Chronic Hepatitis C Virus
Conditions
Brief summary
This was an efficacy and safety study of grazoprevir (MK-5172) in combination with elbasvir (MK-8742) in treatment-naive participants with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, or 6 infection. Participants were randomly assigned (3:1 ratio) to immediate treatment or deferred treatment (placebo control). The primary efficacy hypothesis was that the proportion of participants receiving combination therapy in the Immediate Treatment Arm who achieve sustained viral response at 12 weeks after the end of study treatment (SVR12) is superior to 73%.
Interventions
DRUGGrazoprevir 100mg / Elbasvir 50 mg FDC
DRUGPlacebo to Grazoprevir / Elbasvir 50 mg FDC
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
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-typeable or mixed genotype infection (positive for anti-HCV antibody, HCV RNA, or any of the listed GTs at least 6 months prior to screening must be confirmed by screening lab results) * Cirrhosis defined by: liver biopsy showing cirrhosis METAVIR F4; or Fibroscan showing cirrhosis with a result of \>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 by: liver biopsy showing absence of cirrhosis, or Fibroscan with a result of ≤12.5 kPa, or Fibrosure® (Fibrotest®) score of \<= 0.48 and APRI of \<=1 * HCV treatment status of treatment naïve (naïve to all anti-HCV treatment) and can also be ineligible to take pegylated interferon * Female participant not of reproductive potential, or female of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug (using abstinence or acceptable methods 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 cirrhotics, participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score \>6 * Co-infection with hepatitis B virus or human immunodeficiency virus (HIV) * History of malignancy \<=5 years prior to signing informed consent 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 * Evidence of hepatocellular carcinoma (HCC) or under evaluation for HCC * 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 of screening * Pregnant, breast-feeding, or expecting to conceive or donate eggs from Day 1 throughout treatment and 14 days after the last dose of study medication or longer if dictated by local regulations * 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 disorder (e.g., celiac sprue disease) * Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the course of the trial * Evidence of 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 Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | Week 24 (12 weeks after the end of treatment) | Hepatitis C Virus (HCV) ribonucleic acid (RNA) was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR12 was defined as HCV RNA \<Lower Limit of Quantification (\<15 IU/mL) 12 weeks after the end of all study therapy. |
| Percentage of Participants Experiencing at Least One Adverse Event | Up to Week 14 (14 days after the Blinded Treatment was completed) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
| Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event | Up to Week 12 (end of Blinded Treatment) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response at 24 Weeks After the End of Treatment (SVR24) | Week 36 (24 weeks after the end of treatment) | Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR24 was defined as HCV RNA \<Lower Limit of Quantitation (\<15 IU/mL) 24 weeks after the end of all study therapy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response at 4 Weeks After the End of Treatment (SVR4) | Week 16 (4 weeks after the end of treatment) | Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR4 was defined as HCV RNA \<Lower Limit of Quantitation (\<15 IU/mL) 4 weeks after the end of all study therapy. |
Participant flow
Recruitment details
For Subject Disposition, Period 1 covers Day 1 through Week 12 for both treatment groups. Period 2 covers Week 12 through Week 36 for the Immediate Treatment Group (ITG) and Week 12 through Week 28 for the Deferred Treatment Group (DTG). Period 3 covers Week 28 through Week 52 for the DTG; the ITG completed the study with Period 2.
Pre-assignment details
A total of 469 participants were screened and 421 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment Group Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period | 316 |
| Deferred Treatment Group Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks. | 105 |
| Total | 421 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Death | 1 | 0 |
| Period 1 | Lost to Follow-up | 1 | 0 |
| Period 2 | Death | 1 | 0 |
| Period 2 | Lost to Follow-up | 1 | 0 |
| Period 2 | Withdrawal by Subject | 0 | 2 |
| Period 3 | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Immediate Treatment Group | Deferred Treatment Group | Total |
|---|---|---|---|
| Age, Continuous | 52.2 Years STANDARD_DEVIATION 11.1 | 53.8 Years STANDARD_DEVIATION 11.2 | 52.6 Years STANDARD_DEVIATION 11.2 |
| HCV Genotype Genotype 1a | 157 Participants | 54 Participants | 211 Participants |
| HCV Genotype Genotype 1b | 131 Participants | 40 Participants | 171 Participants |
| HCV Genotype Genotype 4 | 18 Participants | 8 Participants | 26 Participants |
| HCV Genotype Genotype 6 | 10 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Female | 145 Participants | 49 Participants | 194 Participants |
| Sex: Female, Male Male | 171 Participants | 56 Participants | 227 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 147 / 316 | 60 / 105 | 42 / 103 |
| serious Total, serious adverse events | 15 / 316 | 4 / 105 | 3 / 103 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12)
Hepatitis C Virus (HCV) ribonucleic acid (RNA) was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR12 was defined as HCV RNA \<Lower Limit of Quantification (\<15 IU/mL) 12 weeks after the end of all study therapy.
Time frame: Week 24 (12 weeks after the end of treatment)
Population: The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | 94.6 Percentage of participants |
Comparison: Superiority of SVR12 in the Immediate Treatment group was tested against the historical response rate of 73%.p-value: <0.001One-sided, one-sample exact test
Primary
Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event
An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: Up to Week 12 (end of Blinded Treatment)
Population: The All Subjects as Treated population included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the blinded treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event | 0.9 Percentage of participants |
| Deferred Treatment Group | Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event | 1.0 Percentage of participants |
95% CI: [-4.4, 2]
Primary
Percentage of Participants Experiencing at Least One Adverse Event
An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: Up to Week 14 (14 days after the Blinded Treatment was completed)
Population: The All Subjects as Treated population included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the blinded treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Percentage of Participants Experiencing at Least One Adverse Event | 67.4 Percentage of participants |
| Deferred Treatment Group | Percentage of Participants Experiencing at Least One Adverse Event | 68.6 Percentage of participants |
95% CI: [-10.8, 9.6]
Secondary
Percentage of Participants Achieving Sustained Virologic Response at 24 Weeks After the End of Treatment (SVR24)
Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR24 was defined as HCV RNA \<Lower Limit of Quantitation (\<15 IU/mL) 24 weeks after the end of all study therapy.
Time frame: Week 36 (24 weeks after the end of treatment)
Population: The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Percentage of Participants Achieving Sustained Virologic Response at 24 Weeks After the End of Treatment (SVR24) | 94.3 Percentage of participants |
Other Pre-specified
Percentage of Participants Achieving Sustained Virologic Response at 4 Weeks After the End of Treatment (SVR4)
Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR4 was defined as HCV RNA \<Lower Limit of Quantitation (\<15 IU/mL) 4 weeks after the end of all study therapy.
Time frame: Week 16 (4 weeks after the end of treatment)
Population: The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Percentage of Participants Achieving Sustained Virologic Response at 4 Weeks After the End of Treatment (SVR4) | 97.2 Percentage of participants |