Decline in Pulmonary Function during Chronic Hepatitis C Virus Therapy With Modified Interferon Alfa and Ribavirin

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

Disclosures

J Viral Hepat. 2013;20(4):e115-e123. 

In This Article

Methods

Patients

A more detailed description of the methods, design and primary results of this trial was published previously.[7] Adult patients with chronic HCV genotype 2 or 3 who had not previously received IFNα therapy were enrolled in the study. Patients with 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, co-infection with hepatitis B virus or HIV, a significant coexisting medical condition, or alcohol or drug dependence were excluded. The hepatologist investigators excluded patients with clinical evidence of preexisting ILD or other clinically severe lung disease.

The institutional review boards of the participating centres approved the study protocol, and all patients provided written informed consent.[7]

Study Design

This phase 2b, randomized, multicenter, active-controlled, open-label, dose-ranging study was conducted at 53 centres in 10 countries between October 2008 and May 2009 (ClinicalTrials.gov Identifier: NCT00759200).[7] Patients enrolled in the study were randomly assigned using a centralized interactive voice response system in a ratio of 4:4:4:3 in blocks of 15, to one of four treatment groups, including three albIFN groups (900, 1200 and 1500 μg q4wk; six injections in each group) and the active control Peg-IFNα-2a (Pegasys, Hoffmann–La Roche Ltd, Basel, Switzerland) group (180 μg qwk; 24 injections), with both agents administered subcutaneously. All patients also received oral RBV (Ribasphere, Three Rivers Pharmaceuticals, Warrendale, PA, USA) 800 mg/d in two divided doses. All patients were treated for 24 weeks, with 24-week follow-up.

The primary objective of the study was to assess the safety and tolerability of the albIFN q4wk regimens.[7] The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<20 IU/mL) at 24 weeks after therapy.

Pulmonary Evaluations

Spirometry (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC] and FEV1/FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) testing were conducted at baseline, treatment weeks 12 and 24 (or end of treatment), and 24 weeks posttreatment. For spirometry and DLCO assessments, patients were referred to a local pulmonary function laboratory that was certified by the central pulmonary function laboratory (Biomedical Systems, Saint Louis, MO, USA) prior to study initiation. Spirometry and DLCO tests were standardized according to American Thoracic Society/European Respiratory Society guidelines,[8,9] and DLCO was corrected for haemoglobin (see details in Supporting Information Data S1). Data were transferred from the local pulmonary function laboratory to the central laboratory, where they were read for quality control purposes and processing prior to being transferred to the study sponsor.

To confirm the abnormalities, spirometry was repeated within 2 weeks for patients with: (i) a ≥ 10% FVC decrease from baseline, if baseline FVC was <80% of the predicted value; (ii) an FVC reduction to <80% of predicted, if baseline FVC was normal (≥80% of predicted); or (iii) a ≥ 10% decrease in FEV1/FVC from baseline. Spirometry and DLCO were repeated within 2 weeks for patients with: (i) a ≥ 15% DLCO decrease from baseline, if baseline DLCO was <80% of the predicted value or (ii) a DLCO reduction to <80% of predicted, if baseline DLCO was normal (≥80% of predicted). These thresholds for reduced absolute values and declines in spirometry and DLCO are considered clinically relevant abnormalities in the context of ILD and therefore were used also to categorize spirometry and DLCO data in the statistical analyses.[10,11]

Chest X-rays (CXRs; postero-anterior and lateral views) were obtained at baseline and week 24 (or end of treatment). Chest x-rays were read centrally (RadPharm, Princeton, NJ, USA), and abnormal CXRs were reviewed by an independent radiologist (Prof David Lynch, National Jewish Health, Denver, CO, USA). Routine computed tomography of the chest was not included in the study protocol due to ethical concern and several country regulations prohibiting unnecessary X-ray exposure. Clinical AEs were coded according to the Medical Dictionary for Regulatory Activities, with severity graded using the Division of Microbiology and Infectious Diseases toxicity rating scale.[12]

Statistical Methods

Sample size was chosen based on the power to detect treatment-related AEs, rather than statistical power for hypothesis testing.[7] A minimum of 100 patients per albIFN treatment group and 75 in the Peg-IFNα-2a control group were targeted to be randomized and treated in this study to provide >80% power to detect an AE occurring at an actual rate of 2%.

All analyses were performed in the intention-to-treat population with all available data (including spirometry and DLCO retesting), using SAS 9 statistical software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and performed at the 5% level of significance. No adjustment was made for multiple comparisons. Likelihood ratio test (or Fisher's exact test when >20% of expected contingency table cell counts were <5) was used for categorical variable comparisons, and analysis of variance was used for continuous variable comparisons. A logistic regression model was built to investigate the relation between DLCO decline (≥ vs <15%) and disease characteristic covariates.

Role of the Funding Source

Novartis Pharma AG (Basel) sponsored the study, which was cofunded by Human Genome Sciences (Rockville, MD, USA).[7] Novartis was responsible for collection and statistical analysis of the data and contributed to patient recruitment, trial management and writing and review of the report. 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 corresponding author had final responsibility for the decision to submit for publication. The authors had full access to the data, wrote this manuscript and take accountability for the accuracy of the reported analysis.

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