SurLym trial: study protocol for a multicentre pragmatic randomised controlled trial on the added value of reconstructive lymphatic surgery to decongestive lymphatic therapy for the treatment of lymphoedema.

INTRODUCTION: Lymphoedema is a chronic condition caused by lymphatic insufficiency. It leads to swelling of the limb/midline region and an increased risk of infection. Lymphoedema is often associated with mental and physical problems limiting quality of life. The first choice of treatment is a conservative treatment, consisting of exercises, skin care, lymph drainage and compression. Reconstructive lymphatic surgery is also often performed, that is, lymphovenous anastomoses, lymph node transfer or a combination. However, robust evidence on the effectiveness of reconstructive lymphatic surgery is missing. Therefore, the objective of this trial is to investigate the added value of reconstructive lymphatic surgery to the conservative treatment in patients with lymphoedema. METHODS AND ANALYSIS: A multicentre randomised controlled and pragmatic trial was started in March 2022 in three Belgian university hospitals. 90 patients with arm lymphoedema and 90 patients with leg lymphoedema will be included. All patients are randomised between conservative treatment alone (control group) or conservative treatment with reconstructive lymphatic surgery (intervention group). Assessments are performed at baseline and at 1, 3, 6, 12, 18, 24 and 36 months. The primary outcome is lymphoedema-specific quality of life at 18 months. Key secondary outcomes are limb volume and duration of wearing the compression garment at 18 months. The approach of reconstructive lymphatic surgery is based on presurgical investigations including clinical examination, lymphofluoroscopy, lymphoscintigraphy, lymph MRI or CT angiography (if needed). All patients receive conservative treatment during 36 months, which is applied by the patient's own physical therapist and by the patient self. From months 7 to 12, the hours a day of wearing the compression garment are gradually decreased. ETHICS AND DISSEMINATION: The study has been approved by the ethical committees of University Hospitals Leuven, Ghent University Hospital and CHU UCL Namur. Results will be disseminated via peer-reviewed journals and presentations. TRIAL REGISTRATION NUMBER: NCT05064176.

Pragmaticism in Cancer Clinical Trials.

Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.

Protocol for a pragmatic randomised controlled feasibility study of MS WorkSmart: an online intervention for Australians with MS who are employed.

INTRODUCTION: Multiple sclerosis (MS) causes a wide variety of symptoms. Loss of income due to sickness and early retirement comprise one-third of the total cost of MS in Australia. An intervention that maximises work productivity and keeps people with MS in the workforce for longer could provide a large societal cost saving and improve quality of life. The aim is to test the feasibility of delivering and evaluating a 10-week digitally delivered intervention called 'MS WorkSmart'. Findings will provide insights into participant profiles and address key methodological and procedural uncertainties (recruitment, retention, intervention adherence and engagement, and selection of primary outcome) in preparation for a subsequent definitive trial. METHODS AND ANALYSIS: A parallel-arm randomised controlled feasibility study, comparing those randomised to receive the MS WorkSmart package plus usual care (n=20) to those receiving usual care only (n=20). Australians with MS, aged 18-60 years, who are employed, and self-report work instability will be recruited from the Australian MS Longitudinal Study. Online surveys, at baseline and 1-month postintervention, will include MS-related work productivity loss and risk of job loss, MS work behaviour self-efficacy, health-related quality of life, fatigue severity, MS symptom impact on work, intention to retire due to MS, MS-related work difficulties, and awareness and readiness for change at work. Qualitative feedback will be obtained via a semistructured survey following the intervention (for participants) and via interviews (coaches). Analyses will be primarily descriptive and focus on the feasibility and acceptability of the intervention and study procedures. Progression criteria will guide decisions around whether to progress to a full trial. ETHICS AND DISSEMINATION: The study has been approved by the University of Tasmania Human Research Ethics Committee (H0024544). Findings will be disseminated via publication in peer-reviewed journals, conference presentations and community presentations. TRIAL REGISTRATION NUMBER: ACTRN12622000826741.

Implementation research: a protocol for two three-arm pragmatic randomised controlled trials on continuous glucose monitoring devices in people with type 1 diabetes in South Africa and Kenya.

BACKGROUND: Self-monitoring of glucose is an essential component of type 1 diabetes (T1D) management. In recent years, continuous glucose monitoring (CGM) has provided an alternative to daily fingerstick testing for the optimisation of insulin dosing and general glucose management in people with T1D. While studies have been conducted to evaluate the impact of CGM on clinical outcomes in the US, Europe and Australia, there are limited data available for low- and middle-income countries (LMICs) and further empirical evidence is needed to inform policy decision around their use in these countries. METHODS: This trial was designed as a pragmatic, parallel-group, open-label, multicentre, three-arm, randomised (1:1:1) controlled trial of continuous or periodic CGM device use versus standard of care in people with T1D in South Africa and Kenya. The primary objective of this trial will be to assess the impact of continuous or periodic CGM device use on glycaemic control as measured by change from baseline glycosylated haemoglobin (HbA1c). Additional assessments will include clinical outcomes (glucose variation, time in/below/above range), safety (adverse events, hospitalisations), quality of life (EQ-5D, T1D distress score, Glucose Monitoring Satisfaction Survey for T1D), and health economic measures (incremental cost-effectiveness ratios, quality adjusted life years). DISCUSSION: This trial aims to address the substantial evidence gap on the impact of CGM device use on clinical outcomes in LMICs, specifically South Africa and Kenya. The trial results will provide evidence to inform policy and treatment decisions in these countries. TRIAL REGISTRATION: NCT05944731 (Kenya), July 6, 2023; NCT05944718 (South Africa), July 13, 2023.

The effect of focused lung ultrasonography on antibiotic prescribing in patients with acute lower respiratory tract infections in Danish general practice: study protocol for a pragmatic randomized controlled trial (PLUS-FLUS).

BACKGROUND: The use of antibiotics is a key driver of antimicrobial resistance and is considered a major threat to global health. In Denmark, approximately 75% of antibiotic prescriptions are issued in general practice, with acute lower respiratory tract infections (LRTIs) being one of the most common indications. Adults who present to general practice with symptoms of acute LRTI often suffer from self-limiting viral infections. However, some patients have bacterial community-acquired pneumonia (CAP), a potential life-threatening infection, that requires immediate antibiotic treatment. Importantly, no single symptom or specific point-of-care test can be used to discriminate the various diagnoses, and diagnostic uncertainty often leads to (over)use of antibiotics. At present, general practitioners (GPs) lack tools to better identify those patients who will benefit from antibiotic treatment. The primary aim of the PLUS-FLUS trial is to determine whether adults who present with symptoms of an acute LRTI in general practice and who have FLUS performed in addition to usual care are treated less frequently with antibiotics than those who only receive usual care. METHODS: Adults (≥ 18 years) presenting to general practice with acute cough (< 21 days) and at least one other symptom of acute LRTI, where the GP suspects a bacterial CAP, will be invited to participate in this pragmatic randomized controlled trial. All participants will receive usual care. Subsequently, participants will be randomized to either the control group (usual care) or to an additional focused lung ultrasonography performed by the GP (+ FLUS). The primary outcome is the proportion of participants with antibiotics prescribed at the index consultation (day 0). Secondary outcomes include comparisons of the clinical course for participants in groups. DISCUSSION: We will examine whether adults who present with symptoms of acute LRTI in general practice, who have FLUS performed in addition to usual care, have antibiotics prescribed less frequently than those given usual care alone. It is highly important that a possible reduction in antibiotic prescriptions does not compromise patients' recovery or clinical course, which we will assess closely. TRIAL REGISTRATION: ClinicalTrials.gov NCT06210282. Registered on January 17, 2024.

PRECIS-2 analysis of pragmatic acupuncture trials: a systematic review.

BACKGROUND: Pragmatic acupuncture trials (PATs) are a research tool for assessing the effectiveness of acupuncture treatments in a real-world setting. This study aimed to provide a comprehensive methodological analysis of PATs using the PRECIS-2(PRagmatic Explanatory Continuum Indicator Summary-2) tool to determine their pragmatism. METHODS: The MEDLINE, EMBASE, Cochrane Central Register for Controlled Trials, CINAHL, Allied and Complementary Medicine Database, China National Knowledge Infrastructure, VIP, WANFANG, Taiwan Periodical Literature Database, KoreaMed, KMbase, Research Information Service System, Oriental Medicine Advanced Searching Integrated System, CiNii and ClinicalTrials.gov were searched. The search included randomised controlled trials (RCTs) and protocols of RCTs that investigated all types of acupuncture and used self-declared pragmatic design. Two authors independently collected the basic information and characteristics of the studies and assessed their pragmatism using the nine PRECIS-2 domains and the additional domain of control. RESULTS: A total of 93 studies were included. The means of eligibility, recruitment, organisation, primary outcome, primary analysis, and control domains were statistically larger than three and were shown to be pragmatic. The means of setting, flexibility:delivery, and follow-up domains were not greater than three and were shown to be non-pragmatic. For flexibility:adherence domain was inappropriate for assessment owing to insufficient information in the studies. CONCLUSIONS: PATs were pragmatic in the domain of eligibility, recruitment, organisation, primary outcome, primary analysis, and control and were not pragmatic in the domain of setting, flexibility:delivery, and follow-up. Future PATs need to strengthen the pragmatism in the setting, flexibility:delivery, and follow-up domains and to describe the flexibility:adherence domain in more detail. TRIAL REGISTRATION: CRD42021236975.

Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Increasing access to mental health supports for 12-17-year-old Indigenous youth with the JoyPop mobile mental health app: study protocol for a randomized controlled trial.

BACKGROUND: Indigenous youth in Northwestern Ontario who need mental health supports experience longer waits than non-Indigenous youth within the region and when compared to youth in urban areas. Limited access and extended waits can exacerbate symptoms, prolong distress, and increase risk for adverse outcomes. Innovative approaches are urgently needed to provide support for Indigenous youth in Northwestern Ontario. Using a randomized controlled trial design, the primary objective of this study is to determine the effectiveness of the JoyPop app compared to usual practice (UP; monitoring) in improving emotion regulation among Indigenous youth (12-17 years) who are awaiting mental health services. The secondary objectives are to (1) assess change in mental health difficulties and treatment readiness between youth in each condition to better understand the app's broader impact as a waitlist tool and (2) conduct an economic analysis to determine whether receiving the app while waiting for mental health services reduces other health service use and associated costs. METHODS: A pragmatic, parallel arm randomized controlled superiority trial will be used. Participants will be randomly allocated in a 1:1 ratio to the control (UP) or intervention (UP + JoyPop) condition. Stratified block randomization will be used to randomly assign participants to each condition. All participants will be monitored through existing waitlist practices, which involve regular phone calls to check in and assess functioning. Participants in the intervention condition will receive access to the JoyPop app for 4 weeks and will be asked to use it at least twice daily. All participants will be asked to complete outcome measures at baseline, after 2 weeks, and after 4 weeks. DISCUSSION: This trial will evaluate the effectiveness of the JoyPop app as a tool to support Indigenous youth waiting for mental health services. Should findings show that using the JoyPop app is beneficial, there may be support from partners and other organizations to integrate it into usual care pathways. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05898516 [registered on June 1, 2023].

Effectiveness of a community-based multicomponent lifestyle intervention (the ADA programme) to improve the quality of life of French breast cancer survivors: protocol for a pragmatic cluster randomised trial and embedded qualitative study.

INTRODUCTION: Breast cancer survivors (BCSs) are often faced with multiple mental and physical sequelae and are at increased risk of emotional distress, degraded health-related quality of life (HRQoL), chronic pain and fatigue.Physical activity is strongly associated with improved HRQoL and survival rates; however, adherence rates to recommendations for a healthy lifestyle are seldom satisfactory among BCSs. Also, few studies have examined the effectiveness of multicomponent and personalised interventions that integrate physical activity and motivational techniques to improve the HRQoL of BCS. METHOD AND ANALYSIS: "Activité physique adaptée Doublée d'un Accompagnement d'après cancer" (ADA) is an integrated programme of physical activity enriched with a dietary and supportive care approach targeting BCS in the early post-treatment phase. The effectiveness of the ADA intervention will be evaluated using a cluster randomised controlled trial design with two arms (ADA programme vs usual care; 1:1 ratio).The ADA intervention aims to recruit 160 participants and will be implemented by Siel Bleu, a non-profit association specialised in health prevention via adapted physical activity. Measurements will be performed at baseline, 3, 6 and 12 months after the start of the intervention. The primary outcome will be participants' HRQoL, at 12 months measured by the Functional Assessment of Chronic Illness Therapy-Fatigue global score. Secondary outcome will include participants' physical, social, emotional and functional well-being. The effect of the intervention on physical activity level, motivation for physical activity, relation to food and self-efficacy will also be evaluated. ETHICS AND DISSEMINATION: The study was approved by the 'CPP Paris XI' Institutional Review Board on 5 May 2022 (Ref no.: 21.04512.000048-22004). The study's findings will be shared through various channels, including academic publications, simplified reports for wider audiences and active engagement with medical and institutional organisations as well as patients' associations. TRIAL REGISTRATION NUMBER: NCT05658341.

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.

Distributive randomization: a pragmatic fractional factorial design to screen or evaluate multiple simultaneous interventions in a clinical trial.

BACKGROUND: In some medical indications, numerous interventions have a weak presumption of efficacy, but a good track record or presumption of safety. This makes it feasible to evaluate them simultaneously. This study evaluates a pragmatic fractional factorial trial design that randomly allocates a pre-specified number of interventions to each participant, and statistically tests main intervention effects. We compare it to factorial trials, parallel-arm trials and multiple head-to-head trials, and derive some good practices for its design and analysis. METHODS: We simulated various scenarios involving 4 to 20 candidate interventions among which 2 to 8 could be simultaneously allocated. A binary outcome was assumed. One or two interventions were assumed effective, with various interactions (positive, negative, none). Efficient combinatorics algorithms were created. Sample sizes and power were obtained by simulations in which the statistical test was either difference of proportions or multivariate logistic regression Wald test with or without interaction terms for adjustment, with Bonferroni multiplicity-adjusted alpha risk for both. Native R code is provided without need for compiling or packages. RESULTS: Distributive trials reduce sample sizes 2- to sevenfold compared to parallel arm trials, and increase them 1- to twofold compared to factorial trials, mostly when fewer allocations than for the factorial design are possible. An unexpectedly effective intervention causes small decreases in power (< 10%) if its effect is additive, but large decreases (possibly down to 0) if not, as for factorial designs. These large decreases are prevented by using interaction terms to adjust the analysis, but these additional estimands have a sample size cost and are better pre-specified. The issue can also be managed by adding a true control arm without any intervention. CONCLUSION: Distributive randomization is a viable design for mass parallel evaluation of interventions in constrained trial populations. It should be introduced first in clinical settings where many undercharacterized interventions are potentially available, such as disease prevention strategies, digital behavioral interventions, dietary supplements for chronic conditions, or emerging diseases. Pre-trial simulations are recommended, for which tools are provided.

Flexor Injury Rehabilitation Splint Trial (FIRST): protocol for a pragmatic randomised controlled trial comparing three splints for finger flexor tendon repairs.

BACKGROUND: Without surgical repair, flexor tendon injuries do not heal and patients' ability to bend fingers and grip objects is impaired. However, flexor tendon repair surgery also requires optimal rehabilitation. There are currently three custom-made splints used in the rehabilitation of zone I/II flexor tendon repairs, each with different assumed harm/benefit profiles: the dorsal forearm and hand-based splint (long), the Manchester short splint (short), and the relative motion flexion splint (mini). There is, however, no robust evidence as to which splint, if any, is most clinical or cost effective. The Flexor Injury Rehabilitation Splint Trial (FIRST) was designed to address this evidence gap. METHODS: FIRST is a parallel group, superiority, analyst-blind, multi-centre, individual participant-randomised controlled trial. Participants will be assigned 1:1:1 to receive either the long, short, or mini splint. We aim to recruit 429 participants undergoing rehabilitation following zone I/II flexor tendon repair surgery. Potential participants will initially be identified prior to surgery, in NHS hand clinics across the UK, and consented and randomised at their splint fitting appointment post-surgery. The primary outcome will be the mean post-randomisation score on the patient-reported wrist and hand evaluation measure (PRWHE), assessed at 6, 12, 26, and 52 weeks post randomisation. Secondary outcome measures include blinded grip strength and active range of movement (AROM) assessments, adverse events, adherence to the splinting protocol (measured via temperature sensors inserted into the splints), quality of life assessment, and further patient-reported outcomes. An economic evaluation will assess the cost-effectiveness of each splint, and a qualitative sub-study will evaluate participants' preferences for, and experiences of wearing, the splints. Furthermore, a mediation analysis will determine the relationship between patient preferences, splint adherence, and splint effectiveness. DISCUSSION: FIRST will compare the three splints with respect to clinical efficacy, complications, quality of life and cost-effectiveness. FIRST is a pragmatic trial which will recruit from 26 NHS sites to allow findings to be generalisable to current clinical practice in the UK. It will also provide significant insights into patient experiences of splint wear and how adherence to splinting may impact outcomes. TRIAL REGISTRATION: ISRCTN: 10236011.

SCALE-UP II: protocol for a pragmatic randomised trial examining population health management interventions to increase the uptake of at-home COVID-19 testing in community health centres.

INTRODUCTION: SCALE-UP II aims to investigate the effectiveness of population health management interventions using text messaging (TM), chatbots and patient navigation (PN) in increasing the uptake of at-home COVID-19 testing among patients in historically marginalised communities, specifically, those receiving care at community health centres (CHCs). METHODS AND ANALYSIS: The trial is a multisite, randomised pragmatic clinical trial. Eligible patients are >18 years old with a primary care visit in the last 3 years at one of the participating CHCs. Demographic data will be obtained from CHC electronic health records. Patients will be randomised to one of two factorial designs based on smartphone ownership. Patients who self-report replying to a text message that they have a smartphone will be randomised in a 2×2×2 factorial fashion to receive (1) chatbot or TM; (2) PN (yes or no); and (3) repeated offers to interact with the interventions every 10 or 30 days. Participants who do not self-report as having a smartphone will be randomised in a 2×2 factorial fashion to receive (1) TM with or without PN; and (2) repeated offers every 10 or 30 days. The interventions will be sent in English or Spanish, with an option to request at-home COVID-19 test kits. The primary outcome is the proportion of participants using at-home COVID-19 tests during a 90-day follow-up. The study will evaluate the main effects and interactions among interventions, implementation outcomes and predictors and moderators of study outcomes. Statistical analyses will include logistic regression, stratified subgroup analyses and adjustment for stratification factors. ETHICS AND DISSEMINATION: The protocol was approved by the University of Utah Institutional Review Board. On completion, study data will be made available in compliance with National Institutes of Health data sharing policies. Results will be disseminated through study partners and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05533918 and NCT05533359.

Decentralising chronic disease management in sub-Saharan Africa: a protocol for the qualitative process evaluation of community-based integrated management of HIV, diabetes and hypertension in Tanzania and Uganda.

INTRODUCTION: Sub-Saharan Africa continues to experience a syndemic of HIV and non-communicable diseases (NCDs). Vertical (stand-alone) HIV programming has provided high-quality care in the region, with almost 80% of people living with HIV in regular care and 90% virally suppressed. While integrated health education and concurrent management of HIV, hypertension and diabetes are being scaled up in clinics, innovative, more efficient and cost-effective interventions that include decentralisation into the community are required to respond to the increased burden of comorbid HIV/NCD disease. METHODS AND ANALYSIS: This protocol describes procedures for a process evaluation running concurrently with a pragmatic cluster-randomised trial (INTE-COMM) in Tanzania and Uganda that will compare community-based integrated care (HIV, diabetes and hypertension) with standard facility-based integrated care. The INTE-COMM intervention will manage multiple conditions (HIV, hypertension and diabetes) in the community via health monitoring and adherence/lifestyle advice (medicine, diet and exercise) provided by community nurses and trained lay workers, as well as the devolvement of NCD drug dispensing to the community level. Based on Bronfenbrenner's ecological systems theory, the process evaluation will use qualitative methods to investigate sociostructural factors shaping care delivery and outcomes in up to 10 standard care facilities and/or intervention community sites with linked healthcare facilities. Multistakeholder interviews (patients, community health workers and volunteers, healthcare providers, policymakers, clinical researchers and international and non-governmental organisations), focus group discussions (community leaders and members) and non-participant observations (community meetings and drug dispensing) will explore implementation from diverse perspectives at three timepoints in the trial implementation. Iterative sampling and analysis, moving between data collection points and data analysis to test emerging theories, will continue until saturation is reached. This process of analytic reflexivity and triangulation across methods and sources will provide findings to explain the main trial findings and offer clear directions for future efforts to sustain and scale up community-integrated care for HIV, diabetes and hypertension. ETHICS AND DISSEMINATION: The protocol has been approved by the University College of London (UK), the London School of Hygiene and Tropical Medicine Ethics Committee (UK), the Uganda National Council for Science and Technology and the Uganda Virus Research Institute Research and Ethics Committee (Uganda) and the Medical Research Coordinating Committee of the National Institute for Medical Research (Tanzania). The University College of London is the trial sponsor. Dissemination of findings will be done through journal publications and stakeholder meetings (with study participants, healthcare providers, policymakers and other stakeholders), local and international conferences, policy briefs, peer-reviewed journal articles and publications. TRIAL REGISTRATION NUMBER: ISRCTN15319595.

Effectiveness and cost-effectiveness of a collaborative deprescribing intervention of proton-pump-inhibitors on community-dwelling older adults: Protocol for the C-SENIoR, a pragmatic non-randomized controlled trial.

INTRODUCTION: Worldwide, demographic ageing is a major social, economic and health challenge. Despite the increase in life expectancy, elderly often live with multiple chronic conditions, exposing them to multiple medications. Concerns have been raised about the growing issue of inappropriate long-term usage of proton-pump inhibitors (PPI), which have been associated with adverse outcomes and increased healthcare costs. Deprescribing is a recommended intervention to reduce or withdraw medicines that might be causing harm or might no longer be of benefit. This protocol details a trial to assess the effectiveness and cost-effectiveness of a collaborative deprescribing intervention of PPI among community-dwelling elderly, involving community pharmacists and general practitioners. METHODS AND ANALYSIS: A pragmatic, multicentre, two-arm, non-randomised controlled trial of a structured PPI collaborative deprescribing intervention in the primary care setting with a 6-month follow-up will be conducted. Patients must be 65 years old or older, live in the community and have been using PPI for more than 8 weeks. We hypothesize that the intervention will reduce the PPI usage in the intervention group compared to the control group. The primary outcome is the successful discontinuation or dose decrease of any PPI, defined as a statistically significant absolute 20% reduction in medication use between the intervention and control groups at 3- and 6-month follow-ups. An economic evaluation will be conducted alongside the trial. This study was approved by the Ethics Research Committee of Nova Medical School, NOVA University of Lisbon and by the Ethics Committee from the Local Health Unit Alto Minho, Portugal. DISCUSSION: This pragmatic trial will provide evidence on the effectiveness and cost-effectiveness of a patient-centred collaborative deprescribing intervention in the community setting in Portugal. It will also inform improvements for the development of future multi-faceted interventions that aim to optimise medication for the community-dwelling elderly. CLINICAL TRIAL REGISTRATION: ISRCTN 49637686.

Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study.

INTRODUCTION: The prevalence of both obesity and gestational diabetes mellitus (GDM) has increased, and each is associated with adverse perinatal outcomes including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy and caesarean delivery. Women with GDM who are also overweight or obese have higher rates of pregnancy complications when compared with normal-weight women with GDM, which may occur in part due to suboptimal glycaemic control. The current recommendations for glycaemic targets in pregnant women with diabetes are based on limited evidence and exceed the mean fasting (70.9±7.8 mg/dL) and 1-hour postprandial (108.9±12.9 mg/dL) glucose values in pregnant individuals without diabetes. Our prior work demonstrated that the use of intensive (fasting <90 mg/dL and 1-hour postprandial <120 mg/dL) compared with standard (fasting <95 mg/dL and 1-hour postprandial <140 mg/dL) glycaemic targets resulted in improved glycaemic control without increasing the risk for hypoglycaemia in pregnant individuals with GDM, but the impact of intensive glycaemic targets on perinatal outcomes is unknown. METHODS AND ANALYSIS: The Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus: A Multicenter Randomized Trial (iGDM Trial) is a large, pragmatic randomised clinical trial designed to investigate the impact of intensive versus standard glycaemic targets on perinatal outcomes in women with GDM who are overweight and obese. During the 5-year project period, a multidisciplinary team of investigators from five medical centres representing regions of the USA with high rates of obesity will randomise 828 overweight and obese women with GDM to either intensive or standard glycaemic targets. We will test the central hypothesis that intensive glycaemic targets will result in lower rates of neonatal composite morbidity including large for gestational age birth weight, neonatal hypoglycaemia, respiratory distress syndrome and need for phototherapy when compared with standard glycaemic targets using the intention-to-treat approach to analysis. ETHICS AND DISSEMINATION: The Institutional Review Board (IRB) at Indiana University School of Medicine approved this study (IRB# 11435; initial approval date 25 August 2021). We will submit the results of the trial for publication in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05124808.

To allow or avoid pain during shoulder rehabilitation exercises for patients with chronic rotator cuff tendinopathy-Study protocol for a randomized controlled trial (the PASE trial).

BACKGROUND: Rotator cuff (RC) tendinopathy is the most reported shoulder disorder in the general population with highest prevalence in overhead athletes and adult working-age population. A growing body of evidence support exercise therapy as an effective intervention, but to date there are no prospective randomized controlled trials addressing pain as an intervention variable. METHODS: A single-site, prospective, pragmatic, assessor-blinded randomized controlled superiority trial. Eighty-four patients aged 18-55 years with chronic (symptom duration over 3 months) RC tendinopathy are randomized 1:1 to receive shoulder exercise during which pain is either allowed or avoided. The intervention period lasts 26 weeks. During that period, participants in both groups are offered 8 individual on-site sessions with an assigned sports physiotherapist. Participants perform home exercises and are provided with a pain and exercise logbook and asked to report completed home-based exercise sessions and reasons for not completing sessions (pain or other reasons). Patients are also asked to report load and the number of sets and repetitions per sets for each exercise session. The logbooks are collected continuously throughout the intervention period. The primary and secondary outcomes are obtained at baseline, 6 weeks, 26 weeks, and 1 year after baseline. The primary outcome is patient-reported pain and disability using the Shoulder PAin and Disability Index (SPADI). Secondary outcomes are patient-reported pain and disability using Disability Arm Shoulder and Hand short-form (Quick DASH), and shoulder pain using Numeric Pain Rating Scale. Objective outcomes are shoulder range of motion, isometric shoulder muscle strength, pain sensitivity, working ability, and structural changes in the supraspinatus tendon and muscle using ultrasound. DISCUSSION: The results of this study will contribute knowledge about the treatment strategies for patients with RC tendinopathy and help physiotherapists in clinical decision-making. This is the first randomized controlled trial comparing the effects of allowing pain versus avoiding pain during shoulder exercises in patients with chronic RC tendinopathy. If tolerating pain during and after exercise proves to be effective, it will potentially expand our understanding of "exercising into pain" for this patient group, as there is currently no consensus. TRIAL REGISTRATION: ClinicalTrials.gov NCT05124769. Registered on August 11, 2021.