A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials

Collard, Harold R.; Bradford, Williamson Z.; Cottin, Vincent; Flaherty, Kevin R.; King, Talmadge E.; Koch, Gary G.; Kolb, Martin; Martínez, Fernando J.; Montgomery, Βruce; Raghu, Ganesh; Richeldi, Luca; Rose, Dan; Wells, Adrian; Brown, Kevin K.

doi:10.1183/09031936.00200614

Cited by 50 publications

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“…Real-world data gathered from national registries and post-marketing surveillance will help to address some of the uncertainties [20]. Ongoing and future clinical trials will necessarily include background antifibrotic therapy [10,21]. We have come a long way in a short time, but there is still much to be learnt about this complex disease.…”

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confidence: 99%

“…However, in other countries, including the USA, regulatory bodies required further evidence of efficacy. Lessons were learnt and enabled enrichment of the ASCEND study cohort (a phase 3 study of 52 weeks duration) for patients at risk of disease progression, a strategy that has been used successfully in the study of agents for other diseases [10]. A major change was the centralisation of review of IPF diagnosis.…”

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Therapy for idiopathic pulmonary fibrosis: lessons from pooled data analyses

Troy

Corte

2015

Eur Respir J

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@ERSpublicationsThe pooled analysis of three large phase 3 trials sheds further light on the role of antifibrotic therapy in IPF http://ow.ly/UNTWQ In 2014, two landmark clinical trials (ASCEND and INPULSIS) were published demonstrating, for the first time, a treatment benefit for patients with idiopathic pulmonary fibrosis (IPF). Both pirfenidone and nintedanib were shown to have a clear therapeutic benefit in slowing the relentless disease progression evident in IPF patients. The results of these studies have had a major impact upon management of IPF patients worldwide, with subsequent changes made to international guidelines, which now recommend in favour of antifibrotic therapy. However, this is not the whole story: there are many unanswered questions with regard to the real-world treatment benefit and use of antifibrotic therapy. In this issue of the European Respiratory Journal, NOBLE et al.[1] present the pooled data of the three multinational, phase 3, placebo-controlled trials of pirfenidone in IPF patients, the ASCEND, and CAPACITY 004 and 006 studies. Examining the combined patient population reveals important insights about specific subgroups along with broader inferences that are only possible through pooled analysis.The history of clinical trials of pirfenidone in IPF patients is intriguing: 2011 saw the publication of two concurrent phase 3 trials (CAPACITY 004 and 006) [2]. These followed on from the promising findings of pre-clinical [3][4][5] and phase 2 studies [6,7], and a large phase 3 trial conducted in Japanese patients [8]. Unexpectedly, the results of the CAPACITY studies were disparate: CAPACITY 004 showed a significant reduction in forced vital capacity (FVC) decline and an improvement in progression-free survival at 72 weeks [2]; CAPACITY 006 was a negative study, with failure to meet either of these end-points [2].Why were the CAPACITY 004 and 006 results conflicting when the study populations were ostensibly the same? Subtle differences, in fact, did exist between the patient cohorts [2]. Interestingly, a difference in the change in FVC in the placebo arm was evident between the two studies. Further scrutiny revealed a greater degree of airflow limitation, as indicated by a lower spirometric ratio, in 006 than in 004. Perhaps this could explain the observed variation in physiological behaviour.Pirfenidone was subsequently approved for use across Europe based on its treatment effect demonstrated in the pooled analysis of the CAPACITY trials and previous data from Japanese studies [7][8][9]. However, in other countries, including the USA, regulatory bodies required further evidence of efficacy. Lessons were learnt and enabled enrichment of the ASCEND study cohort (a phase 3 study of 52 weeks duration) for patients at risk of disease progression, a strategy that has been used successfully in the study of agents for other diseases [10]. A major change was the centralisation of review of IPF diagnosis. The primary end-point remained "change in percentage predicted FVC or death", with the...

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Therapy for idiopathic pulmonary fibrosis: lessons from pooled data analyses

Troy

Corte

2015

Eur Respir J

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“…Accurately predicting disease progression would allow clinicians to make treatment decisions and counsel patients more appropriately. It would also allow for cohort enrichment in clinical trials designed around primary endpoints of disease progression (7). Disease progression in IPF is most commonly defined by decline in FVC (6,(8)(9)(10)(11), but there are other definitions, including worsening symptoms (e.g., worsening dyspnea) (12,13), worsening physical function (14)(15)(16), and the occurrence of acute respiratory worsening requiring hospitalization (6,9,17,18).…”

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Predictors of Mortality Poorly Predict Common Measures of Disease Progression in Idiopathic Pulmonary Fibrosis

Ley¹,

Bradford²,

Vittinghoff

et al. 2016

Am J Respir Crit Care Med

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Rationale: Mortality prediction is well studied in idiopathic pulmonary fibrosis (IPF), but little is known about predictors of premortality disease progression. Identification of patients at risk for disease progression would be useful for clinical decision-making and designing clinical trials.Objectives: To develop prediction models for disease progression in IPF.Methods: In a large clinical trial cohort of patients with IPF (n = 1,113), we comprehensively screened multivariate models of candidate baseline and past-change predictors for disease progression defined by 48-week worsening of FVC, dyspnea (University of California, San Diego Shortness of Breath Questionnaire [UCSD SOBQ]), 6-minute-walk distance (6MWD), and occurrence of respiratory hospitalization, or death. Progression outcomes were modeled as appropriate, by slope change using linear regression models and time to binary outcomes using Cox proportional hazards models. Measurements and Main Results:The overall cohort experienced considerable disease progression. Top-performing prediction models did not meaningfully predict most measures of disease progression. For example, prediction modeling explained less than or equal to 1% of the observed variation in 48-week slope change in FVC, UCSD SOBQ, and 6MWD. Models performed better for binary measures of time to disease progression but were still largely inaccurate (cross-validated C statistic <0.63 for >10% decline in FVC or death, <0.68 for >20-U increase in UCSD SOBQ or death, <0.70 for >100 m decline in 6MWD or death). Models for time to respiratory hospitalization or death (C statistic <0.77) or death alone (C statistic <0.81) demonstrated acceptable discriminative performance.Conclusions: Clinical prediction models poorly predicted physiologic and functional disease progression in IPF. This is in contrast to respiratory hospitalization and mortality prediction.

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“…Despite the enticing appeal of sildenafil as a therapy for IPF, there remain many questions that can only be answered in the context of well-planned, randomised, controlled studies [21]. Who should be targeted and at what point in their disease course?…”

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