All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials.King TE Jr 1 , Albera C, Bradford WZ, Costabel U, du Bois RM, Leff JA, Nathan SD, Sahn SA, Valeyre D, Noble PW. La versione definitiva è disponibile alla URL:http: //www.atsjournals.org/doi/abs/10.1164 Rationale: FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials.Objectives: To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. Methods:The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. Measurements and Main Results:A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. Conclusions:The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of allcause mortality trials in this population are substantial and likely prohibitive.

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Background Patients with Progressive Idiopathic Fibrotic Interstitial Lung Diseases (PIF-ILD) such as idiopathic pulmonary fibrosis have a short disease trajectory and have a similar prognosis to lung cancer patients. They have clear symptom control and quality of life (Qol) needs. The objective of this review was to evaluate the evidence for the use of pharmacological and non-pharmacological methods in improving dyspnoea, other symptoms and Qol for patients with PIF-ILD. In addition we assessed the use of outcome scales and economic evaluation of interventions. Methods Studies were identified by searching eleven databases, relevant websites and hand searching key journals. Relevant studies were selected, assessed and data extracted independently by two researchers using standardised proformas. Meta-analyses were performed where appropriate and results presented as pooled mean difference with 95%CI. Effect sizes were also calculated where possible. A descriptive summary of other studies has been given. Results 35 papers with 18 interventions were included. Metaanalyses were only possible for 3 interventions. Meta-analysis showed no significant treatment effect of IFN gamma 1b or sildenafil on 6MWD or dyspnea. A positive treatment effect of pulmonary rehabilitation on 6MWD (effect size (95% CI) 27.4 (4.1, 50.7) p=0.02) was seen. Separate analysis showed a positive effect of pulmonary rehabilitation on dyspnea and a trend towards significant results for pulmonary rehabilitation and sildenafil in improving quality of life. There was weak evidence for the improvement of 6MWD using oxygen, dyspnea using prednisolone, diamorphine, D-pencillamine and colchicine, cough using interferon alpha and thalidomide, anxiety using diamorphine, fatigue using pulmonary rehabilitation and Qol using thalidomide and doxycycline which warrants further research. There were a wide range of outcome scales used and no studies with economic evaluation. Conclusion There is strong evidence for the use of pulmonary rehabilitation to improve 6MWD and moderate evidence for its use in improving dyspnoea and Qol. In addition, there is moderate evidence for sildenafil in improving Qol. There is weak evidence for a number of other interventions. Further research using economic evaluation and uniform outcome measures is needed.

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