Clinical Trial Result Information

Protocol number
NR16155

Title of Study
A randomized, partially blinded, multi-center, Phase II study investigating the efficacy and safety of Pegasys and Pegasys with Ribavirin in treatment-naïve patients with chronic hepatitis C co-infected with human immunodeficiency virus.

Sponsor
Roche Laboratories Inc.

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
A multi-center, randomized, partially blinded, placebo-controlled (for ribavirin), Phase II study in patients co-infected with chronic hepatitis C (CHC) and human immunodeficiency virus type 1 (HIV-1) receiving PEGASYS monotherapy for 14 weeks followed by continued monotherapy (responders at Week 12, Arm A) or equal randomization to PEGASYS plus ribavirin (non-responders at Week 12, Arm B) or PEGASYS plus placebo (non-responders at Week 12, Arm C) for 34 weeks. PEGASYS was administered once weekly 180 µg by subcutaneous (sc) injection, and oral ribavirin 400 mg was given twice daily. Non-responders at Week 24 were to be withdrawn from study treatment.

Study center(s)
19 centers in the United States.

Phase of development
IV

Objectives
Primary: To investigate the viral response at Week 72 of PEGASYS monotherapy 12-week responders who continued on PEGASYS monotherapy for a total of 48 weeks, and of PEGASYS monotherapy 12-week non-responders who had ribavirin or ribavirin placebo added at Week 14 for a continued treatment period of 34 weeks.

Secondary: To investigate (1) Viral response at Weeks 24, 36, 48, and 60 in the 3 arms (2) Viral response to PEGASYS monotherapy at Weeks 4 and 12; (3) Safety and effect of PEGASYS and PEGASYS plus ribavirin therapies on HIV-1 infection; (4) Effect of treatment on quality of life in the 3 arms; and (5) HIV-1 RNA levels at 4, 8, 12, 24, 36, 48, 52, 60, and 72 weeks.

Methodology
The study consisted of a screening phase, a 48-week treatment phase, and a 24-week treatment-free follow-up phase. After screening, all eligible patients began treatment with PEGASYS monotherapy. At Week 12, patients were tested for viral response. Responders (≥2-log10 decrease or undetectable [<50 IU/mL] HCV-RNA at Week 12) continued PEGASYS® monotherapy for a total of 48 weeks. Non-responders (<2-log10 decrease and detectable HCV-RNA [≥50 IU/mL] at Week 12) were equally randomized at Week 14 to continued PEGASYS therapy plus ribavirin or PEGASYS plus placebo for an additional 34 weeks of therapy. During the treatment period, patients were periodically assessed for HCV-RNA,, HIV-1 RNA, CD4 and CD8 cell counts and quality of life. At Week 24, patients were tested for viral response (undetectable HCV-RNA [<50 IU/mL]), and non-responders (detectable HCV-RNA) were to be discontinued from study treatment. Patients who were prematurely discontinued were followed for 12 weeks after the last dose of study medication, and patients who completed the 48-week treatment period were followed for 24 weeks for safety and sustained viral response (SVR).

Number of patients (planned/analyzed)
150 planned, 155 enrolled, and 154 received study medication.

Diagnosis and main criteria for inclusion
Male and female outpatients ≥18 years of age with serologic evidence of CHC (anti-HCV antibody test), detectable HCV-RNA in plasma (≥50 IU/mL), chronic liver disease consistent with CHC (biopsy within past 24 months), Child-Pugh Grade A classification, CD4 cell count ≥200 cells/mm3 or CD4 count of 100–199 cells/mm3 (inclusive) with a plasma HIV-1 RNA <5000 copies/mL, serologic evidence of HIV-1 infection (HIV-1 antibody or HIV-1 RNA), stable disease, and stable antiretroviral therapy. The study population was to include ≥20% African-Americans, and ≤20% of patients were to have mild to moderate liver cirrhosis and no evidence of hepatocellular carcinoma.

Test product, dose and mode of administration or test procedure
PEGASYS (1-mL aliquot in 2-mL vial) 180 µg/sc/week; ribavirin 400 mg/po/bid.

Duration of treatment
48 weeks.

Reference therapy, dose and mode of administration or reference procedure
Placebo tablets/po.

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: SVR in each of the 3 treatment arms. Secondary efficacy parameters: (1) Overall SVR for PEGASYS monotherapy (estimated from Arms A and C and from discontinuations before Week 14); (2) Viral response at Weeks 4, 12, 24, 36, 48, and 60 in each treatment arm; (3) Time to initial viral response in each of the 3 treatment arms; (4) Actual and change from baseline in HIV-1 RNA up to Week 72 and in CD4/CD8 cell counts up to Week72; (5) Alterations in HAART drugs, doses, or regimens after 8 weeks of study treatment; and (6) Actual and change from baseline in all domains of the Hepatitis Quality of Life Questionnaire (HQLQ), Physical Component Summary, and Mental Component Summary up to Week 72. Viral response parameters: (1) Decrease of ≥2-log10 or undetectable HCV-RNA (<50 IU/mL) prior to Week 14; or (2) undetectable HCV-RNA (<50 IU/mL) after Week 14. Safety parameters: (1) Adverse events; (2) Death; (3) Serious adverse events; (4) Clinical laboratory tests; (5) Vital signs; (6) Body weight; (7) Physical examinations; (8) Dose adjustments; and (9) Premature withdrawals for adverse events or laboratory abnormalities.

Statistical methods
Viral response was calculated as the proportion of treated patients with a response at a given time point and was summarized descriptively including 95% confidence intervals for the intent-to-treat population. Patients without a viral assessment were considered non-responders. No hypothesis testing was performed, and a per-protocol analysis was not warranted. Changes from baseline were analyzed using available data (no imputation for missing values) and 2 definitions of baseline (before PEGASYS therapy and before the assigned Week-14 therapy).

Summary (efficacy, safety, other results)
Efficacy –Of the 155 patients enrolled, 154 received study medication (1 patient did not receive study medication and was not included in any analysis). At Week 14, 55 Week 12 responders continued on PEGASYS monotherapy and 76 Week12 non-responders were randomized to PEGASYS plus ribavirin (n=37) or PEGASYS plus placebo (n=39). A SVR was achieved by 35% of Week-12 responders on PEGASYS monotherapy. The overall SVR for co-infected patients treated with 48 weeks of PEGASYS therapy was projected to be 12% (19/154). All Week12 non-responders on PEGASYS + placebo failed to achieve a SVR.. Only 1 Week12 non-responder and 1 Week12 responder (randomized in error) achieved a SVR with PEGASYS + ribavirin. The proportion of patients with undetectable HCV-RNA (<50 IU/mL) at Week 24 in the PEGASYS monotherapy group was 58% and remained fairly constant to Week 48 (55% , end of treatment); relapse was identified by Week 60 (12 weeks post treatment). The decrease in HQLQ scores during treatment indicated a general decline in the patients’ quality of life during therapy in each of the treatment groups; however, scores returned to or approached baseline after therapy ended.

Safety – Patients co-infected with CHC and HIV-1 tolerated both PEGASYS monotherapy and combination therapy with PEGASYS and ribavirin over a 48-week treatment period. Adverse events were common, reported by 98% of patients before Week 14 and in 87%–95% after Week 14. The most frequent adverse events were those previously associated with interferon alpha (IFNα) therapy (eg, fatigue, myalgia, headache, neutropenia, nausea, pyrexia, rigors, insomnia, depression, and arthralgia). One death (coronary artery thrombosis considered unrelated to study treatment), 24 serious adverse events (in 13% of all patients), and 3 AIDS–defining events occurred. Dose modification and premature discontinuation of study medication occurred in 25% and 6% of patients, respectively, before Week 14 and in 8%–19% and 11%–13% of patients, respectively, after Week 14. Dose modifications before Week 14 were mainly due to neutropenia/decreased neutrophil count (21%). Neutrophil, platelet, and lymphocyte counts and hemoglobin concentration decreased during study treatment but generally recovered during the treatment-free follow-up period. About 31% of patients had a 5%–10% decrease in body weight after Week 14, and 15% of patients had a >10% decrease. Certain expected events were specifically assessed. Neutropenia and anemia were usually managed with granulocyte colony-stimulating factor and epoetin, respectively, or with dose modification of study treatment. Two patients on PEGASYS monotherapy (1 before and 1 after Week 14) had study treatment discontinued because of neutropenia, and 5 patients (1 on PEGASYS monotherapy before Week 14, 3 on PEGASYS plus placebo, and 1 on PEGASYS plus ribavirin) had study treatment discontinued because of anemia. Mean HIV-1 RNA viral load was relatively stable. In general, CD8 cells decreased and CD4 cells increased as a percentage of total lymphocytes during study treatment, but both returned to near baseline after treatment ended.

Conclusions
In patients co-infected with CHC and HIV-1, Week 12 responders to PEGASYS monotherapy achieved a 35% SVR after 48 weeks of therapy and 24 weeks of follow-up. From this study, the SVR for co-infected patients treated with PEGASYS for 48 weeks was projected to be 12%. None of the Week 12 non-responders achieved a sustained response with continued PEGASYS plus placebo. Combination therapy with ribavirin did not improve response among Week 12 non-responders to monotherapy. PEGASYS did not appear to affect the course of HIV-1, and its safety and tolerability were similar to other IFNα therapies. Adverse effects of treatment were usually manageable with specific treatment and/or dose reduction, or occasionally with treatment discontinuation.

Publications (references, if available)
Khalili M. Peginterferon alfa-2a with or without ribavirin in HCV/HIV coinfection; partially blinded, randomized multicenter trial. Digestive Diseases and Sciences 2005; 50 (6): 1148-1155.

Date of report
1/27/2004