Practical and methodological challenges when conducting a cluster randomized trial: Examples and recommendations.

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.

Adherence to key recommendations for design and analysis of stepped-wedge cluster randomized trials: A review of trials published 2016-2022.

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.

Restricted mean survival time to estimate an intervention effect in a cluster randomized trial.

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.

Cluster randomized trials in nursing homes should better be planned as open-cohort than as closed-cohort.

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.

Patient and public involvement is suboptimal in randomized controlled trials addressing a chronic condition.

OBJECTIVES: To describe patient and public involvement (PPI) in randomized controlled trials (RCTs) addressing a chronic condition and to analyze whether PPI is associated with trial characteristics. STUDY DESIGN AND SETTING: We used PubMed search to identify RCTs addressing a chronic condition and published in journals with a mandatory PPI statement. RESULTS: Across 101 RCTs; 40 (40%) reported PPI at any stage of the research process. PPI contribution occurred mostly at the design stage of RCTs (n = 36), especially for assessing the burden of the intervention (n = 24), and at the conduct stage (n = 21), with the elaboration of communication materials (n = 14). Less than one-third (13/40) of RCTs included PPI in the development or choice of outcome measures. As compared with non-PPI RCTs, PPI RCTs more frequently were published in The BMJ, had a corresponding author from the United Kingdom, reported a public funding source, had a higher inclusion rate, used usual care as a control and evaluated a digital intervention. PPI RCTs were associated with less frequent use of placebo as a control group. CONCLUSION: Our results underline that PPI is not uncommon in RCTs of chronic conditions but infrequently occurred at a key stage. Yet, the engagement of patients as a real partner in RCTs of chronic conditions should be enhanced.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

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.

Heterogeneity in the definition of delirium in ICUs and association with the intervention effect in randomized controlled trials: a meta-epidemiological study.

PURPOSE: To evaluate the heterogeneity in the definition of delirium in randomized controlled trials (RCTs) included in meta-analyses of delirium in intensive care units (ICUs) and to explore whether intervention effect depends on the definition used. METHODS: We searched PubMed for meta-analyses including RCTs evaluating prevention or treatment strategies of delirium in ICU. The definition of delirium was collected from RCTs and classified as validated (DSM criteria, CAM-ICU, ICDSC, NEECHAM, DRS-R98) or non-validated (non-validated scales, set of symptoms, physician appreciation or not reported). We conducted a meta-epidemiological analysis to compare intervention effects between trials using or not a validated definition by a two-step method as primary analysis and a multilevel model as secondary analysis. A ratio of odds ratios (ROR) < 1 indicated larger intervention effects in trials using a non-validated definition. RESULTS: Of 149 RCTs (41 meta-analyses), 109 (73.1%) used a validated definition and 40 (26.8%) did not (including 31 [20.8%] not reporting the definition). The primary analysis of 7 meta-analyses (30 RCTs) found no significant difference in intervention effects between trials using a validated definition and the others (ROR = 0.54, 95% CI 0.27-1.08), whereas the secondary multilevel analysis including 12 meta-analyses (67 RCTs) found significantly larger effects for trials using a non-validated versus a validated definition (ROR = 0.36, 95% CI 0.21-0.62). CONCLUSION: The definition of delirium was heterogeneous across RCTs, with one-fifth not reporting how they evaluated delirium. We did not find a significant association with intervention effect in the primary analysis. The secondary analysis including more studies revealed significantly larger intervention effects in trials using a non-validated versus a validated definition.

EMDR for symptoms of depression, stress and burnout in health care workers exposed to COVID-19 (HARD): A study protocol for a trial within a cohort study.

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.

Health care workers are at increased risk of stress, anxiety, depression, burnout and PTSD following the COVID-19 pandemic.In this study, the effectiveness of EMDR in reducing depression, burnout and PTSD in health care workers exposed to COVID-19 is investigated.In this study, an original 'trial within a cohort' (TwiC) design that consists of a cohort study with an embedded pragmatic randomized trial is used.The study is fully web-based, including online screening, consent and assessments.

A scoping review described diversity in methods of randomization and reporting of baseline balance in stepped-wedge cluster randomized trials.

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 randomization-most 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.

Intervention effect estimates in randomised controlled trials conducted in primary care versus secondary or tertiary care settings: a meta-epidemiological study.

BACKGROUND: Many clinical practice guidelines are based on randomised controlled trials conducted in secondary or tertiary care setting and general practitioners frequently question their relevance for primary care patients. Our aim was to compare the intervention effect estimates between primary care setting randomised controlled trials (PC-RCTs) and secondary or tertiary care setting randomised controlled trials (ST-RCTs). METHODS: Meta-epidemiological study of meta-analyses (MAs) of a binary outcome including at least one PC-RCT and one ST-RCT. PC-RCTs were defined as trials recruiting patients in general practices, primary care practices, family practices, community centers or community pharmacies. ST-RCTs were defined as trials recruiting in hospitals, including hospitalized patients, hospital outpatients and patients from emergency departments. For each MA, we estimated a ratio of odds ratio (ROR) by using random-effects meta-regression, with an ROR less than 1 indicating lower estimates of the intervention effect in PC-RCTs than ST-RCTs. Finally, we estimated a combined ROR across MAs by using a random-effects meta-analysis. We performed subgroup analyses considering the type of outcomes (objective vs subjective), type of experimental intervention (pharmacological vs non-pharmacological), and control group (active vs inactive) as well as analyses adjusted on items of the Cochrane Risk of Bias tool. RESULTS: Among 1765 screened reviews, 76 MAs with 230 PC-RCTs and 384 ST-RCTs were selected. The main medical fields were pneumology (13.2%) and psychiatry or addictology (38.2%). Intervention effect estimates did not significantly differ between PC-RCTs and ST-RCTs (ROR = 0.97, 95% confidence interval 0.88 to 1.08), with moderate heterogeneity across MAs (I2 = 45%). Subgroup and adjusted analyses led to consistent results. CONCLUSION: We did not observe any significant difference in intervention effect estimates between PC-RCTs and ST-RCTs. Nevertheless, most of the medical fields in this meta-epidemiological study were not representative of the pathologies encountered in primary care. Further studies with pathologies more frequently encountered in primary care are needed.

Heterogeneity in pragmatic randomised trials: sources and management.

BACKGROUND: Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient characteristics contributes to heterogeneity in their response to the intervention. However, there are many other sources of heterogeneity in outcomes. Based on the expertise and judgements of the authors, we identify different sources of clinical and methodological heterogeneity, which translate into heterogeneity in patient responses-some we consider as desirable and some as undesirable. For each of them, we discuss and, using real-world trial examples, illustrate how heterogeneity should be managed over the whole course of the trial. MAIN TEXT: Heterogeneity in centres and patients should be welcomed rather than limited. Interventions can be flexible or tailored and control interventions are expected to reflect usual care, avoiding use of a placebo. Co-interventions should be allowed; adherence should not be enforced. All these elements introduce heterogeneity in interventions (experimental or control), which has to be welcomed because it mimics reality. Outcomes should be objective and possibly routinely collected; standardised assessment, blinding and adjudication should be avoided as much as possible because this is not how assessment would be done outside a trial setting. The statistical analysis strategy must be guided by the objective to inform decision-making, thus favouring the intention-to-treat principle. Pragmatic trials should consider including process analyses to inform an understanding of the trial results. Needed data to conduct these analyses should be collected unobtrusively. Finally, ethical principles must be respected, even though this may seem to conflict with goals of pragmatism; consent procedures could be incorporated in the flow of care.

Impact of Distribution of a Tip Sheet to Increase Early Detection and Prevention Behavior among First-Degree Relatives of Melanoma Patients: A Randomized Cluster Trial.

BACKGROUND: First-degree relatives (FDRs, defined as parents, children, and siblings) of melanoma patients are at a two-to-fivefold increased risk of developing melanoma themselves. FDRs are advised to perform self-skin examination (SSE) and annual medical total cutaneous examination (TCE) performed either by a dermatologist or a general practitioner, and to change their sun-related behavior. This advice is given orally to melanoma patients who are asked to relay the information to their FDRs. OBJECTIVE: Our aim was to determine the impact of providing a tip sheet to melanoma patients intended to their first-degree relatives (FDRs) on early detection and sun-related behaviors in this group at increased risk of melanoma. METHODS: A superiority, cluster-randomized trial was conducted at nine hospital centers. In the intervention group, dermatologists were asked to deliver to melanoma patients (index cases) the tip sheet and oral advice intended to their FDRs. The control group were asked to deliver the usual oral advice alone. The primary outcome was early detection of melanoma in FDRs with a medical TCE performed within one year after the first visit of the index case. Secondary outcomes were SSE and sun-related behaviors in FDRs. RESULTS: A total of 48 index cases and 114 FDRS in the control group, 60 index cases and 166 FDRS in the intervention group were recruited. In the intervention group, 36.1% of FDRs performed a medical TCE as compared to 39.5% of FDRs in the control group (OR 0.9 [95% CI 0.5 to 1.5], p = 0.63). We did not find a between-group difference in SSE and sun-related behaviors. CONCLUSION: A tip sheet added to the usual oral advice did not increase medical TCE among FDRs of melanoma patients. Overall, the rate of TCE among FDRs was low. Research on other strategies is needed to increase melanoma detection in this population.

Management of death-related noncompleters in cluster randomized trials carried out in nursing homes: a methodological review.

BACKGROUND: A noncompleter is defined as a participant who leaves a trial before the end of the planned follow-up. Research in nursing homes is highly exposed to this problem because of high death rates. OBJECTIVES: The aim of this trial is to assess the statistical management of noncompleters in cluster randomized trials carried out in nursing homes. STUDY DESIGN AND SETTING: A methodological review of published cluster randomized trials. RESULTS: We selected 37 articles. For 22 (59%) trials, the design was closed-cohort (i.e., participants included all at the same time when randomizing clusters). In those 22 closed-cohort trials, the median follow-up was 6.5 months (interquartile range 4-12). The median noncompleter rate was 19.5% and the median noncompletions due to death was 73.2%. In only one trial were the baseline characteristics of completers and noncompleters compared. Strategies to deal with noncompleters were an inflation of the planned sample size (11 trials), the use of repeated measurements of the outcome (12 trials), and the use of imputation methods when analyzing data (7 trials). CONCLUSION: In cluster randomized trials of nursing homes, noncompleters are managed as for any missing data, but they are essentially due to death. Methodological and statistical developments and guidance are needed.

Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial.

OBJECTIVE: We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. METHODS: In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. RESULTS: Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). CONCLUSION: This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

Impact of a phone call with a medical student/general practitioner team on morbidity of chronic patients during the first French COVID-19 lockdown (COVIQuest): a cluster randomised trial.

OBJECTIVES: The first COVID-19 lockdown led to a significantly reduced access to healthcare, which may have increased decompensations in frail patients with chronic diseases, especially older patients living with a chronic cardiovascular disease (CVD) or a mental health disorder (MHD). The objective of COVIQuest was to evaluate whether a general practitioner (GP)-initiated phone call to patients with CVD and MHD during the COVID-19 lockdown could reduce the number of hospitalisation(s) over a 1-month period. DESIGN: This is a cluster randomised controlled trial. Clusters were GPs from eight French regions. PARTICIPANTS: Patients ≥70 years old with chronic CVD (COVIQuest_CV subtrial) or ≥18 years old with MHD (COVIQuest_MH subtrial). INTERVENTIONS: A standardised GP-initiated phone call aiming to evaluate patients' need for urgent healthcare, with a control group benefiting from usual care (ie, the contact with the GP was by the patient's initiative). MAIN OUTCOME MEASURES: Hospital admission within 1 month after the phone call. RESULTS: In the COVIQuest_CV subtrial, 131 GPs and 1834 patients were included in the intervention group and 136 GPs and 1510 patients were allocated to the control group. Overall, 65 (3.54%) patients were hospitalised in the intervention group vs 69 (4.57%) in the control group (OR 0.82, 95% CI 0.56 to 1.20; risk difference -0.77, 95% CI -2.28 to 0.74). In the COVIQuest_MH subtrial, 136 GPs and 832 patients were included in the intervention group and 131 GPs and 548 patients were allocated to the control group. Overall, 27 (3.25%) patients were hospitalised in the intervention group vs 12 (2.19%) in the control group (OR 1.52, 95% CI 0.82 to 2.81; risk difference 1.38, 95% CI 0.06 to 2.70). CONCLUSION: A GP-initiated phone call may have been associated with more hospitalisations within 1 month for patients with MHD, but results lack robustness and significance depending on the statistical approach used. TRIAL REGISTRATION NUMBER: NCT04359875.

A Home-Mailed Versus General Practitioner-Delivered Vaginal Self-Sampling Kit for Cervical Cancer Screening: A Cluster Randomized Controlled Trial with a Cost-Effectiveness Analysis.

Objective: We assessed whether general practitioner (GP) delivery of a vaginal self-sampling kit was non-inferior to home-mailed delivery on cervical cancer screening (CCS) participation. Methods: Two hundred and ten French GPs from Indre-et-Loire French department were randomized into two groups, and their unscreened women patients aged 30-65 were included in February-March 2015. In the GP delivery group (n = 105 GPs; 1,806 women), women were sent a reminder letter inviting them to collect a vaginal self-sampling kit at their regular GP's practice. In the home-mailed delivery group (n = 105 GPs; 1,806 women), women were sent a reminder letter with a vaginal self-sampling kit directly at home. The primary outcome was participation in complete CCS within 9 months. A cost-effectiveness analysis was also performed. Results: At 9 months, 14.9% (95% CI: 12.9-16.9) and 27.9% (95% CI: 25.7-30.0) of women in the GP and home-mailed delivery groups participated in complete CCS. The absolute between-group difference was -13.0 percentage points (95% CI: -15.9 to -10.0) in favor of the home-mailed delivery group, crossing the non-inferiority pre-defined non-inferiority margin of 5%. The home-mailed delivery strategy cost 50.81€ more per additional woman screened. Conclusions: The GP delivery was inferior to home-mailed delivery in increasing participation in CCS. Home-mailed delivery of a vaginal self-sampling kit is a cost-effective way to increase CCS in that the additional cost of this strategy seems acceptable. This study is registered at www.Clinicaltrials.gov NCT02255084.

Combining Trauma Script Exposure With rTMS to Reduce Symptoms of Post-Traumatic Stress Disorder: Randomized Controlled Trial.

BACKGROUND: Innovative therapeutic interventions for post-traumatic stress disorder (PTSD) are required. We opted to facilitate fear extinction by combining trauma script exposure with repetitive transcranial magnetic stimulation (rTMS) to reduce symptoms of PTSD. OBJECTIVE: The efficacy and safety of 10 Hz rTMS of the right dorsolateral prefrontal cortex simultaneously with exposure to personal traumatic narrative were studied in patients with PTSD. MATERIALS AND METHODS: This trial was a single-center randomized controlled trial (NCT02584894). Patients were randomly assigned 1:1 to receive eight daily sessions of 110% of motor threshold high frequency (HF) 10 Hz rTMS (110% HF rTMS) or 70% low frequency (LF) 1 Hz rTMS (70% LF rTMS) with trauma script exposure in both groups. Severity of PTSD, depression, and anxiety were assessed before and after study treatment (one month, three months) by an assessor masked to the trial group assignment. The primary outcome was the severity of PTSD assessed by the Clinician Administered PTSD Scale (CAPS). We used mixed linear regression models for statistical comparisons. RESULTS: Thirty-eight patients (65.8% females) were randomly assigned to 110% HF rTMS (n = 18, 31.3 ± 10.0 years, 13 females) or 70% LF rTMS (n = 20, 33.5 ± 11.1 years, 12 females). From baseline to three months, mean CAPS scores decreased by 51% in the 110% HF rTMS group (from 83.7 ± 14.4 to 41.8 ± 31.9) and by 36.9% in the 70% LF rTMS group (from 81.8 ± 15.6 to 51.6 ± 23.7), but with no significant difference in improvement (time by treatment interaction -3.61 [95% confidence interval (CI), -9.70 to 2.47]; p = 0.24; effect size 0.53). One serious adverse event occurred during the study (psychogenic nonepileptic seizure). CONCLUSION: We found no evidence of difference in clinical improvement or remission rates between the 110% HF and 70% LF stimulation. These findings may reflect the importance of exposure procedure and that larger number of participants is needed.

Recruitment and implementation challenges were common in stepped-wedge cluster randomized trials: Results from a methodological review.

OBJECTIVE: To explore challenges in recruitment and intervention implementation in recent stepped-wedge cluster randomized trials (SW-CRTs). STUDY DESIGN AND SETTING: We searched PubMed to identify primary reports of SW-CRTs (2019-2020). Two reviewers independently screened studies and extracted data from each report. A recruitment challenge was defined as a planned number of clusters or participants not achieved or any reported changes made to the design to address recruitment difficulties. An implementation challenge was defined as early, late, or no implementation of the intervention in at least one cluster. RESULTS: Of 55 SW-CRTs, 18 (33%) had a recruitment challenge, 23 (42%) had none, and for 14 (26%) it was impossible to judge. At least one implementation challenge was present in 24 (44%), eight (15%) had none, and for 23 (42%) it was impossible to judge. Of the 35 (64%) trials with recruitment or implementation challenges, 18 (72%) had one or more modifications of their design, most often a modification of the trial duration. CONCLUSION: Investigators must be aware of the risks of recruitment or implementation challenges when considering the use of an SW-CRT design. Mitigating strategies should be adopted when planning the trial. More transparent reporting of planned and actual design features is required.