Hepatitis C Infection
Conditions
Brief summary
This is a 3-part study of Ruzasvir (MK-8408) for participants with hepatitis C infection. Successive participants will be enrolled as dose levels are evaluated to find the maximum safe and well tolerated dose of Ruzasvir. Part I will be for participants with hepatitis C virus (HCV) genotype 3 (GT3) and will run first: Part II will be for participants with HCV genotype 1a (GT1a), and Part III will be for participants with HCV genotype 2b (GT2b). Parts II and III may run concurrently. The primary study hypothesis is that a safe and tolerable dose of Ruzasvir that reduces viral load will be found to support further clinical investigation.
Interventions
DRUGRuzasvir
Ruzasvir capsules, orally, starting at a dose of 60 mg once per day (QD) x 5 days with doses increasing or decreasing as clinically indicated.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) \>=18 to\<=37 kg/m\^2 * In general good health, except for HCV infection * Clinical diagnosis of chronic HCV infection exclusively GT3 (Panels A-D) or exclusively GT1a (Panels E-F), or exclusively GT2b (Panels G-H). * Must agree to follow the smoking restrictions defined by the CRU * Must agree to use an acceptable method of contraception during the study and for 90 days after the last dose of ruzasvir
Exclusion criteria
* Clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases * History of clinically significant hepatic disease, Gilbert's disease or biliary tract disease * History of cancer (malignancy) with the exception of adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix, or successfully-treated malignancies ≥10 years prior to screening * History of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food * Positive for hepatitis B or human immunodeficiency virus (HIV) * Major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to screening * Participated in another investigational trial within 4 weeks prior to the screening visit * QTc interval \>=470 msec (for males) or \>= 480 msec (for females) * Unable to refrain from or anticipates use of any medication (prescription and/or non-prescription) or herbal remedies beginning approximately 2 weeks prior to first study drug dose, throughout the trial until the post-trial visit * Consumes \>2 glasses of alcoholic beverages per day * Regular user (including recreational use) of any illicit drugs or history of drug (including alcohol) abuse within approximately 12 months * Evidence or history of chronic hepatitis not caused by HCV * Previous treatment with other HCV NS5A inhibitors such as MK-8742, daclatasvir, or MK-8325 * Treatment with other HCV therapies such as the HCV protease * Evidence of advanced or decompensated liver disease; evidence of bridging fibrosis or higher grade fibrosis (Metavir score \>=3)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | Baseline and up to Day 5 | Blood was collected at baseline and on Days 1, 2, 3, 4 and 5 to determine HCV RNA levels. Least squares means (LSM) and confidence intervals (CI) were obtained from an analysis of variance (ANOVA) model with maximum log10 HCV RNA change from baseline as response and a fixed effect for treatment. The primary hypothesis was that the mean change from baseline would be a reduction of ≥3 log10. A positive change from baseline indicates a reduction from baseline in log10 HCV RNA. |
| Number of Participants Who Experienced One or More Adverse Events (AEs) | Up to 61 days | An adverse event (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 Study Drug Due To An AE | Up to 5 days | 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. |
Participant flow
Recruitment details
Males or females of non-child bearing potential, with verified Hepatitis C virus (HCV) infection with genotype (GT) GT1a, GT2b or GT3 between the ages of 18 and 65 years (inclusive) were enrolled in this trial. In the GT1a group, one participant was later determined to be GT1b.
Participants by arm
| Arm | Count |
|---|---|
| Ruzasvir 10 mg - GT3 GT3 participants were administered 10 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 30 mg - GT3 GT3 participants were administered 30 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 60 mg - GT3 GT3 participants were administered 60 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 120 mg - GT3 GT3 participants were administered 120 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 10 mg - GT2b GT2b participants were administered 10 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 60 mg - GT2b GT2b participants were administered 60 mg Ruzasvir in capsule form, orally, once per day for 5 days. | 3 |
| Ruzasvir 60 mg - GT1a GT1a participants were administered 60 mg Ruzasvir in capsule form, orally, once per day for 5 days. One participant was later determined to be GT1b. | 4 |
| Total | 22 |
Baseline characteristics
| Characteristic | Ruzasvir 10 mg - GT3 | Ruzasvir 30 mg - GT3 | Ruzasvir 60 mg - GT3 | Ruzasvir 120 mg - GT3 | Ruzasvir 10 mg - GT2b | Ruzasvir 60 mg - GT2b | Ruzasvir 60 mg - GT1a | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.7 Years STANDARD_DEVIATION 6.5 | 36.0 Years STANDARD_DEVIATION 3.5 | 38.0 Years STANDARD_DEVIATION 10.4 | 40.7 Years STANDARD_DEVIATION 13.6 | 56.3 Years STANDARD_DEVIATION 2.1 | 54.0 Years STANDARD_DEVIATION 6.2 | 48.5 Years STANDARD_DEVIATION 6.2 | 45.0 Years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 19 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 2 / 3 | 1 / 3 | 2 / 3 | 2 / 3 | 2 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline
Blood was collected at baseline and on Days 1, 2, 3, 4 and 5 to determine HCV RNA levels. Least squares means (LSM) and confidence intervals (CI) were obtained from an analysis of variance (ANOVA) model with maximum log10 HCV RNA change from baseline as response and a fixed effect for treatment. The primary hypothesis was that the mean change from baseline would be a reduction of ≥3 log10. A positive change from baseline indicates a reduction from baseline in log10 HCV RNA.
Time frame: Baseline and up to Day 5
Population: Participants who complied with the protocol sufficiently to ensure that generated data would exhibit the effects of treatment, according to the underlying scientific model. Compliance covers considerations such as exposure to treatment, availability of measurements and absence of major protocol violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ruzasvir 10 mg - GT3 | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 2.84 log10 IU/mL |
| Ruzasvir 30 mg - GT3 | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.03 log10 IU/mL |
| Ruzasvir 60 mg - GT3 | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.36 log10 IU/mL |
| Ruzasvir 120 mg - GT3 | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 1.81 log10 IU/mL |
| Ruzasvir 10 mg - GT2b | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.82 log10 IU/mL |
| Ruzasvir 60 mg - GT2b | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.62 log10 IU/mL |
| Ruzasvir 60 mg - GT1a | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.63 log10 IU/mL |
| Ruzasvir 60 mg - GT1b | Maximum log10 HCV Ribonucleic Acid (RNA) Change From Baseline | 3.82 log10 IU/mL |
Primary
Number of Participants Who Discontinued Study Drug 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 5 days
Population: All participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ruzasvir 10 mg - GT3 | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 30 mg - GT3 | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 60 mg - GT3 | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 120 mg - GT3 | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 10 mg - GT2b | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 60 mg - GT2b | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
| Ruzasvir 60 mg - GT1a | Number of Participants Who Discontinued Study Drug Due To An AE | 0 Participants |
Primary
Number of Participants Who Experienced One or More Adverse Events (AEs)
An adverse event (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 61 days
Population: All participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ruzasvir 10 mg - GT3 | Number of Participants Who Experienced One or More Adverse Events (AEs) | 0 Participants |
| Ruzasvir 30 mg - GT3 | Number of Participants Who Experienced One or More Adverse Events (AEs) | 0 Participants |
| Ruzasvir 60 mg - GT3 | Number of Participants Who Experienced One or More Adverse Events (AEs) | 2 Participants |
| Ruzasvir 120 mg - GT3 | Number of Participants Who Experienced One or More Adverse Events (AEs) | 1 Participants |
| Ruzasvir 10 mg - GT2b | Number of Participants Who Experienced One or More Adverse Events (AEs) | 2 Participants |
| Ruzasvir 60 mg - GT2b | Number of Participants Who Experienced One or More Adverse Events (AEs) | 2 Participants |
| Ruzasvir 60 mg - GT1a | Number of Participants Who Experienced One or More Adverse Events (AEs) | 2 Participants |