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Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Abstract Background Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes. Main text Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications. Conclusion The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting.

Abstract Background Our objective was to assess the association between intensive care unit (ICU)‐free days and patient outcomes in pediatric prehospital care and to evaluate whether ICU‐free days is a more sensitive outcome measure for emergency medical services research in this population. Methods This study used data from a previous pediatric prehospital trial. The original study enrolled patients ≤12 years of age and compared bag‐valve‐mask‐ventilation (BVM) versus endotracheal intubation (ETI) during prehospital resuscitation. For the current study, we defined ICU‐free days as 30 minus the number of days in the ICU (range, 0–30 days) and assigned 0 ICU‐free days for death within 30 days. We compared ICU‐free days between the original study treatment groups (BVM vs ETI) and with the original trial outcomes of survival to hospital discharge and Pediatric Cerebral Performance Category (PCPC). Results Median ICU‐free days for the BVM group (n = 404) versus ETI group (n = 416) was not statistically different: 0 ICU‐free days (interquartile range, 0–10) versus 0 (0–0), P = 0.219. Median ICU‐free days were greater for BVM group in 3 subgroups: foreign body aspiration 30 (0–30) versus 0 (0–21), P = 0.028; child maltreatment 0 (0–14.2) versus 0 (0‐0), P = 0.004; and respiratory arrest 25 (1–29) versus 7.5 (0–27.7), P = 0.015. In the original trial, neither survival nor PCPC demonstrated differences in all 3 subgroups—survival was greater with BVM for child maltreatment and respiratory arrest and favorable PCPC was greater with BVM for foreign body aspiration. Overall, in the current study, patients with more ICU‐free days also had greater survival to hospital discharge and more favorable PCPC scores. Conclusions This initial study of the association between ICU‐free days and patient outcomes during prehospital pediatric resuscitation appears to support the use of ICU‐free days as a clinical endpoint in this population. ICU‐free days may be more sensitive than either mortality or PCPC alone while capturing aspects of both measures.