Hepatitis C, Chronic
Conditions
Keywords
hepatitis C
Brief summary
The purpose of this study is to test the safety, tolerability, and efficacy of 4 regimens of Vaniprevir + Peg-IFN and Ribavirin as compared to Placebo (PBO) + Peg-IFN/RBV. The primary hypotheses are that Vaniprevir is well tolerated, and that Vaniprevir 600 mg twice daily (b.i.d.) is superior to the control regimen for the percentage of non-cirrhotic (NC) participants achieving undetectable HCV ribonucleic acid (RNA) 24 weeks after the end of study therapy (SVR24).
Interventions
DRUGVaniprevir
Participants took capsules containing 100 mg Vaniprevir twice daily (b.i.d.), three in the morning (300 mg and 600 mg regimens) and three in the evening (600 mg regimen only), orally, for 24 or 48 weeks.
Participants used prefilled syringe containing 180 µg/0.5 mL Peg-IFN, for weekly subcutaneous injection, for 24 or 48 weeks
DRUGRibavirin (RBV)
Participants took tablets containing 200 mg RBV, 5 or 6 tablet dosage based on the participant's weight, with food, for 24 or 48 weeks. The dose was 1000 mg for participants weighing \<=75 kg and 1200 mg for participants weighing \>75 kg.
DRUGPlacebo (PBO)
Participants took PBO capsules matching Vaniprevir capsules, three in the morning and three in the evening, for 24 or 48 weeks.
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Has chronic HCV genotype 1 infection * Is treatment-experienced * For the non-cirrhotic population, has had a liver biopsy without evidence of cirrhosis and hepatocellular carcinoma; for the cirrhotic population, has had a liver biopsy with evidence of cirrhosis and without evidence of hepatocellular carcinoma.
Exclusion criteria
* Has not tolerated previous course peg-IFN and RBV * Is unlikely to tolerate at least 24 weeks of continuous therapy with Peg-IFN and RBV * Is co-infected with Human Immunodeficiency Virus (HIV) and/or hepatitis B * Consumes excessive amounts of alcohol * Has a history of drug or alcohol abuse * If female, participant is pregnant or breastfeeding * Has been in a clinical trail with an investigational drug in the last 30 days * Has used IFN/Peg-IFN and RBV in the last 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d. | Up to 72 weeks | The percentage of non-cirrhotic participants with undetectable Hepatits C virus (HCV) ribonucleic acid (RNA) 24 weeks after completing treatment was determined for each Vaniprevir 600 mg b.i.d. and control regimen. Results for Vaniprevir 300 mg are presented as a Secondary Outcome Measure. |
| Number of Participants Experiencing an Adverse Event (AE) | Up to 73 weeks | The number of non-cirrhotic participants experiencing AEs during the active Vaniprevir/PBO treatment and 14-day follow-up periods was monitored for each treatment regimen. An AE was defined as any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a Sponsor product, whether or not considered related to the use of the product. |
| Number of Participants Discontinuing From Study Treatment Due to AEs | Up to 48 weeks | The number of non-cirrhotic participants withdrawing from study treatment due to AEs during the active Vaniprevir/PBO treatment and 14-day follow-up periods was monitored for each treatment regimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 300 mg b.i.d. | 72 weeks | The percentage of non-cirrhotic participants treated with Vaniprevir 300 mg b.i.d. with undetectable HCV RNA 24 weeks after completing treatment was determined. |
| Percentage of Participants Achieving cEVR | Up to Week 60 | The percentage of non-cirrhotic participants with complete early viral response (cEVR; undetectable HCV RNA at Week 12) was determined for each Vaniprevir dose. Since each of the Vaniprevir 600 mg arms had the same treatment history at this point in the study, the data were pooled for analysis. |
| Percentage of Participants Achieving SVR24 After 24 Weeks of Vaniprevir 600 mg b.i.d. | Week 48 | The percentage of participants achieving SVR24 after the 24-week Vaniprevir 600 mg b.i.d. regimen at Week 48 was compared to the control regimen. |
Participant flow
Recruitment details
Non-cirrhotic (NC) and cirrhotic (C) participants were screened and enrolled separately in this study. The NC population was used for all safety, tolerability, and efficacy outcome measures. Primary analyses of the outcome measures only included the NC population. Adverse events (AEs) were monitored in both the NC and C populations.
Participants by arm
| Arm | Count |
|---|---|
| 24-wk Vaniprevir 600 mg + Peg-IFN/RBV Vaniprevir 600 mg and RBV (1000 mg or 1200 mg total daily dose based on body weight) twice daily (b.i.d.) and peg-IFN 180 mcg injection once weekly for 24 weeks. | 58 |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV Vaniprevir 600 mg and RBV (1000 mg or 1200 mg total daily dose based on body weight) b.i.d. and peg-IFN 180 mcg injection once weekly for 24 weeks, followed by PBO and RBV (1000 mg or 1200 mg based on body weight) b.i.d. and peg-IFN 180 mcg injection once weekly for an additional 24 weeks. | 58 |
| 48-wk Vaniprevir 300 mg + Peg-IFN/RBV Vaniprevir 300 mg and RBV (1000 mg or 1200 mg total daily dose based on body weight) b.i.d. and peg-IFN 180 mcg injection once weekly for 48 weeks. | 56 |
| 48-wk Vaniprevir 600 mg + Peg-IFN/RBV Vaniprevir 600 mg and RBV (1000 mg or 1200 mg total daily dose based on body weight) b.i.d. and peg-IFN 180 mcg injection once weekly for 48 weeks. | 57 |
| 48-wk PBO + Peg-IFN/RBV PBO and RBV (1000 mg or 1200 mg total daily dose based on body weight) twice daily (b.i.d.) and Peg-IFN 180 mcg injection once weekly for 48 weeks. | 56 |
| Total | 285 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study (C Population) | Lost to Follow-up | 0 | 2 | 0 | 0 | 0 |
| Overall Study (C Population) | Withdrawal by Subject | 1 | 1 | 1 | 1 | 0 |
| Overall Study (NC Population) | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study (NC Population) | Lost to Follow-up | 2 | 1 | 1 | 2 | 2 |
| Overall Study (NC Population) | Other | 0 | 0 | 0 | 0 | 1 |
| Overall Study (NC Population) | Withdrawal by Subject | 2 | 3 | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | 24-wk Vaniprevir 600 mg + Peg-IFN/RBV | 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | 48-wk Vaniprevir 300 mg + Peg-IFN/RBV | 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | 48-wk PBO + Peg-IFN/RBV | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 50.0 Years STANDARD_DEVIATION 8.4 | 51.6 Years STANDARD_DEVIATION 8.1 | 50.6 Years STANDARD_DEVIATION 7.5 | 52.1 Years STANDARD_DEVIATION 8.7 | 49.9 Years STANDARD_DEVIATION 7.8 | 50.8 Years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 25 Participants | 24 Participants | 16 Participants | 19 Participants | 21 Participants | 105 Participants |
| Sex: Female, Male Male | 33 Participants | 34 Participants | 40 Participants | 38 Participants | 35 Participants | 180 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 56 | 56 / 56 | 55 / 56 | 61 / 61 | 55 / 56 |
| serious Total, serious adverse events | 2 / 56 | 5 / 56 | 6 / 56 | 9 / 61 | 1 / 56 |
Outcome results
Primary
Number of Participants Discontinuing From Study Treatment Due to AEs
The number of non-cirrhotic participants withdrawing from study treatment due to AEs during the active Vaniprevir/PBO treatment and 14-day follow-up periods was monitored for each treatment regimen.
Time frame: Up to 48 weeks
Population: The All-Patients-as-Treated (APaT) population was employed for safety analyses. The APaT population consists of all randomized non-cirrhotic patients who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Number of Participants Discontinuing From Study Treatment Due to AEs | 2 Number of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Number of Participants Discontinuing From Study Treatment Due to AEs | 3 Number of participants |
| 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Number of Participants Discontinuing From Study Treatment Due to AEs | 2 Number of participants |
| 48-wk PBO + Peg-IFN/RBV | Number of Participants Discontinuing From Study Treatment Due to AEs | 4 Number of participants |
| 48-wk PBO + Peg-IFN/RBV | Number of Participants Discontinuing From Study Treatment Due to AEs | 1 Number of participants |
Primary
Number of Participants Experiencing an Adverse Event (AE)
The number of non-cirrhotic participants experiencing AEs during the active Vaniprevir/PBO treatment and 14-day follow-up periods was monitored for each treatment regimen. An AE was defined as any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a Sponsor product, whether or not considered related to the use of the product.
Time frame: Up to 73 weeks
Population: The All-Patients-as-Treated (APaT) population was employed for safety analyses. The APaT population consists of all non-cirrhotic randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Number of Participants Experiencing an Adverse Event (AE) | 38 Number of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Number of Participants Experiencing an Adverse Event (AE) | 42 Number of participants |
| 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Number of Participants Experiencing an Adverse Event (AE) | 40 Number of participants |
| 48-wk PBO + Peg-IFN/RBV | Number of Participants Experiencing an Adverse Event (AE) | 46 Number of participants |
| 48-wk PBO + Peg-IFN/RBV | Number of Participants Experiencing an Adverse Event (AE) | 41 Number of participants |
Primary
Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d.
The percentage of non-cirrhotic participants with undetectable Hepatits C virus (HCV) ribonucleic acid (RNA) 24 weeks after completing treatment was determined for each Vaniprevir 600 mg b.i.d. and control regimen. Results for Vaniprevir 300 mg are presented as a Secondary Outcome Measure.
Time frame: Up to 72 weeks
Population: The Full Analysis Set (FAS) population consists of all non-cirrhotic participants who received at least 1 dose of study treatment, have post-dose endpoint data, and have baseline data for measures that require baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d. | 71.1 Percentage of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d. | 84.2 Percentage of participants |
| 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d. | 78.0 Percentage of participants |
| 48-wk PBO + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 600 mg b.i.d. | 19.0 Percentage of participants |
p-value: <0.00195% CI: [34.5, 69.1]Miettinen and Nurminen method
p-value: <0.00195% CI: [45.2, 78.3]Miettinen and Nurminen method
p-value: <0.00195% CI: [40.2, 73.4]Miettinen and Nurminen
Secondary
Percentage of Participants Achieving cEVR
The percentage of non-cirrhotic participants with complete early viral response (cEVR; undetectable HCV RNA at Week 12) was determined for each Vaniprevir dose. Since each of the Vaniprevir 600 mg arms had the same treatment history at this point in the study, the data were pooled for analysis.
Time frame: Up to Week 60
Population: The Full Analysis Set (FAS) population consists of all non-cirrhotic participants who received at least 1 dose of study treatment, have post-dose endpoint data, and have baseline data for measures that require baseline data. The 3 Vaniprevir 600 mg b.i.d. arms were combined in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving cEVR | 92.0 Percentage of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Percentage of Participants Achieving cEVR | 85.4 Percentage of participants |
| 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving cEVR | 9.5 Percentage of participants |
95% CI: [69.5, 90.2]
95% CI: [60.1, 86.7]
Secondary
Percentage of Participants Achieving SVR24 After 24 Weeks of Vaniprevir 600 mg b.i.d.
The percentage of participants achieving SVR24 after the 24-week Vaniprevir 600 mg b.i.d. regimen at Week 48 was compared to the control regimen.
Time frame: Week 48
Population: The Full Analysis Set (FAS) population consists of all non-cirrhotic participants who received at least 1 dose of study treatment, have post-dose endpoint data, and have baseline data for measures that require baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 After 24 Weeks of Vaniprevir 600 mg b.i.d. | 71.1 Percentage of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 After 24 Weeks of Vaniprevir 600 mg b.i.d. | 36.6 Percentage of participants |
95% CI: [15.5, 53.4]Miettinen and Nurminen method
Secondary
Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 300 mg b.i.d.
The percentage of non-cirrhotic participants treated with Vaniprevir 300 mg b.i.d. with undetectable HCV RNA 24 weeks after completing treatment was determined.
Time frame: 72 weeks
Population: The Full Analysis Set (FAS) population consists of all non-cirrhotic participants who received at least 1 dose of study treatment, have post-dose endpoint data, and have baseline data for measures that require baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24- or 48-wk Vaniprevir 600 mg + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 300 mg b.i.d. | 66.7 Percentage of participants |
| 24-wk Vaniprevir 600 mg, 24-wk PBO + Peg-IFN/RBV | Percentage of Participants Achieving SVR24 Following Treatment With Vaniprevir 300 mg b.i.d. | 19.0 Percentage of participants |
p-value: <0.00195% CI: [29.2, 63.2]Miettinen and Nurminen