In randomized clinical trials with a time-to-event outcome, the intervention effect could be quantified by a difference in restricted mean survival time (ΔRMST) between the intervention and control groups, defined as the expected survival duration gain due to the intervention over a fixed follow-up period. In cluster randomized trials (CRTs), social units are randomized to intervention or control groups; the correlation between survival times of the individuals within the same cluster must be taken into account in the statistical analysis. In a previous work, we proposed the use of pseudo-values regression, based on generalized estimating equations (GEEs), for estimating ΔRMST in CRTs. We showed that this method correctly estimated the ΔRMST and controlled the type I error rate in CRTs with at least 50 clusters. Here, we propose methods for CRTs with a small number of clusters (<50). We evaluated the performance of four bias-corrections of the GEE sandwich variance estimator of the intervention effect. We also considered the use of a Student t distribution as an alternative to the normal distribution of the GEE Wald test statistic for testing the intervention effect and constructing the confidence interval. With a simulation study, assuming proportional or non-proportional hazards, we showed that the Student t distribution outperformed the normal distribution in terms of type I error rate, and the Fay and Graubard bias-corrected variance led to an appropriate type I error rate whatever the number of clusters. Therefore, we recommend the use of the Fay and Graubard variance estimator combined with a Student t distribution for the pseudo-values regression to correctly estimate the variance of the intervention effect. Finally, we provide an illustrative analysis of the DEMETER trial evaluating the use of a specific endotracheal tube for subglottic secretion drainage to prevent ventilator-associated pneumonia, by comparing each of the methods considered.

BACKGROUND:Guidance exists to inform the content of statistical analysis plans in clinical trials. Though not explicitly stated, this guidance is generally focused on clinical trials in which the randomization units are individual patients and not groups of patients. There are critical considerations for the analysis of cluster randomized trials, such as accounting for clustering, the risk of imbalances between the arms due to post-randomization recruitment, and the need to use small sample corrections when the number of clusters is small. METHODS:This paper outlines the protocol for the development of a set of reporting guidelines for the content of statistical analysis plans for cluster randomized trials (including variations such as the stepped wedge cluster randomized trial and other cluster cross-over designs) by extending the minimum reporting analysis requirements as previously defined for individually randomized trials to cluster randomized trials. The guideline will be developed using a consensus-based approach, modifying existing reporting items from the guideline for individually randomized trials and extending to include new items. DISCUSSION:The guideline will be developed so it can be used independently of the guideline for individually randomized designs. The consensus guidelines will be published in an open-access journal, including key guidance as well as exploration and elaboration.

Introduction: Progressive interstitial lung diseases (ILDs) are rare but severe diseases, with high mortality and morbidity, with no effective pharmacological treatment allowing for long-term remission, and therefore no clear therapeutic recommendations. Several ILDs present inflammatory components (ILDic), which may justify the use of anti-inflammatory and immunosuppressive drugs, as first-step therapy. Except for systemic sclerosis (SSc)-ILD and sarcoidosis, the evidence in favor of this approach is very weak. The EvER-ILD2 study is the first one to prospectively evaluate the efficacy and safety of rituximab (RTX) versus placebo in a broad range of progressive ILD outside sarcoidosis and connective tissue diseases. A pharmacokinetic-pharmacodynamic analysis based on RTX serum concentrations will allow identification of potential factors associated with therapeutic response and/or adverse effects. Methods: EvER-ILD2 study is a French multicentre, prospective, randomized, double blind, placebo-controlled, superiority trial. Patients with progressive ILDic will be randomized into 2 groups of treatment: one course of RTX (RTX group) and one course of placebo (Placebo group). The primary outcome is the change in Forced Vital Capacity (FVC, mL) from baseline to 6 months. Several clinical, biological, and quality of life secondary outcomes will be measured at 3 and 6 months. A sample size of 126 patients (63 patients per group) would allow to show a 100 mL difference between groups in the change of FVC from baseline to 6 months, based on a common standard deviation for FVC change of 200 mL with a power of 80% and a two-sided alpha of 5%. Ethics and dissemination: The protocol was approved by the French Research Ethics Committee (CPP Ile de France VI) on September 27, 2022, and by the French competent authority on October 02, 2022. This article refers to protocol V1, dated September 2022. An independent data safety monitoring board will review safety data for the duration of the trial. Results will be disseminated via peer reviewed publication and presentation at international conferences. Trial registration number: NCT05596786 (clinicaltrials.gov), EU-CT number 2022-500,375-31-00 (European Medicines agency). (c) 2024 SPLF and Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

L'analyse principale de l'essai EVER-ILD a montré qu'une bithérapie par Rituximab et Mycophénolate Mofétil, chez des patients atteints de pneumopathie interstitielle non spécifique (PINS), était associée à une meilleure évolution de la capacité vitale forcée (CVF) sur 6 mois, en comparaison à un traitement par placebo et MMF, tout en conservant un profil de sécurité satisfaisant. Dans cette étude, nous rapportons les résultats de l'essai EVER-ILD après 12 mois de suivi. EVER-ILD est un essai randomisé (1: 1) comparant l'efficacité du Rituximab (1000 mg, jour 1 et jour 15) vs son placebo, en sus du MMF (2 g par jour pendant 6 mois) chez des patients atteints de PINS. Après ces 6 mois de traitement et sans levée de l'aveugle, le médecin référent de chaque patient était libre de choisir le traitement le plus adapté pour son patient, selon les recommandations en vigueur. À 12 mois (± 3 mois), les données disponibles étaient recueillies à partir des dossiers médicaux des patients. L'essai est enregistré sur ClinicalTrials.gov NCT02990286. Sur les 122 patients initialement randomisés, la CVF en % de la valeur prédite à 12 mois était disponible pour 103 patients (52 du groupe Rituximab, 51 du groupe Placebo). Il n'y avait pas de différence entre les 2 groupes concernant les traitements administrés après le 6e mois. Il n'a pas été mis en évidence de différence significative d'évolution de la CVF en % de la valeur prédite entre les groupes Rituximab + MMF et Placebo + MMF sur les 12 mois de suivi (interaction groupe*temps = 0,26; p = 0,14). La survie sans progression (SSP) était meilleure dans le groupe Rituximab + MMF à 365 jours (différence de Temps de Survie Moyen Restreint (RMST) = 46,4 jours; IC 95 % 6,59–86,2; p = 0,0223). À 365 jours, les patients du groupe Rituximab + MMF avaient une meilleure SSP que ceux du groupe Placebo + MMF. Il pourrait être utile d'évaluer l'intérêt d'un traitement d'entretien par Rituximab.

BACKGROUND/AIMS:The stepped-wedge cluster randomized trial (SW-CRT), in which clusters are randomized to a time at which they will transition to the intervention condition - rather than a trial arm - is a relatively new design. SW-CRTs have additional design and analytical considerations compared to conventional parallel arm trials. To inform future methodological development, including guidance for trialists and the selection of parameters for statistical simulation studies, we conducted a review of recently published SW-CRTs. Specific objectives were to describe (1) the types of designs used in practice, (2) adherence to key requirements for statistical analysis, and (3) practices around covariate adjustment. We also examined changes in adherence over time and by journal impact factor. METHODS:We used electronic searches to identify primary reports of SW-CRTs published 2016-2022. Two reviewers extracted information from each trial report and its protocol, if available, and resolved disagreements through discussion. RESULTS:We identified 160 eligible trials, randomizing a median (Q1-Q3) of 11 (8-18) clusters to 5 (4-7) sequences. The majority (122, 76%) were cross-sectional (almost all with continuous recruitment), 23 (14%) were closed cohorts and 15 (9%) open cohorts. Many trials had complex design features such as multiple or multivariate primary outcomes (50, 31%) or time-dependent repeated measures (27, 22%). The most common type of primary outcome was binary (51%); continuous outcomes were less common (26%). The most frequently used method of analysis was a generalized linear mixed model (112, 70%); generalized estimating equations were used less frequently (12, 8%). Among 142 trials with fewer than 40 clusters, only 9 (6%) reported using methods appropriate for a small number of clusters. Statistical analyses clearly adjusted for time effects in 119 (74%), for within-cluster correlations in 132 (83%), and for distinct between-period correlations in 13 (8%). Covariates were included in the primary analysis of the primary outcome in 82 (51%) and were most often individual-level covariates; however, clear and complete pre-specification of covariates was uncommon. Adherence to some key methodological requirements (adjusting for time effects, accounting for within-period correlation) was higher among trials published in higher versus lower impact factor journals. Substantial improvements over time were not observed although a slight improvement was observed in the proportion accounting for a distinct between-period correlation. CONCLUSIONS:Future methods development should prioritize methods for SW-CRTs with binary or time-to-event outcomes, small numbers of clusters, continuous recruitment designs, multivariate outcomes, or time-dependent repeated measures. Trialists, journal editors, and peer reviewers should be aware that SW-CRTs have additional methodological requirements over parallel arm designs including the need to account for period effects as well as complex intracluster correlations.

Background/Aims Stepped-wedge cluster randomized trials tend to require fewer clusters than standard parallel-arm designs due to the switches between control and intervention conditions, but there are no recommendations for the minimum number of clusters. Trials randomizing an extremely small number of clusters are not uncommon, but the justification for small numbers of clusters is often unclear and appropriate analysis is often lacking. In addition, stepped-wedge cluster randomized trials are methodologically more complex due to their longitudinal correlation structure, and ignoring the distinct within- and between-period intracluster correlations can underestimate the sample size in small stepped-wedge cluster randomized trials. We conducted a review of published small stepped-wedge cluster randomized trials to understand how and why they are used, and to characterize approaches used in their design and analysis.Methods Electronic searches were used to identify primary reports of full-scale stepped-wedge cluster randomized trials published during the period 2016-2022; the subset that randomized two to six clusters was identified. Two reviewers independently extracted information from each report and any available protocol. Disagreements were resolved through discussion.Results We identified 61 stepped-wedge cluster randomized trials that randomized two to six clusters: median sample size (Q1-Q3) 1426 (420-7553) participants. Twelve (19.7%) gave some indication that the evaluation was considered a "preliminary" evaluation and 16 (26.2%) recognized the small number of clusters as a limitation. Sixteen (26.2%) provided an explanation for the limited number of clusters: the need to minimize contamination (e.g. by merging adjacent units), limited availability of clusters, and logistical considerations were common explanations. Majority (51, 83.6%) presented sample size or power calculations, but only one assumed distinct within- and between-period intracluster correlations. Few (10, 16.4%) utilized restricted randomization methods; more than half (34, 55.7%) identified baseline imbalances. The most common statistical method for analysis was the generalized linear mixed model (44, 72.1%). Only four trials (6.6%) reported statistical analyses considering small numbers of clusters: one used generalized estimating equations with small-sample correction, two used generalized linear mixed model with small-sample correction, and one used Bayesian analysis. Another eight (13.1%) used fixed-effects regression, the performance of which requires further evaluation under stepped-wedge cluster randomized trials with small numbers of clusters. None used permutation tests or cluster-period level analysis.Conclusion Methods appropriate for the design and analysis of small stepped-wedge cluster randomized trials have not been widely adopted in practice. Greater awareness is required that the use of standard sample size calculation methods can provide spuriously low numbers of required clusters. Methods such as generalized estimating equations or generalized linear mixed models with small-sample corrections, Bayesian approaches, and permutation tests may be more appropriate for the analysis of small stepped-wedge cluster randomized trials. Future research is needed to establish best practices for stepped-wedge cluster randomized trials with a small number of clusters.

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The use of cluster randomized trial design to answer research questions is increasing. This design and associated variants such as the cluster randomized crossover and stepped wedge are useful to assess complex interventions in a pragmatic way but when adopting such designs, one may face specific implementation challenges. This article summarizes common challenges faced when conducting cluster randomized trials, cluster randomized crossover trials, and stepped wedge trials, and provides recommendations.

Objectives: In stepped-wedge cluster randomized trials (SW-CRTs), clusters are randomized not to treatment and control arms but to sequences dictating the times of crossing from control to intervention conditions. Randomization is an essential feature of this design but application of standard methods to promote and report on balance at baseline is not straightforward. We aimed to describe current methods of randomization and reporting of balance at baseline in SW-CRTs.Study Design and Setting: We used electronic searches to identify primary reports of SW-CRTs published between 2016 and 2022. Results: Across 160 identified trials, the median number of clusters randomized was 11 (Q1-Q3: 8-18). Sixty-three (39%) used restricted randomizationdmost often stratification based on a single cluster-level covariate; 12 (19%) of these adjusted for the covariate(s) in the primary analysis. Overall, 50 (31%) and 134 (84%) reported on balance at baseline on cluster- and individual-level characteristics, respectively. Balance on individual-level characteristics was most often reported by condition in cross-sectional designs and by sequence in cohort designs. Authors reported baseline imbalances in 72 (45%) trials.Conclusion: SW-CRTs often randomize a small number of clusters using unrestricted allocation. Investigators need guidance on appropriate methods of randomization and assessment and reporting of balance at baseline. (c) 2023 Elsevier Inc. All rights reserved.

Background: Two designs are frequently used in cluster randomized trials in nursing homes: closed cohort and open cohort. The former design includes residents at the beginning of the trial and then follows them. In the latter design, participants are enrolled at the beginning of the trial or while it is ongoing; at dates of assessment, all residents present in the nursing home are assessed. The open-cohort design is much less used than the closed-cohort design, but it offers several advantages such as less exposure to individual attrition.Objective: To assess whether an open-cohort design could have been feasible in trials with a closed-cohort design.Study design and setting: 22 closed-cohort trials in nursing homes.Results: An open-cohort design was considered a relevant alternative for 20 trials. For 16 trials, a resident newly admitted could not opt of the intervention, and for all trials, the resident could benefit from an intervention effect, if it existed. For 2 trials, newly admitted residents could not benefit from the intervention effect, if it existed.Conclusion: The open-cohort design is well adapted for most of the interventions assessed in nursing homes by means of a cluster randomized trial and should be considered more often.

Background Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. Methods In a randomised, double-blind, two-parallel group, placebo-controlled trial ( NCT02990286 ), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. Findings Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 ( se 1.13) in the rituximab+MMF group and −2.01 ( se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41–6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23–0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. Interpretation Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

Patient and public involvement (PPI) in randomised controlled trials (RCTs) could improve the impact of health research. PPI may be particularly relevant for RCTs on chronic conditions. We aimed to evaluate the frequency and nature of patient and public involvement in randomised controlled trials (RCTs) addressing a chronic condition, to analyse whether PPI is associated with trial characteristics and to assess the quality of PPI reporting. We performed a methodological review. We searched PubMed in July 2021 for RCTs addressing a chronic condition in adults and published in journals from the BMJ group with a mandatory PPI statement. Our main outcome measures were number of RCTs with PPI and stages at which PPI was used; general and methodological characteristics of trials with and without PPI and quality of PPI reporting using the GRIPP2 guidelines. We involved two patient contributors in almost all stages of our review. 101 RCTs from 100 articles were included. Of these, 40 (40%) reported PPI at any stage of the research process. PPI contribution occurred mostly at the design stage of RCTs (36/40) especially for assessing the burden of the intervention (n=24) and at the conduct stage (21/40), with the elaboration of patient/public communication materials (n=14). The stages less likely to involve PPI were analysis and drafting of the manuscript. RCTs with PPI were more likely to be published in the BMJ, to have a corresponding author from the UK, to report a public funding source, to have a higher inclusion rate and to evaluate a digital intervention than non-PPI-RCTs. PPI-RCTs were associated with a less frequent use of placebo as control group. We found no significant association with the use of patient-reported or patient-important outcomes. Adherence to the reporting guidelines was poor as no RCTs adhere to the five GRIPP2 items. Our results underline that PPI is not uncommon in RCTs on chronic conditions but rarely occurred at a decisive stage such as choice of outcomes, definition of eligibility criteria or interpretation of study findings. Yet, it seems important to enhance engagement of patients as a real partner in RCTs on chronic conditions. Public involvement , Essais contrôlés randomisés , Revue méthodologique Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts.

For time-to-event outcomes, the difference in restricted mean survival time is a measure of the intervention effect, an alternative to the hazard ratio, corresponding to the expected survival duration gain due to the intervention up to a predefined time t*. We extended two existing approaches of restricted mean survival time estimation for independent data to clustered data in the framework of cluster randomized trials: one based on the direct integration of Kaplan-Meier curves and the other based on pseudo-values regression. Then, we conducted a simulation study to assess and compare the statistical performance of the proposed methods, varying the number and size of clusters, the degree of clustering, and the magnitude of the intervention effect under proportional and non-proportional hazards assumption. We found that the extended methods well estimated the variance and controlled the type I error if there was a sufficient number of clusters (≥ 50) under both proportional and non-proportional hazards assumption. For cluster randomized trials with a limited number of clusters (< 50), a permutation test for pseudo-values regression was implemented and corrected the type I error. We also provided a procedure to estimate permutation-based confidence intervals which produced adequate coverage. All the extended methods performed similarly, but the pseudo-values regression offered the possibility to adjust for covariates. Finally, we illustrated each considered method with a cluster randomized trial evaluating the effectiveness of an asthma-control education program.

Objectives: Two designs are frequently used in cluster randomized trials in nursing homes: closed cohort and open cohort. The former design includes residents at the beginning of the trial and then follows them. In the latter design, participants are enrolled at the beginning of the trial or although it is ongoing; at dates of assessment, all residents present in the nursing home are assessed. The open-cohort design is much less used than the closed-cohort design, but it offers several advantages such as less exposure to individual attrition. Objective was to assess whether an open-cohort design could have been feasible in trials with a closed-cohort design. Study Design and Setting: Twenty-two closed-cohort trials in nursing homes. Results: An open-cohort design was considered a relevant alternative for 20 trials. For 16 trials, a resident newly admitted could not opt out of the intervention, and for all trials, the resident could benefit from an intervention effect if it existed. For two trials, newly admitted residents could not benefit from the intervention effect, if it existed. Conclusion: The open-cohort design is well-adapted for most of the interventions assessed in nursing homes by means of a cluster randomized trial and should be considered more often. & COPY; 2023 Elsevier Inc. All rights reserved.

Background: Stressful events during a pandemic are a major cause of serious health problems, such as burnout, depression and posttraumatic stress disorder (PTSD) among health care workers (HCWs). During three years, HCWs, on the frontline to fight the COVID-19 pandemic, have been at an increased risk of high levels of stress, anxiety, depression, burnout and PTSD. Regarding potential psychological interventions, Eye Movement Desensitization & Reprocessing (EMDR) is a structured, strongly recommended therapy based on its well-known efficacy in reducing PTSD symptoms and anxiety. Objectives: This study, designed as a trial within a cohort (TwiC), aims to 1) estimate the prevalence of depression, burnout and PTSD in a sample of HCWs after experiencing the COVID-19 emergency (cohort part) and 2) assess the efficacy and acceptability of ‘EMDR + usual care’ for HCWs from the cohort who report significant psychological symptoms (trial part). Methods: The study, designed as a TwiC, consists of a prospective cohort study (n = 3000) with an embedded, pragmatic, randomized open-label superiority trial with two groups (n = 900). Participants included in the trial part are HCWs recruited for the cohort with significant symptoms on at least one psychological dimension (depression, burnout, PTSD) at baseline, 3 months or 6 months, determined by using the Patient Health Questionnaire (PHQ-9), Professional Quality of Life (ProQOL) scale, and PTSD Checklist for the DSM-5 (PCL-5). The intervention consists of 12 separate EMDR sessions with a certified therapist. The control group receives usual care. The trial has three primary outcomes: changes in depression, burnout and PTSD scores from randomization to 6 months. All participants are followed up for 12 months. Conclusions: This study provides empirical evidence about the impact of the COVID-19 pandemic and the mental health burden it places on HCWs and assesses the effectiveness of EMDR as a psychological intervention. Trial registration NCT04570202