Hepatitis C Virus Infection
Conditions
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.
Interventions
DRUG200 mg MK-1075
Two 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
DRUG400 mg MK-1075
Four 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
DRUG800 mg MK-1075
Eight 100 mg tablets of MK-1075 administered orally, once daily for 7 consecutive days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | 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. |
| Number of Participants Who Discontinued Treatment Due to an AE | 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. |
| Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 | 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
| Measure | Time frame | Description |
|---|---|---|
| AUC 0-last of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 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. |
| 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 | 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. |
| C24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 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). |
| Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-1075 Following Multiple Dose Oral Administration of MK-1075 | 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). |
| AUC 0-24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 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. |
| 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 | 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. |
Participant flow
Recruitment details
Males or females of non-child bearing potential with verified Genotype 1 (GT1) or Genotype 3 (GT3) Hepatitis C Virus (HCV) infection, between the ages of 18 and 65 years (inclusive) were enrolled in this trial.
Pre-assignment details
GT1 and GT3 participants planned to receive 200 mg MK-1075 were not treated based on available data from previous studies.
Participants by arm
| Arm | Count |
|---|---|
| GT1 400 mg MK-1075 Fasted GT1 participants were administered 400 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days | 3 |
| GT1 MK-1075 600 mg Fasted GT1 participants were administered 600 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days | 3 |
| GT3 400 mg MK-1075 Fasted GT3 participants were administered 400 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days | 3 |
| GT3 600 mg MK-1075 Fasted GT3 participants were administered 600 mg MK-1075 in tablet form, orally, once daily for 7 consecutive days | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | GT1 400 mg MK-1075 | GT1 MK-1075 600 mg | GT3 400 mg MK-1075 | GT3 600 mg MK-1075 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.3 Years STANDARD_DEVIATION 9.3 | 39.7 Years STANDARD_DEVIATION 11 | 39.0 Years STANDARD_DEVIATION 3 | 46.0 Years STANDARD_DEVIATION 7 | 41.0 Years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 2 / 6 | 3 / 3 | 2 / 3 | 3 / 3 | 2 / 3 | 1 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075
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.
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
Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol deviations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 400 mg MK-1075 | Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 | 3.465 log10 IU/mL |
| GT1 MK-1075 600 mg | Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 | 4.122 log10 IU/mL |
| GT3 400 mg MK-1075 | Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 | 4.071 log10 IU/mL |
| GT3 600 mg MK-1075 | Change From Baseline in Maximum log10 HCV RNA Following Multiple Dose Oral Administration of MK-1075 | 5.132 log10 IU/mL |
Primary
Number of Participants Who Discontinued Treatment Due to an AE
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.
Time frame: Up to Day 7
Population: Participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GT1 400 mg MK-1075 | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| GT1 MK-1075 600 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| GT3 400 mg MK-1075 | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| GT3 600 mg MK-1075 | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
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.
Time frame: Up to Day 42
Population: Participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GT1 400 mg MK-1075 | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| GT1 MK-1075 600 mg | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
| GT3 400 mg MK-1075 | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| GT3 600 mg MK-1075 | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
Secondary
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
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.
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
Population: AUC 0-24hr were not determined because concentrations of MK-1075 at 24 hour were not quantifiable
Secondary
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
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.
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
Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GT1 400 mg MK-1075 | 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 | 1.1 hr*μmol/L | Geometric Coefficient of Variation 41.3 |
| GT1 MK-1075 600 mg | 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 | 0.89 hr*μmol/L | Geometric Coefficient of Variation 54.2 |
Secondary
AUC 0-24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075
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.
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
Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GT1 400 mg MK-1075 | AUC 0-24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 35.3 hr*μmol/L | Geometric Coefficient of Variation 12.9 |
| GT1 MK-1075 600 mg | AUC 0-24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 51.2 hr*μmol/L | Geometric Coefficient of Variation 12 |
Secondary
AUC 0-last of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075
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.
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
Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GT1 400 mg MK-1075 | AUC 0-last of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 62.2 hr*μmol/L | Geometric Coefficient of Variation 29.6 |
| GT1 MK-1075 600 mg | AUC 0-last of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 90.6 hr*μmol/L | Geometric Coefficient of Variation 20.9 |
Secondary
C24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075
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).
Time frame: Day 7 at 24 hours postdose
Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GT1 400 mg MK-1075 | C24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 0.561 μmol/L | Geometric Coefficient of Variation 39.9 |
| GT1 MK-1075 600 mg | C24hr of Metabolite M1 Following Multiple Dose Oral Administration of MK-1075 | 0.947 μmol/L | Geometric Coefficient of Variation 25.8 |
Secondary
Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-1075 Following Multiple Dose Oral Administration of MK-1075
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).
Time frame: Day 7 at 24 hours postdose
Population: C24hr were not determined because concentrations of MK-1075 at 24 hour were not quantifiable.