Hepatitis C Infection
Conditions
Brief summary
This is an efficacy and safety study of grazoprevir (MK-5172) in combination with elbasvir (MK-8742) with or without ribavirin (RBV) in participants with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, or 6 infections who have failed prior therapy with pegylated interferon and RBV. The primary study hypothesis is that in at least one of the study arms, the percentage of participants achieving sustained viral response 12 weeks after the end of all study treatment (SVR12) will be superior to 58%.
Interventions
FDC tablet containing grazoprevir 100 mg and elbasvir 50 mg.
DRUGRibavirin
200 mg capsule
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
* Documented chronic HCV GT1, GT4, or GT6 with no evidence of non-typable or mixed genotype infection (positive for anti-HCV antibody, HCV ribonucleic acid \[RNA\], or any of the listed GTs at least 6 months prior to screening must be confirmed by screening lab results) * Cirrhosis defined as liver biopsy showing METAVIR F4; or Fibroscan showing result \>12.5 kilopascals (kPa); or FibroSure® (Fibrotest®) score of \>0.75 and an aspartate aminotransferase (AST):platelet ratio index (APRI) of \>2 * Absence of cirrhosis defined as liver biopsy showing absence of cirrhosis; or Fibroscan result of ≤ 12.5 kPa; or Fibrosure® (Fibrotest®) score of ≤ 0.48 and APRI ≤ 1 * Previous HCV treatment status of peginterferon/RBV Null responder; or peginterferon/RBV Partial responder; or peginterferon/RBV Treatment Relapse * For human immunodeficiency virus (HIV) co-infected participants: documented HIV-1 infection; currently naïve to treatment with any antiretroviral therapy (ART) and have no plans to initiate ART treatment while participating in this study; or be on HIV ART for at least 8 weeks prior to study entry (dual nucleoside reverse transcriptase inhibitor \[NRTI\] backbone of tenofovir or abacavir and either emtricitabine or lamivudine plus raltegravir (or dolutegravir or rilpivirine) (no changes in HIV regimen allowed within 4 weeks of randomization); cluster of differentiation 4 (CD4)+ T-cell count \>200 cells/mm\^3 at screening; documented undetectable plasma HIV-1 RNA at least 8 weeks prior to screening; participants not on ART, HIV RNA must be \<50,000 copies/mL; must have at least one viable antiretroviral regimen alternative beyond their current regimen in the event of HIV virologic failure and the development of antiretroviral drug resistance * Agree to use two acceptable methods of birth control from at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations; a male participant who is not (or whose partner is not) of reproductive potential is eligible without requiring the use of contraception
Exclusion criteria
* 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 advanced liver disease * For participants with cirrhosis, participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score \>6, must be excluded * Co-infected with hepatitis B virus * Has had previous direct-acting antiviral treatment * History of malignancy \<=5 years prior except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy * Has cirrhosis and liver imaging showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC * Taking or plans to take any HIV therapy that includes a ritonavir-boosted or unboosted protease inhibitor, efavirenz or etravirine * 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 * Clinically-relevant drug or alcohol abuse within 12 months * Pregnant, breast-feeding, or expecting to conceive or donate eggs or sperm from Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations; or is a male whose female partner(s) is/are pregnant * History of organ transplant (including hematopoietic stem cell transplants) other than cornea and hair * Poor venous access * History of gastric surgery (e.g., stapling, bypass) or history of malabsorption disorders (e.g., celiac sprue disease) * Hemoglobinopathy, including, but not limited to, thalassemia major * Any medical condition requiring, or likely to require, chronic systemic corticosteroids, tumor necrosis factor (TNF) antagonists, or other immunosuppressant drugs during the course of the trial * For participants with HIV, history of opportunistic infection in the preceding 6 months * For participants with HIV, use of HIV drugs other than a dual NRTI backbone of tenofovir or abacavir and either emtricitabine or lamivudine plus raltegravir (or dolutegravir or rilpivirine) * Evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12) | 12 weeks after the end of all study treatment (up to 28 weeks) | HCV RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. |
| Number of Participants Experiencing Adverse Events (AE) | Up to 18 weeks | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants Discontinuing Study Treatment Due to an AE | Up to 16 weeks | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 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 Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24) | 24 weeks after the end of all study treatment (up to 40 weeks) | HCV RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Grazoprevir + Elbasvir 12 Weeks Participants received grazoprevir 100 mg/elbasvir 50 mg FDC tablets q.d. by mouth for 12 weeks. | 105 |
| Grazoprevir + Elbasvir + RBV 12 Weeks Participants received grazoprevir 100 mg/elbasvir 50 mg FDC tablets q.d. by mouth, along with RBV capsules b.i.d. by mouth (weight-based dosing; 800 to 1400 mg total daily dose), for 12 weeks. | 104 |
| Grazoprevir + Elbasvir 16 Weeks Participants received grazoprevir 100 mg/elbasvir 50 mg FDC tablets q.d. by mouth for 16 weeks. | 105 |
| Grazoprevir + Elbasvir + RBV 16 Weeks Participants received grazoprevir 100 mg/elbasvir 50 mg FDC tablets q.d. by mouth, along with RBV capsules b.i.d. by mouth (weight-based dosing; 800 to 1400 mg total daily dose), for 16 weeks. | 106 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Grazoprevir + Elbasvir 12 Weeks | Grazoprevir + Elbasvir + RBV 12 Weeks | Grazoprevir + Elbasvir 16 Weeks | Grazoprevir + Elbasvir + RBV 16 Weeks | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.71 Years STANDARD_DEVIATION 9.81 | 55.46 Years STANDARD_DEVIATION 8.26 | 54.91 Years STANDARD_DEVIATION 9.79 | 54.98 Years STANDARD_DEVIATION 9.61 | 55.27 Years STANDARD_DEVIATION 9.37 |
| Sex: Female, Male Female | 39 Participants | 32 Participants | 36 Participants | 42 Participants | 149 Participants |
| Sex: Female, Male Male | 66 Participants | 72 Participants | 69 Participants | 64 Participants | 271 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 105 | 72 / 104 | 58 / 105 | 84 / 106 |
| serious Total, serious adverse events | 6 / 105 | 8 / 104 | 4 / 105 | 6 / 106 |
Outcome results
Primary
Number of Participants Discontinuing Study Treatment Due to an AE
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 16 weeks
Population: The All Participants as Treated (APaT) population consists of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir 12 Weeks | Number of Participants Discontinuing Study Treatment Due to an AE | 1 Number of participants |
| Grazoprevir + Elbasvir + RBV 12 Weeks | Number of Participants Discontinuing Study Treatment Due to an AE | 1 Number of participants |
| Grazoprevir + Elbasvir 16 Weeks | Number of Participants Discontinuing Study Treatment Due to an AE | 0 Number of participants |
| Grazoprevir + Elbasvir + RBV 16 Weeks | Number of Participants Discontinuing Study Treatment Due to an AE | 5 Number of participants |
Primary
Number of Participants Experiencing Adverse Events (AE)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 18 weeks
Population: The All Participants as Treated (APaT) population consists of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir 12 Weeks | Number of Participants Experiencing Adverse Events (AE) | 74 Number of participants |
| Grazoprevir + Elbasvir + RBV 12 Weeks | Number of Participants Experiencing Adverse Events (AE) | 85 Number of participants |
| Grazoprevir + Elbasvir 16 Weeks | Number of Participants Experiencing Adverse Events (AE) | 77 Number of participants |
| Grazoprevir + Elbasvir + RBV 16 Weeks | Number of Participants Experiencing Adverse Events (AE) | 95 Number of participants |
Primary
Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12)
HCV RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay.
Time frame: 12 weeks after the end of all study treatment (up to 28 weeks)
Population: The Full Analysis Set (FAS) population consists of all randomized subjects who receive at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir 12 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12) | 92.4 Percentage of participants |
| Grazoprevir + Elbasvir + RBV 12 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12) | 94.2 Percentage of participants |
| Grazoprevir + Elbasvir 16 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12) | 92.4 Percentage of participants |
| Grazoprevir + Elbasvir + RBV 16 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 12 Weeks After Completing Study Therapy (SVR12) | 98.1 Percentage of participants |
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR12 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR12 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR12 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR12 rate \>58%.p-value: <0.001One-sided Exact Test
Secondary
Percentage of Participants Achieving Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24)
HCV RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay.
Time frame: 24 weeks after the end of all study treatment (up to 40 weeks)
Population: The Full Analysis Set (FAS) population consists of all randomized subjects who receive at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir 12 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24) | 91.4 Percentage of participants |
| Grazoprevir + Elbasvir + RBV 12 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24) | 94.2 Percentage of participants |
| Grazoprevir + Elbasvir 16 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24) | 89.5 Percentage of participants |
| Grazoprevir + Elbasvir + RBV 16 Weeks | Percentage of Participants Achieving Undetectable HCV RNA 24 Weeks After the End of All Treatment (SVR24) | 95.3 Percentage of participants |
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR24 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR24 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR24 rate \>58%.p-value: <0.001One-sided Exact Test
Comparison: The hypothesis was that at least 1 treatment arm would have a SVR24 rate \>58%.p-value: <0.001One-sided Exact Test