Elsevier

The Lancet

Volume 374, Issue 9685, 18–24 July 2009, Pages 222-228
The Lancet

Articles
Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(09)60551-1Get rights and content

Summary

Background

Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists. We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function.

Methods

826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 μg interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week. Eligible patients were aged 40–79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55–90% of the predicted value, and a haemoglobin-corrected carbon monoxide diffusing capacity of 35–90% of the predicted value. The primary endpoint was overall survival time from randomisation measured at the second interim analysis, when the proportion of deaths had reached 75% of those expected by the study conclusion. This study is registered with ClinicalTrials.gov, number NCT00075998.

Findings

At the second interim analysis, the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo (1·15, 95% CI 0·77–1·71, p=0·497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41–84) on treatment, 80 (15%) patients on interferon gamma-1b and 35 (13%) on placebo had died. Almost all patients reported at least one adverse event, and more patients on interferon gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (eg, pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group.

Interpretation

We cannot recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function.

Funding

InterMune.

Introduction

Idiopathic pulmonary fibrosis is a diffuse parenchymal lung disease of unknown origin that is characterised by worsening dyspnoea, reduced lung volume, and impaired gas exchange.1, 2 The outlook is poor; median survival is about 2–5 years from diagnosis.1, 2, 3, 4, 5 The clinical course is characterised by an insidious decline in pulmonary function and progressive worsening of other symptoms (dyspnoea, cough, or fatigue) that limit and eventually preclude routine physical activities. Results of some studies suggest that the disease follows a variable course in which periods of relative stability are punctuated by episodes of accelerated decline, possibly resulting in respiratory failure and death.6, 7 These findings, coupled with the absence of proven effective treatments, provide a strong rationale for the development of drugs to improve survival.

Interferon gamma-1b is a purified protein that is manufactured in Escherichia coli from recombinant DNA encoding human interferon γ.8 The drug is approved to reduce the frequency and severity of infections in patients with chronic granulomatous disease, and to delay time to disease progression in patients with severe malignant osteopetrosis.9, 10 A large, randomised trial11 did not show improved progression-free survival for patients with idiopathic pulmonary fibrosis given interferon gamma-1b compared with placebo. However, analysis of the intention-to-treat population did show improved survival in patients given interferon gamma-1b (p=0·08), and exploratory subgroup analyses indicated that those with mild-to-moderate severity of disease had the best improvement.11 A meta-analysis12 of 390 patients from the previous study11 and two smaller studies,13, 14, 15 suggested that treatment with interferon gamma-1b was associated with a reduction in mortality for all severities of disease compared with the control group (placebo11, 13, 15 or colchicine12). The aim of INSPIRE (INternational study of Survival outcomes in idiopathic Pulmonary fibrosis with InteRfEron gamma-1b) was to assess the effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of baseline pulmonary function.

Section snippets

Patients

1373 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries (Belgium, France, Germany, Ireland, Italy, Spain, and UK), the USA, and Canada and screened for eligibility between Dec 15, 2003, and April 12, 2006. The study took place in teaching and community hospitals and clinics. The trial was discontinued on March 5, 2007, and the last patient visit was on May 2, 2009.

Eligible patients were 40–79 years of age, had been diagnosed with idiopathic

Results

Figure 1 shows the trial profile. Overall 99% (817 patients) of enrolled patients completed the study; five patients were lost to follow-up, and four withdrew consent. Table 1 shows baseline characteristics of participants assigned to interferon gamma-1b or placebo. Most patients were white men and the mean age of the whole group was 66 years (SD 7·8). High-resolution CT findings were sufficient to diagnose definite idiopathic pulmonary fibrosis in 485 (88%) and 235 (85%) patients on interferon

Discussion

We assessed a well defined population of patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function, in a study of patients who had high adherence to the protocol and assigned treatment. Treatment with interferon gamma-1b did not improve survival in patients compared with placebo, and consequently the data monitoring committee recommended early termination of the trial after the second interim analysis 152 weeks after enrolment began. Consistent with

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    IFN γ

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