Hepatitis C Virus (HCV) Infection
Conditions
Brief summary
The purpose of this study was to evaluate the efficacy of 8 and 12 weeks of treatment with a fixed dose combination (FDC) of elbasvir (EBR) 50 mg + grazoprevir (GZR) 100 mg (i.e., MK-5172A) as assessed by the percentage of participants with hepatitis C virus (HCV) genotype (GT) 4 infection that achieve sustained virologic response (HCV ribonucleic acid \[RNA\] \< Lower Limit of Quantification \[LLOQ\]) 12 weeks after the end of study therapy (SVR12). This study also evaluated the safety and tolerability of EBR/GZR.
Interventions
DRUGEBR/GZR (50 mg/100 mg) FDC
One FDC tablet taken once daily by mouth for 8 or 12 weeks depending upon randomization.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Be a current resident of France * Have HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening * Have documented chronic HCV GT4 (with no evidence of non-typeable or mixed genotype) infection * Have liver biopsy performed within 24 months of Day 1 of this study (if participant has cirrhosis, there is no time restriction on biopsy), or have FibroScan® performed within 12 months of Day 1 of this study with interpretable result in kilopascals (kPa) as follows: Fibrosis score of F0-F2, Fibrosis score of F3, or Cirrhosis (F4) * Have a prior treatment history of either HCV TN or HCV TE with interferon (IFN) +/- ribavirin (RBV) +/- Sofosbuvir (SOF) (on-treatment failure, relapser, or other/intolerant) * Females who are of reproductive potential must agree to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have her partner use) acceptable contraception during heterosexual activity * If Human Immunodeficiency Virus (HIV) co-infected, then have HIV-1 infection documented prior to screening
Exclusion criteria
* Had prior treatment (defined as 1 dose or more) with direct-acting antiviral (DAA) therapy * 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 active advanced liver disease * Classified as Child-Pugh B or C or has a Child Pugh-Turcotte score (CPT) \> 6 * Has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC * Hepatitis B virus surface antigen (HBsAg) positive at screening. Participants who are HBsAg negative and hepatitis B core antibody (anti-HBc) positive at screening may be included * Under evaluation for active or suspected malignancy, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer Currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another such study during the course of this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12) | 12 weeks after completing study treatment (Arm 1: Week 20 / Arm 2: Week 24) | The percentage of participants to achieve SVR12 was determined for each arm (SVR12 was defined as HCV ribonucleic acid \[RNA\] \< lower limit of quantification \[LLOQ\] at 12 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL. |
| Number of Participants With ≥ 1 Adverse Events (AEs) | Up to 14 weeks | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants Who Discontinued From Study Treatment Due to an AE | Up to Study Week 12 | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24) | 24 weeks after completing study treatment (Arm 1: Week 32 / Arm 2: Week 36) | The percentage of participants to achieve SVR24 was determined for each arm (SVR24 was defined as HCV RNA \< LLOQ at 24 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL. |
| Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | Day 1 | Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS3 gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a direct-acting antiviral (DAA) and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS3. |
| Prevalence of Baseline NS5A RASs to EBR or GZR | Day 1 | Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS5A gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a DAA and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS5A. |
Countries
France
Participant flow
Recruitment details
Adult male and female participants with chronic hepatitis C virus (HCV) genotype 4 (GT4) infection were enrolled at 12 study centers in France.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: EBR/GZR for 8 Weeks Treatment-naïve HCV GT4 participants with stage 0-2 fibrosis (F0-F2) received EBR/GZR FDC (50 mg/100 mg) for 8 weeks, followed by 24 weeks of follow-up. | 53 |
| Arm 2: EBR/GZR for 12 Weeks Treatment-naïve HCV GT4 participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis received EBR/GZR FDC (50 mg/100 mg) for 12 weeks, followed by 24 weeks of follow-up. | 64 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 2: EBR/GZR for 12 Weeks | Total | Arm 1: EBR/GZR for 8 Weeks |
|---|---|---|---|
| Age, Continuous | 56.0 Years STANDARD_DEVIATION 9.7 | 54.0 Years STANDARD_DEVIATION 11.4 | 51.5 Years STANDARD_DEVIATION 12.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 49 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) White | 29 Participants | 57 Participants | 28 Participants |
| Sex: Female, Male Female | 32 Participants | 61 Participants | 29 Participants |
| Sex: Female, Male Male | 32 Participants | 56 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 1 / 64 |
| other Total, other adverse events | 27 / 53 | 38 / 64 |
| serious Total, serious adverse events | 2 / 53 | 2 / 64 |
Outcome results
Primary
Number of Participants Who Discontinued From Study Treatment Due to an AE
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to Study Week 12
Population: All randomized participants who received ≥1 dose of study treatment are included, classified according to treatment duration actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Number of Participants Who Discontinued From Study Treatment Due to an AE | 0 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Number of Participants Who Discontinued From Study Treatment Due to an AE | 0 Participants |
Primary
Number of Participants With ≥ 1 Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 14 weeks
Population: All randomized participants who received ≥1 dose of study treatment are included, classified according to treatment duration actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Number of Participants With ≥ 1 Adverse Events (AEs) | 33 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Number of Participants With ≥ 1 Adverse Events (AEs) | 46 Participants |
Primary
Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12)
The percentage of participants to achieve SVR12 was determined for each arm (SVR12 was defined as HCV ribonucleic acid \[RNA\] \< lower limit of quantification \[LLOQ\] at 12 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL.
Time frame: 12 weeks after completing study treatment (Arm 1: Week 20 / Arm 2: Week 24)
Population: All randomized participants who received ≥1 dose of study treatment are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12) | 94.3 Percentage of Participants |
| Arm 2: EBR/GZR for 12 Weeks | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12) | 95.3 Percentage of Participants |
Secondary
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24)
The percentage of participants to achieve SVR24 was determined for each arm (SVR24 was defined as HCV RNA \< LLOQ at 24 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL.
Time frame: 24 weeks after completing study treatment (Arm 1: Week 32 / Arm 2: Week 36)
Population: All randomized participants who received ≥1 dose of study treatment are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24) | 94.3 Percentage of Participants |
| Arm 2: EBR/GZR for 12 Weeks | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24) | 93.8 Percentage of Participants |
Secondary
Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR
Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS3 gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a direct-acting antiviral (DAA) and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS3.
Time frame: Day 1
Population: All randomized participants with baseline sequencing data for NS3 are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4 | 5 Participants |
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4D | 3 Participants |
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4-Other | 6 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4 | 6 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4D | 3 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR | GT4-Other | 9 Participants |
Secondary
Prevalence of Baseline NS5A RASs to EBR or GZR
Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS5A gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a DAA and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS5A.
Time frame: Day 1
Population: All randomized participants with baseline sequencing data for NS5A are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4 | 3 Participants |
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4D | 10 Participants |
| Arm 1: EBR/GZR for 8 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4-Other | 13 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4 | 2 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4D | 16 Participants |
| Arm 2: EBR/GZR for 12 Weeks | Prevalence of Baseline NS5A RASs to EBR or GZR | GT4-Other | 21 Participants |