Non-steroid agents for idiopathic pulmonary fibrosis

Spagnolo, Paolo; Giovane, Cinzia Del; Luppi, Fabrizio; Cerri, Stefania; Balduzzi, Sara; Walters, E. Haydn; D'Amico, Roberto; Richeldi, Luca

doi:10.1002/14651858.cd003134.pub2

Cited by 125 publications

(144 citation statements)

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“…In the years that followed, the change of view regarding the pathogenesis of IPF, coupled with the lack of efficacy of this approach, led to a strong negative recommendation for both prednisone monotherapy and combination therapy in the recent guidelines [1]. No placebo-controlled trials were identified in a recent meta-analysis to support the use of steroids in IPF [38,39].…”

Section: Completed Clinical Trialsmentioning

confidence: 99%

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Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future

2013

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During the past decade important progress has been made regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is the most devastating form of idiopathic interstitial pneumonia with a median survival of 3 years. The knowledge gained has been used to design multicentre, randomised, placebo-controlled trials in order to investigate agents with different mechanisms of action. Encouraging results have led to licensing of the first IPF-specific drug, pirfenidone. However, the road to successful treatment is still long. The main aim for the future should be the careful design of clinical trials, by choosing the most clinically meaningful end-point and keeping in mind that combination of various agents may be more effective. This approach has been used in the treatment of lung cancer with which IPF presents many similarities. @ERSpublications Progress toward the treatment of IPF and aims for future clinical trials

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Section: Completed Clinical Trialsmentioning

confidence: 99%

“…A recent Cochrane review, including the four studies mentioned above, has shown that treatment with pirfenidone reduced the risk for disease progression by 30% (HR 0.70, 95% CI 0.56-0.88) [39]. Based on the results of these studies, pirfenidone was licensed in Europe in 2011, for patients with mild-to-moderate disease.…”

Section: Pirfenidonementioning

confidence: 99%

Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future

2013

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“…This situation has been eased recently by the publication of several positive studies that have utilised forced vital capacity (FVC) or vital capacity (VC) as a logical end-point, given that it is a measure of how the individual's function has been affected and, importantly, a measure that has been shown to be amenable to therapy [60,61,63,70,72,73] Retaining the large numbers of patients that would need to be enrolled and followed for sufficiently long periods to obtain the required number of events to prove a mortality effect is problematic. The reasons for hospitalisations are varied, not always directly related to the lung fibrosing process and could not, therefore, be expected to be reduced in numbers by a drug that targets the fibrosing process.…”

Section: The Current Uncertainty About How To Measure Efficacy In Trimentioning

confidence: 99%

Section: The Current Uncertainty About How To Measure Efficacy In Trimentioning

confidence: 99%

“…In a meta analysis of clinical trials of adjuvant therapy regimens in NSCLC involving .7,000 individuals, first published online in 2008, significant improvements in disease-free survival were demonstrated with relative risks ranging from 0.88 to 0.89 [77]. A more recent literature search of all randomised controlled trials that studied novel adjuvant therapies for patients with NSCLC showed that in 14 studies involving .15,000 patients [78-91], a statistically significant treatment effect on progression-free survival was seen with hazard ratios ranging from 0.6 to 0.83, with a single exception [90] in which the hazard ratio in favour of therapy was reduced to 0.37.In light of the biological and behavioural similarities between IPF and cancer, and the widespread utilisation of progressionfree survival in cancer trials, it is interesting to note that an independent meta-analysis of the magnitude of effect on progression-free survival of the novel agent pirfenidone in the three phase III IPF studies [60,61,63,70,72], performed under the aegis of the Cochrane collaboration [72], showed a hazard ratio of 0.7, favouring pirfenidone. This magnitude of progression-free survival benefit, is, therefore, strikingly similar to that seen in NSCLC trials.…”

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confidence: 99%

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A progression-free end-point for idiopathic pulmonary fibrosis trials: lessons from cancer

Vancheri

Bois

2012

Eur Respir J

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.KEYWORDS: Clinical trials, fibroblast/myofibroblast, forced vital capacity, lung cancer, pulmonary fibrosis, pulmonary function tests I diopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterised by an accumulation of myofibroblasts in the alveolar wall, aberrant matrix deposition and subsequent distortion of the normal lung architecture. The disease results in progressive morbidity, worsening quality of life and an increasing dependence on others for the most basic of functional needs. The current paradigm of the pathogenetic process that results in IPF is that the disease is initiated by recurrent injury to the alveolar epithelium and evolves into an aberrant fibroproliferative response which progresses [1]. The cause(s) of the repeated injury is unknown but is thought to be the product of one or more environmental triggers operating within an individual whose genotype makes them susceptible to the disease [2]. More recently, IPF has been assimilated to a neoproliferative disorder based on the evidence that a number of pathogenic features of IPF are shared with cancer biology [3]. Genetic and epigenetic changes, delayed apoptosis and altered response to regulatory signals by myofibroblasts, reduced cellular communications and abnormal activation of specific signalling pathways have been shown to be hallmarks common to IPF and cancer. Consistent with this, COOL et al. [4] reported that ''fibroblast foci'', the characteristic defining lesions in IPF, are interconnected, forming a three-dimensional reticulum that resembles the tissue infiltration typical of cancer. The absence of monoclonality noted within the fibroblast foci and their incapacity to metastasise ...

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