MK-5172/MK-3682 with MK-8742 or MK-8408 in HCV GT3, GT4, GT5 and GT6 Infected Subjects.

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2014-003347-35-DK
• Date of registration: 15/09/2014
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: MK-5172/MK-3682 with MK-8742 or MK-8408 in HCV GT3, GT4, GT5 and GT6 Infected Subjects.
• Scientific title: A Phase II, Randomized, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-3682 with Either MK-8742 or MK-8408 in Subjects with Chronic HCV GT3, GT4, GT5 and GT6 Infection. - MK-5172/MK-3682 with MK-8742 or MK-8408 in HCV GT3, GT4, GT5 and GT6 Infected Subjects.
• Date of first enrolment: 30/10/2014
• Target sample size: 500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003347-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 22
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Canada, Denmark, France, Germany, Israel, Italy, New Zealand, Switzerland, United Kingdom, United States

Contacts

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Key inclusion & exclusion criteria

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, GT4, GT5 or GT6
4. Be otherwise healthy at the time of screening
5. have liver disease staging assessment as follows:
Absence of cirrhosis is defined as any one of the following (both Part A and Part B):
• Liver biopsy performed within 24 months of Day 1
• Fibroscan performed within 12 months of Day 1 a result of =12.5 kPa
• A Fibrosure® (Fibrotest®) score of =0.48 and APRI Index of =1 during Screening
Compensated cirrhosis is defined as any one of the following (Part B only):
• A liver biopsy performed prior to Day 1 showing cirrhosis (F4)
• Fibroscan performed within 12 calendar months of Day 1 with a result >12.5 kPa
• A FibroSure® (Fibrotest®) performed during Screening with a score of >0.75 and an (APRI) of >2.
6. Have a prior treatment history of:
• HCV treatment-naïve (defined as no prior exposure to any interferon, ribavirin, or other approved or experimental HCV-specific direct-acting antiviral agent) (both Part A and Part B)
• Prior virologic failure after treatment with a Peg-IFN/RBV regimen (Part B only):
7. 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
b. The subject is a female who is not of reproductive potential, defined as a female who either: (1) is postmenopausal and have a documented FSH level in the postmenopausal range at pretrial (screening); (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, for 6 months after taking the last dose of study drug , by complying with one of the following: (1) practice abstinence† from heterosexual activity OR (2) use (or have their partner use) two forms of acceptable contraception during heterosexual activity. Acceptable methods of contraception are‡:
• oral contraceptives (Part B and C only)
• intrauterine device (IUD) with or without local hormone release
• diaphragm with spermicide
• cervical cap with spermicide
• contraceptive sponge with spermicide
• male condom with spermicide or female condom with spermicide

If male, subjects must agree to use a condom with spermicide or abstain from sexual intercourse during the trial until 6 months after the last dose of trial drug
Spermicides alone are not an acceptable method of contraception.

8. provide written informed consent for the trial.
For Part B only:
For HIV coinfected subjects :
1. Have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay at any time prior to study entry
2. meet one of the following criteria:
a. not currently be on antiretroviral therapy (ART) and have no plans to initiate ART treatment while participating in this study.
i. subjects not on ART must have CD4+ T-cell count >500 cells/mm3 at screening
b. have well controlled HIV on ART, defined as:
i. must have achieved virologic suppression on HIV Antiretroviral Therapy (ART) at leas
Exclusion criteria:
The following applies to Parts A, B and C (unless otherwise specified):
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 (Part B only):
a. subjects that are Child-Pugh Class B or C, or who have a Pugh-Turcotte (CPT) score >5, must be excluded.

4. is coinfected with hepatitis B virus.

6. For subjects with HIV, has a history of opportunistic infection in the preceding 6 months prior to screening.

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 other active or suspected malignancy.

8. has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.

9. is taking or plans to take any of the prohibited medications listed in the protocol or is taking herbal supplements from 2 weeks prior to Day 1 through 2 weeks after the study treatment period.

12. 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 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 6 months after the last dose of study drug or longer if dictated by local regulations.

13. Parts B and C only: is a male whose female partner(s) is/are pregnant (this is a contraindication for ribavirin use).

14. 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 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, or sarcoidosis.
f. Part B and C only: Hemoglobinopathy, including but not limited to, thalassemia major.
g. Central nervous system (CNS) trauma requiring intubation, intracranial pressure monitoring, brain meningeal or skull

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Chronic hepatitis C infected patient
MedDRA version: 20.0 Level: LLT Classification code 10019751 Term: Hepatitis C virus System Organ Class: 100000004848

Therapeutic area: Diseases [C] - Virus Diseases [C02]

Intervention(s)

Product Name: MK-3682
Product Code: MK-3682
Pharmaceutical Form: Tablet
INN or Proposed INN: MK-3682
Current Sponsor code: MK-3682
Other descriptive name: MK-3682
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Product Name: MK-5172
Product Code: MK-5172
Pharmaceutical Form: Tablet
INN or Proposed INN: MK-5172
Current Sponsor code: MK-5172
Other descriptive name: MK-5172
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: MK-8408
Product Code: MK-8408
Pharmaceutical Form: Capsule
INN or Proposed INN: MK-8408
Current Sponsor code: MK-8408
Other descriptive name: MK-8408
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Product Name: MK-8742
Product Code: MK-8742
Pharmaceutical Form: Tablet
INN or Proposed INN: MK-8742
Current Sponsor code: MK-8742
Other descriptive name: MK-8742
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Product Name: MK-3682B (Fixed dose combination of MK-5172 (50mg); MK-3682 (225 mg); Mk-8408 (30 mg) per tablet)
Product Code: MK-3682B
Pharmaceutical Form: Tablet
INN or Proposed INN: MK-3682
Current Sponsor code: MK-3682
Other descriptive name: MK-3682
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 225-
INN or Proposed INN: MK-5172
Current Sponsor code: MK-5172
Other descriptive name: MK-5172
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
INN or Proposed INN: MK-8408
Current Sponsor code: MK-8408
Other descriptive name: MK-8408
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Trade Name: Rebetol
Product Name: Rebetol
Product Code: Rebetol
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ribavirin
CAS Number: 36791-04-5
Other descriptive name: Rebetol SUB 10297MIG
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint will be the proportion of subjects in each treatment arm achieving SVR12 (defined as HCV RNA

Secondary Objective: 1.Evaluate the efficacy of the combination regimens of MK5172 & MK3682 with MK8742 (Part A only) or MK8408 (Parts A and B), +/- ribavirin (Part B), as assessed by the proportion of GT3-infected subjects in each arm achieving SVR24 defined as HCV RNA In Part B, this secondary objective will be evaluated within each GT3-infected subject population (treatment-naïve vs. treatment-experienced, HIV/HCV co-infected vs. mono-infected, and cirrhotic vs. non-cirrhotic) separately.
In addition, the following objectives will be evaluated for the GT3-infected HIV co-infected population:
2.Among GT3-infected HIV-1 co-infected patients, evaluate the proportion of subjects who develop HIV-1 virologic failure (HIV-1 RNA 200 copies/mL, in subjects compliant with their HIV antiretroviral therapy).
3.Among GT3-infected HIV-1 co-infected patients, evaluate the effect of the study regimens on CD4+ T-cell counts.

Timepoint(s) of evaluation of this end point: 12 weeks after completion of study therapy

Main Objective: 1.Objective: To evaluate the efficacy of the combination regimens of MK-5172 and MK-3682 (300 mg or 450 mg) with either MK-8742 (Part A only) or MK-8408 (Parts A and B), with or without ribavirin (Part B), as assessed by the proportion of GT3-infected subjects in each arm achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy), defined as HCV RNA 2.Objective: To evaluate the safety and tolerability of the combination regimens of MK-5172 and MK-3682 (300 mg or 450 mg) with either MK-8742 (Part A only) or MK-8408 (Parts A and B), with or without ribavirin, in GT3-infected subjects in each arm.

Secondary Outcome(s)

Secondary end point(s): The secondary efficacy endpoint will be the proportion of subjects in each treatment arm achieving SVR24 (defined as HCV RNA

Timepoint(s) of evaluation of this end point: 24 weeks after completion of study therapy

Secondary ID(s)

NCT02332720

MK-3682-012

Source(s) of Monetary Support

Merck Sharp & Dohme Corp. a subsidiary of Merck & Co Inc