A Multiple-Dose Study to Evaluate MK-1075 in Hepatitis C Virus (HCV) Infected Participants (MK-1075-004)

• ClinicalTrials.gov Identifier: NCT02461563
• Recruitment Status: Completed
• First Posted: June 3, 2015
• Results First Posted: November 13, 2018
• Last Update Posted: November 13, 2018
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This study will evaluate safety, pharmacokinetics (PK), and the ability of MK-1075 to suppress viral load (VL) in HCV-infected participants during 7 days of once daily dose administration. The primary hypothesis is at a once-daily dose that is sufficiently safe and well tolerated in HCV-infected participants, the mean maximum HCV RNA (log10 IU/mL) reduction is at least 3 log10 IU/mL as compared to baseline following multiple dose oral administration of MK-1075 in HCV genotype 1 (GT1) and genotype 3 (GT3) infected participants.

Condition or disease	Intervention/treatment	Phase
Hepatitis C Virus Infection	Drug: 200 mg MK-1075; Drug: 400 mg MK-1075; Drug: 800 mg MK-1075	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multiple-Dose Study to Evaluate the Safety, Pharmacodynamics and Pharmacokinetics of MK-1075 in GT3 and GT1 HCV Infected Patients
• Actual Study Start Date: June 23, 2015
• Actual Primary Completion Date: December 23, 2015
• Actual Study Completion Date: December 23, 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: GT1: 200 mg MK-1075; Fasted GT1 participants are administered 200 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 200 mg MK-1075; Two 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Experimental: GT1: 400 mg MK-1075; Fasted GT1 participants are administered 400 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 400 mg MK-1075; Four 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Experimental: GT1: 800 mg MK-1075; Fasted GT1 participants are administered 800 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 800 mg MK-1075; Eight 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Experimental: GT3: 200 mg MK-1075; Fasted GT3 participants are administered 200 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 200 mg MK-1075; Two 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Experimental: GT3: 400 mg MK-1075; Fasted GT3 participants are administered 400 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 400 mg MK-1075; Four 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Experimental: GT3: 800 mg MK-1075; Fasted GT3 participants are administered 800 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days	Drug: 800 mg MK-1075; Eight 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to Day 42 ]
   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
2. Number of Participants Who Discontinued Treatment Due to an AE [ Time Frame: Up to Day 7 ]
   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
3. Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 1 (pre-dose, 2, 4, 8, 12, and 24 hours postdose); Days 3, 4, 5, 6 (pre-dose); Day 7 (predose, 4, 12, 24, 48, 72, 96, 120, and 192 hours postdose); Days 21, 28 and 42 ]
   Blood was collected on Days 1, 3, 4, 5, 6, 7, 21, 28 and 42, where baseline measurement was defined as the measurement obtained pre-dose on the first day of dosing. Change from baseline in log10 HCV RNA levels, was determined, and the maximum reduction in HCV RNA was analyzed by an ANOVA model with a fixed effect for treatment. The primary hypothesis is, with a posterior probability larger than 70%, there is at least a 3 log10 reduction from baseline in HCV RNA.

Secondary Outcome Measures :

1. Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of MK-1075 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose ]
   Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC 0-24hr of MK-1075 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on MK-1075 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3). AUC was calculated using the linear-up/log-down trapezoidal method.
2. AUC 0-24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose ]
   Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC 0-24hr of the MK-1075 metabolite M1 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on M1 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3). AUC was calculated using the linear-up/log-down trapezoidal method.
3. Area Under the Plasma Concentration Time Curve From Time 0 to Last (AUC 0-last) of MK-1075 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
   Blood was collected from pre-dose up to 120 hours post-dose in order to determine the plasma AUC 0-last of MK-1075 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on MK-1075 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3). AUC was calculated using the linear-up/log-down trapezoidal method.
4. AUC 0-last of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
   Blood was collected from pre-dose up to 120 hours post-dose in order to determine the plasma AUC 0-last of M1 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on M1 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3). AUC was calculated using the linear-up/log-down trapezoidal method.
5. Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-1075 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at 24 hours postdose ]
   Blood was collected at 24 hours post-dose in order to determine the plasma C24hr of MK- 1075 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on MK-1075 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3).
6. C24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 [ Time Frame: Day 7 at 24 hours postdose ]
   Blood was collected at 24 hours post-dose in order to determine the plasma C24hr of MK-1075 metabolite M1 for pooled GT1 and GT3 genotypes. A non-compartmental analysis on M1 plasma concentrations was performed where actual sampling times, converted to elapsed time relative to dosing times, by using the software Phoenix WinNonlin® Professional (Version 6.3).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Female of non-childbearing potential
• Have a body mass index (BMI) >=18 to =< 37 kg/m^2
• Excepting HCV infection, be in good health
• Have a clinical diagnosis of chronic HCV infection, exclusively GT1 or exclusively GT3
• Agree to follow smoking restrictions

Exclusion Criteria:

• Has a history of clinically significant, not stably controlled endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological abnormalities or diseases.
• Have been treated with amiodarone within the prior year, or is currently on beta-blockers or verapamil
• Has a history of cancer (malignancy)
• Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
• Is positive for hepatitis B surface antigen or human immunodeficiency virus (HIV)
• Has had major surgery, donated or lost approximately 500 mL blood within 4 weeks prior to screening visit
• Has participated in another drug trial within 4 weeks prior to screening visit
• Is taking a non-permitted medication to treat a co-morbid condition
• Consumes greater than 2 glasses of alcoholic beverages
• Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 12 months
• Has evidence or history of chronic hepatitis not caused by HCV, including but not limited to non-HCV viral hepatitis, non-alcoholic steatohepatitis (NASH), drug-induced hepatitis, or autoimmune hepatitis
• Has been treated with other HCV inhibitors, such as sofosbuvir or VX-135
• Has evidence of advanced or decompensated liver disease, bridging fibrosis or higher grade fibrosis from a prior liver biopsy

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02461563
• Other Study ID Numbers: 1075-004; 2015-001687-18 ( EudraCT Number )
• First Posted: June 3, 2015
• Results First Posted: November 13, 2018
• Last Update Posted: November 13, 2018
• Last Verified: April 2018

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections