Clinical trials of investigational agents for IPF: a review of a Cochrane report

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Abstract

The magnitude of treatment effect can be assessed by a number of methods. One reliable method of collectively analysing data from randomised clinical trials is that used in Cochrane reviews. These systematic reviews identify and analyse the available evidence using the reliable method of meta-analysis. These often combine data from studies to provide robust evaluations of overall treatment effects. In 2003, a review of data from studies of corticosteroid use in IPF patients found no evidence of a treatment effect. Similarly, very little evidence was found to support the use of immunomodulatory agents. A recent update of these Cochrane reviews failed to identify any new evidence supporting the use of corticosteroids in IPF. However, a review of non-steroid agents for the treatment of IPF identified data from 15 RCTs that was suitable for analysis. Two trials of interferon gamma-1b were pooled and analysed, but no treatment effect was observed in terms of survival. Meta-analysis of three Phase III studies of pirfenidone treatment in IPF patients suggested that progression-free survival was significantly increased by 30%, demonstrating a reduction in the decline of lung function in IPF patients. In addition, there are numerous ongoing trials investigating potential therapeutic agents which provides hope for IPF patients and their doctors.

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Most cited references 13

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Pirfenidone in idiopathic pulmonary fibrosis.

H Taniguchi, M Ebina, Y Kondoh … (2010)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

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

Talmadge E King, Carlo Albera, Williamson Bradford … (2009)

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. 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 microg 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. 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. 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. InterMune.

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Rationale for systematic reviews.

C D Mulrow (1994)

Systematic literature reviews including meta-analyses are invaluable scientific activities. The rationale for such reviews is well established. Health care providers, researchers, and policy makers are inundated with unmanageable amounts of information; they need systematic reviews to efficiently integrate existing information and provide data for rational decision making. Systematic reviews establish whether scientific findings are consistent and can be generalised across populations, settings, and treatment variations, or whether findings vary significantly by particular subsets. Meta-analyses in particular can increase power and precision of estimates of treatment effects and exposure risks. Finally, explicit methods used in systematic reviews limit bias and, hopefully, will improve reliability and accuracy of conclusions.

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Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Print): 2013

Publication date (Electronic): 16 April 2013

Volume: 14

Issue: Suppl 1

Page: S4

Affiliations

[1 ]Luca. Richeldi, Centre for Rare Lung Disease, University of Modena and Reggio Emilia, Modena, Italy

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Publisher ID: 1465-9921-14-S1-S4

DOI: 10.1186/1465-9921-14-S1-S4

PMC ID: 3643529

PubMed ID: 23734867

SO-VID: 35d8d6b0-6294-41f1-9f9e-204d9422c81d

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Conference name: AIR: Advancing IPF Research. Working together to translate IPF research into practice

Clinical trials of investigational agents for IPF: a review of a Cochrane report

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Most cited references 13

Pirfenidone in idiopathic pulmonary fibrosis.

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

Rationale for systematic reviews.

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