Hepatitis C
Conditions
Keywords
Genotype 1
Brief summary
The PROVE3 trial is a partially double blinded, randomized, Phase 2 research study of an investigational drug, Telaprevir (VX-950) or Placebo, with Pegylated Interferon Alfa 2a (Peg-IFN-alfa-2a, Pegasys®), and Ribavirin (RBV, Copegus®) in people with genotype 1 hepatitis C who have not achieved a Sustained Viral Response (SVR) with a previous treatment of interferon therapy.
Interventions
DRUGTelaprevir
tablet
DRUGRibavirin
tablet
Solution for injection
DRUGMatching Placebo
Tablet
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males and females between 18 and 70 years old * Detectable plasma hepatitis C virus (HCV) ribonucleic acid (RNA) greater than or equal to (\>=) 10,000 international units per milliliter (IU/mL) * Must have chronic hepatitis C (genotype 1) and have already received at least one prior course of pegylated interferon alfa 2a with ribavirin * Cannot also be infected with Human Immunodeficiency Virus or hepatitis B * Must be judged to be in general good health and able to receive Pegasys® and Copegus® * No drug or alcohol abuse in the last year * Must agree to use two effective methods of birth control during the study and for 6 months after you stop taking study medication. One of the methods needs to be a 'barrier' method (condom or diaphragm) * If you are a woman, you cannot be in this study if you are pregnant or nursing
Exclusion criteria
* Participation in any clinical trial of a HCV protease inhibitor of any duration * Prior response to therapy and failure to achieve SVR which was due to treatment non-compliance * Any other cause of significant liver disease in addition to hepatitis C; this may include but is not limited to, hepatitis B, drug or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson's disease, nonalcoholic steatohepatitis, or primary biliary cirrhosis * Diagnosed or suspected hepatocellular carcinoma * History of or current evidence of decompensated liver disease * Participation in any clinical trial of an investigational drug within 90 days before drug administration or participation in more than 2 drug studies in the last 12 months (exclusive of the current study)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing | 24 weeks after the completion of study drug dosing (up to Week 72) | The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to 2 weeks after last dose of study drug (up to Week 50) | AE: any adverse change from the subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording or clinical laboratory assessment value which occurs during the course of the study, whether it is considered related to the study drug or not. An adverse event includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of study drug. SAE: medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Study drug includes all investigational agents (including placebo, if applicable) administered during the course of the study. |
| Number of Subjects With Viral Relapse | After last dose of study drug up to 24 week antiviral follow-up (up to Week 72) | Viral relapse was defined as having detectable HCV RNA during antiviral follow-up. The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL). |
| Maximum (Cmax), Minimum (Cmin) and Average (Cavg) Plasma Concentration of Telaprevir | Week 2, 4, 8, 12, 16, 24 | Only subjects who received telaprevir were to be analyzed for this outcome. Maximum, minimum and average plasma concentrations observed during assessment period were reported. |
| Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing | Completion of study drug dosing (up to Week 48) | The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL). |
| Percentage of Subjects With Undetectable Plasma HCV RNA | Up to Week 96 (24 weeks after last dose of study drug for PBO group; 48 weeks after last dose of study drug for telaprevir groups) | Percentage of subjects with undetectable HCV RNA at 24 weeks after last dose of study drug for treatment group PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week and at 48 weeks after last dose of study drug for treatment groups Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week, Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week and Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week were presented. The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL). |
Countries
Canada, Germany, Netherlands, Puerto Rico, United States
Participant flow
Pre-assignment details
A total of 465 subjects were enrolled, of which 12 subjects discontinued the study prior to study drug administration. A total of 453 subjects started treatment.
Participants by arm
| Arm | Count |
|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week Single loading dose of telaprevir 1125 milligram (mg) tablet orally on Day 1 followed by 750 mg telaprevir tablet thrice daily for 12 weeks in combination with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) 180 microgram per week (mcg/week) subcutaneous injection and ribavirin (RBV) tablet orally twice daily at a dose of 1000 milligram per day (mg/day) for subjects weighing less than (\<) 75 kilogram (kg) and 1200 mg/day for subjects weighing greater than or equal to (\>=) 75 kg, for 24 weeks. | 115 |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week Single loading dose of telaprevir 1125 mg tablet orally on Day 1 followed by 750 mg telaprevir tablet thrice daily for 24 weeks in combination with Peg-IFN-alfa-2a 180 mcg/week subcutaneous injection and RBV tablet orally twice daily at a dose of 1000 mg/day for subjects weighing \<75 kg and 1200 mg/day for subjects weighing \>=75 kg, for 48 weeks. | 113 |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week Single loading dose of telaprevir 1125 mg tablet orally on Day 1 followed by 750 mg telaprevir tablet thrice daily in combination with Peg-IFN-alfa-2a 180 mcg/week subcutaneous injection, for 24 weeks. | 111 |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week Placebo (PBO) matched to telaprevir tablet orally thrice daily for 24 weeks in combination with Peg-IFN-alfa-2a 180 mcg/week subcutaneous injection and RBV tablet orally twice daily at a dose of 1000 mg/day for subjects weighing \<75 kg and 1200 mg/day for subjects weighing \>=75 kg, for 48 weeks. | 114 |
| Total | 453 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 29 | 10 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 1 |
| Overall Study | Other | 1 | 2 | 0 | 5 |
| Overall Study | Virologic Stopping Rule | 17 | 26 | 41 | 67 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 114 Participants | 111 Participants | 108 Participants | 113 Participants | 446 Participants |
| Age, Continuous | 49.7 years STANDARD_DEVIATION 7.8 | 52.0 years STANDARD_DEVIATION 5.5 | 51.9 years STANDARD_DEVIATION 7.1 | 49.8 years STANDARD_DEVIATION 7.2 | 50.8 years STANDARD_DEVIATION 7 |
| Region of Enrollment Europe | 14 participants | 10 participants | 10 participants | 13 participants | 47 participants |
| Region of Enrollment North America | 101 participants | 103 participants | 101 participants | 101 participants | 406 participants |
| Sex: Female, Male Female | 37 Participants | 33 Participants | 39 Participants | 38 Participants | 147 Participants |
| Sex: Female, Male Male | 78 Participants | 80 Participants | 72 Participants | 76 Participants | 306 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 | 112 / 115 | 112 / 113 | 105 / 111 | 111 / 114 |
| serious Total, serious adverse events | 6 / 115 | 16 / 113 | 6 / 111 | 9 / 114 |
Outcome results
Primary
Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing
The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL).
Time frame: 24 weeks after the completion of study drug dosing (up to Week 72)
Population: Full Analysis Set = subjects who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing | 51.3 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing | 53.1 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing | 24.3 percentage of participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Percentage of Subjects With Undetectable Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 24 After the Completion of Study Drug Dosing | 14.0 percentage of participants |
p-value: <0.00195% CI: [4.14, 16.36]Regression, Logistic
p-value: <0.00195% CI: [4.72, 19.2]Regression, Logistic
p-value: 0.02495% CI: [1.12, 4.75]Regression, Logistic
Secondary
Maximum (Cmax), Minimum (Cmin) and Average (Cavg) Plasma Concentration of Telaprevir
Only subjects who received telaprevir were to be analyzed for this outcome. Maximum, minimum and average plasma concentrations observed during assessment period were reported.
Time frame: Week 2, 4, 8, 12, 16, 24
Population: Pharmacokinetic population included all subjects who provided pharmacokinetic assessments and had evaluable and interpretable data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Maximum (Cmax), Minimum (Cmin) and Average (Cavg) Plasma Concentration of Telaprevir | Cmax | 2755 nanogram per milliliter (ng/mL) | Standard Deviation 811 |
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Maximum (Cmax), Minimum (Cmin) and Average (Cavg) Plasma Concentration of Telaprevir | Cmin | 2335 nanogram per milliliter (ng/mL) | Standard Deviation 733 |
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Maximum (Cmax), Minimum (Cmin) and Average (Cavg) Plasma Concentration of Telaprevir | Cavg | 2610 nanogram per milliliter (ng/mL) | Standard Deviation 780 |
Secondary
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE: any adverse change from the subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording or clinical laboratory assessment value which occurs during the course of the study, whether it is considered related to the study drug or not. An adverse event includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of study drug. SAE: medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Study drug includes all investigational agents (including placebo, if applicable) administered during the course of the study.
Time frame: Baseline up to 2 weeks after last dose of study drug (up to Week 50)
Population: Full Analysis Set = subjects who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 112 participants |
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 6 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 16 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 113 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 105 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 6 participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 111 participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 9 participants |
Secondary
Number of Subjects With Viral Relapse
Viral relapse was defined as having detectable HCV RNA during antiviral follow-up. The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL).
Time frame: After last dose of study drug up to 24 week antiviral follow-up (up to Week 72)
Population: Analysis population included subjects who completed their assigned study drug treatment and had undetectable HCV RNA at the completion of treatment (up to Week 48).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Number of Subjects With Viral Relapse | 26 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Number of Subjects With Viral Relapse | 10 participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Number of Subjects With Viral Relapse | 32 participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Number of Subjects With Viral Relapse | 18 participants |
Secondary
Percentage of Subjects With Undetectable Plasma HCV RNA
Percentage of subjects with undetectable HCV RNA at 24 weeks after last dose of study drug for treatment group PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week and at 48 weeks after last dose of study drug for treatment groups Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week, Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week and Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week were presented. The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL).
Time frame: Up to Week 96 (24 weeks after last dose of study drug for PBO group; 48 weeks after last dose of study drug for telaprevir groups)
Population: Full Analysis Set = subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Percentage of Subjects With Undetectable Plasma HCV RNA | 48.7 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Percentage of Subjects With Undetectable Plasma HCV RNA | 44.2 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Percentage of Subjects With Undetectable Plasma HCV RNA | 22.5 percentage of participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Percentage of Subjects With Undetectable Plasma HCV RNA | 14.0 percentage of participants |
p-value: <0.00195% CI: [3.41, 12.96]Regression, Logistic
p-value: <0.00195% CI: [2.91, 11.27]Regression, Logistic
p-value: 0.06795% CI: [0.95, 4]Regression, Logistic
Secondary
Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing
The plasma HCV RNA level was measured using Roche TaqMan HCV RNA assay. The lower limit of detection was 10 international units per milliliter (IU/mL).
Time frame: Completion of study drug dosing (up to Week 48)
Population: Full Analysis Set = subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telaprevir 12 Week+Peg-IFN-alfa-2a,RBV 24 Week | Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing | 75.7 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a,RBV 48 Week | Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing | 67.3 percentage of participants |
| Telaprevir 24 Week+Peg-IFN-alfa-2a 24 Week | Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing | 54.1 percentage of participants |
| PBO 24 Week+Peg-IFN-alfa-2a, RBV 48 Week | Percentage of Subjects With Undetectable Plasma HCV RNA at Completion of Study Drug Dosing | 29.8 percentage of participants |