidence of decompensated liver disease manifested by the presence of or history of ascites, gastric or variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver disease. If hepatic cirrhosis is determined by liver biopsy (Stage 4 Metavir or Stage 5, 6 Ishak) participants must be excluded.
• Is on peritoneal dialysis for management of Kidney disease
• In the opinion of the investigator the subject has a high likelihood of receiving a renal transplant during the study treatment period (up to 24 weeks from Day 1).
• Is coinfected with hepatitis B virus (e.g. HBsAg positive) or HIV.
• 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 has evidence of hepatocellular carcinoma (HCC) or is under evaluation for other active or suspected malignancy.
• 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.
• Has a clinical diagnosis of substance abuse of the following specified drugs within specified timeframes:
- 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 the investigator to be capable of complying with study procedures, OR
NOTE: Subjects receiving opiate agonist substitution therapy are not excluded from the study if, in the opinion of the investigator, the subject is capable of complying with all study procedures
- history of marijuana use is deemed excessive by a physician investigator or is interfering with the subject's daily function. If subject's marijuana use is not deemed excessive and does not interfere with daily function, subject must be instructed to discontinue any current use of recreational marijuana prior to entry into trial and throughout the trial period.
• Female subject who is pregnant or breast-feeding, or expecting to conceive or donate eggs from at least 2 weeks prior to Day 1 and throughout treatment, or longer if dictated by local regulations or male subject who is expecting to donate sperm from at least 2 weeks prior to Day 1 and throughout treatment, or longer if dictated by local regulations.
• Has any of the following conditions:
- Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair.
- Poor venous access in non-dialysis patients that precludes routine peripheral blood sampling required for this trial.
- Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease).
- Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial.
- Has uncontrolled or poorly controlled hypertension including but not limited to hypertensive emergency or hospitalization for hypertension in preceding 3 months.
- Diagnosed with a significant cardiovascular disorder (e.g. MI or unstable angina) or has had a cardiovascular procedure (e.g. CABG or PTCA) within 3 months prior to signing informed consent.
- Has new or worsening signs or symptoms of congestive heart failure within 3 months of signing informed consent.
- Has severe active peripheral vascular disease, (e.g., manifested by claudication with minimal activity, a non-healing ischemic ulcer, or disease which is likely to require intervention such as with bypass or angioplasty).
- Has a recent (within 3 months prior to signing informed consent) diagnosis, episode or recurrence of stroke, TIA or neurological disorder, including but not limited to seizures, blackouts, or a recent (within 3 months prior to signing informed consent) change in the dose or class of medications used to treat these conditions. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The SVR12 rate of the subjects in the immediate treatment and intensive PK arms |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. the SVR4 and SVR24 rates of the subjects within the immediate treatment and the intensive PK arms.
2. the SVR4 , SVR12 and SVR24 rates in the deferred treatment arm following the end of all active study therapy
3. the SVR4 , SVR12 and SVR24 rates following the end of all active study therapy for all treatment arms combined
4. the emergence of viral resistance to MK-5172 and MK-8742 when administered as a combination regimen
5. the proportion of subjects achieving TND, TD(u) and TD(q) at end of treatment
6. the PK endpoints for MK-5172, MK-8742 are AUC0-24, C2hr and Ctrough.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After administration, SVR4 , SVR12, SVR24 and End of Treatment |
|
| 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) | Yes |
| 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 16 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Estonia |
| France |
| Israel |
| Korea, Republic of |
| Lithuania |
| Netherlands |
| Spain |
| Sweden |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 8 |
| 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 | 8 |
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