Hepatitis C
Conditions
Keywords
Hepatitis, HCV, Hepatitis C
Brief summary
The aim of the study is to investigate in subjects receiving their first course of peg-interferon α-2b plus ribavirin therapy for chronic HCV infection
Detailed description
The aim of the study is to investigate in subjects receiving their first course of peg-interferon α-2b plus ribavirin therapy for chronic HCV infection (genotype 1) whether the addition of infliximab to a standard regimen of pegylated interferon α-2b in combination with ribavirin: * increases the proportion of subjects attaining a sustained virological response SVR (undetectable blood Hepatitis C viral load 6 months after treatment) * improves the safety profile compared to the same regimen without infliximab
Interventions
DRUGInfliximab
Infliximab weight based injection at baseline, weeks 2,6,14,22,30,38,46
DRUGPlacebo
Placebo
Sponsors
Centocor, Inc.
Nizar Zein
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects, \>18 years of age with proven chronic (greater than 6 months) hepatitis C infection (genotype 1) who have never been treated with pegylated interferon α-2b and /or ribavirin. Criteria for inclusion in this trial are as follows: * Male or female, 18 years of age or older * Positive HCV RNA, Genotype 1, treatment naïve (never received pegylated interferon and / or ribavirin) * Evidence of chronic HCV infection for at least six months prior to screening * Findings on liver biopsy within the past 36 months that are consistent with the presence of chronic hepatitis C infection. * Negative hepatitis B surface antigen * No evidence of hemochromatosis * Hemoglobin ≥12 g/dL for females and ≥13 g/dL for males * WBC ≥3.0 x 109/L and neutrophils ≥1.5 x 109/L * Platelets ≥80 x109/L * Direct Bilirubin WNL +/- 50% of central laboratory normal range. Total bilirubin ≤1.6. * Albumin within normal limits * Serum creatinine within normal limits. * Serum thyroid stimulating hormone (TSH) levels within normal limits * Men and women of childbearing potential must use two forms of adequate birth control measures for the duration of the study and should continue such precautions for 6 months after receiving the last infusion. * Subjects with a history of mild depression may be considered for entry into this study. * No history of latent or active TB.
Exclusion criteria
* Women who are pregnant, nursing, or planning pregnancy within 6 months after the last infusion and men with partners who are pregnant at baseline or intend to become pregnant within 6 months after the last infusion. * Known allergy against infliximab, ribavirin, or pegylated interferon * Decompensated liver disease characterized as decreased hepatic synthetic functioning with abnormal albumin and bilirubin levels, prolonged prothrombin time or complications including ascites or recent variceal bleeding * have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidiomycosis (Valley Fever) * History of autoimmune hepatitis or a history of poorly controlled autoimmune disease * Use of other systemic anti-inflammatory medication except NSAIDs and low dose systemic steroids * Previous treatment with monoclonal antibodies or antibody fragments * History of receiving human/murine recombinant products or a known allergy to murine products * Documentation of seropositive for human immunodeficiency virus (HIV) * History of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results * History of serious infections (e.g., hepatitis, pneumonia or pyelonephritis) in the previous 3 months * Opportunistic infection within 6 months prior to screening * History of lymphoproliferative disease * Currently have any known malignancy or have a history of malignancy within the previous 5 years, with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence * Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease * Treatment with any other therapeutic agent targeted at reducing TNF within 3 months of screening * Presence of a transplanted solid organ * Concomitant diagnosis or history of congestive heart failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Comparison of the Percentage of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of Treatment. | 72 Weeks from initiation of treatment | A comparison of the Proportion of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of TreatmentSVR in both study arms |
| Number of Participants Achieving Sustained Virological Response (SVR) | 24 weeks after completion of all study medications | HCV RNA negativity at 24 weeks after completion of all study medications |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| A Comparison of the Percentage of Participants With Non-detectable HCV-RNA After 24 Weeks of Therapy. | 24 weeks | A comparison of the proportion of the subject population with non-detectable HCV-RNA after 24 wks of therapy. |
| Percentage of Participants Experiencing Serious Adverse Events | 72 Weeks from initiation of treatment | The severity of adverse events was graded according to modified World Health Organization grades as mild, moderate, severe, or life-threatening |
| Percentage of Participants Experiencing Medically Significant Infections | 72 weeks from initiation of treatment | Medically significant infection was defined as an infection requiring the use of intravenous antibiotics or hospitalization. |
Countries
United States
Participant flow
Recruitment details
Enrollment 2007-2011 Data Lock Nov 22, 2012 Sites 1. The Cleveland Clinic 2. University Hospitals of Cleveland 3. Cedar Sinai Medical Center, Los Angeles, 4. The Liver Institute at Methodist Dallas 5. Brooke Army Medical Center, San Antonio 6. Advanced Medical Research Center, Daytona Beach. 7. University of Louisville, Louisville
Pre-assignment details
220 subjects screened and 149 randomized Reasons for exclusion were multiple including malignancy, liver failure, negative HCV RNA, abnormal lab values, poorly controlled diabetes, psych disorders, positive tuberculosis skin test, seizure disorder, inability to get labs or liver biopsy, pregnancy, patient declining, other (cardiomypathy, MS, etc.)
Participants by arm
| Arm | Count |
|---|---|
| A Infliximab Infliximab: 48 weeks of therapy with the combination of PEG INF-2b/RBV plus adjuvant infliximab
Infliximab : Infliximab weight based injection at baseline, weeks 2,6,14,22,30,38,46
All patients received triple therapy (pegylated interferon (PEG IFN)/ribavirin/infliximab) at approved doses | 73 |
| B Placebo Placebo: 48 weeks of therapy with Placebo and PEG INF-2b/RBV
Placebo : Placebo
All patients received triple therapy (pegylated interferon (PEG IFN)/ribavirin/placebo) at approved doses. Placebo infusions were timed similar to infliximab for patients in arm A of the study | 73 |
| Total | 146 |
Baseline characteristics
| Characteristic | B Placebo | A Infliximab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 73 Participants | 73 Participants | 146 Participants |
| Age, Continuous | 47.2 years STANDARD_DEVIATION 9.38 | 46.7 years STANDARD_DEVIATION 9.78 | 46.9 years STANDARD_DEVIATION 9.58 |
| Region of Enrollment United States | 73 participants | 73 participants | 146 participants |
| Sex: Female, Male Female | 31 Participants | 33 Participants | 64 Participants |
| Sex: Female, Male Male | 42 Participants | 40 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 1 / 73 |
| other Total, other adverse events | 73 / 73 | 73 / 73 |
| serious Total, serious adverse events | 21 / 73 | 13 / 73 |
Outcome results
Primary
A Comparison of the Percentage of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of Treatment.
A comparison of the Proportion of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of TreatmentSVR in both study arms
Time frame: 72 Weeks from initiation of treatment
Population: Included all patients who received at least one dose of treatment in both study arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A Infliximab | A Comparison of the Percentage of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of Treatment. | 28.8 percentage of participants |
| B Placebo | A Comparison of the Percentage of Chronic Hepatitis C Subjects (Treatment Naive,Genotype 1) Who Achieve SVR at Week 72, After 48 Weeks of Treatment. | 31.5 percentage of participants |
p-value: 0.718t-test, 2 sided
Primary
Number of Participants Achieving Sustained Virological Response (SVR)
HCV RNA negativity at 24 weeks after completion of all study medications
Time frame: 24 weeks after completion of all study medications
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A Infliximab | Number of Participants Achieving Sustained Virological Response (SVR) | 21 Participants |
| B Placebo | Number of Participants Achieving Sustained Virological Response (SVR) | 23 Participants |
Comparison: SVR was the primary outcome to calculate sample size. Assuming a 25% difference in the rate of SVR between the the two groups, a power of 0.85 and an alpha level of 0.05, 75 patients for each group was estimated. This analysis included patients randomized and received at least one dose of study drugs. A 2-sided probability value of \< 0.05 was considered statistically significant. Univariate and multivariable logistic regression were used for factors associated with an SVR.p-value: 0.718t-test, 2 sided
Secondary
A Comparison of the Percentage of Participants With Non-detectable HCV-RNA After 24 Weeks of Therapy.
A comparison of the proportion of the subject population with non-detectable HCV-RNA after 24 wks of therapy.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A Infliximab | A Comparison of the Percentage of Participants With Non-detectable HCV-RNA After 24 Weeks of Therapy. | 40 Participants |
| B Placebo | A Comparison of the Percentage of Participants With Non-detectable HCV-RNA After 24 Weeks of Therapy. | 41 Participants |
Secondary
Percentage of Participants Experiencing Medically Significant Infections
Medically significant infection was defined as an infection requiring the use of intravenous antibiotics or hospitalization.
Time frame: 72 weeks from initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A Infliximab | Percentage of Participants Experiencing Medically Significant Infections | 10 Participants |
| B Placebo | Percentage of Participants Experiencing Medically Significant Infections | 3 Participants |
Secondary
Percentage of Participants Experiencing Serious Adverse Events
The severity of adverse events was graded according to modified World Health Organization grades as mild, moderate, severe, or life-threatening
Time frame: 72 Weeks from initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A Infliximab | Percentage of Participants Experiencing Serious Adverse Events | 21 Participants |
| B Placebo | Percentage of Participants Experiencing Serious Adverse Events | 13 Participants |