A cluster-randomised controlled feasibility trial evaluating the Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS).

INTRODUCTION: There is a high prevalence of cognitive difficulties in MS, but despite this, there are few programmes targeting cognition that focus on the ability to function well in everyday life. The Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS), an occupation-focused cognitive intervention, was developed to address this. It addresses both the functional difficulties and the wide-ranging symptoms that present in MS. OBJECTIVE: Here we report on the results of a cluster-randomised controlled feasibility trial (ISRCTN11462710; registered 4th September 2019) evaluating the COB-MS in terms of feasibility and initial efficacy as a cognitive intervention for people with MS. METHOD: The eight-session COB-MS intervention was delivered remotely by occupational therapists to participants with MS in the intervention group. Following the end of the trial the COB-MS was delivered to the wait-list control group. Data was collected from people with MS experiencing cognitive difficulties at baseline, post-intervention, 12-weeks, and 6-month follow-up. The primary outcome measure was the Goal Attainment Scaling at 12 weeks. Data was also collected in the domains of cognition, quality of life, and mood. RESULTS: One hundred and eighteen people with MS and cognitive difficulties were randomised to either usual care (n = 60) or COB-MS intervention (n = 58). Ninety-four participants were retained at 6-month follow-up. The COB-MS was found to be feasible, including trial procedures and protocol. Data indicates that the COB-MS is accepted by participants and had positive impacts on daily life. Those allocated to the COB-MS group had a significant improvement in the primary outcome compared to the control condition. Progression criteria set for the feasibility trial have been met therefore further testing of the COB-MS at a definitive trial is supported by the results. CONCLUSION: The results provide a strong basis for a pathway to a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. TRIAL REGISTRATION: ISRCTN11462710 Date of registration: 4th September 2019.

Effectiveness of a School-Based Oral Health Promotion Program on Dental Caries Among Iraqi School Children: A Cluster Randomised Controlled Trial.

AIM: To assess the effectiveness of a school-based oral health promotion program on dental caries of permanent dentition among Iraqi children. METHODS: A cluster randomised controlled trial was conducted with a parallel study group, comprising 8-10-year-old schoolchildren, 186 in each group. At the beginning of the study, subjects in the intervention group received oral health education and a single dose of 5% sodium fluoride varnish for all teeth surfaces while the control group only received oral health education. The primary outcome data in this study were caries increment and incidence after six months. The secondary outcome data was any change in oral health behaviors in the students of both groups after 3 months. The caries status was recorded according to International Caries Detection and Assessment System (ICDAS). Statistical analyses included the Chi-square test, McNemar test, independent t-test, simple and multiple logistic regression models. RESULTS: Study participants included 372 children with no significant difference in baseline characteristics between intervention and control groups. An increase was evident in the mean scores of DMFS, DMFT, number of children with DMFT > 0, and DS > 0 for both control and intervention groups at six-month follow-up but this increase was significantly higher for the control than intervention group (P < .001). Among all variables included in the multiple logistic regression model, just being in the intervention group showed a significant effect in which children in the control group had a 4.2-fold (95% CI: 2.36-7.54) greater chance for developing new caries than children in the intervention group. There was a statistically significant increase in the percentage of children with favourable levels of behaviors between baseline and 3-month follow-up (P < .05, P < .001). CONCLUSION: Providing access to oral health services such as oral examination, fluoride varnish application, and oral health education to reduce dental caries and improve oral health practices seems to be effective among primary schoolchildren.

Effect of low-cost kitchen with improved cookstove on birthweight of neonates in Shahjadpur, Bangladesh: a cluster-randomised controlled trial.

Background: Smoke from biomass fuels used for cooking in traditional cookstoves contains a variety of health-damaging pollutants. Inhalation of these pollutants by pregnant women has been linked to abnormal foetal development and adverse pregnancy outcomes, including low birthweight (LBW). There is a dearth of data on environmental interventions that have the potential to reduce exposure to biomass fuel during pregnancy and improve birth outcomes. International Centre for Diarrheal Disease Research, Bangladesh (icddr,b) therefore, designed a low-cost kitchen with an improved cookstove and examined the impact of this intervention on the birthweight of neonates. Methods: icddr,b conducted a cluster-randomised controlled trial of a 'low-cost kitchen with improved cookstove' intervention among 1,267 pregnant women who used traditional cookstoves in a rural sub-district of Bangladesh. All participants were enrolled during the first trimester of pregnancy among 104 randomly selected clusters after obtaining informed consent. The model kitchens were installed in 628 participants' households of the intervention group, and 639 participants continued to use traditional cookstoves as the control group. The primary outcome was the proportion of LBW neonates between the intervention and control groups. The study also examined if the intervention would reduce CO exposure, measured by the differences in maternal blood carbon monoxide saturation (SpCO) levels and prevalence of LBW in neonates. We performed a generalized structural equation model for jointly assessing the simultaneous relationships of biomass fuel exposure to LBW of neonates and the relationships of LBW of neonates to maternal blood SpCO level. This trial was registered with ClinicalTrials.gov (NCT02923882). Findings: We found that in the intervention group using 'low-cost kitchen with improved cookstove', the risk of LBW reduced by 37% (adjusted risk ratio: 0.63, 95% CI [0.45, 0.89]). Between the second and third trimester, the mean maternal blood SpCO level was significantly reduced from 10.4% to 8.9% (p-value <0.01) in the intervention group but remained unchanged in the control group (11.6% and 11.5%). Of the total effects of the intervention on the risk of LBW, 48.3% was mediated through maternal blood SpCO level. Interpretation: The risk of LBW among rural neonates was reduced in the intervention group using 'low-cost kitchen with improved cookstove', which may be attributed to the reduction in maternal blood SpCO level. Additional research is needed to identify other mechanisms through which biomass fuel exposure might lead to adverse pregnancy outcomes. Funding: Grand Challenges Canada: Rising Stars in Global Health Programme.

Statistical analysis plan for cluster randomised trial to evaluate a community-level complementary food safety and hygiene and nutrition intervention in Mali: the MaaCiwara study.

BACKGROUND: Diarrheal disease is a significant cause of morbidity and mortality in under-fives in many low- and middle-income countries. Changes in food safety, hygiene practices, and nutrition around the weaning period may reduce the risk of disease and improve infant development. The MaaCiwara study aims to evaluate the effectiveness of a community-based educational intervention designed to improve food safety and hygiene behaviours, as well as child nutrition. This update article describes the statistical analysis plan for the MaaCiwara study in detail. METHODS AND DESIGN: The MaaCiwara study is a parallel group, two-arm, superiority cluster randomised controlled trial with baseline measures, involving 120 clusters of rural and urban communities. These clusters are randomised to either receive the community-based behaviour change intervention or to the control group. The study participants will be mother-child pairs, with children aged between 6 and 36 months. Data collection involves a day of observation and interviews with each participating mother-child pair, conducted at baseline, 4 months, and 15 months post-intervention. The primary analysis aims to estimate the effectiveness of the intervention on changes to complementary food safety and preparation behaviours, food and water contamination, and diarrhoea. The primary outcomes will be analysed generalised linear mixed models, at individual level, accounting for clusters and rural/urban status to estimate the difference in outcomes between the intervention and control groups. Secondary outcomes include maternal autonomy, enteric infection, nutrition, child anthropometry, and development scores. In addition, structural equation analysis will be conducted to examine the causal relationships between the different outcomes. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) register: ISRCTN14390796 . Registered on 13 December 2021.

Community health promotion and medical provision and impact on neonates (CHAMPION2) and support to rural India's public education system and impact on numeracy and literacy scores (STRIPES2): an update to the study protocol (v 11) for a cluster randomised trial in Madhya Pradesh, India.

BACKGROUND: This update outlines amendments to the CHAMPION2/STRIPES2 cluster randomised trial protocol primarily made due to the COVID-19 pandemic and nationwide lockdown in India in 2020. These amendments were in line with national guidelines for health research during the COVID-19 pandemic. METHODS: We did not change the original trial design, eligibility, and outcomes. Amendments were introduced to minimise the risk of COVID-19 transmission and ensure safety and wellbeing of trial staff, participants, and other villagers. CHAMPION2 intervention: participatory learning and action (PLA) and fixed day service (FDS) meeting were revised to incorporate social distancing and hygiene precautions. During the COVID-19 pandemic, PLA participation was limited to pregnant women and birthing partners. STRIPES2 intervention: before/after-school classes were halted for a period and then modified temporarily (reducing class sizes, and/or changing meeting places) with hygiene and safe distancing practices introduced. DATA COLLECTION: The research team gathered as much information as possible from participants by telephone. If the participant had no telephone or could not be contacted by telephone, data were collected in person. COVID-19 precautions: trial teams were trained on COVID-19 precautions and used personal protective equipment whilst in the villages for trial-related activities. After restarting the trial between June and September 2020 in a phased manner, some trial activities were suspended again in all the trial villages from April to June 2021 due to the second wave of COVID-19 cases and lockdown imposed in Satna, Madhya Pradesh. Trial timelines were also revised, with outcomes measured later than originally planned. TRIAL REGISTRATION: Clinical Trial Registry of India CTRI/2019/05/019296. Registered 23 May 2019. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2 .

Effects of brief family psychoeducation on family caregiver burden of people with schizophrenia provided by psychiatric visiting nurses: a cluster randomised controlled trial.

BACKGROUND: The purpose of this study was to examine the effects of a brief family psychoeducation (BFP) programme provided by psychiatric visiting nurses on caregiver burden of family caregivers of people with schizophrenia through a cluster randomised controlled trial (cRCT). METHODS: The study was a two-arm, parallel-group cRCT. Forty-seven psychiatric visiting nurse agencies were randomly allocated to the BFP programme group (intervention group) or treatment as usual group (TAU; control group). Caregivers of people with schizophrenia were recruited by psychiatric visiting nurses using a randomly ordered list. The primary outcome was caregiver burden, measured using the Japanese version of the Zarit Burden Interview. Outcome assessments were conducted at baseline, 1-month follow-up, and 6-month follow-up. Intention-to-treat analysis was conducted to examine the effects of the BFP programme on caregiver burden. RESULTS: Thirty-four psychiatric visiting nurse agencies and 83 family caregivers of people with schizophrenia participated in the study. The participant attrition rate was less than 20%. Adherence to the program was 100%. Compared with TAU group, the BFP programme group had decreased caregiver burden. However, this improvement was not significant at 1-month follow-up (adjusted mean difference [aMD] = 0.27, 95% CI = - 5.48 to 6.03, p = 0.93, d = 0.01) or 6-month follow-up (aMD = - 2.12, 95% CI = - 7.80 to 3.56, p = 0.45, d = 0.11). CONCLUSIONS: The BFP programme provided by psychiatric visiting nurses did not achieve significant decreases in caregiver burden. This result may be attributed to the difficulty in continuing the research due to the COVID-19 pandemic, which prevented us from achieving the targeted sample size necessary to meet the statistical power requirements, as well as to the participation of caregivers with relatively low burden. However, the program had the advantage of high adherence to treatment plan. Further studies should be conducted with a larger sample size and a more diverse sample that includes caregivers with a higher care burden. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000038044) on 2019/09/18.

Update to: Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore.

BACKGROUND: This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. METHODS: The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. DISCUSSION: The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

The IMPROVE trial: study protocol for a pragmatic cluster randomised controlled trial to assess the effectiveness of using lay health workers to improve uptake and completion of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is a programme of exercise and education and the most effective treatment for the symptoms and disability associated with chronic obstructive pulmonary disease. However, the benefits of PR are limited by poor uptake and completion. This trial will determine whether using trained volunteer lay health workers, called "PR buddies," improves uptake and completion of PR and is cost-effective. This trial protocol outlines the methods for evaluating effectiveness, cost-effectiveness, and acceptability. METHODS: The IMPROVE trial is a pragmatic, open, cluster randomised controlled trial planned in 38 PR services across England and Wales. PR services will be randomised to either intervention arm-offering support from PR buddies to patients with chronic obstructive pulmonary disease-or to usual care as the control arm. PR staff in trial sites randomised to the intervention arm will receive training in recruiting and training PR buddies. They will deliver training to volunteers, recruited from among people who have recently completed PR in their service. The 3-day PR-buddy training programme covers communication skills, confidentiality, boundaries of the PR-buddy role and behaviour change techniques to help patients overcome obstacles to attending PR. An internal pilot will test the implementation of the trial in eight sites (four intervention sites and four in control arm). The primary outcome of the trial is the uptake and completion of PR. A process evaluation will investigate the acceptability of the intervention to patients, PR staff and the volunteer PR buddies, and intervention fidelity. We will also conduct a cost-effectiveness analysis. DISCUSSION: Improving outcomes for chronic obstructive pulmonary disease and access to PR are priorities for the UK National Health Service (NHS) in its long-term plan. The trial hypothesis is that volunteer PR buddies, who are recruited and trained by local PR teams, are an effective and cost-effective way to improve the uptake and completion rates of PR. The trial is pragmatic, since it will test whether the intervention can be incorporated into NHS PR services. Information obtained in this trial may be used to influence policy on the use of PR buddies in PR and other similar services in the NHS. TRIAL REGISTRATION: ISRCTN12658458. Registered on 23/01/2023.

Primary care involvement in clinical research - prerequisites, motivators, and barriers: results from a study series.

BACKGROUND: Long-term reinforcement in the role of primary care and improvement the healthcare system as a whole requires the involvement of GPs in clinical research processes. However, many clinical studies fail due to failure to achieve sample population targets amongst GPs and their patients. This issue has been identified and discussed, but effective strategies to overcome it are still lacking. One of the reasons is that the positions, requirements, and experiences of GPs on participating in clinical research have hardly been examined up to now. METHODS: The years 2021 and 2022 saw three quantitative and qualitative surveys amongst GPs in Germany with the aim of shedding light on the attitudes, experiences, and potential issues regarding the involvement of primary care in clinical research projects and participation in cluster-randomised controlled trials (cRCTs) in a general sense. This overview summarises and abstracts conclusions gained from the exploratory series of studies and compares the results with the current research situation. From here, this contribution will then develop an approach towards optimising the integration of GPs into clinical research. RESULTS: Most of the GPs asked associated clinical research with opportunities and potential such as closing gaps in healthcare, using evidence-based instruments, optimising diagnostic and therapeutic management, and reinforcement of multiprofessional healthcare. Even so, many GPs unsure as to how far primary care in particular would stand to benefit from studies of this type in the long term. Respondents were also divided on willingness to participate in clinical research. GPs having already participated in Innovation Fund projects generally saw a benefit regarding intervention and cost-benefit relationship. However, some also reported major hurdles and stress factors such as excessive documentation and enrolment requirements, greater interference in practice routines, and sometimes poor integration into project processes such as in communication and opportunities to play an active role in the project. CONCLUSIONS: Results from the studies presented provide indications as to how GPs perceive clinical research projects and cRCTs as a whole and from their existing project experience, and on the requirements that studies would have to meet for GPs to be willing to participate. In particular, making sure that clinical studies fully conform with GPs would play a major role; this especially applies to freedom to make medical decisions, limitation of documentation obligations, interference in regular practice routine, greater involvement in research planning, and long-term reinforcement in the role of primary care. Clinical research projects and cRCTs should be planned, designed, and communicated for clear and visible relevance to everyday primary care.

Insecticide-treated bed nets and residual indoor spraying reduce malaria in areas with low transmission: a reanalysis of the Maltrials study.

BACKGROUND: The malaria incidence data from a malaria prevention study from the Rift Valley, Central Ethiopia, were reanalysed. The objective was to investigate whether including an administrative structure within the society, which may have required consideration in the protocol or previous analysis, would provide divergent outcomes on the effect measures of the interventions. METHODS: A cluster-randomized controlled trial lasting 121 weeks with 176 clusters in four groups with 6071 households with 34,548 persons was done: interventions combining indoor residual spraying (IRS) and insecticide-treated nets (ITNs), IRS alone, ITNs alone and routine use. The primary outcome was malaria incidence. A multilevel negative binomial regression model was employed to examine the impact of the kebele (smallest administrative unit) and the proximity of homes to the primary mosquito breeding sites as potential residual confounders (levels). The study also assessed whether these factors influenced the effect measures of the interventions. RESULTS: The study's initial findings revealed 1183 malaria episodes among 1059 persons, with comparable effects observed across the four intervention groups. In the reanalysis, the results showed that both ITN + IRS (incidence rate ratio [IRR] 0.63, P < 0.001) and ITN alone (IRR 0.78, P = 0.011) were associated with a greater reduction in malaria cases compared to IRS (IRR 0.90; P = 0.28) or the control (reference) group. The combined usage of IRS with ITN yields better outcomes compared to the standalone use of ITN and surpasses the effectiveness of IRS in isolation. CONCLUSION: The findings indicate that implementing a combination of IRS and ITN and also ITN alone decrease malaria incidence. Furthermore, there was an observed synergistic impact when ITN and IRS were used in combination. Considering relevant social structures as potential residual confounders is of paramount importance. TRIAL REGISTRATION: PACTR201411000882128 (08 September 2014).

Lower urinary tract symptoms in men: the TRIUMPH cluster RCT.

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery. Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care. Design: This was a two-arm cluster randomised controlled trial. Setting: The trial was set in 30 NHS general practice sites in England. Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms. Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention. Main outcome measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms. Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014). Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.. Trial registration: This trial is registered as ISRCTN11669964. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Urinary problems among men become more common with age. Nearly one-third of all men aged > 65 years experience some urinary symptoms, which can have a substantial effect on their daily lives. Symptoms include needing to pass urine more often, urgently or during the night, and difficulties in passing urine. Men are usually diagnosed and treated by their general practitioner, and should be offered advice on controlling their symptoms themselves (e.g. lifestyle changes and exercises) before trying tablets or surgery. However, it is not known how helpful such advice is, and how general practices can effectively provide it. Thirty general practices in the West of England and Wessex took part in the study. Practices were split into two groups, with each practice providing either the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions care package or the practice's usual care to all of its patients in the trial. The TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package included a booklet of advice to help control urinary symptoms, with a nurse or healthcare assistant directing men to relevant sections according to their symptoms, and providing follow-up contacts. We mainly assessed the benefits of the TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package, compared with usual care, by using a questionnaire on urinary symptoms completed by participants. A total of 1077 men with urinary symptoms that bothered them joined the study. The main result was that men reported greater improvement in urinary symptoms with the TRIUMPH care package than with usual care, 12 months after joining the study. We also found that men receiving the TRIUMPH care package had a slight improvement in quality of life and outlook on their urinary symptoms. There was no difference between the two groups in the number of patients referred to hospital for treatment, the type, number and severity of side effects or cost to the NHS. Overall, the TRIUMPH care package was more effective in treating men with urinary symptoms than usual care by their general practice.

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study: statistical analysis plan.

RATIONALE: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). METHODS AND DESIGN: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10-14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. PURPOSE: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. TRIAL REGISTRATION: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . PROTOCOL: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions-none.

Statistical analysis plan for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice: identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i).

BACKGROUND: The Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i) trial is being conducted to establish whether 'screening and intervention', consisting of usual school practice plus a pathway comprising screening, feedback and a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety), bring clinical and health economic benefits compared to usual school practice and assessment only - 'usual school practice', for children aged 8-9 years in the following: (1) the 'target population', who initially screen positive for anxiety problems according to a two-item parent-report child anxiety questionnaire - iCATS-2, and (2) the 'total population', comprising all children in participating classes. This article describes the detailed statistical analysis plan for the trial. METHODS AND DESIGN: iCATS-i2i is a definitive, superiority, pragmatic, school-based cluster randomised controlled trial (with internal pilot), with two parallel groups. Schools are randomised 1:1 to receive either screening and intervention or usual school practice. This article describes the following: trial objectives and outcomes; statistical analysis principles, including detailed estimand information necessary for aligning trial objectives, conduct, analyses and interpretation when there are different analysis populations and outcome measures to be considered; and planned main analyses, sensitivity and additional analyses. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN76119074. Registered on 4 January 2022.

Analysing cluster randomised controlled trials using GLMM, GEE1, GEE2, and QIF: results from four case studies.

BACKGROUND: Using four case studies, we aim to provide practical guidance and recommendations for the analysis of cluster randomised controlled trials. METHODS: Four modelling approaches (Generalized Linear Mixed Models with parameters estimated by maximum likelihood/restricted maximum likelihood; Generalized Linear Models with parameters estimated by Generalized Estimating Equations (1st order or second order) and Quadratic Inference Function, for analysing correlated individual participant level outcomes in cluster randomised controlled trials were identified after we reviewed the literature. We systematically searched the online bibliography databases of MEDLINE, EMBASE, PsycINFO (via OVID), CINAHL (via EBSCO), and SCOPUS. We identified the above-mentioned four statistical analytical approaches and applied them to four case studies of cluster randomised controlled trials with the number of clusters ranging from 10 to 100, and individual participants ranging from 748 to 9,207. Results were obtained for both continuous and binary outcomes using R and SAS statistical packages. RESULTS: The intracluster correlation coefficient (ICC) estimates for the case studies were less than 0.05 and are consistent with the observed ICC values commonly reported in primary care and community-based cluster randomised controlled trials. In most cases, the four methods produced similar results. However, in a few analyses, quadratic inference function produced different results compared to the generalized linear mixed model, first-order generalized estimating equations, and second-order generalized estimating equations, especially in trials with small to moderate numbers of clusters. CONCLUSION: This paper demonstrates the analysis of cluster randomised controlled trials with four modelling approaches. The results obtained were similar in most cases, however, for trials with few clusters we do recommend that the quadratic inference function should be used with caution, and where possible a small sample correction should be used. The generalisability of our results is limited to studies with similar features to our case studies, for example, studies with a similar-sized ICC. It is important to conduct simulation studies to comprehensively evaluate the performance of the four modelling approaches.

Structured alcohol cessation support program versus current practice in acute alcoholic pancreatitis (PANDA): Study protocol for a multicentre cluster randomised controlled trial.

BACKGROUND/OBJECTIVES: The most important risk factor for recurrent pancreatitis after an episode of acute alcoholic pancreatitis is continuation of alcohol use. Current guidelines do not recommend any specific treatment strategy regarding alcohol cessation. The PANDA trial investigates whether implementation of a structured alcohol cessation support program prevents pancreatitis recurrence after a first episode of acute alcoholic pancreatitis. METHODS: PANDA is a nationwide cluster randomised superiority trial. Participating hospitals are randomised for the investigational management, consisting of a structured alcohol cessation support program, or current practice. Patients with a first episode of acute pancreatitis caused by harmful drinking (AUDIT score >7 and < 16 for men and >6 and < 14 for women) will be included. The primary endpoint is recurrence of acute pancreatitis. Secondary endpoints include cessation or reduction of alcohol use, other alcohol-related diseases, mortality, quality of life, quality-adjusted life years (QALYs) and costs. The follow-up period comprises one year after inclusion. DISCUSSION: This is the first multicentre trial with a cluster randomised trial design to investigate whether a structured alcohol cessation support program reduces recurrent acute pancreatitis in patients after a first episode of acute alcoholic pancreatitis, as compared with current practice. TRIAL REGISTRATION: Netherlands Trial Registry (NL8852). Prospectively registered.

Evaluating an intervention to improve the safety and experience of transitions from hospital to home for older people (Your Care Needs You): a protocol for a cluster randomised controlled trial and process evaluation.

BACKGROUND: Older patients often experience safety issues when transitioning from hospital to home. The 'Your Care Needs You' (YCNY) intervention aims to support older people to 'know more' and 'do more' whilst in hospital so that they are better prepared for managing at home. METHODS: A multi-centre cluster randomised controlled trial (cRCT) will evaluate the effectiveness and cost-effectiveness of the YCNY intervention. Forty acute hospital wards (clusters) in England from varying medical specialities will be randomised to deliver YCNY or care-as-usual on a 1:1 basis. The primary outcome will be unplanned hospital readmission rates within 30 days of discharge. This will be extracted from routinely collected data of at least 5440 patients (aged 75 years and older) discharged to their own homes during the 4- to 5-month YCNY intervention period. A nested cohort of up to 1000 patients will be recruited to the study to collect secondary outcomes via follow-up questionnaires at 5-, 30- and 90-day post-discharge. These will include measures of patient experience of transitions, patient-reported safety events, quality of life and healthcare resource use. Unplanned hospital readmission rates at 60 and 90 days of discharge will be collected from routine data. A process evaluation (primarily interviews and observations with patients, carers and staff) will be conducted to understand the implementation of the intervention and the contextual factors that shape this, as well as the intervention's underlying mechanisms of action. Fidelity of intervention delivery will also be assessed across all intervention wards. DISCUSSION: This study will establish the effectiveness and cost-effectiveness of the YCNY intervention which aims to improve patient safety and experience for older people during transitions of care. The process evaluation will generate insights about how the YCNY intervention was implemented, what elements of the intervention work and for whom, and how to optimise its implementation so that it can be delivered with high fidelity in routine service contexts. TRIAL REGISTRATION: UK Clinical Research Network Portfolio: 44559; ISTCRN: ISRCTN17062524. Registered on 11/02/2020.

Team based collaborative care model, facilitated by mHealth enabled and trained nurses, for management of heart failure with reduced ejection fraction in India (TIME-HF): design and rationale of a parallel group, open label, multi-centric cluster randomised controlled trial.

Background: Heart failure (HF) is a debilitating condition associated with enormous public health burden. Management of HF is complex as it requires care-coordination with different cadres of health care providers. We propose to develop a team based collaborative care model (CCM), facilitated by trained nurses, for management of HF with the support of mHealth and evaluate its acceptability and effectiveness in Indian setting. Methods: The proposed study will use mixed-methods research. Formative qualitative research will identify barriers and facilitators for implementing CCM for the management of HF. Subsequently, a cluster randomised controlled trial (RCT) involving 22 centres (tertiary-care hospitals) and more than 1500 HF patients will be conducted to assess the efficacy of the CCM in improving the overall survival as well as days alive and out of hospital (DAOH) at two-years (CTRI/2021/11/037797). The DAOH will be calculated by subtracting days in hospital and days from death until end of study follow-up from the total follow-up time. Poisson regression with a robust variance estimate and an offset term to account for clustering will be employed in the analyses of DAOH. A rate ratio and its 95% confidence interval (CI) will be estimated. The scalability of the proposed intervention model will be assessed through economic analyses (cost-effectiveness) and the acceptability of the intervention at both the provider and patient level will be understood through both qualitative and quantitative process evaluation methods. Potential Impact: The TIME-HF trial will provide evidence on whether a CCM with mHealth support is effective in improving the clinical outcomes of HF with reduced ejection fraction in India. The findings may change the practice of management of HF in low and middle-income countries.

School-based relationship and sexuality education intervention engaging adolescent boys for the reductions of teenage pregnancy: the JACK cluster RCT.

Background: The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by the World Health Organization and the United Nations Educational, Scientific and Cultural Organization. Objectives: To evaluate the effects of If I Were Jack on the avoidance of unprotected sex and other sexual health outcomes. Design: A cluster randomised trial, incorporating health economics and process evaluations. Setting: Sixty-six schools across the four nations of the UK. Participants: Students aged 13-14 years. Intervention: A school-based, teacher-delivered, gender-transformative RSE intervention (If I Were Jack) versus standard RSE. Main outcome measures: Self-reported avoidance of unprotected sex (sexual abstinence or reliable contraceptive use at last sex) after 12-14 months. Secondary outcomes included knowledge, attitudes, skills, intentions and sexual behaviours. Results: The analysis population comprised 6556 students: 86.6% of students in the intervention group avoided unprotected sex, compared with 86.4% in the control group {adjusted odds ratio 0.85 [95% confidence interval (CI) 0.58 to 1.26], p = 0.42}. An exploratory post hoc analysis showed no difference for sexual abstinence [78.30% intervention group vs. 78.25% control group; adjusted odds ratio 0.85 (95% CI 0.58 to 1.24), p = 0.39], but more intervention group students than control group students used reliable contraception at last sex [39.62% vs. 26.36%; adjusted odds ratio 0.52 (95% CI 0.29 to 0.920), p = 0.025]. Students in schools allocated to receive the intervention had significantly higher scores on knowledge [adjusted mean difference 0.18 (95% CI 0.024 to 0.34), p = 0.02], gender-equitable attitudes and intentions to avoid unintended pregnancy [adjusted mean difference 0.61 (95% CI 0.16 to 1.07), p = 0.01] than students in schools allocated to receive the control. There were positive but non-significant differences in sexual self-efficacy and communication skills. The total mean incremental cost of the intervention compared with standard RSE was £2.83 (95% CI -£2.64 to £8.29) per student. Over a 20-year time horizon, the intervention is likely to be cost-effective owing to its impact on unprotected sex because it would result in 379 (95% CI 231 to 477) fewer unintended pregnancies, 680 (95% CI 189 to 1467) fewer sexually transmitted infections and a gain of 10 (95% CI 5 to 16) quality-adjusted life-years per 100,000 students for a cost saving of £9.89 (95% CI -£15.60 to -£3.83). Limitations: The trial is underpowered to detect some effects because four schools withdrew and the intraclass correlation coefficient (0.12) was larger than that in sample size calculation (0.01). Conclusions: We present, to our knowledge, the first evidence from a randomised trial that a school-based, male engagement gender-transformative RSE intervention, although not effective in increasing avoidance of unprotected sex (defined as sexual abstinence or use of reliable contraception at last sex) among all students, did increase the use of reliable contraception at last sex among students who were, or became, sexually active by 12-14 months after the intervention. The trial demonstrated that engaging all adolescents early through RSE is important so that, as they become sexually active, rates of unprotected sex are reduced, and that doing so is likely to be cost-effective. Future work: Future studies should consider the longer-term effects of gender-transformative RSE as students become sexually active. Gender-transformative RSE could be adapted to address broader sexual health and other settings. Trial registration: This trial is registered as ISRCTN10751359. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (PHR 15/181/01) and will be published in full in Public Health Research; Vol. 11, No. 8. See the NIHR Journals Library website for further project information.

Adolescent pregnancy is often thought to be an issue for young women alone, but it is important to engage young men to tackle the problem and find solutions. The If I Were Jack intervention was especially designed to engage with boys as well as girls aged 14 years and to promote positive masculinity and gender equality to prevent adolescent pregnancy and promote positive sexual health. It uses tailored interactive films and resources, made with the help of students and teachers, to make it relevant to each of the four UK nations. This relationship and sexuality education intervention encourages adolescents to avoid unprotected sex by delaying sexual activity until they feel ready and to use reliable contraception once sexually active. It also promotes knowledge, attitudes (such as beliefs about gender and masculinities), skills and intentions for safe and pleasurable relationships. In this trial, we compared students in 33 schools randomly allocated to deliver the intervention with students in 33 schools that continued with their usual relationship and sexuality education practices. Four schools withdrew, two because of COVID-19 school closures. This left a total of 6556 students who completed questionnaires at the start of the study and 12­14 months later. Responses from all these students showed that If I Were Jack had a positive impact on knowledge, attitudes and intentions required for safe and pleasurable relationships, but did not have a significant effect on overall avoidance of unprotected sex. This was because the intervention had no effect on delaying sexual activity. However, we found that the intervention was effective in increasing the use of reliable contraception as students became sexually active, as well as for those who already were sexually active prior to receiving the intervention. We also found that If I Were Jack was likely to provide value for money by reducing unintended pregnancies and improving sexual health.

The effect of universal testing and treatment for HIV on health-related quality of life - An analysis of data from the HPTN 071 (PopART) cluster randomised trial.

Background: HIV treatment has clear Health-Related Quality-of-Life (HRQoL) benefits. However, little is known about how Universal Testing and Treatment (UTT) for HIV affects HRQoL. This study aimed to examine the effect of a combination prevention intervention, including UTT, on HRQoL among People Living with HIV (PLHIV). Methods: Data were from HPTN 071 (PopART), a three-arm cluster randomised controlled trial in 21 communities in Zambia and South Africa (2013-2018). Arm A received the full UTT intervention of door-to-door HIV testing plus access to antiretroviral therapy (ART) regardless of CD4 count, Arm B received the intervention but followed national treatment guidelines (universal ART from 2016), and Arm C received standard care. The intervention effect was measured in a cohort of randomly selected adults, over 36 months. HRQoL scores, and the prevalence of problems in five HRQoL dimensions (mobility, self-care, performing daily activities, pain/discomfort, anxiety/depression) were assessed among all participants using the EuroQol-5-dimensions-5-levels questionnaire (EQ-5D-5L). We compared HRQoL among PLHIV with laboratory confirmed HIV status between arms, using adjusted two-stage cluster-level analyses. Results: At baseline, 7,856 PLHIV provided HRQoL data. At 36 months, the mean HRQoL score was 0.892 (95% confidence interval: 0.887-0.898) in Arm A, 0.886 (0.877-0.894) in Arm B and 0.888 (0.884-0.892) in Arm C. There was no evidence of a difference in HRQoL scores between arms (A vs C, adjusted mean difference: 0.003, -0.001-0.006; B vs C: -0.004, -0.014-0.005). The prevalence of problems with pain/discomfort was lower in Arm A than C (adjusted prevalence ratio: 0.37, 0.14-0.97). There was no evidence of differences for other HRQoL dimensions. Conclusions: The intervention did not change overall HRQoL, suggesting that raising HRQoL among PLHIV might require more than improved testing and treatment. However, PLHIV had fewer problems with pain/discomfort under the full intervention; this benefit of UTT should be maximised during roll-out.

Staff- and service-level factors associated with organisational readiness to implement a clinical pathway for the identification, assessment, and management of anxiety and depression in adults with cancer.

BACKGROUND: Organisational readiness is recognised as a key factor impacting the successful translation of research findings into practice. Within psycho-oncology, measuring organisational readiness and understanding factors impacting organisational readiness is crucial as it is often challenging to implement evidence-based findings into routine cancer care. In this quantitative study, we examined the level of organisational readiness of cancer services preparing to implement a clinical pathway for the screening, assessment, and management of anxiety and depression in adult cancer patients (the ADAPT CP) within a cluster randomised controlled trial and sought to identify staff- and service-level factors associated with organisational readiness. METHODS: Multidisciplinary staff across 12 Australian cancer services were identified. Their perceptions of their services' readiness to implement the ADAPT CP in the cancer stream or treatment modality selected within their service was assessed prior to implementation using the Organizational Readiness for Implementing Change scale. Data collection included staff demographic and professional characteristics, and their perception of the ADAPT CP using a set of 13 study-specific survey items. Service characteristics were captured using a site profile audit form and workflows during site engagement. RESULTS: Fourteen staff- and service-level factors were identified as potentially impacting organisational readiness. To identify factors that best explained organisational readiness, separate univariate analyses were conducted for each factor, followed by a backward elimination regression. Compared to services that implemented the ADAPT CP in one treatment modality, those opting for four treatment modalities had significantly higher organisational readiness scores. Staff in administrative/technical support/non-clinical roles had significantly higher organisational readiness scores compared to psychosocial staff. Higher organisational readiness scores were also significantly related to more positive perceptions of the ADAPT CP. CONCLUSIONS: Readiness to implement an anxiety and depression clinical pathway within 12 oncology services was high. This may be attributed to the extensive engagement with services prior to implementation. The factors associated with organisational readiness highlight the importance of ensuring adequate resourcing and supporting staff to implement change, effectively communicating the value of the change, and taking a whole-of-service approach to implementing the change. Future longitudinal studies may identify factors associated with ongoing readiness and engagement prior to implementation. TRIAL REGISTRATION: The ADAPT RCT was registered prospectively with the ANZCTR on 22/03/2017. Trial ID ACTRN12617000411347. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372486&isReview=true .