Respiratory support with standard low-flow oxygen therapy, high-flow oxygen therapy or continuous positive airway pressure in adults with acute hypoxaemic respiratory failure in a resource-limited setting: protocol for a randomised, open-label, clinical trial - the Acute Respiratory Intervention StudiEs in Africa (ARISE-AFRICA) study.

RATIONALE: Acute hypoxaemic respiratory failure (AHRF) is associated with high mortality in sub-Saharan Africa. This is at least in part due to critical care-related resource constraints including limited access to invasive mechanical ventilation and/or highly skilled acute care workers. Continuous positive airway pressure (CPAP) and high-flow oxygen by nasal cannula (HFNC) may prove useful to reduce intubation, and therefore, improve survival outcomes among critically ill patients, particularly in resource-limited settings, but data in such settings are lacking. The aim of this study is to determine whether CPAP or HFNC as compared with standard oxygen therapy, could reduce mortality among adults presenting with AHRF in a resource-limited setting. METHODS: This is a prospective, multicentre, randomised, controlled, stepped wedge trial, in which patients presenting with AHRF in Uganda will be randomly assigned to standard oxygen therapy delivered through a face mask, HFNC oxygen or CPAP. The primary outcome is all-cause mortality at 28 days. Secondary outcomes include the number of patients with criteria for intubation at day 7, the number of patients intubated at day 28, ventilator-free days at day 28 and tolerance of each respiratory support. ETHICS AND DISSEMINATION: The study has obtained ethical approval from the Research and Ethics Committee, School of Biomedical Sciences, College of Health Sciences, Makerere University as well as the Uganda National Council for Science and Technology. Patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04693403. PROTOCOL VERSION: 8 September 2023; version 5.

Graded Exposure Therapy for Fear Avoidance Behaviour After Concussion (GET FAB): protocol for a multisite Canadian randomised controlled trial.

INTRODUCTION: Persistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic disability after mTBI. This study will evaluate the efficacy of graded exposure therapy (GET) for reducing persistent symptoms following mTBI, with two primary aims: (1) To determine whether GET is more effective than usual care; (2) to identify for whom GET is the most effective treatment option, by evaluating whether baseline fear avoidance moderates differences between GET and an active comparator (prescribed aerobic exercise). Our findings will guide evidence-based care after mTBI and enable better matching of mTBI patients to treatments. METHODS AND ANALYSIS: We will conduct a multisite randomised controlled trial with three arms. Participants (n=220) will be recruited from concussion clinics and emergency departments in three Canadian provinces and randomly assigned (1:2:2 ratio) to receive enhanced usual care, GET or prescribed aerobic exercise. The outcome assessment will occur remotely 14-18 weeks following baseline assessment, after completing the 12-week treatment phase. The primary outcome will be symptom severity (Rivermead Post-concussion Symptoms Questionnaire). ETHICS AND DISSEMINATION: Informed consent will be obtained from all participants. All study procedures were approved by the local research ethics boards (University of British Columbia Clinical Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, University Health Network Research Ethics Board-Panel D). Operational approvals were obtained for Vancouver Coastal Health Research Institute and Provincial Health Services Authority. If GET proves effective, we will disseminate the GET treatment manual and present instructional workshops for clinicians. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT05365776.

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial.

BACKGROUND: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN. METHODS: This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients. DISCUSSION: This study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.

POStoperative INTELLiVENT-adaptive support VEntilation in cardiac surgery patients (POSITiVE) II-study protocol of a randomized clinical trial.

BACKGROUND: One single-center randomized clinical trial showed that INTELLiVENT-adaptive support ventilation (ASV) is superior to conventional ventilation with respect to the quality of ventilation in post-cardiac surgery patients. Other studies showed that this automated ventilation mode reduces the number of manual interventions at the ventilator in various types of critically ill patients. In this multicenter study in patients post-cardiac surgery, we test the hypothesis that INTELLiVENT-ASV is superior to conventional ventilation with respect to the quality of ventilation. METHODS: "POStoperative INTELLiVENT-adaptive support VEntilation in cardiac surgery patients II (POSITiVE II)" is an international, multicenter, two-group randomized clinical superiority trial. In total, 328 cardiac surgery patients will be randomized. Investigators screen patients aged > 18 years of age, scheduled for elective cardiac surgery, and expected to receive postoperative ventilation in the ICU for longer than 2 h. Patients either receive automated ventilation by means of INTELLiVENT-ASV or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is quality of ventilation, defined as the proportion of postoperative ventilation time characterized by exposure to predefined optimal, acceptable, and critical (injurious) ventilatory parameters in the first two postoperative hours. One major secondary endpoint is ICU team staff workload, captured by the ventilator software collecting manual settings on alarms. Patient-centered endpoints include duration of postoperative ventilation and length of stay in ICU. DISCUSSION: POSITiVE II is the first international, multicenter, randomized clinical trial designed to confirm that POStoperative INTELLiVENT-ASV is superior to non-automated conventional ventilation and secondary to determine if this closed-loop ventilation mode reduces ICU team staff workload. The results of POSITiVE II will support intensive care teams in their choices regarding the use of automated ventilation in postoperative care of uncomplicated cardiac surgery patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT06178510 . Registered on December 4, 2023.

Effectiveness of a mobile application for independent computerized cognitive training in patients with mild cognitive impairment: study protocol for the NeNaE Study, a randomized controlled trial.

BACKGROUND: Mild cognitive impairment (MCI) involves cognitive decline beyond typical age-related changes, but without significant daily activity disruption. It can encompass various cognitive domains as the causes of MCI are diverse. MCI as well as frequent comorbid neuropsychiatric conditions like depression and anxiety affect individuals' quality of life. Early interventions are essential, and computerized cognitive training (cCT) is an established treatment method. This paper presents the protocol for the NeuroNation MED Effectiveness Study, evaluating the self-administered mobile cCT intervention ("NeuroNation MED") in individuals with MCI to assess training effects on cognitive domains, health competence, neuropsychiatric symptoms, psychological well-being, and the general application usability. METHODS: This study protocol presents a single-blinded multicenter randomized controlled trial that will be carried out in six study centers in Germany and Luxembourg. We included adults with MCI (existing F06.7 ICD-10-GM diagnosis and TICS ≥ 21 and ≤ 32). The intervention group will use a mobile, multi-domain cCT ("NeuroNation MED") for 12 weeks. Meanwhile, the wait list control group will receive standard medical care or no care. The eligibility of volunteers will be determined through a telephone screening. After completion of the baseline examination, patients will be randomly assigned to one of the experimental conditions in a 2:1 ratio. In total, 286 participants will be included in this study. The primary outcome is the change of cognitive performance measured by the index score of the screening module of the Neuropsychological Assessment Battery. Secondary outcomes are changes in the Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, Health-49, Health Literacy Questionnaire, among others. All of the primary and secondary outcomes will be assessed at baseline and after the 12-week post-allocation period. Furthermore, the intervention group will undergo an assessment of the System Usability Scale, and the training data of the NeuroNation MED application will be analyzed. DISCUSSION: This study aims to assess the effectiveness of a mobile self-administered cCT in enhancing cognitive abilities among individuals diagnosed with MCI. Should the findings confirm the effectiveness of the NeuroNation MED app, it may confer possible benefits for the care management of patients with MCI, owing to the accessibility, cost-effectiveness, and home-based setting it provides. Specifically, the cCT program could provide patients with personalized cognitive training, educational resources, and relaxation techniques, enabling participants to independently engage in cognitive training sessions at home without further supervision. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025133. Registered on November 5, 2021.

The efficacy of simple oral nutritional supplements versus usual care in postoperative patients with gastric cancer: study protocol for a multicenter, open-label, parallel, randomized controlled trial.

BACKGROUND: Body weight loss (BWL) after gastrectomy impact on the short- and long-term outcomes. Oral nutritional supplement (ONS) has potential to prevent BWL in patients after gastrectomy. However, there is no consistent evidence supporting the beneficial effects of ONS on BWL, muscle strength and health-related quality of life (HRQoL). This study aimed to evaluate the effects of ONS formulated primarily with carbohydrate and protein on BWL, muscle strength, and HRQoL. METHODS: This will be a multicenter, open-label, parallel, randomized controlled trial in patients with gastric cancer who will undergo gastrectomy. A total of 120 patients who will undergo gastrectomy will be randomly assigned to the ONS group or usual care (control) group in a 1:1 ratio. The stratification factors will be the clinical stage (I or ≥ II) and surgical procedures (total gastrectomy or other procedure). In the ONS group, the patients will receive 400 kcal (400 ml)/day of ONS from postoperative day 5 to 7, and the intervention will continue postoperatively for 8 weeks. The control group patients will be given a regular diet. The primary outcome will be the percentage of BWL (%BWL) from baseline to 8 weeks postoperatively. The secondary outcomes will be muscle strength (handgrip strength), HRQoL (EORTC QLQ-C30, QLQ-OG25, EQ-5D-5L), nutritional status (hemoglobin, lymphocyte count, albumin), and dietary intake. All analyses will be performed on an intention-to-treat basis. DISCUSSION: This study will provide evidence showing whether or not ONS with simple nutritional ingredients can improve patient adherence and HRQoL by reducing BWL after gastrectomy. If supported by the study results, nutritional support with simple nutrients will be recommended to patients after gastrectomy for gastric cancer. TRIAL REGISTRATION: jRCTs051230012; Japan Registry of Clinical Trails. Registered on Apr. 13, 2023.

A multi-centric, single-blinded, randomized, parallel-group study to evaluate the effectiveness of nasoalveolar moulding treatment in non-syndromic patients with complete unilateral cleft lip, alveolus and palate (NAMUC study): a study protocol for a randomized controlled trial.

BACKGROUND: Cleft lip and palate (CLP) are among the most common congenital anomaly that affects up to 33,000 newborns in India every year. Nasoalveolar moulding (NAM) is a non-surgical treatment performed between 0 and 6 months of age to reduce the cleft and improve nasal aesthetics prior to lip surgery. The NAM treatment has been a controversial treatment option with 51% of the cleft teams in Europe, 37% of teams in the USA and 25 of cleft teams in India adopting this methodology. This treatment adds to the already existing high burden of care for these patients. Furthermore, the supporting evidence for this technique is limited with no high-quality long-term clinical trials available on the effectiveness of this treatment. METHOD: The NAMUC study is an investigator-initiated, multi-centre, single-blinded randomized controlled trial with a parallel group design. The study will compare the effectiveness of NAM treatment provided prior to lip surgery against the no-treatment control group in 274 patients with non-syndromic unilateral complete cleft lip and palate. The primary endpoint of the trial is the nasolabial aesthetics measured using the Asher McDade index at 5 years of age. The secondary outcomes include dentofacial development, speech, hearing, cost-effectiveness, quality of life, patient perception, feeding and intangible benefits. Randomization will be carried out via central online system and stratified based on cleft width, birth weight and clinical trial site. DISCUSSION: We expect the results from this study on the effectiveness of treatment with NAM appliance in the long term along with the cost-effectiveness evaluation can eliminate the dilemma and differences in clinical care across the globe. TRIAL REGISTRATION: ClinicalTrials.gov CTRI/2022/11/047426 (Clinical Trials Registry India). Registered on 18 November 2022. The first patient was recruited on 11 December 2022. CTR India does not pick up on Google search with just the trial number. The following steps have to be carried out to pick up. How to search: ( https://ctri.nic.in/Clinicaltrials/advsearch.php -use the search boxes by entering the following details: Interventional trial > November 2022 > NAMUC).

FIRE Stones: impact of forced diuresis on the residual fragment rate after flexible ureteroscopy for destruction of kidney stones with laser-protocol for a randomized controlled two-parallel group multicenter trial with blinding evaluation.

BACKGROUND: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical. OBJECTIVE: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser. METHODS/DESIGN: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist. DISCUSSION: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00.

Effect of in-line filtration in newborns: study protocol of the Intravenous Neonatal Central Access Safety (INCAS) randomized controlled trial.

BACKGROUND: Particulate contamination due to infusion therapy (administration of parenteral nutrition and medications) carries a potential health risk for infants in neonatal intensive care units (NICUs). This particulate consists of metals, drug crystals, glass fragments, or cotton fibers and can be generated by drug packaging, incomplete reconstitution, and chemical incompatibilities. In-line filters have been shown to remove micro-organisms, endotoxin, air, and particles in critically ill adults and older infants, but its benefits in newborn remain to be demonstrated. Moreover, 50% of inflammatory episodes in the setting of NICUs are blood culture-negative. These episodes could be partly related to the presence of particles in the infusion lines. METHODS: A multicenter randomized single-blind controlled trial was designed. All infants admitted to NICUs for which prolonged infusion therapy is expected will be enrolled in the study and randomized to the Filter or Control arm. All patients will be monitored until discharge, and data will be analyzed according to a "full analysis set." The primary outcome is the frequency of patients with at least one sepsis-like event, defined by any association of suspected sepsis symptoms with a level of c-reactive protein (CRP) > 5 mg/L in a negative-culture contest. The frequency of sepsis, phlebitis, luminal obstruction, and the duration of mechanical ventilation and of catheter days will be evaluated as secondary outcomes. The sample size was calculated at 368 patients per arm. DISCUSSION: This is the first multicenter randomized control trial that compares in-line filtration of parenteral nutrition and other intravenous drugs to infusion without filters. Sepsis-like events are commonly diagnosed in clinical practice and are more frequent than sepsis in a positive culture contest. The risk of these episodes in the target population is estimated at 30-35%, but this data is not confirmed in the literature. If the use of in-line filters results in a significant decrease in sepsis-like events and/or in any other complications, the use of in-line filters in all intravenous administration systems may be recommended in NICUs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05537389, registered on 12 September 2022 ( https://classic. CLINICALTRIALS: gov/ct2/show/results/NCT05537389?view=results ).

Study protocol for an adaptive, multi-arm, multi-stage (MAMS) randomised controlled trial of brief remotely delivered psychosocial interventions for people with serious mental health problems who have experienced a recent suicidal crisis: Remote Approaches to Psychosocial Intervention Delivery (RAPID).

BACKGROUND: People with serious mental health problems (SMHP) are more likely to be admitted to psychiatric hospital following contact with crisis services. Admissions can have significant personal costs, be traumatic and are the most expensive form of mental health care. There is an urgent need for treatments to reduce suicidal thoughts and behaviours and reduce avoidable psychiatric admissions. METHODS: A multi-stage, multi-arm (MAMS) randomised controlled trial (RCT) with four arms conducted over two stages to determine the clinical and cost effectiveness of three psychosocial treatments, compared to treatment as usual (TAU), for people with SMHP who have had recent suicidal crisis. Primary outcome is any psychiatric hospital admissions over a 6-month period. We will assess the impact on suicidal thoughts and behaviour, hope, recovery, anxiety and depression. The remote treatments delivered over 3 months are structured peer support (PREVAIL); a safety planning approach (SAFETEL) delivered by assistant psychologists; and a CBT-based suicide prevention app accessed via a smartphone (BrighterSide). Recruitment is at five UK sites. Stage 1 includes an internal pilot with a priori progression criteria. In stage 1, the randomisation ratio was 1:1:1:2 in favour of TAU. This has been amended to 2:2:3 in favour of TAU following an unplanned change to remove the BrighterSide arm following the release of efficacy data from an independent RCT. Randomisation is via an independent remote web-based randomisation system using randomly permuted blocks, stratified by site. An interim analysis will be performed using data from the first 385 participants from PREVAIL, SAFETEL and TAU with outcome data at 6 months. If one arm is dropped for lack of benefit in stage 2, the allocation ratio of future participants will be 1:1. The expected total sample size is 1064 participants (1118 inclusive of BrighterSide participants). DISCUSSION: There is a need for evidence-based interventions to reduce psychiatric admissions, via reduction of suicidality. Our focus on remote delivery of established brief psychosocial interventions, utilisation of different modalities of delivery that can provide sustainable and scalable solutions, which are also suitable for a pandemic or national crisis context, will significantly advance treatment options. TRIAL REGISTRATION: ISRCTN33079589. Registered on June 20, 2022.

Preoperative electroacupuncture versus sham electroacupuncture for the treatment of postoperative ileus after laparoscopic surgery for colorectal cancer in China: a study protocol for a multicentre, randomised, sham-controlled trial.

INTRODUCTION: Postoperative ileus (POI) is a postoperative complication that can cause lingering recovery after colorectal resection and a heavy healthcare system burden. Acupuncture aims to prevent postoperative complications, reduce the duration of POI, help recovery and shorten hospital stays. We hypothesise that preoperative electroacupuncture (EA) can promote POI recovery under the enhanced recovery after surgery protocol after laparoscopic surgery in patients with POI. METHODS AND ANALYSIS: This is a multicentre, randomised, sham-controlled trial. A total of 80 patients will be enrolled and randomly assigned to the EA or sham electroacupuncture (SA) group. The eligible patients will receive EA or SA for one session per day with treatment frequency starting on preoperative day 1 for four consecutive days. The primary outcome is the time to first defecation. The secondary outcomes include the time to first flatus, length of postoperative hospital stay, time to tolerability of semiliquid and solid food, postoperative nausea, vomiting, pain and extent of abdominal distention, time to first ambulation, preoperative anxiety, 30-day readmission rate, the usage of anaesthetics and analgesics during operation, length of postanaesthesia care unit stay. A mechanistic study by single-cell RNA sequencing in which postintervention normal intestinal tissue samples will be collected. The results of this study will provide evidence of the effects of acupuncture on POI and promote good clinical decision to millions of patients globally every year. ETHICS AND DISSEMINATION: This study has been approved by the ethical application of Beijing University of Chinese Medicine (2022BZYLL0401), Beijing Friendship Hospital Affiliated to Capital Medical University(2022-P2-368-02), Cancer Hospital Chinese Academy of Medical Science (23/175-3917), Huanxing Cancer Hospital (2023-002-02). The results will be published in a medical journal. In addition, we plan to present them at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300077633.

Psychosocial outcomes following emergency laparotomy (POLO) study: a study protocol for a multicentre mixed-methods prospective cohort study assessing the psycho-social outcomes following emergency laparotomy in adults.

INTRODUCTION: Morbidity from an emergency laparotomy (EmLap) is difficult to define and poorly understood. Morbidity is a holistic concept, reliant upon an interplay of bio-psychosocial outcomes that evolve long after discharge. To date, no previous study has explored the psychosocial outcomes following EmLap as a collective, nor their change over time. This study aims to describe the holistic morbidity following EmLap within the first year following surgery. METHODS AND ANALYSIS: This is a multicentre, mixed-methods prospective 12-month cohort study with two participant populations: patient participants and family caregivers (FCGs). A target of 160 adult patients who undergo EmLap and can give informed consent will be included in the patient participant group. Patient participants will be asked to complete three patient surveys, incorporating validated patient-reported outcome measures (PROMs) to assess bio-psychosocial outcomes (EuroQol five-dimension five-level (EQ5D-5L), Gastrointestinal Quality Life Index-36, Patient Health Questionnaire-9, Generalised Anxiety Disorder 7, International Trauma Questionnaire, Caregiver Interaction Scale and Fatigue Severity Scale) in the 12 months following surgery. A subgroup of 15 patient participants will be asked to take part in two semistructured interviews at 6 and 12 months. A target of 15 associated family caregivers will be included in the FCG group. FCGs will be asked to take part in a semi-structured interview at 6 months to assess the EmLap impact on the wider support network. The primary outcome will be a change in quality of life (EQ5D-5L) at 12 months. Secondary outcomes will be changes in bio-psychosocial status at 3 and 12 months. Qualitative analysis will allow contextualisation of PROMS and further explore themes of EmLap morbidity. It is anticipated that the results of this study will help inform and develop standards of aftercare for future EmLap patients. ETHICS AND DISSEMINATION: This study has received ethical approval (Wales REC7;12/WA/0297) and will be undertaken in accordance with the principles of Good Clinical Practice. We intend to disseminate study results in peer-reviewed journals and medical conferences, as well as a lay report to study participants. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT05281627.

Identifying suicidal risk factors in the French Overseas Territories with multimethod psychological autopsy (AUTOPSOM): a mixed-methods study protocol.

INTRODUCTION: Understanding suicide in more isolated territories is a challenge because of the entanglement of cultural identity with historical, geographical and sociocultural specificities. This knowledge is a necessary precondition for the implementation of targeted prevention strategies in regions such as the French overseas territories (FOT), where data concerning suicidal risk factors is still incomplete. We aim to untangle sociocultural and clinical suicide risk factors by integrating a novel anthropological and psycholinguistic approach into the psychological autopsy method. This article describes the protocol of the clinical study 'Contribution of Psychological Autopsy to the Understanding of Suicidal Behaviours in Overseas France' (AUTOPSOM study), designed to identify common or new specific suicide risk factors in four FOT. METHODS AND ANALYSIS: A multicentre epidemiological study will be carried out in four FOTs (French Polynesia, Martinique, La Reunion and French Guiana) and at a comparison site in mainland France (La Somme). The methodology will be based on a mixed-methods (quantitative and qualitative) approach using a psychological autopsy to collect clinical data and life events in the deceased's life. We implemented an exploratory multimethod strategy that combines a succession of epidemiological, anthropological, psycholinguistic and psychological methods with a semiautomated analysis of the discourse of relatives bereaved by suicide. ETHICS AND DISSEMINATION: The study protocol (first version) was approved by the French Ethics Committee (CPP OUEST II, approval #22.04267.000122) and the Ethics Committee of French Polynesia (JOPF of 5 April 2022; CEPF opinion n°91 of 29 March 2022). The overall results and the perspectives established at the end of the study will be communicated to the bereaved relatives according to their will and serve for local suicide prevention purposes. TRIAL REGISTRATION NUMBER: NCT05773898.

Serplulimab combined with gemcitabine, nab-paclitaxel and stereotactic body radiotherapy as the first-line treatment for patients with metastatic pancreatic adenocarcinoma in China: a multicentre, single-arm, phase II trial (ICSBR) protocol.

INTRODUCTION: Patients with pancreatic ductal adenocarcinoma (PDAC) remain a poor prognosis despite the development of chemotherapy. Although programmed cell death 1 (PD-1) blockade has shown great efficacy in various solid tumours, its application in treating PDAC is limited. Recent studies have indicated that chemotherapy or stereotactic body radiotherapy (SBRT) may improve the antitumour effect of PD-1 blockade in patients with PDAC. The objective of this study is to evaluate the efficacy and safety of combined therapy comprising PD-1 blockade, gemcitabine plus nab-paclitaxel chemotherapy and SBRT for patients with metastatic PDAC. METHODS AND ANALYSIS: This is a multicentre, single-arm, prospective phase II clinical trial. Forty-three patients diagnosed with metastatic PDAC will be enrolled. The eligible patients will be intravenously administered 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel on days 1 and 8 of the 21-day cycle. Serplulimab (200 mg) will be administered intravenously on day 1 of the 21-day cycle. Furthermore, during the second cycle, the patients will undergo SBRT with doses of 33 Gy in five fractions for primary lesions or doses of 24 Gy in three fractions for metastases. The primary endpoint is the 6-month progression-free survival (PFS) rate. The secondary endpoints overall survival, PFS, overall response rate, disease control rate, time to progression, duration of response, duration of disease control and safety. Moreover, this trial seeks to investigate biomarkers such as circulating tumour DNA and circulating hybrid cells in patients diagnosed with metastatic PDAC. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. The study results will be presented at international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300073237.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.

Reflections on the challenges of conducting an international multicentre randomized controlled trial of balance training in addition to pulmonary rehabilitation and its impact on fall incidence in people with COPD.

BACKGROUND: Pulmonary rehabilitation (PR) is accepted as standard care for individuals with COPD. We conducted an international, multi-centred randomized controlled trial (RCT) to determine if adding balance training to PR would reduce the incidence of falls in people with COPD. While there have been many trials investigating the effectiveness of PR, few have involved international collaboration. Successful execution of rehabilitation trials requires a significant investment of time, staffing, and resources. With the recent completion of the Balance Training for Fall Reduction in COPD RCT, we report on the design, implementation, and execution of our trial using project management phases. We also highlight our lessons learned for consideration in future multi-centre rehabilitation trials. METHODS: This was a retrospective review of the planning, preparation, timelines, and personnel training involved in the execution of this study using four of the five project management phases described by Farrell et al. in 2010: (1) initiation, (2) planning, (3) execution, and (4) monitoring and controlling. We report descriptive statistics as percentages and counts and summarize our lessons learned. RESULTS: Ten outpatient PR programs in three continents participated. Thirty-one personnel worked on the trial across all sites. Enrolment began in January 2017 and was suspended in March 2020 due to the COVID-19 pandemic. Approximately 1275 patients were screened, 455 (36%) were eligible, 258 (57%) consented, 243 (53%) participated, and 130 (61%) completed the 12-month follow-up assessment. Lessons learned through our experience included (1) ensuring awareness of funder policies and considering the impact on collaborating sites; (2) preparing for the possibility of human resource and program disruptions; (3) anticipating site dropout and having a contingency plan in place; (4) planning and monitoring process measure data before, during, and after trial initiation; (5) ensuring frequent and consistent communication with and between collaborating sites; (6) maximizing features of database platform to ensure data set completeness and controlled data access; and (7) identifying strategies for increasing patient engagement in a high-demand study. CONCLUSIONS: We identify seven lessons learned through our experience conducting an international, multicentre rehabilitation-based RCT. These lessons can provide guidance to other trialists conducting studies with similar logistics and may assist with future trial planning and implementation.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Feasibility and efficacy of virtual reality rehabilitation compared with conventional physiotherapy for upper extremity impairment due to ischaemic stroke: protocol for a randomised controlled trial.

INTRODUCTION: Approximately half of all stroke survivors have persistent upper extremity functional impairment, leading to reduced self-care, independence and quality of life. High-intensity, task-oriented virtual reality rehabilitation improves motor recovery. However, its clinical efficacy over standard rehabilitation remains uncertain. This study aims to evaluate the feasibility and efficacy of a virtual reality-based comprehensive rehabilitation gaming system (VR-cRGS) in stroke survivors with upper extremity impairment and to characterise the structural and functional plasticity of the affected regions in the brain due to the proposed rehabilitation. METHODS AND ANALYSIS: This study is a multicentric, open-label, randomised controlled trial with an intention-to-treat analysis. A total of 162 patients will be enrolled in two academic institutes in India that specialise in stroke care. Patients with a first-ever ischaemic stroke (18-70 years and 1-6 months of stroke onset) with upper extremity impairment with 1 and 1+ grades of spasticity as per the modified Ashworth Scale and 3, 4 or 5 stages on Brunnstrom recovery staging will be enrolled. They will be randomised (1:1) into two treatment groups to receive 12 weeks of training either on VR-cRGS or on conventional physiotherapy. The primary feasibility outcome is compliance with the treatment. The primary efficacy outcome is the functional recovery of the upper extremity assessed by the Fugl-Meyer Assessment-Upper Extremity and Wolf Motor Function Test. The secondary outcomes are the Barthel Index and the 36-item Short-Form Health Survey. Multimodal brain imaging will be done in all enrolled patients at baseline and post-treatment to evaluate the structural and functional connectivity changes. The outcome measures will be analysed using paired t-tests or non-parametric tests. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Ethics Review Board of the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India (SCT/IEC/1415/AUGUST-2019) and the National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India (NIMHANS/IEC (BS and NS DIV.)/32nd Meeting/21). All participants will sign an informed consent form prior to participation. The study results will be disseminated through scholarly publication. TRIAL REGISTRATION NUMBER: CTRI/2021/11/038339.