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Abstract Background Hypertension (HT) is an orchestrator of atherosclerotic cardiovascular disease (ASCVD) in people living with type 2 diabetes (T2D). Control of systolic blood pressure (SBP) and HT as a whole is suboptimal in diabetes, partly due to the scarcity of doctors. While nurse-led interventions are pragmatic and cost-effective in the control of HT in primary health care, their effectiveness on SBP control among patients with T2D in Uganda is scantly known. Aim We evaluated the effectiveness of a nurse-led management intervention on SBP among T2D patients with a high ASCVD risk in Uganda. Methods A two-armed cluster randomized controlled trial compared the nurse-led management intervention with usual doctor-led care. The intervention involved training nurses to provide structured health education, protocol-based HT/CVD management, 24-h phone calls, and 2-monthly text messages for 6 months. The primary outcome was the mean difference in SBP change among patients with T2D with a high ASCVD risk in the intervention and control groups after 6 months. The secondary outcome was the absolute difference in the number of patients at target for SBP, total cholesterol (TC), fasting blood glucose (FBG), glycated hemoglobin (HbA1C), low-density lipoprotein (LDL), triglycerides (TG), and body mass index (BMI) after the intervention. The study was analyzed according to the intention-to-treat principle. Generalized estimating equations were used to assess intra-cluster effect modifiers. Statistical significance was set at 0.05 for all analyses. Results Eight clinics (n = 388 patients) were included (intervention 4 clinics; n = 192; control 4 clinics; n = 196). A nurse-led intervention reduced SBP by -11.21 ± 16.02 mmHg with a mean difference between the groups of -13.75 mmHg (95% CI -16.48 to -11.02, p

Abstract Background The Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP). Methods/design LAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering. Conclusion The SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results. Trial registration ClinicalTrials.gov ID NCT04424511 . Registered on 11 June 2020.

Abstract Background Physical activity behavioral interventions to change individual-level drivers of activity, like motivation, attitudes, and self-efficacy, are often not sustained beyond the intervention period. Interventions at both environmental and individual levels might facilitate durable change. This community-based study seeks to test a multilevel, multicomponent intervention to increase moderate intensity physical activity among people with low incomes living in U.S. public housing developments, over a 2 year period. Methods The study design is a prospective, cluster randomized controlled trial, with housing developments (n=12) as the units of randomization. In a four-group, factorial trial, we will compare an environmental intervention (E) alone (3 developments), an individual intervention (I) alone (3 developments), an environmental plus individual (E+I) intervention (3 developments), against an assessment only control group (3 developments). The environmental only intervention consists of community health workers leading walking groups and indoor activities, a walking advocacy program for residents, and provision of walking maps/signage. The individual only intervention consists of a 12-week automated telephone program to increase physical activity motivation and self-efficacy. All residents are invited to participate in the intervention activities being delivered at their development. The primary outcome is change in moderate intensity physical activity measured via an accelerometer-based device among an evaluation cohort (n=50 individuals at each of the 12 developments) from baseline to 24-month follow up. Mediation (e.g., neighborhood walkability, motivation) and moderation (e.g., neighborhood stress) of our interventions will be assessed. Lastly, we will interview key informants to assess factors from the Consolidated Framework for Implementation Research domains to inform future implementation. Discussion We hypothesize participants living in developments in any of the three intervention groups (E only, I only, and E+I combined) will increase minutes of moderate intensity physical activity more than participants in control group developments. We expect delivery of an intervention package targeting environmental and social factors to become active, combined with the individual level intervention, will improve overall physical activity levels to recommended guidelines at the development level. If effective, this trial has the potential for implementation through other federal and state housing authorities. Trial registration Clinical Trails.gov PRS Protocol Registration and Results System, NCT05147298 . Registered 28 November 2021.

Abstract Background It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5–15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3rd June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. Methods The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. Results The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. Conclusions Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033

Abstract Background Healthcare costs are rising, and a substantial proportion of medical care is of little value. De-implementation of low-value practices is important for improving overall health outcomes and reducing costs. We aimed to identify and synthesize randomized controlled trials (RCTs) on de-implementation interventions and to provide guidance to improve future research. Methods MEDLINE and Scopus up to May 24, 2021, for individual and cluster RCTs comparing de-implementation interventions to usual care, another intervention, or placebo. We applied independent duplicate assessment of eligibility, study characteristics, outcomes, intervention categories, implementation theories, and risk of bias. Results Of the 227 eligible trials, 145 (64%) were cluster randomized trials (median 24 clusters; median follow-up time 305 days), and 82 (36%) were individually randomized trials (median follow-up time 274 days). Of the trials, 118 (52%) were published after 2010, 149 (66%) were conducted in a primary care setting, 163 (72%) aimed to reduce the use of drug treatment, 194 (85%) measured the total volume of care, and 64 (28%) low-value care use as outcomes. Of the trials, 48 (21%) described a theoretical basis for the intervention, and 40 (18%) had the study tailored by context-specific factors. Of the de-implementation interventions, 193 (85%) were targeted at physicians, 115 (51%) tested educational sessions, and 152 (67%) multicomponent interventions. Missing data led to high risk of bias in 137 (60%) trials, followed by baseline imbalances in 99 (44%), and deficiencies in allocation concealment in 56 (25%). Conclusions De-implementation trials were mainly conducted in primary care and typically aimed to reduce low-value drug treatments. Limitations of current de-implementation research may have led to unreliable effect estimates and decreased clinical applicability of studied de-implementation strategies. We identified potential research gaps, including de-implementation in secondary and tertiary care settings, and interventions targeted at other than physicians. Future trials could be improved by favoring simpler intervention designs, better control of potential confounders, larger number of clusters in cluster trials, considering context-specific factors when planning the intervention (tailoring), and using a theoretical basis in intervention design. Registration OSF Open Science Framework hk4b2

Abstract Background Among rural Chinese patients with non-communicable diseases (NCDs), low socioeconomic status increases the risk of developing NCDs and associated financial burdens in paying for medicines and treatments. Despite the chronic disease medicine reimbursement policy of the local government in Nantong City, China, various barriers prevent patients from registering for and benefitting from the policy. This study aims to develop a behavior science-based intervention program for promoting the adoption of the policy and to evaluate the effectiveness of the program compared with usual practices. Methods Barriers and opportunities affecting stakeholders in adopting the policy were identified through contextual research and summarized through behavior mapping. The intervention is designed to target these barriers and opportunities through behavior science theories and will be evaluated through a 6-month cluster randomized controlled trial in Tongzhou District, Nantong, China. A total of 30 villages from two townships are randomized in a 1:1 ratio to either the intervention or the control arm (usual practices). Village doctors in the intervention arm (1) receive systematic training on policy details, registration procedures, and intervention protocol, (2) promote the policy and encourage registration, (3) follow up with patients in the first, third, and sixth months after the intervention, and (4) receive financial incentives based on performance. The primary outcome is policy registration rate and the secondary outcomes include the number of patients registering for the policy, medical costs saved, frequency of village doctor visits, and health measures such as blood pressure and glucose levels. Discussion This study is one of very few that aims to promote adoption of NCDs outpatient medication reimbursement policies, and the first study to evaluate the impact of these policies on patients’ financial and physical wellbeing in China. The simple, feasible, and scalable intervention is designed based on the theories of behavior science and is applicable to similar low-income regions nationwide where outpatient medical costs remain a financial burden for patients. Trial registration ClinicalTrials.gov NCT04731194 , registered on 29 January 2021; Chinese Clinical Trial Registry ChiCTR2100042152 , registered on 14 January 14 2021.

Abstract Background Stepped wedge trials are an appealing and potentially powerful cluster randomized trial design. However, they are frequently implemented with a small number of clusters. Standard analysis methods for these trials such as a linear mixed model with estimation via maximum likelihood or restricted maximum likelihood (REML) rely on asymptotic properties and have been shown to yield inflated type I error when applied to studies with a small number of clusters. Small-sample methods such as the Kenward-Roger approximation in combination with REML can potentially improve estimation of the fixed effects such as the treatment effect. A Bayesian approach may also be promising for such multilevel models but has not yet seen much application in cluster randomized trials. Methods We conducted a simulation study comparing the performance of REML with and without a Kenward-Roger approximation to a Bayesian approach using weakly informative prior distributions on the intracluster correlation parameters. We considered a continuous outcome and a range of stepped wedge trial configurations with between 4 and 40 clusters. To assess method performance we calculated bias and mean squared error for the treatment effect and correlation parameters and the coverage of 95% confidence/credible intervals and relative percent error in model-based standard error for the treatment effect. Results Both REML with a Kenward-Roger standard error and degrees of freedom correction and the Bayesian method performed similarly well for the estimation of the treatment effect, while intracluster correlation parameter estimates obtained via the Bayesian method were less variable than REML estimates with different relative levels of bias. Conclusions The use of REML with a Kenward-Roger approximation may be sufficient for the analysis of stepped wedge cluster randomized trials with a small number of clusters. However, a Bayesian approach with weakly informative prior distributions on the intracluster correlation parameters offers a viable alternative, particularly when there is interest in the probability-based inferences permitted within this paradigm.

Abstract Background There are currently no methodological studies on the performance of the statistical models for estimating intervention effects based on the time-to-recurrent-event (TTRE) in stepped wedge cluster randomised trial (SWCRT) using an open cohort design. This study aims to address this by evaluating the performance of these statistical models using an open cohort design with the Monte Carlo simulation in various settings and their application using an actual example. Methods Using Monte Carlo simulations, we evaluated the performance of the existing extended Cox proportional hazard models, i.e., the Andersen-Gill (AG), Prentice-Williams-Peterson Total-Time (PWP-TT), and Prentice-Williams-Peterson Gap-time (PWP-GT) models, using the settings of several event generation models and true intervention effects, with and without stratification by clusters. Unidirectional switching in SWCRT was represented using time-dependent covariates. Results Using Monte Carlo simulations with the various described settings, in situations where inter-individual variability do not exist, the PWP-GT model with stratification by clusters showed the best performance in most settings and reasonable performance in the others. The only situation in which the performance of the PWP-TT model with stratification by clusters was not inferior to that of the PWP-GT model with stratification by clusters was when there was a certain amount of follow-up period, and the timing of the trial entry was random within the trial period, including the follow-up period. In situations where inter-individual variability existed, the PWP-GT model consistently underperformed compared to the PWP-TT model. The AG model performed well only in a specific setting. By analysing actual examples, it was found that almost all the statistical models suggested that the risk of events during the intervention condition may be somewhat higher than in the control, although the difference was not statistically significant. Conclusions When estimating the TTRE-based intervention effects of SWCRT in various settings using an open cohort design, the PWP-GT model with stratification by clusters performed most reasonably in situations where inter-individual variability was not present. However, if inter-individual variability was present, the PWP-TT model with stratification by clusters performed best.

Abstract Background The shortage of available organs for life-saving transplants persists worldwide. While a majority support donating their organs or tissue when they die, many have not registered their wish to do so. When registered, next of kin are much more likely to follow-through with the decision to donate. In many countries, most people visit their family physician office each year and this setting is a promising, yet underused, site where more people could register for deceased organ donation. Our primary aim was to evaluate the effectiveness of an intervention to promote organ donation registration in family physician’s offices. Methods We developed an intervention to address barriers and enablers to organ donation registration that involved physician office reception staff inviting patients to register on a tablet in the waiting room while they waited for their appointment. We conducted a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate the intervention. We recruited six family physician offices in Canada. All offices began with usual care and then every two weeks, one office (randomly assigned) started the intervention until all offices delivered the intervention. The primary outcome was registration for deceased organ donation in the provincial organ registration registry, assessed within the 7 days of the physician visit. At the end of the trial, we also conducted interviews with clinic staff to assess any barriers and enablers to delivering the intervention. Results The trial involved 24,616 patient visits by 13,562 unique patients: 12,484 visits in the intervention period and 12,132 in the control period. There was no statistically significant difference in the percentage of patients registered for deceased organ donation in the intervention versus control period (48.0% vs 46.2%; absolute difference after accounting for the secular trend: 0.12%; 95% CI: − 2.30, 2.54; p=0.92). Interviews with clinic staff indicated location of the tablet within a waiting room, patient rapport, existing registration, confidence and motivation to deliver the intervention and competing priorities as barriers and enablers to delivery. Conclusions Our intervention did not increase donor registration. Nonetheless, family physician offices may still remain a promising setting to develop and evaluate better interventions to increase organ donation registration. Trial registration NCT03213171

Abstract Background Despite the overwhelming prevalence and health implications of obesity, it is rarely adequately addressed in a health care setting. PATHWEIGH is a pragmatic approach to weight management that uses tools built into the electronic medical record to overcome barriers and guide care. Implementation strategies are employed to facilitate adoption and use of the PATHWEIGH tools and processes. The current study will compare the effectiveness of PATHWEIGH versus standard of care (SOC) on patient weight loss in primary care and explore factors for its successful implementation. Methods A stepped wedge cluster randomized trial design will be used within an effectiveness-implementation hybrid study. Adult patient weight loss and weight loss maintenance will be compared in PATHWEIGH versus SOC in 57 family and internal medicine clinics in a large health system in Colorado, USA. Effectiveness will be evaluated using generalized linear mixed models to determine statistical differences in weight loss and weight loss maintenance at 6, 12, and 18 months. Patient-, provider-, and clinic-level predictors will be identified using mediator and moderator analyses. Conceptually guided by the Practical, Robust, Implementation and Sustainability Model (PRISM), a mixed methods approach including quantitative (practice surveys, use tracking) and qualitative (interviews, observations) data collection will be used to determine factors impeding and facilitating adoption, implementation, and maintenance of PATHWEIGH and evaluate specified implementation strategies. A cost analysis of the practice and system costs and resources required by PATHWEIGH relative to the reimbursement collected will be performed. Discussion The effectiveness and implementation of PATHWEIGH, and their interrelatedness, for patient weight loss are collectively the focus of the current trial. Findings from this study are expected to serve as a blueprint for available and effective weight management in primary care medical practice. Trial registration ClinicalTrials.gov NCT04678752 . Registered on December 21, 2020.

Abstract Background Reducing sugar-sweetened beverage (SSB) consumption is a promising dietary target for childhood obesity prevention. This paper describes the design and methods of a cluster randomized trial of H2GO!, a youth empowerment intervention to prevent childhood obesity through reducing SSB consumption among a low-income, ethnically diverse sample of youth. Methods This cluster randomized controlled trial is an academic-community partnership with the Massachusetts Alliance of Boys and Girls Clubs (BGC). Ten BGC sites will be randomly assigned to the H2GO! intervention or a wait-list, usual care control. Eligible study participants will be N = 450 parent-child pairs (youth ages 9–12 years and their parents/caregivers) recruited from participating BGCs. The 6-week in-person H2GO! intervention consists of 12 group-based sessions delivered by BGC staff and youth-led activities. An innovative feature of the intervention is the development of youth-produced narratives as a strategy to facilitate youth empowerment and parental engagement. Child outcomes include measured body mass index z scores (zBMI), beverage intake, and youth empowerment. Parent outcomes include beverage intake and availability of SSBs at home. Outcomes will be measured at baseline and at 2, 6, and 12 months. With a 75% retention rate, the study is powered to detect a minimum group difference of 0.1 zBMI units over 12 months. Discussion Empowering youth may be a promising intervention approach to prevent childhood obesity through reducing SSB consumption. This intervention was designed to be delivered through BGCs and is hypothesized to be efficacious, relevant, and acceptable for the target population of low-income and ethnically diverse youth. Trial registration ClinicalTrials.gov NCT04265794 . Registered 11 February 2020.

Abstract Background and aim Some parallel-group cluster-randomized trials use covariate-constrained rather than simple randomization. This is done to increase the chance of balancing the groups on cluster- and patient-level baseline characteristics. This study assessed how well two covariate-constrained randomization methods balanced baseline characteristics compared with simple randomization. Methods We conducted a mock 3-year cluster-randomized trial, with no active intervention, that started April 1, 2014, and ended March 31, 2017. We included a total of 11,832 patients from 72 hemodialysis centers (clusters) in Ontario, Canada. We randomly allocated the 72 clusters into two groups in a 1:1 ratio on a single date using individual- and cluster-level data available until April 1, 2013. Initially, we generated 1000 allocation schemes using simple randomization. Then, as an alternative, we performed covariate-constrained randomization based on historical data from these centers. In one analysis, we restricted on a set of 11 individual-level prognostic variables; in the other, we restricted on principal components generated using 29 baseline historical variables. We created 300,000 different allocations for the covariate-constrained randomizations, and we restricted our analysis to the 30,000 best allocations based on the smallest sum of the penalized standardized differences. We then randomly sampled 1000 schemes from the 30,000 best allocations. We summarized our results with each randomization approach as the median (25th and 75th percentile) number of balanced baseline characteristics. There were 156 baseline characteristics, and a variable was balanced when the between-group standardized difference was ≤ 10%. Results The three randomization techniques had at least 125 of 156 balanced baseline characteristics in 90% of sampled allocations. The median number of balanced baseline characteristics using simple randomization was 147 (142, 150). The corresponding value for covariate-constrained randomization using 11 prognostic characteristics was 149 (146, 151), while for principal components, the value was 150 (147, 151). Conclusion In this setting with 72 clusters, constraining the randomization using historical information achieved better balance on baseline characteristics compared with simple randomization; however, the magnitude of benefit was modest.

Abstract Background Depression and chronic diseases are frequently comorbid public health problems. However, clinical guidelines often fail to consider comorbidities. This study protocol describes a cluster randomized trial (CRT) aimed to compare the effectiveness of a collaborative, computer-assisted, psycho-educational intervention versus enhanced usual care (EUC) in the treatment of depressed patients with hypertension and/or diabetes in primary care clinics (PCC) in Santiago, Chile. Methods Two-arm, single-blind, CRT carried out at two municipalities in Santiago, Chile. Eight PCC will be randomly assigned (1:1 ratio within each municipality, 4 PCC in each municipality) to the INTERVENTION or EUC. A total of 360 depressed patients, aged at least 18 years, with Patient Health Questionnaire-9 Item [PHQ-9] scores ≥15, and enrolled in the Cardiovascular Health Program at the participating PCC. Patients with alcohol/substance abuse; current treatment for depression, bipolar disorder, or psychosis; illiteracy; severe impairment; and resident in long-term care facilities, will be excluded. Patients in both arms will be invited to use the Web page of the project, which includes basic health education information. Patients in the INTERVENTION will receive eight sessions of a computer-assisted, psycho-educational intervention delivered by trained therapists, a structured telephone calls to monitor progress, and usual medical care for chronic diseases. Therapists will receive biweekly and monthly supervision by psychologist and psychiatrist, respectively. A monthly meeting will be held between the PCC team and a member of the research team to ensure continuity of care. Patients in EUC will receive depression treatment according to clinical guidelines and usual medical care for chronic diseases. Outcome assessments will be conducted at 3, 6, and 12 months after enrollment. The primary outcome will be depression improvement at 6 months, defined as ≥50% reduction in baseline PHQ-9 scores. Intention-to-treat analyses will be performed. Discussion This study will be one of the first to provide evidence for the effectiveness of a collaborative, computer-assisted, psycho-educational intervention for depressed patients with chronic disease at primary care in a Latin American country. Trial registration retrospectively registered in ClinicalTrials.gov , first posted: November 3, 2020, under identifier: NCT04613076 .

Abstract Ayudhaya et al. examined the effect of Behavioral Activation on daily step count and heart rate variability among older adults with depression in a study labeled a cluster randomized controlled trial (cRCT). However, only one cluster was assigned to either of the study conditions. Such a design would have zero degrees of freedom for inferential testing, because the variation due to cluster membership cannot be estimated apart from the variation due to treatment assignment. Thus, the intervention effect is completely confounded with the cluster effect. The study should be labeled a quasi-experimental study, not a cRCT. Accordingly, the numerical results should be interpreted as associations but not evidence for causal relationships.

Abstract Background Less than 19% of those needing tuberculosis (TB) preventive treatment complete it, due to losses in several steps of the cascade of care for latent TB infection. A cluster randomized trial of a programmatic public health intervention to improve management of latent TB infection in household contacts was conducted in Rio de Janeiro. Interventions included contact registry, initial and in-service training, and a TB booklet. We conducted a follow-up study starting one month after the conclusion of this trial, to measure the effect of interventions implemented, and to identify remaining barriers and facilitators to latent TB infection treatment, from different perspectives. Methods In two health clinics in Rio de Janeiro that received the interventions in the trial, data for the latent TB infection cascade of care for household contacts was collected over a five-month period. The number of household contacts initiating treatment per 100 index-TB patients was compared with the cascade of care data obtained before and during the intervention trial. Semi-structured open-ended questionnaires were administered to healthcare workers, household contacts and index-TB patients regarding knowledge and perceptions about TB and study interventions. Results In this follow-up study, 184 household contacts per 100 index-TB patients were identified. When compared to the intervention period, there were 65 fewer household contacts per 100 index-TB patients, (95% CI -115, − 15) but the number starting latent TB infection treatment was sustained (difference -2, 95% CI -8,5). A total of 31 index-TB patients, 22 household contacts and 19 health care workers were interviewed. Among index-TB patients, 61% said all their household contacts had been tested for latent TB infection. All health care workers said it was very important to test household contacts, and 95% mentioned that possessing correct knowledge on the benefits of latent TB infection treatment was the main facilitator to enable them to recommend this treatment. Conclusion In this follow-up study, we observed a sustained effect of interventions to strengthen the latent TB infection cascade of care on increasing the number of household contacts starting latent TB infection treatment.

Abstract Background More than half of the unaccompanied young refugees (UYRs) resettled in Europe report elevated levels of posttraumatic stress symptoms (PTSS) and comorbid symptoms. Earlier studies have highlighted the effectiveness of the trauma-focused preventive group intervention “Mein Weg” (English “My Way”), and the feasibility of trauma-focused cognitive behavioral therapy (TF-CBT) for UYRs. Both interventions are deemed to be empirically supported treatments (ESTs). However, UYRs seldom receive ESTs or, in fact, any treatment at all. In view of the high need and the limited treatment resources available, a stepped-care approach is indicated but has not been evaluated so far. The purpose of this trial is to compare the stepped-care approach BETTER CARE with usual care enhanced with screening and indication (usual care+). Methods In a cluster randomized controlled trial involving N = 540 UYRs living in up to N = 54 child and youth welfare service (CYWS) facilities, BETTER CARE will be compared with usual care+. We will randomize clusters comprising a CYWS facility with at least one eligible psychotherapist. BETTER CARE consists of step (1) screening and indication and either step (2) preventive trauma-focused group intervention “Mein Weg” delivered by trained CYWS staff or step (3) TF-CBT delivered by trained community therapists and supported by trained translators if necessary. Participants will be assessed 6 and 12 months after randomization. The primary outcome is the severity of PTSS after 12 months. Secondary outcomes are depressive and anxiety symptoms, quality of life, and proxy reported PTSS. Furthermore, drug use, health costs, benefits, and long-term effects on integration/acculturation will be assessed. Discussion The trial will directly integrate a stepped-care approach into existing structures of the German child welfare and (mental) health system. It could, therefore, serve as a blueprint for how to implement ESTs for UYRs. If successful, screening, prevention, and intervention will be sustainably implemented in CYWS in southern Germany. Trial registration German Clinical Trials Register DRKS00017453 . Registered on 11 December 2019.

Abstract Background In order to correctly assess the effect of intervention from stratified cluster randomized trials (CRTs), it is necessary to adjust for both clustering and stratification, as failure to do so leads to misleading conclusions about the intervention effect. We have conducted a systematic survey to examine the current practices about analysis and reporting of stratified CRTs. Method We used the search terms to identify the stratified CRTs from MEDLINE since the inception to July 2019. In phase 1, we screened the title and abstract for English-only studies and selected, including the main results paper of the identified protocols, for the next phase. In phase 2, we screened the full text and selected studies for data abstraction. The data abstraction form was piloted and developed using the REDCap. We abstracted data on multiple design and methodological aspects of the study including whether the primary method adjusted for both clustering and stratification, reporting of sample size, randomization, and results. Results We screened 2686 studies in the phase 1 and selected 286 studies for phase 2—among them 185 studies were selected for data abstraction. Most of the selected studies were two-arm 140/185 (76%) and parallel-group 165/185 (89%) trials. Among these 185 studies, 27 (15%) of them did not provide any sample size or power calculation, while 105 (57%) studies did not mention any method used for randomization within each stratum. Further, 43 (23%) and 150 (81%) of 185 studies did not provide the definition of all the strata, while more than 60% of the studies did not include all the stratification variable(s) in the flow chart or baseline characteristics table. More than half 114/185 (62%) of the studies did not adjust the primary method for both clustering and stratification. Conclusion Stratification helps to achieve the balance among intervention groups. However, to correctly assess the intervention effect from stratified CRTs, it is important to adjust the primary analysis for both stratification and clustering. There are significant deficiencies in the reporting of methodological aspects of stratified CRTs, which require substantial improvements in several areas including definition of strata, inclusion of stratification variable(s) in the flow chart or baseline characteristics table, and reporting the stratum-specific number of clusters and individuals in the intervention groups.

Abstract Background Dental anxiety (DA) has an impact on the quality of dental treatment and may have long-lasting implications for children. A recent study introducing experiential learning (EL) into children’s oral health promotion resulted in better oral hygiene. The purpose of the study is to evaluate whether EL can reduce children’s DA. Methods In September 2018, we recruited 988 children aged 7–8 years from 24 classes to participate in a cluster-randomized trial. Classes were randomly assigned to EL (in which children received a lively presentation on oral health and participated in a role play in a simulated dental clinic in the classroom) or the Tell-Show-Do (TSD) group (in which children received a conventional TSD behavior management). The primary outcome was the prevalence of high DA after the procedure of pit and fissure sealant (PFS), assessed by a modified Children’s Fear Survey Schedule-Dental Subscale. Secondary outcomes were changes in blood pressures (BP) and pulse rates (PR) before and after the PFS procedure. The intervention effects were estimated by means of mixed effect models, which included covariates of gender and school (and baseline value for BP and PR only), and a random cluster effect. Results In 396 children of the EL group who received the PFS treatment, the prevalence of high DA (score ≥ 38) was 18.5%, compared with 24.3% in 391 children of the TSD group (OR = 0.65; 95% confidence interval, 0.46–0.93; P = 0.019). The increases in BP and PR after the PFS were also significantly less in the EL group. Conclusion School-based experiential learning intervention before a dental visit is feasible and effective in reducing children’s dental anxiety during PFS. Trial registration The trial was registered in Chinese Clinical Trial Registry on 5 January 2020 (No.: ChiCTR2000028878 , retrospectively registered).

Abstract Background In a cross-sectional stepped-wedge trial with unequal cluster sizes, attained power in the trial depends on the realized allocation of the clusters. This attained power may differ from the expected power calculated using standard formulae by averaging the attained powers over all allocations the randomization algorithm can generate. We investigated the effect of design factors and allocation characteristics on attained power and developed models to predict attained power based on allocation characteristics. Method Based on data simulated and analyzed using linear mixed-effects models, we evaluated the distribution of attained powers under different scenarios with varying intraclass correlation coefficient (ICC) of the responses, coefficient of variation (CV) of the cluster sizes, number of cluster-size groups, distributions of group sizes, and number of clusters. We explored the relationship between attained power and two allocation characteristics: the individual-level correlation between treatment status and time period, and the absolute treatment group imbalance. When computational time was excessive due to a scenario having a large number of possible allocations, we developed regression models to predict attained power using the treatment-vs-time period correlation and absolute treatment group imbalance as predictors. Results The risk of attained power falling more than 5% below the expected or nominal power decreased as the ICC or number of clusters increased and as the CV decreased. Attained power was strongly affected by the treatment-vs-time period correlation. The absolute treatment group imbalance had much less impact on attained power. The attained power for any allocation was predicted accurately using a logistic regression model with the treatment-vs-time period correlation and the absolute treatment group imbalance as predictors. Conclusion In a stepped-wedge trial with unequal cluster sizes, the risk that randomization yields an allocation with inadequate attained power depends on the ICC, the CV of the cluster sizes, and number of clusters. To reduce the computational burden of simulating attained power for allocations, the attained power can be predicted via regression modeling. Trial designers can reduce the risk of low attained power by restricting the randomization algorithm to avoid allocations with large treatment-vs-time period correlations.

Abstract Background Cluster randomized trials are common in health research in low- and middle-income countries raising issues that challenge interpretation of standard ethical guidelines. While the Ottawa Statement on the ethical design and conduct of cluster randomized trials provides guidance for researchers and research ethics committees, it does not explicitly focus on low- and middle-income settings. Main body In this paper, we use the lens of the Ottawa Statement to analyze two cluster randomized trials conducted in low- and middle-income settings in order to identify gaps or ethical issues requiring further analysis and guidance. The PolyIran trial was a parallel-arm, cluster trial examining the effectiveness of a polypill for prevention of cardiovascular disease in Golestan province, Iran. The PASTAL trial was an adaptive, multistage, parallel-arm, cluster trial evaluating the effect of incentives for human immunodeficiency virus self-testing and follow-up on male partners of pregnant women in Malawi. Through an in-depth case analysis of these two studies we highlight several issues in need of further exploration. First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious. Particularly in the case of implementation interventions, locally available care is required as the comparator to address questions of comparative effectiveness. However, locally available care might be lower than standards set out in national guidelines. Third, while the need for access to effective interventions post-trial is widely recognized, it is often not possible to guarantee this upfront. Clarity on what is required of researchers and sponsors is needed. Fourth, there is a pressing need for ethics education and capacity building regarding cluster randomized trials in these settings. Conclusion We identify four issues in cluster randomized trials conducted in low- and middle-income countries for which further ethical analysis and guidance is required.

Abstract Background Delays in diagnosis and treatment of tuberculosis (TB) remain common in high-burden countries. To improve case detection, substantial investments have been made to scale-up Xpert MTB/RIF (Xpert), a cartridge-based nucleic acid amplification test that can detect TB within 2 hours, as a replacement for sputum smear microscopy. However, the optimal strategy for implementation of Xpert testing remains unclear. Methods The Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial uses an ultra-pragmatic, hybrid type II effectiveness-implementation design to assess the effectiveness and implementation of a streamlined strategy for delivery of Xpert testing in real-world settings. Twenty health centers with TB microscopy units were selected to participate in the trial, with ten health centers randomized to the intervention strategy (onsite molecular testing using GeneXpert Edge, process redesign to facilitate same-day TB diagnosis and treatment, and performance feedback) or routine care (onsite sputum smear microscopy plus referral of sputum samples to Xpert testing sites). The primary outcome is the number of patients with microbiologically confirmed TB who were initiated on treatment within 14 days of presentation to the health center, which reflects successful completion of the TB diagnostic evaluation process. Secondary outcomes include health outcomes (6-month vital status), as well as measures of the reach, adoption, and implementation of the intervention strategy. Discussion The design elements and implementation approach for the XPEL-TB trial were intentionally selected to minimize disruptions to routine care procedures, with the goal of limiting their influence on key primary and secondary outcomes. Trial findings may result in increased support and funding for rapid, onsite molecular testing as the standard-of-care for all patients being evaluated for TB. Trial registration US National Institutes of Health’s ClinicalTrials.gov, NCT03044158 . Registered 06 February 2017. Pan African Clinical Trials Registry, PACTR201610001763265 . Registered 03 September 2016.

Abstract Background Severe Acute Malnutrition (SAM) remains a major cause of child mortality. To improve the management and survival of children the World Health Organization (WHO) endorsed the protocol for the management of SAM. The protocol suggested the integration of psychosocial stimulation as part of the medico-nutritional care process to prevent the long-term adverse developmental impact of the SAM. However, there is little scientific evidence behind the recommended stimulation intervention. Method A parallel-group cluster-randomized controlled trial will be conducted among 144 children with SAM age 6–59 months in Southern Ethiopia. The study will have two groups where: children with SAM admitted in the intervention health facilities will receive psychosocial stimulation in addition to the routine inpatient care and for 6 months after discharge. Children with SAM admitted in the SC of the control health facilities will receive the routine inpatient care without psychosocial stimulation and home-based follow up for 6 months after discharge. All mothers/ caregivers will also receive uniform health education on child health-related issues. The primary outcome of the study will be child development while the secondary outcomes will include child growth and treatment outcome. All outcomes will be assessed four times: at enrollment, upon discharge from the SC, at 3 and 6 months of follow up. The data will be analyzed using STATA Version 15 Statistical Software. The anthropometric Z-scores and percentile of the median will be calculated child using WHO Anthro Version 3.2.2 Statistical Software. To assess the overall effect of the intervention by controlling other potential contributing factors, a generalized linear mixed model will be used. Discussion The present study will have an important contribution in generating supplementary evidence regarding the effect of psychosocial stimulation interventions on the development and growth outcomes of children with SAM. The study will further address the impact of the intervention on treatment outcome indicators that are still under-researched areas requiring new scientific evidence. Trial registration Pan African Clinical Trials Registry -PACTR201901730324304. Registered 25 November 2018, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=5739

Abstract Background Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters. Methods Data on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized. Results The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up. Conclusion ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogeneity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references for trials designed around prevalence and incidence of clinical outcomes. Adequately powered trials are critical to estimate the benefit of interventions to malaria in a reliable and reproducible fashion. Trial registration: ClinicalTrials.govNCT01872702. Registered 7 June 2013. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT01872702

Abstract Background Early prevention is a promising strategy for reducing obesity in childhood, and Early Years settings are ideal venues for interventions. This work evaluated an educational intervention with the primary aim of preventing overweight and obesity in pre-school children. Methods A pragmatic, cluster randomised trial with a parallel, matched-pair design was undertaken. Interventions were targeted at both the cluster (Early Years’ Centres, matched by geographical area) and individual participant level (families: mother and 2-year old child). At the cluster level, a staff training intervention used the educational resource Be Active, Eat Healthy. Policies and provision for healthy eating and physical activity were evaluated at baseline and 12-months. The intervention at participant level was the Healthy Heroes Activity Pack: delivered over 6 months by Centre staff to promote healthy eating and physical activity in a fun, interactive way. Child and parent height and weight were measured at four time-points over 2 years. The trial primary outcome was the change in BMI z-score of the child between ages 2 and 4 years. Secondary outcomes consisted of parent-reported measures administered at baseline and two-year follow-up. Results Five pairs of Early Years’ Centres were recruited. Four pairs were analysed as one Centre withdrew (47 intervention families; 34 control families). At the cluster level, improvement in Centre policies and practices was similar for both groups (p = 0.830). At the participant level, the intervention group reduced their mean BMI z-score between age 2 and 4 years (p = 0.002; change difference 0.49; 95% CI 0.17 to 0.80) whereas the control group showed increasing BMI z-score throughout. Changes in parent-reported outcomes and parent BMI (p = 0.582) were similar in both groups. Conclusions The Healthy Heroes educational resource deterred excess weight gain in pre-school children from poor socioeconomic areas. With training, Early Years’ staff can implement the Healthy Heroes programme. Trial registration ISRCTN22620137 Registered 21st December 2016.

Abstract Background Tuberculosis is one of the greatest global health concerns and disease management is challenging particularly in low- and middle-income countries. Despite improvements in addressing this epidemic in Georgia, tuberculosis remains a significant public health concern due to sub-optimal patient management. Low remuneration for specialists, limited private-sector interest in provision of infectious disease care and incomplete integration in primary care are at the core of this problem. Methods This protocol sets out the methods of a two-arm cluster randomized control trial which aims to generate evidence on the effectiveness of a performance-based financing and integrated care intervention on tuberculosis loss to follow-up and treatment adherence. The trial will be implemented in health facilities (clusters) under-performing in tuberculosis management. Eligible and consenting facilities will be randomly assigned to either intervention or control (standard care). Health providers within intervention sites will form a case management team and be trained in the delivery of integrated tuberculosis care; performance-related payments based on monthly records of patients adhering to treatment and quality of care assessments will be disbursed to health providers in these facilities. The primary outcomes include loss to follow-up among adult pulmonary drug-sensitive and drug-resistant tuberculosis patients. Secondary outcomes are adherence to treatment among drug-sensitive and drug-resistant tuberculosis patients and treatment success among drug-sensitive tuberculosis patients. Data on socio-demographic characteristics, tuberculosis diagnosis and treatment regimen will also be collected. The required sample size to detect a 6% reduction in loss to follow-up among drug-sensitive tuberculosis patients and a 20% reduction in loss to follow-up among drug-resistant tuberculosis patients is 948 and 136 patients, respectively. Discussion The trial contributes to a limited body of rigorous evidence and literature on the effectiveness of supply-side performance-based financing interventions on tuberculosis patient outcomes. Realist and health economic evaluations will be conducted in parallel with the trial, and associated composite findings will serve as a resource for the Georgian and wider regional Ministries of Health in relation to future tuberculosis and wider health policies. The trial and complementing evaluations are part of Results4TB, a multidisciplinary collaboration engaging researchers and Georgian policy and practice stakeholders in the design and evaluation of a context-sensitive tuberculosis management intervention. Trial registration ISRCTN, ISRCTN14667607. Registered on 14 January 2019.

Abstract Background Adherence to tuberculosis (TB) treatment is challenging because of many factors. The World Health Organization has recommended the use of digital adherence monitoring technologies in its End TB Strategy. However, evidence on improving adherence is limited. EvriMED is a real-time medication-monitoring device which was found to be feasible and acceptable in a few studies in Asia. In Tanzania, however, there may be challenges in implementing evriMED due to stigmatization, network and power access, accuracy, and cost effectiveness, which may have implications for treatment outcome. We propose a pragmatic cluster randomized trial to investigate the effectiveness of evriMED with reminder cues and tailored feedback on adherence to TB treatment in Kilimanjaro, Tanzania. Methods/design We will create clusters in Kilimanjaro based on level of health care facility. Clusters will be randomized in an intervention arm, where evriMED will be implemented, or a control arm, where standard practice directly observed treatment will be followed. TB patients in intervention clusters will take their medication from the evriMED pillbox and receive tailored feedback. We will use the ‘Stages of Change’ model, which assumes that a person has to go through the stages of pre-contemplation, contemplation, preparation, action, and evaluation to change behavior for tailored feedback on adherence reports from the device. Discussion If the intervention shows a significant effect on adherence and the devices are accepted, accurate, and sustainable, the intervention can be scaled up within the National Tuberculosis Programmes. Trial registration Pan African Clinical Trials Registry, PACTR201811755733759. Registered on 8 November 2018.

Abstract Background Type 2 diabetes is increasing globally, with the highest burden in low- to middle-income countries (LMICs) such as the Philippines. Developing effective interventions could improve detection, prevention, and treatment of diabetes. The Cardiovascular Health Awareness Program (CHAP), an evidence-based Canadian intervention, may be an appropriate model for LMICs due to its low cost, ease of implementation, and focus on health promotion and disease prevention. The primary aim of this study is to adapt the CHAP model to a Philippine context as the Community Health Assessment Program in the Philippines (CHAP-P) and evaluate the effect of CHAP-P on glycated hemoglobin (HbA1c) compared to a random sample of community residents in control communities. Methods Six-month, 26-community (13 intervention, 13 control) parallel cluster randomized controlled trial in Zamboanga Peninsula, an Administrative Region in the southern Philippines. Criteria for community selection include: adequate political stability, connection with local champions, travel feasibility, and refrigerated space for materials. The community-based intervention, CHAP-P sessions, are volunteer-led group sessions with chronic condition assessment, blood pressure monitoring, and health education. Three participant groups will be involved: 1) Random sample of community participants aged 40 or older, 100 per community (1300 control, 1300 intervention participants total); 2) Community members aged 40 years or older who attended at least one CHAP-P session; 3) Community health workers and staff facilitating sessions. Primary outcome: mean difference in HbA1c at 6 months in intervention group individuals compared to control. Secondary outcomes: modifiable risk factors, health utilization and access (individual); diabetes detection and management (cluster). Evaluation also includes community process evaluation and cost-effectiveness analysis. Discussion CHAP has been shown to be effective in a Canadian setting. Individual components of CHAP-P have been piloted locally and shown to be acceptable and feasible. This study will improve understanding of how best to adapt this model to an LMIC setting, in order to maximize prevention, detection, and management of diabetes. Results may inform policy and practice in the Philippines and have the potential to be applied to other LMICs. Trial registration ClinicalTrials.gov (NCT03481335), registered March 29, 2018.

Abstract Background In rural south Asia, hypertension remains a significant public health issue with sub-optimal blood pressure (BP) control rates. The goal of the trial is to evaluate the effectiveness and cost-effectiveness of a multicomponent intervention (MCI) compared to usual care on lowering BP among adults with hypertension in rural south-Asian communities. This article describes the statistical analysis plan for the primary and secondary objectives related to intervention effectiveness based on clinical and patient-reported endpoints. Methods/Design The study is a cluster randomized trial which will enroll 2550 participants aged ≥ 40 years with hypertension from rural communities in Bangladesh, Pakistan, and Sri Lanka. The unit of randomization is a cluster defined by 250–300 households. Thirty clusters, 10 from each country, are randomized in a 1:1 ratio to either MCI or usual care, stratified by country and their distance from the clinic. All participants will be assessed every six months over a two-year period after baseline with measurements of systolic and diastolic BP, antihypertensive and statin medication use, medication adherence, physical activity level, anthropometric parameters, smoking status, and dietary habits. The primary objective is to assess the effectiveness of MCI as compared with usual care in terms of mean change in systolic BP from baseline to final follow-up at two years. The primary outcome will be modelled using a generalized linear mixed-model for repeated measures based on a participant-level analysis. The model will include cluster random-effects and will use a non-independence residual correlation matrix to account for repeated measures on the same participant. Sensitivity analyses for the primary endpoint will be based on multiple imputation as well as pattern mixture model tipping point analyses. Secondary outcomes will be analyzed using the same modeling approach as for the primary outcome, with appropriate distributions within the exponential family and corresponding link functions. Discussion The a priori statistical analysis plan will avoid reporting bias and data-driven analysis for the primary and key secondary outcomes. The results of the study will provide evidence of the benefits and risks of the MCI for BP control in rural communities in south Asian countries with low-resourced public health infrastructure. Trial registration Clinicaltrials.gov, NCT02657746. Registered on 14 January 2016.

Abstract Background Chronic spinal pain affects many in the United States and is associated with rising healthcare costs - but not improved outcomes. Education and self-care promotion are hallmarks of the recommended approach for this condition. Pain Neuroscience Education (PNE) is a method of educating patients about the neurophysiology of pain that aims to reconceptualize pain from an indicator of damage to an interpretation of input signals by the brain and nervous system. PNE has shown efficacy in controlled situations when delivered by experts, but its effectiveness has not been investigated among trained clinicians in a pragmatic setting. Methods A cluster randomized trial will randomly assign 16 clinic regions to either receive PNE training or continue with usual care. Patients with chronic neck or back pain will be enrolled to provide outcome data. Measures will be collected at baseline, 2 weeks, and 12 weeks. The primary outcome will be the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function computer-adapted test (PF-CAT). Pre-specified statistical analyses will compare outcomes between clinic regions assigned to PNE treatment or usual care while using random effects to account for region-level clustering. Discussion Pain Neuroscience Education has been shown efficacious for a variety of patient-centered outcomes for those with chronic pain, but it has not yet been investigated outside of controlled settings. This trial has the potential to promote PNE as a low-cost intervention for chronic spinal pain and affect physical therapy education. Trial registration ClinicalTrials.gov identifier NCT03168165, registered May 30, 2017.

Abstract Background In France smoking initiation rates amongst 11 to 16 year-olds are worryingly high. Several studies show that early initiation to psycho-active substances is a strong predictor of tobacco addiction. Decreasing the age at which tobacco use starts represents a key challenge for reducing tobacco usage. Implementing an intervention trial using educational workshops based on the Theory of Planned Behavior (TPB) and covering the 4 years of secondary school could be effective. Methods “PEPITES” is an interventional research, using a cluster randomized design. It will allow assessing the effectiveness of interventions both in reducing the tobacco initiation rate and the regular smoking rate of secondary school pupils. We will also evaluate the process of the implementation of the study and thus will help to the transferability of the intervention. A partnership convention was signed between the JDB Foundation and the National Education authority which designated 6 secondary state schools for the PEPITES trial. The 6 schools were randomly allocated to 3 groups of 2 clusters each: 1 control group, 2 different intervention groups with 2 workshops per year during 4 years; In one of this group the 2 last workshops will be dedicated to measure the loss of taste due to tobacco smoking. In each school, all pupils in year 1 with a signed parental authorization (744 pupils) have been included in the trial. The interventions targets one of the variables of the TPB and the reinforcement of psycho-social competencies. We estimated that we could detect a reduction of increase ≥5.5 and 8% respectively in the 2 principal outcomes (risk α of 5%, and β of 80%). Discussion Carrying out a randomized prevention trial in the school environment raises specific problems which it seems useful to detail for other educational actors who would like to perform a similar study. This discussion concerns the acceptation and cooperation of the National Education partners, the risks of contamination, the information given to parents and pupils and their consent, and the representativeness of the schools involved. Trial registration ISRCTN85812512. Registered 15 May 2018 by BioMed Central. (retrospectively registered).

Abstract Background National diabetes audits in the UK show room for improvement in the quality of care delivered to people with type 2 diabetes in primary care. Systematic reviews of quality improvement interventions show that such approaches can be effective but there is wide variability between trials and little understanding concerning what explains this variability. A national cohort study of primary care across 99 UK practices identified modifiable predictors of healthcare professionals’ prescribing, advising and foot examination. Our objective was to evaluate the effectiveness of an implementation intervention to improve six guideline-recommended health professional behaviours in managing type 2 diabetes in primary care: prescribing for blood pressure and glycaemic control, providing physical activity and nutrition advice and providing updated diabetes education and foot examination. Methods Two-armed cluster randomised trial involving 44 general practices. Primary outcomes (at 12 months follow-up): from electronic medical records, the proportion of patients receiving additional prescriptions for blood pressure and insulin initiation for glycaemic control and having a foot examination; and from a patient survey of a random sample of 100 patients per practice, reported receipt of updated diabetes education and physical activity and nutrition advice. Results The implementation intervention did not lead to statistically significant improvement on any of the six clinical behaviours. 1,138,105 prescriptions were assessed. Intervention (29% to 37% patients) and control arms (31% to 35%) increased insulin initiation relative to baseline but were not statistically significantly different at follow-up (IRR 1.18, 95%CI 0.95–1.48). Intervention (45% to 53%) and control practices (45% to 50%) increased blood pressure prescription from baseline to follow-up but were not statistically significantly different at follow-up (IRR 1.05, 95%CI 0.96 to 1.16). Intervention (75 to 78%) and control practices (74 to 79%) increased foot examination relative to baseline; control practices increased statistically significantly more (OR 0.84, 95%CI 0.75–0.94). Fewer patients in intervention (33%) than control practices (40%) reported receiving updated diabetes education (OR = 0.74, 95%CI 0.57–0.97). No statistically significant differences were observed in patient reports of having had a discussion about nutrition (intervention = 73%; control = 72%; OR = 0.98, 95%CI 0.59–1.64) or physical activity (intervention = 57%; control = 62%; OR = 0.79, 95%CI 0.56–1.11). Development and delivery of the intervention cost £1191 per practice. Conclusions There was no measurable benefit to practices’ participation in this intervention. Despite widespread use of outreach interventions worldwide, there is a need to better understand which techniques at which intensity are optimally suited to address the multiple clinical behaviours involved in improving care for type 2 diabetes. Trial registration ISRCTN, ISRCTN66498413. Registered April 4, 2013

Abstract Background In Bangladesh, the targets on reduction of maternal mortality and utilization of related obstetric services provided by skilled health personnel in Millennium Development Goals 5 remains unmet, and the progress in reduction of neonatal mortality lag behind that in the reduction of infant and under-five mortalities, remaining as an essential issue towards the achievement of maternal and neonatal health targets in health related Sustainable Development Goals (SDGs). As access to appropriate perinatal care is crucial to reduce maternal and neonatal deaths, recently several mobile platform-based health programs sponsored by donor countries and Non-Governmental Organizations have targeted to reduce maternal and child mortality. On the other hand, good health-care is necessary for the development. Thus, we designed this implementation research to improve maternal and child health care for targeting SDGs. Methods/design This cluster randomized trial will be conducted in Lohagora of Narail District and Dhamrai of Dhaka District. Participants are pregnant women in the respective areas. The total sample size is 3000 where 500 pregnant women will get Mother and Child Handbook (MCH) and messages using mobile phone on health care during pregnancy and antenatal care about one year in each area. The other 500 in each area will get health education using only MCH book. The rest 1000 participants will be controlled; it means 500 in each area. We randomly assigned the intervention and controlled area based on smallest administrative area (Unions) in Bangladesh. The data collection and health education will be provided through trained research officers starting from February 2017 to August 2018. Each health education session is conducting in their house. The study proposal was reviewed and approved by NCCD, Japan and Bangladesh Medical Research Council (BMRC), Bangladesh. The data will be analyzed using STATA and SPSS software. Discussion For the improvement of maternal and neonatal care, this community-based intervention using mobile phone and handbook will do great contribution. Thus, a developing country where resources are limited received the highest benefit. Such intervention will guide to design for prevention of other diseases too. Trial registration UMIN000025628 Registered June 13, 2016.

Abstract Background Acute malnutrition is a continuum condition, but severe and moderate forms are treated separately, with different protocols and therapeutic products, managed by separate United Nations agencies. The Combined Protocol for Acute Malnutrition Study (ComPAS) aims to simplify and unify the treatment of uncomplicated severe and moderate acute malnutrition (SAM and MAM) for children 6–59 months into one protocol in order to improve the global coverage, quality, continuity of care and cost-effectiveness of acute malnutrition treatment in resource-constrained settings. Methods/design This study is a multi-site, cluster randomized non-inferiority trial with 12 clusters in Kenya and 12 clusters in South Sudan. Participants are 3600 children aged 6–59 months with uncomplicated acute malnutrition. This study will evaluate the impact of a simplified and combined protocol for the treatment of SAM and MAM compared to the standard protocol, which is the national treatment protocol in each country. We will assess recovery rate as a primary outcome and coverage, defaulting, death, length of stay, average weekly weight gain and average weekly mid-upper arm circumference (MUAC) gain as secondary outcomes. Recovery rate is defined across both treatment arms as MUAC ≥125 mm and no oedema for two consecutive visits. Per-protocol and intention-to-treat analyses will be conducted. Discussion If the combined protocol is shown to be non-inferior to the standard protocol, updating guidelines to use the combined protocol would eliminate the need for separate products, resources and procedures for MAM treatment. This would likely be more cost-effective, increase availability of services, enable earlier case finding and treatment before deterioration of MAM into SAM, promote better continuity of care and improve community perceptions of the programme. Trial registration ISRCTN, ISRCTN30393230. Registered on 16 March 2017.

Abstract Background Shared decision-making (SDM) is a model of interaction between doctors and patients in which both actors contribute to the medical decision-making process. SDM has raised great interest in mental healthcare over the last decade, as it is considered a fundamental part of patient-centered care. However, there is no research evaluating the efficacy of SDM compared to usual care (CAU), as it relates to quality of care and more specifically treatment adherence, in bipolar disorder (BD). Methods/Design This is a 12-month multi-centre, cluster-randomized controlled trial comparing the efficacy of SDM to CAU. Adult BD patients (n = 300) will be eligible after stabilization for at least 4 weeks following an acute mood episode. The intervention will consist of applying the standardized SDM process as developed by the Ottawa Hospital Research Institute in order to choose the maintenance treatment of BD. A multidisciplinary team developed a decision aid “choose my long-term treatment with my doctor” for BD patients to clarify possible therapeutic options. Primary outcome will assess the patient’s level of adherence (based on hetero-evaluation) of ongoing treatment at 12 months. Secondary outcomes will assess the difference between the 2 groups of patients in terms of adherence to maintenance drug therapy based on other measures (self-assessment scale and plasma levels of mood stabilizers). Additionally, other dimensions will be assessed: decisional conflict, satisfaction with care and involvement in decision making, beliefs about treatment, therapeutic relationship, knowledge about information for medical decision and clinical outcomes (depression, mania, functioning and quality of life). The primary endpoint will be analysed without adjustment by comparison of adherence scores between the two groups using Student t-tests or Mann–Whitney tests according to the variable distribution. A set of secondary analyses will be adjusted for covariates of clinical interest using generalized linear mixed regression models. Discussion This will be the first study evaluating the effect of an SDM intervention on patient adherence in BD. This is also an innovative protocol because it proposes the development of an evidence-based tool that should help patients and clinicians to initiate discussions regarding the use of BD treatment. Trial registration The study has been registered with ClinicalTrials.gov as NCT03245593.

Abstract Background One-year dual antiplatelet therapy (DAPT), generally aspirin in combination with a P2Y12 receptor inhibitor, has been a standard treatment for patients undergoing percutaneous coronary intervention (PCI). Prolonged DAPT has proven itself effective in further reducing cardiovascular events, yet with increased risk of bleeding. Thus, it is of great necessity to find an alternative drug that is as effective but safer and more economic than the P2Y12 inhibitors after termination of one-year DAPT. Methods We will conduct a cluster randomized controlled trial in 3600 eligible post-PCI patients from 36 tertiary hospitals (100 patients per hospital) across mainland China. The hospitals served as clusters are randomized in a 2:1 ratio to Guanxinning tablet (GXNT) plus aspirin or aspirin alone for 12 months, with other conventional treatment applied in both groups. After the treatment period, all patients will be followed up for another 12 months. The primary outcome measure is composite cardiovascular events including cardiovascular death, non-fatal myocardial infarction, stent thrombosis, revascularization, ischemic stroke, and re-admission due to unstable angina. Secondary outcome measures are all-cause mortality, each individual component of the primary outcome measure, and stopping or reducing the rate of nitroglycerin administration. Adverse events, including bleeding, will be closely monitored during the whole trial period. In addition, a cost-effectiveness study of GXNT for the study population will be conducted along with this trial. Discussion This trial aims to determine whether the addition of GXNT will further improve prognosis without increasing bleeding risk for patients with coronary artery disease who have switched from DAPT to aspirin alone after PCI. Completion of this clinical trial might provide a novel, promising, and safer alternative to P2Y12 inhibitors for prolonged antiplatelet therapy in post-PCI patients. Trial registration Chinese Clinical Trial Registry, ChiCTR-IIR-17010688. Registered on 20 February 2017.

Abstract Background Oral cholera vaccine (OCV) is a feasible tool to prevent or mitigate cholera outbreaks. A better understanding of the vaccine’s efficacy among different age groups and how rapidly its protection wanes could help guide vaccination policy. Methods To estimate the level and duration of OCV efficacy, we re-analyzed data from a previously published cluster-randomized, double-blind, placebo controlled trial with five years of follow-up. We used a Cox proportional hazards model and modeled the potentially time-dependent effect of age categories on both vaccine efficacy and risk of infection in the placebo group. In addition, we investigated the impact of an outbreak period on model estimation. Results Vaccine efficacy was 38% (95% CI: -2%,62%) for those vaccinated from ages 1 to under 5 years old, 85% (95% CI: 67%,93%) for those 5 to under 15 years, and 69% (95% CI: 49%,81%) for those vaccinated at ages 15 years and older. Among adult vaccinees, efficacy did not appear to wane during the trial, but there was insufficient data to assess the waning of efficacy among child vaccinees. Conclusions Through this re-analysis we were able to detect a statistically significant difference in OCV efficacy when the vaccine was administered to children under 5 years old vs. children 5 years and older. The estimated efficacies are more similar to the previously published analysis based on the first two years of follow-up than the analysis based on all five years. Trial registration ClinicalTrials.gov identifier NCT00289224

Abstract Background There is a worldwide shortage of organs available for transplant, leading to preventable mortality associated with end-stage organ disease. While most citizens in many countries with an intent-to-donate “opt-in” system support organ donation, registration rates remain low. In Canada, most Canadians support organ donation but less than 25% in most provinces have registered their desire to donate their organs when they die. The family physician office is a promising yet underused setting in which to promote organ donor registration and address known barriers and enablers to registering for deceased organ and tissue donation. We developed a protocol to evaluate an intervention to promote registration for organ and tissue donation in family physician waiting rooms. Methods/design This protocol describes a planned, stepped-wedge, cluster randomized registry trial in six family physician offices in Ontario, Canada to evaluate the effectiveness of reception staff providing patients with a pamphlet that addresses barriers and enablers to registration including a description of how to register for organ donation. An Internet-enabled tablet will also be provided in waiting rooms so that interested patients can register while waiting for their appointments. Family physicians and reception staff will be provided with training and/or materials to support any conversations about organ donation with their patients. Following a 2-week control period, the six offices will cross sequentially into the intervention arm in randomized sequence at 2-week intervals until all offices deliver the intervention. The primary outcome will be the proportion of patients visiting the office who are registered organ donors 7 days following their office visit. We will evaluate this outcome using routinely collected registry data from provincial administrative databases. A post-trial qualitative evaluation process will assess the experiences of reception staff and family physicians with the intervention and the stepped-wedge trial design. Discussion Promoting registration for organ donation in family physician offices is a potentially useful strategy for increasing registration for organ donation. Increased registration may ultimately help to increase the number of organs available for transplant. The results of this trial will provide important preliminary data on the effectiveness of using family physician offices to promote registration for organ donation. Trial registration ClinicalTrials.gov, ID: NCT03213171 . Registered on 11 July 2017.

Abstract Background Back pain is a leading contributor to disability, healthcare costs, and lost work. Family physicians are the most common first point of contact in the healthcare system for people with back pain, but physiotherapists (PTs) may be able to support the primary care team through evidence-based primary care. A cluster randomized trial is needed to determine the clinical, health system, and societal impact of a primary care model that integrates physiotherapists at the first visit for people with back pain. Prior to conducting a future fully powered cluster randomized trial, we need to demonstrate feasibility of the methods. Therefore, the purpose of this pilot study will be to: 1) Determine feasibility of patient recruitment, assessment procedures, and retention. 2) Determine the feasibility of training and implementation of a new PT-led primary care model for low back pain (LBP) 3) Explore the perspectives of patients and healthcare providers (HCPs) related to their experiences and attitudes towards the new service delivery model, barriers/facilitators to implementation, perceived satisfaction, perceived value, and impact on clinic processes and patient outcomes. Methods This pilot cluster randomized controlled trial will enroll four sites and randomize them to implement a new PT-led primary care model for back pain or a usual physician-led primary care model. All adults booking a primary care visit for back pain will be invited to participate. Feasibility outcomes will include: recruitment and retention rates, completeness of assessment data, PT training participation and confidence after training, and PT treatment fidelity. Secondary outcomes will include the clinical, health system, cost, and process outcomes planned for the future fully powered cluster trial. Results will be analyzed and reported descriptively and qualitatively. To explore perspectives of both HCPs and patients, we will conduct semi-structured qualitative interviews with patients and focus groups with HCPs from participants in the PT-led primary care sites. Discussion If this pilot demonstrates feasibility, a fully powered trial will provide evidence that has the potential to transform primary care for back pain. The full trial will inform future service design, whether these models should be more widely implemented, and training agendas. Trial registration ClinicalTrials.gov, NCT03320148 . Submitted for registration on 17 September 2017.

Abstract Background The Building on Existing Tools to Improve Chronic Disease Prevention and Screening (BETTER) cluster randomized trial in primary care settings demonstrated a 30% improvement in adherence to evidence-based Chronic Disease Prevention and Screening (CDPS) activities. CDPS activities included healthy activities, lifestyle modifications, and screening tests. We present a protocol for the adaptation of BETTER to a public health setting, and testing the adaptation in a cluster randomized trial (BETTER HEALTH: Durham) among low income neighbourhoods in Durham Region, Ontario (Canada). Methods The BETTER intervention consists of a personalized prevention visit between a participant and a prevention practitioner, which is focused on the participant’s eligible CDPS activities, and uses Brief Action Planning, to empower the participant to set achievable short-term goals. BETTER HEALTH: Durham aims to establish that the BETTER intervention can be adapted and proven effective among 40–64 year old residents of low income areas when provided in the community by public health nurses trained as prevention practitioners. Focus groups and key informant interviews among stakeholders and eligible residents of low income areas will inform the adaptation, along with feedback from the trial’s Community Advisory Committee. We have created a sampling frame of 16 clusters composed of census dissemination areas in the lowest urban quintile of median household income, and will sample 10 clusters to be randomly allocated to immediate intervention or six month wait list control. Accounting for the clustered design effect, the trial will have 80% power to detect an absolute 30% difference in the primary outcome, a composite score of completed eligible CDPS actions six months after enrollment. The prevention practitioner will attempt to link participants without a primary care provider (PCP) to a local PCP. The implementation of BETTER HEALTH: Durham will be evaluated by focus groups and key informant interviews. Discussion The effectiveness of BETTER HEALTH: Durham will be tested for delivery in low income neighbourhoods by a public health department. Trial Registration: NCT03052959, registered February 10, 2017.

Abstract Background Malawi introduced an ambitious public health program known as “Option B+” which provides all HIV-infected pregnant and breastfeeding women with lifelong combination antiretroviral therapy, regardless of WHO clinical stage or CD4 cell count. The PMTCT Uptake and REtention (PURE) study aimed at evaluating the effect of peer-support on care-seeking and retention in care. Methods/design PURE Malawi was a three-arm cluster randomized controlled trial that compared facility-based and community-based models of peer support to standard of care under Option B+ strategy. Each arm was expected to enroll a minimum of 360 women with a total minimum sample size of 1080 participants. 21 sites (clusters) were selected for inclusion in the study. This paper describes the site selection, recruitment, enrollment process and baseline characteristics of study sites and women enrolled in the trial. Results Study implementation was managed by 3 partner organizations; each responsible for 7 study sites. The trial was conducted in the South East, South West, and Central West zones of Malawi, the zones where the implementing partners operate. Study sites included 2 district hospitals, 2 mission hospitals, 2 rural hospitals, 13 health centers and 1 private clinic. Enrollment occurred from November 2013 to November 2014, over a median period of 31 weeks (range 17–51) by site. A total of 1269 HIV-infected pregnant (1094) and breastfeeding (175) women, who were eligible to initiate ART under Option B+, were enrolled. Each site reached or surpassed the minimum sample size. Comparing the number of women enrolled versus antenatal cohort reports, sites recruited a median of 90% (IQR 75–100) of eligible reported women. In the majority of sites the ratio of pregnant and lactating women enrolled in the study was similar to the ratio of reported pregnant and lactating women starting ART in the same sites. The median age of all women was 27 (IQR 22–31) years. All women have ≥20 months of possible follow-up time; 96% ≥ 2 years (24–32 months). Conclusion The PURE Malawi study showed that 3 implementing partner organizations could successfully recruit a complex cohort of pregnant and lactating women across 3 geographical zones in Malawi within a reasonable timeline. Trial registration This study is registered at clinicaltrials.gov - ID Number NCT02005835 . Registered 4 December, 2013.

Abstract Background Selection bias and non-participation bias are major methodological concerns which impact external validity. Cluster-randomized controlled trials are especially prone to selection bias as it is impractical to blind clusters to their allocation into intervention or control. This study assessed the impact of selection bias in a large cluster-randomized controlled trial. Methods The Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE) study examined the impact of a remote pharmacist-led intervention in twelve medical offices. To assess eligibility, a standardized form containing patient demographics and medical information was completed for each screened patient. Eligible patients were approached by the study coordinator for recruitment. Both the study coordinator and the patient were aware of the site’s allocation prior to consent. Patients who consented or declined to participate were compared across control and intervention arms for differing characteristics. Statistical significance was determined using a two-tailed, equal variance t-test and a chi-square test with adjusted Bonferroni p-values. Results were adjusted for random cluster variation. Results There were 2749 completed screening forms returned to research staff with 461 subjects who had either consented or declined participation. Patients with poorly controlled diabetes were found to be significantly more likely to decline participation in intervention sites compared to those in control sites. A higher mean diastolic blood pressure was seen in patients with uncontrolled hypertension who declined in the control sites compared to those who declined in the intervention sites. However, these findings were no longer significant after adjustment for random variation among the sites. After this adjustment, females were now found to be significantly more likely to consent than males (odds ratio = 1.41; 95% confidence interval = 1.03, 1.92). Conclusions Though there appeared to be a higher consent rate for females than for males, the overall impact of potential selection bias and refusal to participate was minimal. Without rigorous methodology, selection bias may be a threat to external validity in cluster-randomized trials. Trial registration NCT01983813 . Date of registration: Oct. 28, 2013.

Abstract Background Osteoporosis is a debilitating disease. Adequate calcium consumption and physical activity are the two major modifiable risk factors. This paper describes the major outcomes and efficacy of a workplace-based targeted behaviour change intervention to improve the dietary and physical activity behaviours of working women in sedentary occupations in Singapore. Methods A cluster-randomized design was used, comparing the efficacy of a tailored intervention to standard care. Workplaces were the units of randomization and intervention. Sixteen workplaces were recruited from a pool of 97, and randomly assigned to intervention and control arms (eight workplaces in each). Women meeting specified inclusion criteria were then recruited to participate. Workplaces in the intervention arm received three participatory workshops and organization-wide educational activities. Workplaces in the control/standard care arm received print resources. Outcome measures were calcium intake (milligrams/day) and physical activity level (duration: minutes/week), measured at baseline, 4 weeks and 6 months post intervention. Adjusted cluster-level analyses were conducted comparing changes in intervention versus control groups, following intention-to-treat principles and CONSORT guidelines. Results Workplaces in the intervention group reported a significantly greater increase in calcium intake and duration of load-bearing moderate to vigorous physical activity (MVPA) compared with the standard care control group. Four weeks after intervention, the difference in adjusted mean calcium intake was 343.2 mg/day (95 % CI = 337.4 to 349.0, p

Abstract Background Despite randomization, baseline imbalance and confounding bias may occur in cluster randomized trials (CRTs). Covariate imbalance may jeopardize the validity of statistical inferences if they occur on prognostic factors. Thus, the diagnosis of a such imbalance is essential to adjust statistical analysis if required. Methods We developed a tool based on the c-statistic of the propensity score (PS) model to detect global baseline covariate imbalance in CRTs and assess the risk of confounding bias. We performed a simulation study to assess the performance of the proposed tool and applied this method to analyze the data from 2 published CRTs. Results The proposed method had good performance for large sample sizes (n =500 per arm) and when the number of unbalanced covariates was not too small as compared with the total number of baseline covariates (≥40 % of unbalanced covariates). We also provide a strategy for pre selection of the covariates needed to be included in the PS model to enhance imbalance detection. Conclusion The proposed tool could be useful in deciding whether covariate adjustment is required before performing statistical analyses of CRTs.