Hepatitis C
Conditions
Brief summary
This is a randomized, parallel-group, placebo-controlled, multi-site, multinational, double-blind followed by open label period, Phase 3 trial of 100 mg of grazoprevir (MK-5172) in combination with 50 mg of elbasvir (MK-8742) (grazoprevir/elbasvir fixed-dose combination \[FDC\]) in treatment-naïve (TN) participants with chronic hepatitis C virus (HCV), genotype (GT) 1, 4 or 6 infection. The primary hypothesis is that the percentage of participants receiving grazoprevir/elbasvir FDC in the Immediate Treatment Group (ITG) achieving Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) will be superior to the historical reference rate of 73%.
Interventions
FDC tablet containing 100 mg of grazoprevir and 50 mg of elbasvir taken q.d. by mouth for 12 weeks.
DRUGPlacebo
Placebo tablet matching grazoprevir/elbasvir FDC tablet taken q.d. by mouth for 12 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 No maximum
Healthy volunteers
No
Inclusion criteria
* Has documented chronic HCV GT1, GT4, or GT6 (with no evidence of non-typeable or mixed genotype) infection * Meets clinical criteria for presence or absence of cirrhosis based on liver disease staging assessment * Is abstinent or uses acceptable method(s) of contraception
Exclusion criteria
* Has evidence of decompensated liver disease * Is coinfected with hepatitis B virus or human immunodeficiency virus (HIV) * Shows evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC * Has a clinically-relevant drug or alcohol abuse within 12 months of screening * Is pregnant or breast-feeding * Has any condition or abnormality that might confound the results of the trial or pose an additional risk to the participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | 12 weeks after end of all therapy (Study Week 24) | Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\<LLOQ) at 12 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in the primary efficacy analysis. |
| Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period and First 14 Follow-up Days | DB Treatment period plus 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. An AE can therefore be any unfavourable and unintended sign, 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 pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. |
| Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period | DB Treatment period (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. An AE can therefore be any unfavourable and unintended sign, 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 pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. A participant could discontinue from treatment but continue to participate in the study as long as consent was not withdrawn. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | 24 weeks after end of all therapy (Study Week 36) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in the secondary efficacy analysis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Study Therapy (SVR4) | 4 weeks after end of all therapy (Study Week 16) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR4 was defined as HCV RNA \<LLOQ at 4 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in this efficacy analysis. |
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 489 participants were randomized to treatment, and 488 participants received ≥1 dose of study drug during the blinded period. One participant randomized to the ITG withdrew consent after randomization, but prior to receiving study drug.
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir Participants received a grazoprevir/elbasvir FDC tablet q.d. by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and were followed-up for 24 weeks to Week 36. | 365 |
| Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir Participants received a placebo tablet q.d. by mouth for 12 weeks (placebo treatment period). After a 4-week Follow-Up period, participants received open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants were then followed-up for 24 weeks to Week 52. | 123 |
| Total | 488 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (Double-blind [DB]) | Adverse Event | 1 | 1 |
| Period 1 (Double-blind [DB]) | Lack of Efficacy | 5 | 0 |
| Period 1 (Double-blind [DB]) | Not Treated | 1 | 0 |
| Period 1 (Double-blind [DB]) | Withdrawal by Subject | 1 | 0 |
| Period 2 (ITG Follow-up/DTG Open Label) | Adverse Event | 0 | 2 |
| Period 2 (ITG Follow-up/DTG Open Label) | Lack of Efficacy | 0 | 1 |
Baseline characteristics
| Characteristic | Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Total |
|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 12.9 | 48.6 years STANDARD_DEVIATION 12.9 | 48.3 years STANDARD_DEVIATION 12.9 |
| Sex: Female, Male Female | 205 Participants | 67 Participants | 272 Participants |
| Sex: Female, Male Male | 160 Participants | 56 Participants | 216 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 | 85 / 365 | 30 / 123 | 21 / 121 |
| serious Total, serious adverse events | 9 / 365 | 3 / 123 | 6 / 121 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12)
Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\<LLOQ) at 12 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in the primary efficacy analysis.
Time frame: 12 weeks after end of all therapy (Study Week 24)
Population: All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in the primary efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | 94.2 percentage of participants |
Comparison: A one-sided Wald test was used to test the null hypothesis, which was that the SVR12 rate for the ITG was ≤ the historical reference rate of 73%. The historical reference SVR rate for treatment-naive genotype 1 predominantly Asian participants treated with pegylated interferon/ribavirin was derived from 2 studies (PMCID: PMC417, PMCID: PMC3644280) after adjusting for an expected improved safety profile related to an interferon-free regimen.p-value: <0.001one-sided asymptotic test
Primary
Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period 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. An AE can therefore be any unfavourable and unintended sign, 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 pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period.
Time frame: DB Treatment period plus first 14 follow-up days (up to 14 weeks)
Population: All randomized participants who received at least one dose of study treatment during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period and First 14 Follow-up Days | 50.7 percentage of participants |
| Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period and First 14 Follow-up Days | 51.2 percentage of participants |
Comparison: Estimates and 95% CIs were calculated for between-treatment differences (ITG minus DTG) in the percentage of participants with events using the Miettinen and Nurminen method.95% CI: [-10.6, 9.6]
Primary
Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period
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. An AE can therefore be any unfavourable and unintended sign, 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 pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. A participant could discontinue from treatment but continue to participate in the study as long as consent was not withdrawn. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period.
Time frame: DB Treatment period (up to 12 weeks)
Population: All randomized participants who received at least one dose of study treatment during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period | 0.3 percentage of participants |
| Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period | 0.8 percentage of participants |
Comparison: Estimates and 95% CIs were calculated for between-treatment differences (ITG minus DTG) in the percentage of participants with events using the Miettinen and Nurminen method.95% CI: [-4.2, 0.9]
Secondary
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24)
Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in the secondary efficacy analysis.
Time frame: 24 weeks after end of all therapy (Study Week 36)
Population: All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in the secondary efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | 94.0 percentage of participants |
Other Pre-specified
Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Study Therapy (SVR4)
Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR4 was defined as HCV RNA \<LLOQ at 4 weeks after the end of all study therapy. As pre-specified in the protocol, the Deferred Treatment Group was not included in this efficacy analysis.
Time frame: 4 weeks after end of all therapy (Study Week 16)
Population: All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in this efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Study Therapy (SVR4) | 96.2 percentage of participants |