Challenges in idiopathic pulmonary fibrosis trials: the point on end-points

Albera, Carlo

doi:10.1183/09059180.00001711

Cited by 20 publications

(21 citation statements)

References 42 publications

(44 reference statements)

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“…80 Few studies have used PFS and different studies appear to use different composite end points. Caution is, therefore, required in their interpretation.…”

Section: Progression-free Survivalmentioning

confidence: 99%

“…The IPF NMA focused on the FVC end point as clinical evidence has established a correlation with disease progression 80 and, thus, FVC drives the economic model (discussed in Chapter 4, Independent economic evaluation). Ten studies met the inclusion criteria and were included in the analysis ( Table 54).…”

Section: Network Meta-analysismentioning

confidence: 99%

“…The FVC and 6MWT are suggested to be the best predictors of mortality at baseline in IPF. 80 Other outcomes include HRQoL, PFS, peripheral oxygen saturation (SpO 2 ) during the SMWT, respiratory hospitalisations, and time to disease progression.…”

Section: Other Searchesmentioning

confidence: 99%

“…80 HRCT scans were performed in accordance with predetermined protocol at baseline and 6-month intervals. Three expert radiologists independently evaluated the pattern of lung fibrosis.…”

Section: Respiratory Hospitalisationmentioning

confidence: 99%

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The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

Loveman

Copley

Colquitt

et al. 2015

Health Technology Assessment

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease that generally affects people over 60 years old. The main symptoms are shortness of breath and cough, and as the disease progresses there is a considerable impact on day-to-day life. Few treatments are currently available.ObjectivesTo conduct a systematic review of clinical effectiveness and an analysis of cost-effectiveness of treatments for IPF based on an economic model informed by systematic reviews of cost-effectiveness and quality of life.Data sourcesEleven electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, and The Cochrane Library and the Centre for Reviews and Dissemination databases, were searched from database inception to July 2013. Reference lists of relevant publications were also checked and experts consulted.MethodsTwo reviewers independently screened references for the systematic reviews, extracted and checked data from the included studies and appraised their risk of bias. An advisory group was consulted about the choice of interventions until consensus was reached about eligibility. A narrative review with meta-analysis was undertaken, and a network meta-analysis (NMA) was performed. A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Parameter values were obtained from NMA and systematic reviews. Univariate and probabilistic sensitivity analyses were undertaken. The model perspective is NHS and Personal Social Services, and discount rate is 3.5% for costs and health benefits.ResultsFourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, threeN-acetylcysteine (NAC) (alone or in combination), four pirfenidone, one BIBF 1120, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good, with a low risk of bias. The current evidence suggests that some treatments appear to be clinically effective. The model base-case results show increased survival for five pharmacological treatments, compared with best supportive care, at increased cost. General recommendations cannot be made of their cost-effectiveness owing to limitations in the evidence base.LimitationsFew direct comparisons of treatments were identified. An indirect comparison through a NMA was performed; however, caution is recommended in the interpretation of these results. In relation to the economic model, there is an assumption that pharmacological treatments have a constant effect on the relative rate of per cent predicted forced vital capacity decline.ConclusionsFew interventions have any statistically significant effect on IPF and a lack of studies on palliative care approaches was identified. Research is required into the effects of symptom control interventions, in particular pulmonary rehabilitation and thalidomide. Other research priorities include a well-conducted randomised controlled trial on inhaled NAC therapy and an updated evidence synthesis once the results of ongoing studies are reported.Study registrationThis study is registered as PROSPERO CRD42012002116.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…80 Few studies have used PFS and different studies appear to use different composite end points. Caution is, therefore, required in their interpretation.…”

Section: Progression-free Survivalmentioning

confidence: 99%

Section: Network Meta-analysismentioning

confidence: 99%

Section: Other Searchesmentioning

confidence: 99%

“…80 HRCT scans were performed in accordance with predetermined protocol at baseline and 6-month intervals. Three expert radiologists independently evaluated the pattern of lung fibrosis.…”

Section: Respiratory Hospitalisationmentioning

confidence: 99%

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The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

Loveman

Copley

Colquitt

et al. 2015

Health Technology Assessment

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“…The challenges inherent in finding completely effective agents have been addressed in a number of recent reviews [9][10][11][12][13]. Part of the problem is disagreement about how to judge drug efficacy.…”

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confidence: 99%

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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Idiopathic Pulmonary Fibrosis Clinical Trials: Evolving Concepts

Martínez

2013

Idiopathic Pulmonary Fibrosis

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Challenges in idiopathic pulmonary fibrosis trials: the point on end-points

Cited by 20 publications

References 42 publications

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

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

Idiopathic Pulmonary Fibrosis Clinical Trials: Evolving Concepts

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