Hepatitis C
Conditions
Keywords
Chronic hepatitis C, Cyclophilin inhibitor
Brief summary
This study will assess the safety and efficacy of alisporivir (ALV; DEB025) triple therapy \[i.e., when added to peginterferon alfa-2a (PEG) and ribavirin (RBV)\] to optimize treatment in treatment-naïve participants with hepatitis C virus (HCV) genotype 1 (GT1)
Interventions
DRUGPeginterferon alfa-2a
PEG 180 μg administered via subcutaneous (s.c.) injection once weekly
DRUGAlisporivir
ALV 200 mg soft gel capsules administered orally
DRUGRibavirin
RBV 200 mg tablets (weight-based dose: \< 75 mg = 1000 mg/day; ≥ 75 kg = 1200 mg/day) administered orally in a divided daily dose
DRUGALV Placebo
ALV placebo soft gel capsules administered orally
Sponsors
Debiopharm International SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Chronic HCV infection * HCV genotype 1 * No previous treatment for hepatitis C infection * Serum HCV RNA level ≥ 1000 IU/ml assessed by quantitative polymerase chain reaction or equivalent at screening, no upper limit * Liver evaluation prior to baseline: liver biopsy within 3 years or Fibroscan within 6 months
Exclusion criteria
* HCV genotype different from genotype 1 or co-infection with other HCV genotype * Co-infection with Hepatitis B or HIV * Any other cause of relevant liver disease other than HCV * Presence or history of hepatic decompensation * Alanine aminotransferase (ALT) ≥ 10 times upper limit of normal (ULN), more than 1 episode of elevated bilirubin (\> ULN) in past 6 months Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12) | 12 weeks after the end of treatment | SVR12 was defined as hepatitis C virus (HCV) RNA laboratory value below the level of quantification (\< LOQ; i.e., 25 IU/ml) 12 weeks after the end of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4) | after 4 weeks of treatment | RVR4 was defined as serum HCV RNA \< LOQ after 4 weeks of treatment. |
| Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment | after 12 weeks of treatment | EVR was defined as a ≥ 2 log10 decrease in HCV RNA or HCV RNA \< LOQ after 12 weeks of treatment. |
| Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment | after 12 weeks of treatment | pEVR was defined as a ≥ 2 log10 decrease in HCV RNA and still detectable (≥ LOQ) after 12 weeks of treatment. |
| Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment | after 12 weeks of treatment | cEVR was defined as serum HCV RNA \< LOQ after 12 weeks of treatment. |
| Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment | from 4 to 12 weeks of treatment | eRVR was defined as achieving RVR4 and maintaining HCV RNA \< LOQ until Week 12. |
| Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24) | 24 weeks after the end of treatment | SVR24 was defined as HCV RNA laboratory value \< LOQ 24 weeks after the end of treatment. |
| Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | within 48 weeks | ALT abnormalities were summarized as participants who had either: * ALT \> 2 x upper limit of normal (ULN) during the study and \> 2 x ULN at baseline * ALT \> 3 x ULN during the study and \> 2 x ULN at baseline |
| Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | within 48 weeks | Grading was according to the Modified Division of Microbiology & Infectious Diseases (DMID) Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category. |
| Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | within 48 weeks | Grading was according to the DMID Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category. |
| Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | within 48 weeks | Grading was according to the DMID Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category. |
| Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks | at treatment end within 48 weeks | ETR was defined as serum HCV RNA \< LOQ at treatment end (completed or prematurely discontinued). |
Countries
Argentina, Australia, Belgium, Canada, France, Germany, Hong Kong, Hungary, Italy, Mexico, Poland, Puerto Rico, Romania, Russia, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
Of the 1580 patients screened at multiple global sites, 1081 (68.4%) were randomized and 499 (31.6%) discontinued from the study prior to randomization.
Pre-assignment details
Due to mis-randomization, four patients did not have a baseline visit and never started study medications. They were included in screened and randomized, but excluded from the Full Analysis Set and the Safety Set.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm A Alisporivir (ALV) 600 mg BID with PEG and RBV for 1 week, followed by an additional 23 or 47 weeks according to RGT | 274 |
| Treatment Arm B Alisporivir (ALV) 400 mg BID with PEG and RBV for 24 or 48 weeks according to RGT | 270 |
| Treatment Arm C Alisporivir (ALV) 600 mg BID with PEG and RBV for 1 week, followed by 600 mg QD for 47 weeks | 265 |
| Treatment Arm D ALV Placebo with PEG and RBV for 48 weeks | 268 |
| Total | 1,077 |
Baseline characteristics
| Characteristic | Treatment Arm A | Treatment Arm B | Treatment Arm C | Treatment Arm D | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45.9 years STANDARD_DEVIATION 11.08 | 45.8 years STANDARD_DEVIATION 11.95 | 45.5 years STANDARD_DEVIATION 12.15 | 46.3 years STANDARD_DEVIATION 11.53 | 45.9 years STANDARD_DEVIATION 11.67 |
| Sex: Female, Male Female | 113 Participants | 106 Participants | 134 Participants | 114 Participants | 467 Participants |
| Sex: Female, Male Male | 161 Participants | 164 Participants | 131 Participants | 154 Participants | 610 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 | 256 / 273 | 261 / 268 | 250 / 265 | 242 / 265 |
| serious Total, serious adverse events | 24 / 273 | 28 / 268 | 21 / 265 | 28 / 265 |
Outcome results
Primary
Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12)
SVR12 was defined as hepatitis C virus (HCV) RNA laboratory value below the level of quantification (\< LOQ; i.e., 25 IU/ml) 12 weeks after the end of treatment.
Time frame: 12 weeks after the end of treatment
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12) | 68.6 percentage of participants |
| Treatment Arm B | Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12) | 68.9 percentage of participants |
| Treatment Arm C | Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12) | 69.4 percentage of participants |
| Treatment Arm D | Percentage of Participants Who Achieved Sustained Virologic Response (SVR) 12 Weeks After the End of Treatment (SVR12) | 52.5 percentage of participants |
Secondary
Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24)
SVR24 was defined as HCV RNA laboratory value \< LOQ 24 weeks after the end of treatment.
Time frame: 24 weeks after the end of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24) | 68.5 percentage of participants |
| Treatment Arm B | Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24) | 69.0 percentage of participants |
| Treatment Arm C | Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24) | 68.3 percentage of participants |
| Treatment Arm D | Percentage of Participants Who Achieved SVR 24 Weeks After the End of Treatment (SVR24) | 51.7 percentage of participants |
Secondary
Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks
ALT abnormalities were summarized as participants who had either: * ALT \> 2 x upper limit of normal (ULN) during the study and \> 2 x ULN at baseline * ALT \> 3 x ULN during the study and \> 2 x ULN at baseline
Time frame: within 48 weeks
Population: Participants in the Safety Set, defined as having received at least one dose of study medication, with available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm A | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 2 x ULN and > 2 x baseline | 1.5 percentage of participants |
| Treatment Arm A | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 3 x ULN and > 2 x baseline | 0.7 percentage of participants |
| Treatment Arm B | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 3 x ULN and > 2 x baseline | 0.0 percentage of participants |
| Treatment Arm B | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 2 x ULN and > 2 x baseline | 0.4 percentage of participants |
| Treatment Arm C | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 2 x ULN and > 2 x baseline | 1.9 percentage of participants |
| Treatment Arm C | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 3 x ULN and > 2 x baseline | 1.5 percentage of participants |
| Treatment Arm D | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 2 x ULN and > 2 x baseline | 1.5 percentage of participants |
| Treatment Arm D | Percentage of Participants With Alanine Aminotransferase (ALT) Abnormalities Within 48 Weeks | > 3 x ULN and > 2 x baseline | 0.8 percentage of participants |
Secondary
Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment
cEVR was defined as serum HCV RNA \< LOQ after 12 weeks of treatment.
Time frame: after 12 weeks of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment | 89.6 percentage of participants |
| Treatment Arm B | Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment | 96.3 percentage of participants |
| Treatment Arm C | Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment | 89.1 percentage of participants |
| Treatment Arm D | Percentage of Participants With Complete Early Virologic Response (cEVR) After 12 Weeks of Treatment | 70.3 percentage of participants |
Secondary
Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment
EVR was defined as a ≥ 2 log10 decrease in HCV RNA or HCV RNA \< LOQ after 12 weeks of treatment.
Time frame: after 12 weeks of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment | 97.7 percentage of participants |
| Treatment Arm B | Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment | 98.3 percentage of participants |
| Treatment Arm C | Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment | 99.6 percentage of participants |
| Treatment Arm D | Percentage of Participants With Early Virologic Response (EVR) After 12 Weeks of Treatment | 89.8 percentage of participants |
Secondary
Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks
ETR was defined as serum HCV RNA \< LOQ at treatment end (completed or prematurely discontinued).
Time frame: at treatment end within 48 weeks
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks | 88.2 percentage of participants |
| Treatment Arm B | Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks | 87.7 percentage of participants |
| Treatment Arm C | Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks | 87.5 percentage of participants |
| Treatment Arm D | Percentage of Participants With End of Treatment Response (ETR) at Treatment End Within 48 Weeks | 80.0 percentage of participants |
Secondary
Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment
eRVR was defined as achieving RVR4 and maintaining HCV RNA \< LOQ until Week 12.
Time frame: from 4 to 12 weeks of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment | 60.2 percentage of participants |
| Treatment Arm B | Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment | 71.1 percentage of participants |
| Treatment Arm C | Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment | 56.7 percentage of participants |
| Treatment Arm D | Percentage of Participants With Extended Rapid Virologic Response (eRVR) From 4 to 12 Weeks of Treatment | 28.1 percentage of participants |
Secondary
Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks
Grading was according to the Modified Division of Microbiology & Infectious Diseases (DMID) Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category.
Time frame: within 48 weeks
Population: Participants in the Safety Set with available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 3 | 1.8 percentage of participants |
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 4 | 0.4 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 3 | 3.4 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 3 | 0.8 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 3 | 1.9 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Anemia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
Secondary
Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks
Grading was according to the DMID Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category.
Time frame: within 48 weeks
Population: Participants in the Safety Set with available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 3 | 24.4 percentage of participants |
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 4 | 4.4 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 4 | 8.0 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 3 | 24.7 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 3 | 23.1 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 4 | 7.2 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 3 | 12.9 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Neutropenia During Treatment Within 48 Weeks | Grade 4 | 2.7 percentage of participants |
Secondary
Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks
Grading was according to the DMID Toxicity Tables (version 2.0). Participants with multiple abnormalities were counted only once in the worst category.
Time frame: within 48 weeks
Population: Participants in the Safety Set with available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
| Treatment Arm A | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 3 | 6.7 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 3 | 21.9 percentage of participants |
| Treatment Arm B | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 4 | 1.1 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
| Treatment Arm C | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 3 | 12.5 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 4 | 0.0 percentage of participants |
| Treatment Arm D | Percentage of Participants With Grade 3 or 4 Thrombocytopenia During Treatment Within 48 Weeks | Grade 3 | 1.9 percentage of participants |
Secondary
Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment
pEVR was defined as a ≥ 2 log10 decrease in HCV RNA and still detectable (≥ LOQ) after 12 weeks of treatment.
Time frame: after 12 weeks of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment | 8.1 percentage of participants |
| Treatment Arm B | Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment | 2.1 percentage of participants |
| Treatment Arm C | Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment | 10.5 percentage of participants |
| Treatment Arm D | Percentage of Participants With Partial Early Virologic Response (pEVR) After 12 Weeks of Treatment | 19.5 percentage of participants |
Secondary
Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4)
RVR4 was defined as serum HCV RNA \< LOQ after 4 weeks of treatment.
Time frame: after 4 weeks of treatment
Population: Participants in the Full Analysis Set with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm A | Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4) | 60.1 percentage of participants |
| Treatment Arm B | Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4) | 72.5 percentage of participants |
| Treatment Arm C | Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4) | 56.6 percentage of participants |
| Treatment Arm D | Percentage of Participants With Rapid Virologic Response (RVR) After 4 Weeks of Treatment (RVR4) | 28.4 percentage of participants |