Clinical Trial Result Information
Title of Study:
An open-label, multicenter, randomized, safety, feasibility and tolerability pilot study of PEGASYS (peginterferon alfa-2a) plus Copegus (ribavirin) in previous intravenous drug users (IVDUs) who are currently enrolled in a methadone maintenance treatment program.
Fast Facts:
| Protocol number: | ML17251 |
| Sponsor: | Roche Laboratories Inc. |
| Company division: | Pharmaceutical |
| Product name: | PEGASYS |
| Generic name: | peginterferon alfa-2a (40KD) |
| Phase of development: | IV |
| Therapeutic area, approved indication: | Hepatitis C, Chronic |
| Date of report: | 6/1/2007 |
Clinical study summary:
This was a prospective, randomized, multicenter, open-label pilot study in patients with chronic hepatitis C who were previous intravenous drug users now enrolled in a methadone maintenance treatment program, to investigate whether they could tolerate treatment with PEGASYS (peginterferon alfa-2a (40KD)) plus Copegus (ribavirin).
Study center(s) :
6 centers in the United States.
Objectives:
To investigate if treatment-naïve patients with genotype 1, 2, or 3 chronic hepatitis C virus (HCV) infection, who were previous IVDUs enrolled in a physician-supervised methadone maintenance treatment program, could safely tolerate chronic hepatitis C treatment consisting of PEGASYS 180µg once per week for 24 (G2/3) or 48 weeks (G1) plus ribavirin 800mg (G2/3) or 1000mg/1200mg (G1, depending on the patient's weight) respectively, given as two doses per day, either in a self-administered fashion or under directly observed conditions.
Methodology:
All patients were participating in a methadone maintenance program. After screening, eligible patients were equally randomized to one of the two study arms, direct-observe-therapy (DOT) or self-administration (SA) stratified by HCV genotype (genotype 1, genotype 2 or 3) and started on PEGASYS plus ribavirin therapy, with the prescribed regimen determined by HCV genotype. Patients with HCV genotype 1 who did not have a ≥2-log10 decrease in HCV RNA at Week 12 could be prematurely withdrawn from the study at the investigator's discretion. Patients who completed the planned study treatment period continued in a 24-week treatment-free follow-up.
Assessments were performed during screening, at baseline, and at intervals throughout the 24- or 48-week treatment period and the 24-week treatment-free follow-up. Adverse events and concomitant medications were continually monitored and reasons for premature withdrawal recorded. Depression (BDI-II), quality of life (HQLQ), and serum HCV RNA were assessed periodically throughout the treatment and treatment-free follow-up periods.
Number of patients (planned/analyzed):
50 patients planned; 48 enrolled and treated.
Diagnosis and main criteria for inclusion:
Adult patients with chronic HCV infection (genotype 1, 2 or 3) who were HCV treatment naïve, previous IVDUs, and enrolled in a methadone maintenance treatment program with documented attendance for at least 3 months.
Test product, dose and mode of administration or test procedure:
All patients received open-label PEGASYS + Copegus treatment based on HCV genotype. Patients randomized to the direct-observe-therapy (DOT) arm received PEGASYS at the clinic; those randomized to the self-administration (SA) arm administered their PEGASYS dose at home.
Genotype 1: PEGASYS (peginterferon alfa-2a (40KD)) 180µg subcutaneously once weekly + Copegus (ribavirin) 1000 or 1200mg/day (< or ≥75kg, respectively) taken orally in two doses.
Genotype 2 or 3: PEGASYS (peginterferon alfa-2a (40KD)) 180µg subcutaneously once weekly + Copegus (ribavirin) 800mg/day taken orally in two doses.
Duration of treatment:
48 weeks (genotype 1); 24 weeks (genotype 2 or 3).
Reference therapy, dose and mode of administration or reference procedure:
N/A.
Criteria for evaluation (efficacy, safety):
This was primarily a safety study. All efficacy endpoints were secondary.
Primary: Treatment completion rate ie the proportion of patients who were able to complete the prescribed length of PEGASYS plus ribavirin therapy. Standard safety analyses: Adverse events, clinical laboratory test results, vital signs and reasons for discontinuation.
Secondary: Total scores of Beck Depression inventory, and degrees of depression based on the BDI-II; domain scores for the Hepatitis Quality-of-Life Questionnaire (HQLQ); compliance to the prescribed treatment regimen; sustained response rate (proportions of patients with a virological response, ie undetectable HCV RNA [<10IU/mL] at 24 weeks post-treatment); virological response rate (proportions of patients with undetectable HCV RNA at all time points evaluated); proportions of patients with a ≥2 log10 decrease from baseline or undetectable HCV RNA at weeks 4 and 12; biochemical response rate (proportions of patients with normal serum alanine aminotransferase) at all time points evaluated. Standard efficacy analyses: Measurements at weeks 4, 12, 24 and 48 (genotype 1 only) during treatment and at 12 and 24 weeks post-treatment were evaluated.
Statistical methods:
The study size was estimated based on clinical judgement; no statistical power analysis was performed. All data were summarized descriptively using frequency counts and proportions for categorical variables and location and scale statistics for continuous variables. No statistical comparisons were planned or performed.
Summary (efficacy, safety, other results):
Safety: Overall, 77.1% of patients (83.3% in the DOT arm and 70.8% in the SA arm) were able to complete the PEGASYS plus ribavirin therapy as defined by the protocol (i.e., completed the prescribed course of treatment or were withdrawn due to insufficient therapeutic response at Week 12; primary endpoint). Tolerability indices showed a mild depression and a relatively poor quality of life in these patients at baseline, which worsened during the treatment period and returned towards baseline during the treatment-free follow-up period in both study arms. Patients in the DOT arm appeared to have a higher treatment completion rate, lower incidence of moderate/severe depression (33.3% vs. 58.3% of patients, respectively), and better compliance (62.5% vs. 45.8% were > 97% compliant with PEGASYS administration) than patients in the SA arm.
The overall safety of PEGASYS and ribavirin treatment in this patient population was indicated by the few patients who experienced a serious event (6 patients, 13%) or who required premature discontinuation of study treatment due to an adverse event (6 patients, 13%). No deaths occurred. All patients experienced an adverse event, mainly mild or moderate in intensity, with fatigue and nausea experienced by the most patients (73% and 56% of patients, respectively). Depression, headache, arthralgia, insomnia, rash, irritability, neutropenia and vomiting were also frequently reported. Fewer patients in the DOT than the SA arm experienced events associated with interferon and ribavirin therapy (fatigue, pyrexia, vomiting, alopecia, hyperhidrosis, myalgia, pharyngolaryngeal pain, and decreased appetite). A total of 29.2% of patients had a hemoglobin concentration <10 g/dL, 12.5% a neutrophil count < 0.75 × 109 cells/L and 6.3% a platelet count < 50 × 109 cells/L at some time during the study. In each case, the laboratory abnormality was managed with treatment and/or a dose adjustment of one or both of the study drugs, and discontinuation of study treatment was not needed. Dose adjustments of PEGASYS and/or ribavirin for an adverse event or laboratory test result were required in 18.8% and 43.8% of study patients, respectively. Serum triglycerides increased and cholesterol decreased during study treatment, with each returning towards baseline after study treatment ended.
Efficacy: Secondary efficacy endpoints showed a virological response (undetectable [< 10 IU/mL] HCV RNA at Week 12) in 27.6% of patients with HCV genotype 1 and in 100% of patients with HCV genotype 2 or 3, with little or no difference between the two study arms. A sustained virological response at 24 weeks post-treatment was observed in 31.0% of patients with HCV genotype 1 (23.1% and 37.5% in the DOT and SA arms, respectively) and in 63.2% of patients with HCV genotype 2 or 3 (90.9% and 25.0%, respectively). At all time points, a biochemical response was more frequent in patients with HCV genotype 2 or 3 than genotype 1 and among HCV genotype 2 or 3 was more frequent in the DOT than the SA arm.
Conclusions:
Most of the previous intravenous drug users on methadone maintenance in this study were able to complete the protocol-defined course of PEGASYS plus ribavirin therapy for chronic hepatitis C. Few patients had treatment discontinued because of an adverse effect, and many who completed treatment achieved a sustained virological response, all indicating that PEGASYS plus ribavirin can be safely and successfully used to treat this patient population. Patients in the direct-observation therapy arm had a higher treatment completion rate, a lower incidence of moderate/severe depression, and better compliance than patients in the self-administration arm.
Publications (references, if available):
Bonkovsky HL et al. Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients : randomized comparison of direct observed therapy and self administration (abstract). Presentation at Digestive Disease Week Meeting, May 19-24 2007, Washington DC.
Sulkowski M et al. Depression and QoL in direct observed therapy as compared with self administration of PegIFN-α2a in chronic hepatitis C patients on methadone maintenance (abstract). Presentation at College of Problems of Drug Dependence Meeting, June 16-21 2007, Quebec City, Canada.
Click here for the protocol registry listing of this trial.
