Randomized Trial of Albinterferon Alfa-2b Every 4 Weeks for Chronic Hepatitis C Virus Genotype 2/3

S. Pianko; S. Zeuzem; W.-L. Chuang; G. R. Foster; S. K. Sarin; R. Flisiak; C.-M. Lee; P. Andreone; T. Piratvisuth; S. Shah; A. Sood; J. George; M. Gould; P. Komolmit; S. Thongsawat; T. Tanwandee; J. Rasenack; Y. Li; M. Pang; Y. Yin; G. Feutren; I. M. Jacobson

Disclosures

J Viral Hepat. 2012;19(9):623-634. 

In This Article

Methods

Study Oversight

This study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations and with the ethical principles laid down in the Declaration of Helsinki. The institutional review boards of participating centres approved the study protocol. All patients provided written informed consent. Novartis Pharma AG (Basel, Switzerland) and Human Genome Sciences, Inc. (Rockville, MD, USA) sponsored the study. Novartis was responsible for collection and statistical analysis of the data. A trial steering committee comprising study investigators provided input to the protocol and oversight of the conduct of the study, and an independent data-monitoring committee was responsible for ongoing review of safety data during the study. The authors had full access to the data, wrote this manuscript and take responsibility for the accuracy of the reported analysis.

Patient Selection

Adult patients (aged ≥18 years) were enrolled in the study if they had chronic HCV Gt 2 or 3 and had not previously received IFNα therapy. Patients were excluded if they had decompensated liver disease or other causes of chronic liver disease, thrombocytopenia (<90 000 platelets/mm3), neutropenia (<1500 neutrophils/mm3), history of moderate–severe psychiatric disease, immunologically mediated disease, uncontrolled thyroid disease, clinical evidence of pre-existing interstitial or other severe lung diseases (by pulmonary function testing and chest X-rays at screening), co-infection with hepatitis B virus or HIV, a significant coexisting medical condition, or alcohol or drug dependence.

Study Design

This phase 2b, randomized, multicentre, active-controlled, open-label, dose-ranging study was conducted at 53 centres in 10 countries (Australia, Canada, Germany, India, Italy, Poland, Spain, Taiwan, Thailand and UK) between October 2008 and May 2009 (ClinicalTrials.gov identifier NCT00759200). The median number of patients enrolled per site was 5 (range 1–33).

A centralized randomization assigned patients in a 3:4:4:4 ratio, in blocks of 15, to 1 of 4 treatment groups: active control Peg-IFNα-2a (PEGASYS; Hoffmann-La Roche Inc, Basel, Switzerland) 180 μg qwk (24 subcutaneous injections) and albIFN 900, 1200 and 1500 μg q4wk (six subcutaneous injections/group). The initial design included the option of evaluating albIFN 1800 μg q4wk (and additional Peg-IFNα-2a controls, leading to an overall 5:4:4:4:4 randomization) after an interim review of the 6-month data from the lower doses by the data-monitoring committee. This option was not pursued because of the anticipated absence of additional efficacy benefit from the highest albIFN dose, and therefore, only the three lower doses were investigated. All patients were to receive oral RBV 800 mg/day in two divided doses (RIBASPHERE; Three Rivers Pharmaceuticals, Warrendale, PA, USA). At baseline, all eligible patients were randomized using an interactive voice response system (IVRS). Investigators called the IVRS after confirming that patients fulfilled all the inclusion/exclusion criteria. The IVRS assigned randomization numbers to patients, which were used to assign patients to a treatment group. Randomization numbers were not communicated to callers and were generated using the following procedure to ensure that treatment assignment was unbiased: a patient randomization list was produced by the IVRS provider using a validated system that automated the random assignment of patient numbers to randomization numbers. These randomization numbers were linked to the different treatment arms, which in turn were linked to medication numbers. A separate medication randomization list was produced by Novartis Drug Supply Management using a validated system that automated the random assignment of medication numbers to medication packs containing each of the study drugs. The randomization scheme for patients was reviewed and approved by a member of the Novartis Biostatistics Quality Assurance Group.

Randomization was stratified by HCV Gt (2 or 3) and pretreatment serum HCV RNA level (≤ or >800 000 IU/mL). Treatment duration was 24 weeks, with 24-week follow-up. The study protocol specified stepwise (≥1 level) dose reductions of albIFN (steps down to 1200, 900, 700 and 500 μg) and Peg-IFNα-2a (steps down to 135, 90 and 45 μg) to manage haematologic abnormalities and moderate–severe AEs. The use of haematopoietic growth factors was not permitted.

Blood samples for the interleukin 28B (IL28B) single-nucleotide polymorphism rs12979860 Gt were collected retrospectively following the description by Ge et al.[8] of an association between the IL28B Gt and response to IFN therapy. Patients had to provide additional written informed consent for this test, and samples were obtained in one-third of the study population (n = 117).

Efficacy Assessments

The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA < limit of detection (LOD; 20 IU/mL) at 24 weeks after the end of therapy. Secondary efficacy endpoints were rapid virologic response at week 4 (RVR), defined as HCV RNA < limit of quantification (LOQ; 43 IU/mL); early virologic response at week 12 (EVR), defined as HCV RNA <LOQ or >2-log HCV RNA reduction; and end-of-treatment response (ETR), defined as HCV RNA <LOD at the end of treatment. Assessment of HCV RNA levels was accomplished using real-time polymerase chain reaction (CE-marked COBAS® AmpliPrep/COBAS TaqMan® HCV test; Roche Diagnostics, Basel, Switzerland).

Viral Kinetics

Assessments of HCV RNA were conducted in all patients at baseline, weeks 1, 2, 4, 12 and 24 on treatment, and weeks 4, 12 and 24 post-treatment. Intensive viral kinetics were examined in a subset of 38 patients with samples taken postdose at 12 and 24 h, days 3 and 8 and weeks 2, 3, 4, 6, 8, 10 and 12. All samples were obtained predose on injection days.

Safety Assessments

Safety was assessed by physical examination and laboratory tests during treatment and through 24 weeks after completion of therapy to document resolution of any ongoing AEs. Dose reductions of one or both drugs were permitted for clinically significant AEs or laboratory abnormalities. A single dose of albIFN or up to five doses of Peg-IFNα-2a could be withheld before discontinuation of the patient from the study. The severity of AEs was graded using the Division of Microbiology and Infectious Diseases toxicity rating scale.[9]

Statistical Methods

Because the primary objective of the study was to assess the safety and tolerability of the albIFN q4wk regimens, sample size was chosen based on the power to detect treatment-related AEs rather than statistical power for hypothesis testing. With 100 patients per albIFN treatment group, the probability of observing ≥1 AE with an underlying rate of 2% was >80%.

All analyses were performed in the intention-to-treat (ITT) population, defined as the subset of all randomized patients who received ≥1 dose of study agent. Adherence to IFN and RBV therapy was calculated as the total dose received/planned (based on 24 weeks of planned full-dose treatment) and expressed as a percentage. All statistical tests were two sided and performed at the 5% level of significance. All analyses were performed using SAS 9 statistical software (SAS Institute Inc., Cary, NC, USA). The SVR and on-treatment response rates for each treatment group, and the differences between each albIFN group and the Peg-IFNα-2a group were estimated with 95% confidence intervals. Statistical testing was performed using Pearson chi-square test (or Fisher's exact test when >20% of expected contingency table cell counts were <5). Safety was reported, and overall comparisons were made by treatment group.

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