Randomized, Double-Blind, Placebo-Controlled Study of Interferon Gamma-1b (IFN- 1b) Treatment on Biomarkers of Fibrosis, Angiogenesis, and Antimicrobial Activity in Patients with IPF
R. Strieter, R. Enelow, I. Noth, V. Valentine, K. Brown, A. Frost, L. Lancaster, P. Noble, A. Chan, M. Glassberg, M. Kallay, D. Mapel, S. Sahn, M. Wencel, D. Zisman, B. Bradford, M. Burdick, K. Starko. UCLA; U of Virginia; U of Chicago; Oschsner Clinic; National Jewish Med Res Center; Baylor U; Vanderbilt U; Yale U; UC at Davis; U of Miami; Highland Hospital; Lovelace Sci Res; Med U of South Carolina; Wichita Clinic; U of Pennsylvania; InterMune, Inc.,
Rationale: IFN- is a pleiotropic cytokine with anti-fibrotic activities supporting a potential role in IPF.Characterization of the biologic effects of IFN- 1b will enhance understanding of IPF pathogenesis and treatment. Methods: Patients receiving prednisone 10mg qd were randomly assigned to IFN- 1b 200 g sc or placebo tiw for 6 months. At baseline (BL) and 6 months, mRNA was isolated from transbronchial (TBBx) biopsies and BAL cells and examined for biomarkers of fibrosis and angiogenesis; BAL fluid and plasma were examined for the same markers at the protein level and antimicrobial peptides. Safety, oxygenation, DLCO, lung volume, dyspnea, and the 6-minute walk (6-MW) were evaluated. Results: The 32 patients" mean age was 64 yrs; 63% were male. All patients had IPF diagnosis by HRCT with honeycombing in 24; 19 had surgical lung biopsy diagnosis. At BL, the mean SD FVC (% pred), DLCO (% pred), and PaO2 were 67 12, 42 9, and 77 10, respectively. Mean 6-MW distance was 442 meters. Mean TBBx and BAL cell pellet mRNA recovered was 4.5ug and 20.5ug; mean BAL cell count was 1.95x105 (range =0.015-5.55x105); and mean alveolar macrophages, lymphocytes, neutrophils, and eosinophils percents were 75, 13, 10, and 2. BL and 6 month biomarker and clinical evaluations will be compared and may provide further evidence for the biologic basis of IFN- 1b treatment in IPF.
This abstract is funded by: InterMune, Inc and P01-HL67665
Sunday, May 18, 2003 1:30 PM
Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial of Interferon Gamma-1b (IFN- 1b) in Patients with Idiopathic Pulmonary Fibrosis (IPF)
G. Raghu, K. Brown, W. Bradford, K. Starko, P. Noble, D. Schwartz, T. King, IPF Study Group. U Washington, Seattle, WA; National Jewish Med Center, Denver, CO; InterMune, Inc., Brisbane, CA; Yale U, New Haven, CT; Duke U, Durham, NC; UCSF, San Francisco, CA
Rationale: IPF is a devastating disease with a median survival of 2 3 years, and no proven treatment. This study evaluated the safety and efficacy of IFN- 1b in steroid-refractory IPF patients (pt). Methods: IPF pt were randomized to IFN- 1b 200 g or placebo (PBO) SQ tiw for up to 3 years. The primary endpoint was time to death or disease progression ( 10% decrease in % pred FVC or 5 mmHg increase in A-a gradient). Secondary endpoints included dyspnea, disease progression, DLco, FVC, A-a gradient, quality of life, survival, HRCT response, and O2 use. The prespecified data cutoff for the primary analysis was 48 wk after randomization of the 306th patient. Results: 330 pt were randomized. Baseline (BL) mean FVC (64% vs 64%), % pt with surgical lung biopsy (62% vs 67%), and median days follow-up at data cutoff (413 vs 408) were similar in IFN- 1b (n=162) and PBO (n=168) pt. Death or disease progression occurred in 46.3% and 51.8% of IFN- 1b and PBO pt, respectively (11% reduction, p=0.53). Among IFN- 1b and PBO pt, death occurred in 9.9% and 16.7% overall (41% reduction, p=0.08), in 3.3% and 13.0% of the FVC > 60% at BL subgroup (p=0.02), and in 18.1% and 21.1% of the FVC < 60% at BL subgroup (p=0.75), respectively. No significant effects were observed on other secondary endpoints. Exploratory analyses suggest less dyspnea after 1 year and less O2 use in IFN- 1b vs PBO pt. IFN- 1b was well tolerated but IFN- 1b pt had more constitutional sxs and non-fatal pneumonias. These results and 4 additional months of blinded PBO-controlled data will be presented.
This abstract is funded by: InterMune, Inc.
Sunday, May 18, 2003 1:30 PM
Comparison of Interferon Gamma-1b (IFN- ) and Colchicines in the Treatment of Idiopathic Pulmonary Fibrosis: Preliminary Results of a Prospective, Multicenter Randomized Study
K.M. Antoniou, V. Polychronopoulos, M. Dimadi, A. Rapti, C. Lambrakis, P. Latsi, A. Nicholson, N. Bachlitzanakis, N.M. Siafakas, D. Bouros. Pneumonology, General Hospital Venizeleion, Heraklion, Crete, Greece; General Hospital Sismanoglion, Athens, Greece; Chest Hospital Sotiria, Athens, Greece; Histopathology, Royal Brompton, London, England; Pneumonology, University Hospital, Heraklion, Crete, Greece
Introduction: Interferon gamma-1b, has been reported to be of benefit in the treatment of IPF. Colchicine is suggested as first line therapy for patient's refractory to corticosteroids.
Aim: To compare IFN- (200 g SC, 3 wk) and colchicines (1 mg/day, po) plus 10 mg prednisone in a multicenter randomized parallel study.
Methods: Until September 2002, 44 patients (age range 44-82 yr) entered the study after a two-month run in period with prednisone, following a randomized allocation. All patients fulfilled the established criteria for the diagnosis of IPF (70.4% had histological proven disease). Clinical data, PFTs, arterial blood gases and imaging (HRCT, DTPA, CXR) were recorded at baseline and at follow up.
Results: In a median follow up of 15 months, two patients died from the colchicines group and one from the IFN group. After six months of treatment, 53% of patients improved, 30% remained stable and 17% deteriorated in the IFN- group, while 50% remained stable and 50% deteriorated in the colchicine group, according to the ATS/ERS criteria. Patients of the IFN- group tended to have improvement of dyspnea after six months of treatment (p=0.035).
Conclusion: This preliminary data show that IFN- is well tolerated and could be a promising treatment for IPF.
Sunday, May 18, 2003 1:30 PM
[**] Poster Discussion Session (Abstract Page: A168) Session: 1:30 pm-4:15 pm, PULMONARY FIBROSIS: THERAPEUTIC INTERVENTIONS |
