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Single and Multiple Dose Study of Uprifosbuvir (MK-3682/IDX21437) in Healthy and Hepatitis C Virus (HCV)-Infected Participants (MK-3682-001)

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ClinicalTrials.gov Identifier: NCT01974687
Recruitment Status : Completed
First Posted : November 1, 2013
Results First Posted : September 13, 2018
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This is a multi-part study to evaluate the safety, tolerability, and pharmacokinetics (PK) of uprifosbuvir (MK-3682/IDX21437) in healthy participants and in participants infected with Hepatitis C virus (HCV) genotype (GT)1-GT6. The effect of food on the PK of uprifosbuvir will be evaluated. The antiviral activity of uprifosbuvir will also be assessed in HCV-infected participants.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis C Drug: Uprifosbuvir Drug: Placebo Drug: Itraconazole Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 178 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase I/IIa Study Assessing Single and Multiple Doses of IDX21437 in Healthy and HCV-Infected Subjects
Actual Study Start Date : October 31, 2013
Actual Primary Completion Date : September 2, 2015
Actual Study Completion Date : September 11, 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A: Healthy
Healthy participants will receive sequentially higher doses of uprifosbuvir (10 mg - 300 mg) capsules or matching placebo capsules once daily (QD) on Day 1 (Cohorts 1a-3a, 5a), Days 1 and 7 (Cohort 4a), or Day 1 - Day 7 (Cohort 6a). Dosing of next cohort will be based on review of available safety and PK data. Dosing will occur under fasted conditions with the exception of Cohort 4a, in which drug administration will occur under both fasted and fed conditions.
Drug: Uprifosbuvir
Uprifosbuvir 5 mg, 25 mg, or 50 mg capsule, or 150 mg tablet, administered by mouth.
Other Name: MK-3682/IDX21437

Drug: Placebo
Matching placebo to uprifosbuvir capsule administered by mouth.

Experimental: Group B: GT1 HCV-infected, treatment naive on Day 1
HCV GT1 participants with no prior direct-acting antiviral (DAA) exposure will receive a single dose of uprifosbuvir (10 mg - 300 mg) for 1 day across sequential dose cohorts. Dosing will commence following review of available safety and PK data from respective dose cohorts in Group A. All dosing will occur under fasted conditions.
Drug: Uprifosbuvir
Uprifosbuvir 5 mg, 25 mg, or 50 mg capsule, or 150 mg tablet, administered by mouth.
Other Name: MK-3682/IDX21437

Experimental: Group C: GT1 HCV-infected on Days 1-7
HCV GT1 participants will receive uprifosbuvir (50 mg - 400 mg in capsules or 300 mg or 450 mg in tablets) or matching placebo capsules QD for 7 days. Dosing will commence following review of available safety and PK data of Group A. Fed vs. fasted dosing will be dependent on food effect results from Group A.
Drug: Uprifosbuvir
Uprifosbuvir 5 mg, 25 mg, or 50 mg capsule, or 150 mg tablet, administered by mouth.
Other Name: MK-3682/IDX21437

Drug: Placebo
Matching placebo to uprifosbuvir capsule administered by mouth.

Experimental: Group D: GT2 through GT6 HCV-infected on Days 1-7
HCV GT2 - GT6 participants will receive uprifosbuvir (50 mg - 300 mg) capsules QD for 7 days. Dosing will commence following review of available safety and PK data from Group A. Fed vs. fasted dosing will be dependent on food effect results from Group A.
Drug: Uprifosbuvir
Uprifosbuvir 5 mg, 25 mg, or 50 mg capsule, or 150 mg tablet, administered by mouth.
Other Name: MK-3682/IDX21437

Experimental: Group E: GT1 HCV-infected on Days 1-7, mild hepatic impairment
HCV GT1 participants with mildly impaired hepatic function will receive uprifosbuvir (150 mg - 450 mg) capsules QD for 1 or 7 days. Dosing of subsequent cohorts will be based on review of available safety and PK data. Fed vs. fasted dosing will be dependent on food effect results from Group A.
Drug: Uprifosbuvir
Uprifosbuvir 5 mg, 25 mg, or 50 mg capsule, or 150 mg tablet, administered by mouth.
Other Name: MK-3682/IDX21437

Experimental: Group F: GT1 HCV-infected on Days 1-7, + Itraconazole
HCV GT1 participants will receive itraconazole 200 mg twice daily (BID) on Day -5 and itraconazole 200 mg QD from Day -4 to Day 11. Participants will also be co-administered uprifosbuvir 300 mg from Day 1 to Day 7.
Drug: Itraconazole
Itraconazole is supplied as 10 mg/mL oral solution or 100 mg capsules administered by mouth.
Other Name: Sporanox®




Primary Outcome Measures :
  1. Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Event (AE) [ Time Frame: Up to 42 days ]
    An AE was defined as any untoward medical occurrence in a participant administered study drug, and that does not necessarily have a causal relationship with the study drug(s). An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug(s), whether or not related to study drug(s). The percentage of participants who experienced at least one AE is presented.

  2. Percentage of Participants Who Experienced at Least One Treatment-emergent Serious AE (SAE) [ Time Frame: Up to 42 days ]
    An SAE was defined as any untoward medical occurrence that at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. The percentage of participants who experienced at least one SAE is presented.

  3. Percentage of Participants Who Experienced a Treatment-emergent Dose-limiting Toxicity (DLT) [ Time Frame: Up to 13 days ]
    A DLT was defined as any of the following events: Any SAE considered by the investigator to be at least reasonably or possibly related to study drug; Any Grade 3 clinical AE considered by the investigator to be at least reasonably or possibly related to study drug; Any Grade 3 confirmed laboratory abnormalities considered by the investigator to be at least reasonably or possibly related to study drug, except for asymptomatic Grade ¾ cholesterol and triglyceride; Any clinical or laboratory AE of any intensity that is considered by the investigator to be at least reasonably or possibly related to study drug that necessitates permanent discontinuation of study drug; Confirmed increase in QT interval corrected for heart rate using Fridericia's (QTcF) formula ≥60 msec over Baseline or an absolute QTcF ≥500 msec.

  4. Percentage of Participants Who Experienced at Least One Treatment-emergent Grade 1, 2, 3, 4 or 5 Laboratory Abnormality [ Time Frame: Up to 42 days ]
    Laboratory abnormalities were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Treatment-emergent AEs (TEAEs)were graded as: Grade 1: Mild TEAE as Worst Severity; Grade 2: Moderate TEAE as Worst Severity; Grade 3: Severe TEAE as Worst Severity; Grade 4: Potentially Life-Threatening TEAE as Worst Severity; Grade 5: TEAE Leading to Death. The percentage of participants who experienced at least one Grade 1, 2, 3, 4 or 5 laboratory abnormality is presented.

  5. Percentage of Participants Who Discontinued Study Drug Due to a Treatment-emergent AE [ Time Frame: Up to 14 days ]
    The percentage of participants who discontinued study drug due to an AE is presented.

  6. Area Under the Plasma Drug Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration. All participants were fasted.

  7. AUC0-t of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  8. AUC0-t of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  9. AUC0-t of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  10. AUC0-t of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  11. AUC0-t of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  12. AUC0-t of Uprifosbuvir After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  13. AUC0-t of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  14. AUC0-t of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  15. Maximum (Peak) Observed Plasma Drug Concentration (Cmax) of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained. All participants were fasted.

  16. Cmax of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  17. Cmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  18. Cmax of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  19. Cmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained. All participants were fasted.

  20. Cmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  21. Cmax of Uprifosbuvir After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  22. Cmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  23. Cmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  24. Time to Maximum Plasma Concentration (Tmax) of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained. All participants were fasted.

  25. Tmax of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  26. Tmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  27. Tmax of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  28. Tmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  29. Tmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  30. Tmax of Uprifosbuvir After Singe Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  31. Tmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.

  32. Tmax of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  33. Observed Terminal Half-Life (t1/2) of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained. All participants were fasted.

  34. t1/2 of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  35. t1/2 of Uprifosbuvir After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  36. t1/2 of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  37. t1/2 of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  38. t1/2 of Uprifosbuvir After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  39. t1/2 of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  40. t1/2 of Uprifosbuvir After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  41. AUC0-inf of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity for M6, a metabolite of uprifosbuvir, estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only. All participants were fasted.

  42. AUC0-inf of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  43. AUC0-inf of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  44. AUC0-inf of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  45. AUC0-inf of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  46. AUC0-inf of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  47. AUC0-inf of M6 After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  48. AUC0-inf of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  49. AUC0-inf of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.

  50. Cmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained. All participants were fasted.

  51. Cmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  52. Cmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  53. Cmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  54. Cmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  55. Cmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  56. Cmax of M6 After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  57. Cmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  58. Cmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Maximum observed plasma drug concentration was obtained.

  59. Tmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained. All participants were fasted.

  60. Tmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  61. Tmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  62. Tmax of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  63. Tmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  64. Tmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  65. Tmax of M6 After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  66. Tmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1,HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  67. Tmax of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Time to maximum plasma concentration was obtained.

  68. t1/2 of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained. All participants were fasted.

  69. t1/2 of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Fed State in Healthy Participants (Group A - Cohort 4a) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  70. t1/2 of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Healthy Participants (Group A - Cohort 6a) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  71. t1/2 of M6 After Single Dose of Uprifosbuvir as the Capsule Formulation in Genotype 1, HCV-Infected Participants (Group B) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  72. t1/2 of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Capsule Formulation in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  73. t1/2 of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants (Group C) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  74. t1/2 of M6 After Single Dose of Uprifosbuvir as Capsule Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 1e) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  75. t1/2 of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as Capsule or Tablet Formulation in Genotype 1, HCV-Infected Participants With Mildly Impaired Hepatic Function (Child Pugh Class A) (Group E - Cohort 2e and Cohort 3e) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  76. t1/2 of M6 After Multiple Doses of Uprifosbuvir Once-Daily x 7 Days as the Tablet Formulation in Genotype 1, HCV-Infected Participants, With Itraconazole (Group F) [ Time Frame: Days 1 & 7: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.

  77. Cumulative Urine Excretion of Unchanged Uprifosbuvir in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Cumulative urine excretion of unchanged MK-3682 in healthy participants was obtained. All participants were fasted.

  78. Cumulative Urine Excretion of Unchanged M6 in Healthy Participants (Group A) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours postdose ]
    Cumulative urine excretion of unchanged M6 in healthy participants was obtained. All participants were fasted.

  79. Reduction in HCV RNA From Baseline on Day 8 Following Uprifosbuvir 50-450 mg for 7 Days in Genotype 1, 2 and 3, HCV-Infected Participants (Groups C and D) [ Time Frame: Baseline and Day 8 ]
    Reduction in HCV RNA from baseline on Day 8 following uprifosbuvir 50-450 mg for 7 Days in Genotype 1, 2 and 3, HCV-infected participants was obtained.

  80. Maximum Reduction in log10 HCV RNA From Baseline - Normal Participants (From Groups B and C) vs. Mild Hepatic Impairment Participants (Group E) [ Time Frame: Baseline and 28 days after last dose of study drug (Up to 42 days) ]
    Reduction in HCV RNA from baseline on Day 8 following uprifosbuvir 50-450 mg for 7 Days in Genotype (Gt) 1, HCV-infected participants was obtained.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

All Participants:

  • of childbearing potential must have agreed to use a double method of birth control (one of which must be a barrier) from Screening through at least 90 days after the last dose of the study drug
  • must not have consumed grapefruit or grapefruit juice within 7 days of Day -1 and throughout the study

HCV Participants:

  • documented clinical history compatible with chronic hepatitis C.
  • have not received direct-acting antiviral treatment for hepatitis C infection
  • has HCV Genotype 1, 2, 3, 4, 5 or 6

Exclusion Criteria:

All Participants:

  • pregnant or breastfeeding
  • co-infected with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV).
  • decompensated liver disease
  • other clinically significant medical conditions or laboratory abnormalities.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01974687


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01974687     History of Changes
Other Study ID Numbers: 3682-001
U1111-1149-5611 ( Other Identifier: Universal Trial Number (UTN) )
IDX-04B-001 ( Other Identifier: Idenix Protocol Number )
2013-004043-23 ( EudraCT Number )
MK-3682-001 ( Other Identifier: Merck Protocol Number )
First Posted: November 1, 2013    Key Record Dates
Results First Posted: September 13, 2018
Last Update Posted: September 13, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
Hepatitis C virus
HCV

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Itraconazole
Hydroxyitraconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors