Chronic Hepatitis C
Conditions
Brief summary
This study is being done to evaluate the efficacy and safety of the drug combination grazoprevir (GZR; MK-5172) + elbasvir (EBR; MK-8742) in participants with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, or 6 infection and who have cirrhosis and Child-Pugh (CP) score 7-9 moderate hepatic insufficiency (CP-B). The primary hypothesis is that the percentage of HCV-infected participants with hepatic insufficiency (the CP-B population) achieving sustained viral response (SVR) 12 weeks after the end of all treatment (SVR12) will be greater than 60%. Additionally, ten non-cirrhotic (NC) HCV-infected GT1 participants will also be given GZR + EBR at the beginning of the study; this will be done for the purpose of collecting plasma pharmacokinetic (PK) data in HCV GT1-infected participants who do not have hepatic insufficiency.
Detailed description
The study will be conducted sequentially in 3 Parts. Each participant will participate in only one Part. Participants will be enrolled in either Part A, Part B, or Part C: * Part A: CP-B participants will receive GZR 50 mg+ EBR 50 mg; NC participants will receive GZR 100 mg/EBR 50 mg. * Part B: CP-B participants will receive GZR 100 mg + EBR 50 mg. * Part C: CP-B participants will receive either GZR 50 mg or 100 mg + EBR 50 mg. Study progression from Part A to Part B and from Part B to Part C will be based upon a review of safety and efficacy in Parts A and B, respectively. Depending upon safety and efficacy in Part A, the study may progress directly from Part A to Part C using GZR 50 mg + EBR 50 mg, without performing Part B.
Interventions
DRUGGrazoprevir
GZR was supplied as two 25 mg tablets in the Part A CP-B arm, or as either one GZR 100 mg tablet or one fixed-dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg in a single tablet (MK-5172A) in the Part A NC arm. GZR was taken q.d. by mouth.
DRUGElbasvir
EBR was supplied as 50 mg tablets and was taken q.d. by mouth.
DRUGMK-5172A
MK-5172A FDC tablet containing GZR 100 mg + EBR 50 mg taken q.d. by mouth.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Has documented chronic HCV GT1 infection (for Arm 4 participants may have GT4 or GT6 infection) with no evidence of non-typable or mixed genotype infection * Has clinical evidence of hepatic cirrhosis with a score on the Child-Pugh scale from 7 to 9 and not anticipated to receive a liver transplant within the next 36 weeks (for Arm 1, Arm 3, and Arm 4) * Has no evidence of cirrhosis (only for Arm 2 ) * Agrees to remain truly abstinent or use (or have their partner use) an acceptable method of birth control from at least 2 weeks prior to Day 1 and continue until at least 14 days after last dose of study drug, or longer if dictated by local regulations
Exclusion criteria
* Is co-infected with hepatitis B virus or human immunodeficiency virus (HIV) * Has previously received direct-acting antiviral therapy for HCV * Has a 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 under evaluation for other active or suspected malignancy * Has cirrhosis and liver imaging results within 4 weeks prior to screening showing evidence of hepatocellular carcinoma (HCC), or is under evaluation for HCC * Is 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 * Has clinically-relevant drug or alcohol abuse within 12 months of screening * Is pregnant or breast-feeding, or expecting to conceive or donate eggs or sperm from at least 2 weeks prior to Day 1 and continue throughout treatment and follow up, or longer if dictated by local regulations * Has received organ transplants (including hematopoietic stem cell transplants) other than cornea and hair * Has poor venous access * Has a history of gastric surgery (e.g., stapling, bypass) or history of malabsorption disorders (e.g., celiac sprue disease) * Requires, or likely to require, chronic systemic administration of corticosteroids during the course of the trial * Has 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 Sustained Viral Response 12 Weeks After Completing Study Therapy (SVR12) | Week 24 | SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) levels below the lower limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. |
| Number of Participants Experiencing an Adverse Event (AE) During Treatment and First 14 Follow-up Days | 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 Discontinuing Study Drug Due to an AE | Up to 12 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Viral Response 4 Weeks After Completing Study Therapy (SVR4) | Week 16 | SVR4 was defined as HCV RNA levels \<LLoQ 4 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. |
| Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants | Baseline and Weeks 12, 24, and 36 | The MELD score provides an objective and granular assessment of liver improvement as a continuous variable. The calculation of MELD score is based on three biochemical variables (serum bilirubin, creatinine and international normalized ratio \[INR\] of prothrombin time). The MELD equation is as follows: 9.57 x ln(creatinine mg/dL) +3.78 x ln(bilirubin mg/dL) +11.2 x ln (INR) + 6.43. Scores are multiplied by 10 and rounded to the nearest whole number and range from 6 (less ill) to 40 (gravely ill). MELD scores were determined at Baseline (Day 1) and again at Week 12, Follow-up (FU) Week 12 (Week 24), and FU Week 24 (Week 36). Change from baseline in MELD score = Post-baseline MELD score - baseline MELD score. |
| Percentage of Participants Achieving Sustained Viral Response 24 Weeks After Completing Study Therapy (SVR24) | Week 36 | SVR24 was defined as HCV RNA levels \<LLoQ 24 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. |
| Percentage of Participants With HCV RNA Undetectable at Weeks 2, 4, and 12 | Week 2, 4, and 12 | HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. |
| Percentage of Participants With HCV RNA <LLoQ at Weeks 2, 4, and 12 | Weeks 2, 4, and 12 | HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. |
Participant flow
Recruitment details
The screening period lasted for 60 days. Recruitment was halted after enrolling participants in the two Part A arms, as the current clinical development plan is focused on a fixed-dose combination (FDC) product containing grazoprevir (GZR) 100 mg and elbasvir (EBR) 50 mg. No participants were enrolled in Parts B or C.
Participants by arm
| Arm | Count |
|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg CP-B participants take GZR 50 mg + EBR 50 mg q.d. by mouth for 12 weeks. | 30 |
| Part A: NC GZR 100 mg + ER 50 mg NC participants take GZR 100 mg + EBR 50 mg q.d. by mouth for 12 weeks. | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: CP-B GZR 50 mg + EBR 50 mg | Part A: NC GZR 100 mg + ER 50 mg | Total |
|---|---|---|---|
| Age, Continuous | 58.3 Years STANDARD_DEVIATION 7 | 60.4 Years STANDARD_DEVIATION 5.3 | 58.8 Years STANDARD_DEVIATION 6.6 |
| Sex: Female, Male Female | 13 Participants | 5 Participants | 18 Participants |
| Sex: Female, Male Male | 17 Participants | 5 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 30 | 8 / 10 |
| serious Total, serious adverse events | 5 / 30 | 0 / 10 |
Outcome results
Primary
Number of Participants Discontinuing Study Drug 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 12 weeks
Population: The APaT population consisted of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Number of Participants Discontinuing Study Drug Due to an AE | 0 Number of participants |
| Part A: NC GZR 100 mg + ER 50 mg | Number of Participants Discontinuing Study Drug Due to an AE | 0 Number of participants |
Primary
Number of Participants Experiencing an Adverse Event (AE) During Treatment and First 14 Follow-up Days
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: The All Participants as Treated (APaT) population consisted of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Number of Participants Experiencing an Adverse Event (AE) During Treatment and First 14 Follow-up Days | 25 Number of participants |
| Part A: NC GZR 100 mg + ER 50 mg | Number of Participants Experiencing an Adverse Event (AE) During Treatment and First 14 Follow-up Days | 8 Number of participants |
Primary
Percentage of Participants Achieving Sustained Viral Response 12 Weeks After Completing Study Therapy (SVR12)
SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) levels below the lower limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL.
Time frame: Week 24
Population: The Full Analysis Set (FAS) consists of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Percentage of Participants Achieving Sustained Viral Response 12 Weeks After Completing Study Therapy (SVR12) | 90.0 Percentage of participants |
| Part A: NC GZR 100 mg + ER 50 mg | Percentage of Participants Achieving Sustained Viral Response 12 Weeks After Completing Study Therapy (SVR12) | 100.0 Percentage of participants |
Secondary
Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants
The MELD score provides an objective and granular assessment of liver improvement as a continuous variable. The calculation of MELD score is based on three biochemical variables (serum bilirubin, creatinine and international normalized ratio \[INR\] of prothrombin time). The MELD equation is as follows: 9.57 x ln(creatinine mg/dL) +3.78 x ln(bilirubin mg/dL) +11.2 x ln (INR) + 6.43. Scores are multiplied by 10 and rounded to the nearest whole number and range from 6 (less ill) to 40 (gravely ill). MELD scores were determined at Baseline (Day 1) and again at Week 12, Follow-up (FU) Week 12 (Week 24), and FU Week 24 (Week 36). Change from baseline in MELD score = Post-baseline MELD score - baseline MELD score.
Time frame: Baseline and Weeks 12, 24, and 36
Population: All CP-B participants in the FAS (all randomized participants who received at least one dose of study medication) with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants | Week 12 (n=30) | -0.67 Units on a scale | Standard Deviation 1.35 |
| Part A: CP-B GZR 50 mg + EBR 50 mg | Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants | FU Week 12 (Week 24) [n=29] | -0.38 Units on a scale | Standard Deviation 1.74 |
| Part A: CP-B GZR 50 mg + EBR 50 mg | Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants | FU Week 24 (Week 36) [n=29] | -0.34 Units on a scale | Standard Deviation 3.15 |
Secondary
Percentage of Participants Achieving Sustained Viral Response 24 Weeks After Completing Study Therapy (SVR24)
SVR24 was defined as HCV RNA levels \<LLoQ 24 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL.
Time frame: Week 36
Population: The FAS consists of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Percentage of Participants Achieving Sustained Viral Response 24 Weeks After Completing Study Therapy (SVR24) | 90.0 Percentage of participants |
| Part A: NC GZR 100 mg + ER 50 mg | Percentage of Participants Achieving Sustained Viral Response 24 Weeks After Completing Study Therapy (SVR24) | 100.0 Percentage of participants |
Secondary
Percentage of Participants Achieving Sustained Viral Response 4 Weeks After Completing Study Therapy (SVR4)
SVR4 was defined as HCV RNA levels \<LLoQ 4 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL.
Time frame: Week 16
Population: The FAS consists of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CP-B GZR 50 mg + EBR 50 mg | Percentage of Participants Achieving Sustained Viral Response 4 Weeks After Completing Study Therapy (SVR4) | 93.3 Percentage of participants |
| Part A: NC GZR 100 mg + ER 50 mg | Percentage of Participants Achieving Sustained Viral Response 4 Weeks After Completing Study Therapy (SVR4) | 100.0 Percentage of participants |
Secondary
Percentage of Participants With HCV RNA <LLoQ at Weeks 2, 4, and 12
HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL.
Time frame: Weeks 2, 4, and 12
Population: Per protocol, this measure was to be determined in Arm 4 (Part C); however, enrollment was halted after Part A and thus no data are available.
Secondary
Percentage of Participants With HCV RNA Undetectable at Weeks 2, 4, and 12
HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL.
Time frame: Week 2, 4, and 12
Population: Per protocol, this measure was to be determined in Arm 4 (Part C); however, enrollment was halted after Part A and thus no data are available.