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Background: Persons with a past episode of self-harm or severe suicidal ideation are at elevated risk of self-harm as well as dying by suicide. It is well established that suicidal ideation fluctuates over time. Previous studies have shown that a personal safety plan can assist in providing support, when a person experiences suicide ideation, and help seeking professional assistance if needed. The aim of the trial is to determine whether a newly developed safety mobile app is more effective in reducing suicide ideation and other symptoms, compared to a safety plan on paper.Methods/design: The trial is designed as a two-arm, observer-blinded, parallel-group randomized clinical superiority trial, where participants will either receive: (1) Experimental intervention: the safety plan provided as the app MyPlan, or (2) Treatment as Usual: the safety plan in the original paper format. Based on a power calculation, a total of 546 participants, 273 in each arm will be included. They will be recruited from Danish Suicide Prevention Clinics. Both groups will receive standard psychosocial therapeutic care, up to 8-10 sessions of supportive psychotherapy. Primary outcome will be reduction in suicide ideation after 12 months. Follow-up interviews will be conducted at 3, 6, 9, and 12 months after date of inclusion.Discussion: A safety plan is a mandatory part of the treatment in the Suicide Prevention Clinics in Demark. There are no studies investigating the effectiveness of a safety plan app compared to a safety plan on paper on reducing suicide ideation in patients with suicide ideation and suicidal behavior. The trial will gain new knowledge of whether modern technology can augment the effects of traditional personalized safety planning.Trial Registration: ClinicalTrials.gov, NCT02877316 . Registered on 19 August 2016. [ABSTRACT FROM AUTHOR]

Background: In the last few decades, the number of trials using Bayesian methods has grown rapidly. Publications prior to 1990 included only three clinical trials that used Bayesian methods, but that number quickly jumped to 19 in the 1990s and to 99 from 2000 to 2012. While this literature provides many examples of Bayesian Adaptive Designs (BAD), none of the papers that are available walks the reader through the detailed process of conducting a BAD. This paper fills that gap by describing the BAD process used for one comparative effectiveness trial (Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations) that can be generalized for use by others. A BAD was chosen with efficiency in mind. Response-adaptive randomization allows the potential for substantially smaller sample sizes, and can provide faster conclusions about which treatment or treatments are most effective. An Internet-based electronic data capture tool, which features a randomization module, facilitated data capture across study sites and an in-house computation software program was developed to implement the response-adaptive randomization.Results: A process for adapting randomization with minimal interruption to study sites was developed. A new randomization table can be generated quickly and can be seamlessly integrated in the data capture tool with minimal interruption to study sites.Conclusion: This manuscript is the first to detail the technical process used to evaluate a multisite comparative effectiveness trial using adaptive randomization. An important opportunity for the application of Bayesian trials is in comparative effectiveness trials. The specific case study presented in this paper can be used as a model for conducting future clinical trials using a combination of statistical software and a web-based application.Trial Registration: ClinicalTrials.gov Identifier: NCT02260388 , registered on 6 October 2014. [ABSTRACT FROM AUTHOR]

Background: Despite its proven efficacy in reducing recurrence and improving survival, adherence to endocrine therapy (ET) is suboptimal in women with breast cancer (BC). Health-related quality of life (HRQoL) in BC has been widely studied and many positive effects have been highlighted. Recently, a link between HRQoL and compliance with ET has been suggested, which would suggest a potential role for HRQoL assessment in improving compliance with ET. With the advent of digital technologies, electronic collection of HRQoL on a tablet is now possible. Thus, we hypothesize that systematic HRQoL assessment (using a tablet, prior to each consultation, with presentation of scores to clinicians) coupled with therapeutic information could have an impact on 12-month compliance with ET in patients with non-metastatic BC.Methods: In this study, we will include 342 women with non-metastatic hormone receptor-positive BC with an indication for treatment with ET. Patients will be randomly assigned 1:1 by minimization and stratified by age, stage, type of ET prescribed, and presence of comorbidities (or not) in two arms. The intervention will consist of numerical HRQoL assessment using the CHES (Computer-based Health Evaluation System) software before each consultation (with delivery of scores to clinicians) coupled with therapeutic information. Therapeutic information will consist of three workshops related to understanding the prescription, nutrition, and fatigue. A reminder letter will be sent to patients every month. Patients in the control group will follow standard care. HRQoL will be assessed using a classic "paper-pencil" collection at baseline in both arms to ensure comparability between arms and at 12 months. The primary endpoint is 12-month compliance with ET. Patient satisfaction with care and the clinicians' perception of the usefulness of routine HRQoL assessment will also be assessed.Discussion: This study will allow clinicians to identify and better understand the areas in which patients who receive ET have difficulties and thus it will assist clinicians with patient management. Systematic evaluation of HRQoL could provide an additional endpoint for measuring patients' health status and treatment-related symptoms, including ET. If the results of this study are positive, this intervention could be proposed as an integral part of daily clinical practice in patients who receive ET.Trial Registration: ClinicalTrials.govNCT04176809. Registered Nov. 25, 2019. [ABSTRACT FROM AUTHOR]

Background: Recruiting young adults (ages 18-35 years) into weight gain prevention intervention studies is challenging and men are particularly difficult to reach. This paper describes two studies designed to improve recruitment for a randomized trial of weight gain prevention interventions. Study 1 used a quasi-experimental design to test the effect of two types of direct mailings on their overall reach. Study 2 used a randomized design to test the effect of using targeted messages to increase recruitment of men into the trial.Methods: For Study 1, 60,000 male and female young-adult households were randomly assigned to receive either a recruitment brochure or postcard. Visits to recruitment websites during each mailing period were used to assess response to each mailing. Study 2 focused on postcard recruitment only. These households received either a targeted or generic recruitment postcard, where targeted postcards included the word "Men" in the headline text. Response rates to each type of card were categorized based on participant report of mailing received.Results: The reach of the postcards and brochures were similar (421 and 386 website visits, respectively; P = 0.22). Individuals who received the brochure were more likely to initiate the online screener than those who received a postcard (P = 0.01). In Study 2, of those who completed the telephone screening, 60.9 % of men (n = 23) had received the targeted postcard as compared to the generic postcard (39.1 %, P = 0.30). The reverse was true for women (n = 62, 38.7 vs. 61.3 %, P = 0.08).Conclusions: These studies suggest there was little difference in the reach of postcards versus brochures. However, recipients of brochures were more likely to continue to the next stage of study participation. As expected, men's response to the weight gain prevention messages was lower than women's response; but using targeted messages appears to have modestly increased the proportion of male respondents. These studies add to the limited experimental literature on recruitment messaging and provide further indication for using targeted messages to reach underrepresented populations while providing initial evidence on the effect of mailing type on message reach.Trial Registration: The Study of Novel Approaches to Weight Gain Prevention was registered with ClinicalTrials.gov (identifier: NCT01183689 ) on 13 August 2010. [ABSTRACT FROM AUTHOR]

Background: Outpatient chemotherapy is a core treatment for haematological malignancies; however, its toxicities frequently lead to distressing/potentially life-threatening side-effects (neutropenia/infection, nausea/vomiting, mucositis, constipation/diarrhoea, fatigue). Early detection/management of side-effects is vital to improve patient outcomes, decrease morbidity and limit lengthy/costly hospital admissions. The ability to capture patient-reported health data in real-time, is regarded as the 'gold-standard' to allow rapid clinical decision-making/intervention. This paper presents the protocol for a Phase 3 multi-site randomised controlled trial evaluating a novel nurse-led Telehealth intervention for remote monitoring/management of chemotherapy side-effects in Australian haematological cancer patients.Methods/design: Two hundred and twenty-two patients will be recruited from two hospitals. Eligibility criteria include: diagnosis of chronic lymphocytic leukaemia/Hodgkin's/non-Hodgkin's lymphoma; aged ≥ 18 years; receiving ≥ 2 cycles chemotherapy. Patients will be randomised 1:1 to either the control or intervention arm with stratification by diagnosis, chemotherapy toxicity (high versus low), receipt of previous chemotherapy and hospital. Patients allocated to the control arm will receive 'Usual Care' whilst those allocated to the intervention will receive the intervention in addition to 'Usual Care'. Intervention patients will be provided with a computer tablet and software prompting twice-daily completion of physical/emotional scales for up to four chemotherapy cycles. Should patient data exceed pre-determined limits an Email alert is delivered to the treatment team, prompting nurses to view patient data, and contact the patient to provide clinical intervention. In addition, six scheduled nursing interventions will be completed to educate/support patients in use of the software. Patient outcomes will be measured cyclically (midpoint and end of cycles) via pen-and-paper self-report alongside review of the patient medical record. The primary outcome is burden due to nausea, mucositis, constipation and fatigue. Secondary outcomes include: burden due to vomiting and diarrhoea; psychological distress; ability to self-manage health; level of cancer information/support needs and; utilisation of health services. Analyses will be intention-to-treat. A cost-effectiveness analysis is planned.Discussion: This trial is the first in the world to test a remote monitoring/management intervention for adult haematological cancer patients receiving chemotherapy. Future use of such interventions have the potential to improve patient outcomes/safety and decrease health care costs by enabling early detection/clinical intervention.Trial Registration: ACTRN12614000516684 . Date registered: 12 March 2014 (registered retrospectively). [ABSTRACT FROM AUTHOR]

Background: Communities of practice are based on the idea that learning involves a group of people exchanging experiences and knowledge. The e-MPODERA project aims to assess the effectiveness of a virtual community of practice aimed at improving primary healthcare professional attitudes to the empowerment of patients with chronic diseases.Methods: This paper describes the protocol for a cluster randomized controlled trial. We will randomly assign 18 primary-care practices per participating region of Spain (Catalonia, Madrid and Canary Islands) to a virtual community of practice or to usual training. The primary-care practice will be the randomization unit and the primary healthcare professional will be the unit of analysis. We will need a sample of 270 primary healthcare professionals (general practitioners and nurses) and 1382 patients. We will perform randomization after professionals and patients are selected. We will ask the intervention group to participate for 12 months in a virtual community of practice based on a web 2.0 platform. We will measure the primary outcome using the Patient-Provider Orientation Scale questionnaire administered at baseline and after 12 months. Secondary outcomes will be the sociodemographic characteristics of health professionals, sociodemographic and clinical characteristics of patients, the Patient Activation Measure questionnaire for patient activation and outcomes regarding use of the virtual community of practice. We will calculate a linear mixed-effects regression to estimate the effect of participating in the virtual community of practice.Discussion: This cluster randomized controlled trial will show whether a virtual intervention for primary healthcare professionals improves attitudes to the empowerment of patients with chronic diseases.Trial Registration: ClicalTrials.gov, NCT02757781 . Registered on 25 April 2016. Protocol Version. PI15.01 22 January 2016. [ABSTRACT FROM AUTHOR]

Background: The Cord Pilot Trial aimed to assess the feasibility of conducting a large UK randomised trial to compare the effects of alternative polices for timing of cord clamping (immediate within 20 seconds or deferred after at least 2 minutes) for very preterm birth before 32 weeks gestation. Initial recruitment was from March 2013 to February 2014, phase 2 was from March 2014 to February 2015. This paper updates the pilot trial protocol (Trials 15(1):258, 2014) and presents the changes for phase 2.Methods: An electronic randomisation system was introduced at three of the eight pilot sites. For follow-up of children, the Parent Report of Children's Abilities--Revised (PARCA-R) will not be used. For children recruited to the trial during phase 2, follow-up at age 2 years (corrected for gestation at birth) will be by parent completed Ages and Stages Questionnaire (Squire J, Ages and Stages Questionnaires (ASQ), 2009) alone unless funds can be secured for the additional Bayley Scales of Infant Development III (Bayley N, Bayley Scales of Infant and Toddler Development, Third Edition. (Bayley-III), 2005) assessments. To assess accuracy of the cranial ultrasound diagnosis of intraventricular haemorrhage: (i) quality of the scans will be assessed using the British Society of Paediatric Radiology recommendations, and (ii) scan results will be confirmed by independent adjudication. Within and between adjudicator reliability will be assessed. In addition to the analyses planned to assess feasibility of the full trial based on data from the first year of recruitment, data on compliance and outcomes will be presented by allocated group for all women and babies recruited.Trial Registration: ISRCTN21456601, registered on 28 February 2013. [ABSTRACT FROM AUTHOR]

Background: Most positive psychology interventions conducted in the West have been focused on the individual. Family relationships are highly valued in the Chinese collectivist culture, and it is of interest to know whether family-focused interventions can improve the well-being of Chinese people. We have previously reported the effectiveness of a positive psychology family intervention in terms of family well-being. Based on the data derived from the Happy Family Kitchen II project, this paper examines the effectiveness of a community-based positive psychology family intervention on subjective happiness and health-related quality of life.Methods: Thirty-one social service units and schools organized intervention programs for 2070 participants in Hong Kong. In a cluster randomized controlled trial, participants were randomly assigned on the basis of computer-generated numbers into the intervention group or the control group. The intervention programs emphasized one of five positive psychology themes: joy, gratitude, flow, savoring, and listening. The control group engaged in activities unrelated to the intervention, such as arts and crafts workshops. Subjective happiness and mental and physical quality of life were assessed at baseline and at 4 weeks and 12 weeks postintervention.Results: Data of 1261 participants were analyzed. The results showed that the intervention was more effective than the control condition in improving subjective happiness, with a small effect size, at 12 weeks postintervention (β = .15, p = .020, Cohen's d = .16). However, there were no improvements in mental and physical quality of life in the intervention group compared with the control group at 4 weeks (β = .39, p = .494, d = .05; β = -.10, p = 1.000, d = -.01, respectively) and 12 weeks postintervention (β = .71, p = .233, d = .08; β = -.05, p = 1.000, d = -.01, respectively). Furthermore, the booster session was no more effective than the tea gathering session in improving subjective happiness (β = .00, p = .990, d = .00) or mental (β = 1.20, p = 1.000, d = -.04) and physical quality of life (β = .15, p = 1.000, d = -.01).Conclusions: The analyses extend previous findings of salutary effects on family well-being by showing that positive psychology family interventions can improve subjective happiness. Suggestions for future research are proposed.Trial Registration: ClinicalTrials.gov NCT01796275 . Retrospectively registered 19 February 2013. [ABSTRACT FROM AUTHOR]

Background: The high rate of cannabis use among patients with first-episode psychosis (FEP), as well as the associated negative impact on illness course and treatment outcomes, underlines the need for effective interventions in these populations. However, to date, there have been few clinical treatment trials (of pharmacological or psychological interventions) that have specifically focused on addressing comorbid cannabis use among these patients. The aim of this paper is to describe the design of a study protocol for a randomized controlled trial in which the objective is to assess the efficacy of a specific cognitive behavioral therapy program for cannabis cessation in patients with FEP compared to standard treatment (psychoeducation).Methods/design: This is a single-blind randomized study with 1 year of follow-up. Patients are to be randomly assigned to one of two treatments: (1) specific cognitive behavioral therapy for cannabis cessation composed of 1-hour sessions once a week for 16 weeks, in addition to pharmacological treatment scheduled by the psychiatrist, or (2) a control group (psychoeducation + pharmacological treatment) following the same format as the experimental group. Participants in both groups will be evaluated at baseline (pre-treatment), at 16 weeks (post-treatment), and at 3 and 6 months and 1 year of follow-up. The primary outcome will be that patients in the experimental group will have greater cannabis cessation than patients in the control group at post-treatment. The secondary outcome will be that the experimental group will have better clinical and functional outcomes than the control group.Discussion: This study provides the description of a clinical trial design based on specific cognitive behavioral therapy for cannabis cessation in FEP patients, aiming to improve clinical and functional outcome, as well as tackling the addictive disorder.Trial Registration: NCT02319746 ClinicalTrials.gov Identifier. ClinicalTrials.gov Protocol and Results Registration System (PRS) Receipt Release Date: 15 December 2014. [ABSTRACT FROM AUTHOR]

Background: Care for most people with schizophrenia is best delivered in the community and evidence-based guidelines recommend combining both medication and a psychosocial intervention, such as community-based rehabilitation. There is emerging evidence that community-based rehabilitation for schizophrenia is effective at reducing disability in middle-income country settings, yet there is no published evidence on the effectiveness in settings with fewer mental health resources. This paper describes the protocol of a study that aims to evaluate the effectiveness of community-based rehabilitation as an adjunct to health facility-based care in rural Ethiopia.Methods: This is a cluster randomised trial set in a rural district in Ethiopia, with sub-district as the unit of randomisation. Participants will be recruited from an existing cohort of people with schizophrenia receiving treatment in primary care. Fifty-four sub-districts will be randomly allocated in a 1:1 ratio to facility-based care plus community-based rehabilitation (intervention arm) or facility-based care alone (control arm). Facility-based care consists of treatment by a nurse or health officer in primary care (antipsychotic medication, basic psychoeducation and follow-up) with referral to a psychiatric nurse-led outpatient clinic or psychiatric hospital when required. Trained community-based rehabilitation workers will deliver a manualised community-based rehabilitation intervention, with regular individual and group supervision. We aim to recruit 182 people with schizophrenia and their caregivers. Potential participants will be screened for eligibility, including enduring or disabling illness. Participants will be recruited after providing informed consent or, for participants without decision-making capacity, after the primary caregiver gives permission on behalf of the participant. The primary outcome is disability measured with the 36-item WHO Disability Assessment Schedule (WHODAS) version 2.0 at 12 months. The sample size will allow us to detect a 20 % difference in WHODAS 2.0 scores between treatment arms with 85 % power. Secondary outcomes include change in symptom severity, economic activity, physical restraint, discrimination and caregiver burden.Discussion: This is the first trial of community-based rehabilitation for schizophrenia and will determine, as a proof of concept, the added value of community-based rehabilitation compared to facility-based care alone in a low-income country with scarce mental health resources.Trial Registration: Clinical Trials.gov Identifier NCT02160249 . Registered on 3 June 2014. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) creates a complex pathology that can lead to an increase in sedentary behaviours and deleterious changes in body composition. Consequently, individuals with SCI are at increased risk of developing cardiovascular disease and type-2 diabetes mellitus. While the role of physical activity on the reduction of chronic disease risk is well documented in non-disabled individuals the evidence is less conclusive for persons with SCI. The aim of this methodological paper is to outline the design of a study that will assess the role of a home-based exercise intervention on biomarkers of metabolic and cardiovascular health in persons with SCI: the HOMEX-SCI study.Methods/design: Eligible participants will be inactive (physical activity level ≤1.60) individuals, with a chronic (more than 1 year) spinal cord lesion between the second thoracic and the fifth lumbar vertebrae, and aged between 18 and 65 years. Following baseline laboratory testing and lifestyle monitoring, participants will be randomly allocated to a control (CON) group or a 6-week home-based exercise intervention (INT) group. The INT consists of 45 minutes of moderate-intensity (60-65 % peak oxygen uptake) arm-crank exercise four times per week. Participants assigned to the CON group will be asked to maintain their normal lifestyle. The main outcomes of this study (biomarkers of metabolic and cardiovascular health) are obtained from venous blood samples, collected in the fasted and postprandial state. Eight other measurement categories will be assessed: (1) body composition, (2) physical activity, (3) energy intake, (4) measures of health and wellbeing, (5) resting metabolic rate, heart rate and blood pressure, (6) aerobic capacity, (7) immune function, and (8) adipose tissue gene expression.Discussion: This study will explore the feasibility of home-based moderate-intensity exercise and ascertain its impact on metabolic and cardiovascular health in comparison to a lifestyle maintenance CON group. Findings from this study may help to inform new evidence-based physical activity guidelines and also help to elucidate the physiological mechanisms whereby exercise might exert beneficial effects in persons with chronic SCI. The results will also act as a scientific platform for further intervention studies in other diverse and at-risk populations.Trial Registration: International Standard Randomised Controlled Trial Number: ISRCTN57096451 . Registered on 11 July 2014. [ABSTRACT FROM AUTHOR]

Background: Nonprofessional caregivers are highly important in the everyday life of patients with depression. Yet, they may experience increased levels of burden, stress, depression, and anxiety. Therefore, there is a need for interventions that relieve symptoms and are accessible and time-efficient. This paper describes the protocol of a pilot study to evaluate (1) the feasibility of an online self-management intervention, E-care 4 caregivers, for the nonprofessional caregiver of patients with depression, and (2) the initial effects of E-care 4 caregivers on psychological distress, subjective burden, symptoms of anxiety and depression, and quality of life.Methods/design: The study is a randomized controlled trial in which we are comparing the E-care 4 caregivers online intervention with a wait list control group. Eighty-four nonprofessional caregivers of patients with depression aged 18 years or older are being recruited from among the general population. Feasibility is determined by semistructured telephone interviews evaluating the subjects' satisfaction with the intervention and by using a questionnaire on the user-friendliness of the system. The primary outcome measure used to examine the initial effects of the intervention is psychological distress. Secondary outcome measures are subjective burden, symptoms of anxiety and depression, level of mastery, and quality of life. Assessments will be done at baseline and 6 weeks later. Statistical analysis of the effects of the intervention will be carried out on the basis of the intention-to-treat principle.Discussion: E-care 4 caregivers could potentially benefit nonprofessional caregivers, as well as patients and professionals indirectly.Trial Registration: Netherlands Trial Register identifier: NTR5268 . Registered on 30 June 2015. [ABSTRACT FROM AUTHOR]

Background: Addressing the increasing prevalence, and associated disease burden, of diabetes is a priority of health services internationally. Interventions to support patients to effectively self-manage their condition have the potential to reduce the risk of costly and debilitating complications. The utilisation of mobile phones to deliver self-management support allows for patient-centred care at the frequency and intensity that patients desire from outside the clinic environment. Self-Management Support for Blood Glucose (SMS4BG) is a novel text message-based intervention for supporting people with diabetes to improve self-management behaviours and achieve better glycaemic control and is tailored to individual patient preferences, demographics, clinical characteristics, and culture. This study aims to assess whether SMS4BG can improve glycaemic control in adults with poorly controlled diabetes. This paper outlines the rationale and methods of the trial.Methods/design: A two-arm, parallel, randomised controlled trial will be conducted across New Zealand health districts. One thousand participants will be randomised at a 1:1 ratio to receive SMS4BG, a theoretically based and individually tailored automated text message-based diabetes self-management support programme (intervention) in addition to usual care, or usual care alone (control). The primary outcome is change in glycaemic control (HbA1c) at 9 months. Secondary outcomes include glycaemic control at 3 and 6 months, self-efficacy, self-care behaviours, diabetes distress, health-related quality of life, perceived social support, and illness perceptions. Cost information and healthcare utilisation will also be collected as well as intervention satisfaction and interaction.Discussion: This study will provide information on the effectiveness of a text message-based self-management support tool for people with diabetes. If found to be effective it has the potential to provide individualised support to people with diabetes across New Zealand (and internationally), thus extending care outside the clinic environment.Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12614001232628 . [ABSTRACT FROM AUTHOR]

Background: Many people living with HIV suffer from depressive symptoms. In a previous pilot study, self-help cognitive behavioral therapy (in booklet format) was found to be effective in treating depressive symptoms in people with HIV. We developed an online self-help program in Dutch and English (based on the booklet) for people with HIV and depressive symptoms. Besides the main question regarding the effectiveness of the program aimed at lowering depressive symptoms, sub-questions will focus on the moderators of treatment success (for which patients is the program especially beneficial?) and the mechanisms of change underlying the treatment outcome (which mediators affect the outcome of treatment?). In this paper, the protocol of the study will be described.Methods/design: The effectiveness of the program will be investigated by comparing the intervention group with a waiting list-control group in a randomized controlled design, by including a pretest and three post-tests. The self-help program contains four main components: activation, relaxation, changing maladaptive cognitions, and goal attainment. Participants with mild to moderate depressive symptoms will work on the program for 6 to 10 weeks, during which a coach will provide motivational support by telephone once a week. Participants in the control condition will receive weekly minimal support from a coach for 8 weeks, and after the second post-test, they can gain access to the self-help program. Depressive symptoms and possible mediators (e.g., activation, cognitive coping, self-efficacy, and goal adjustment) will be assessed by self-report three times during the intervention/waiting period and at the pretest and first post-test.Discussion: The proposed study aims to evaluate the effectiveness of an online self-help intervention for people with HIV and depressive symptoms. If the intervention is shown to be effective, the program will be implemented. Consequently, many patients with HIV could be reached, and their psychological care may be improved.Trial Registration: Netherlands Trial Register: NTR5407. [ABSTRACT FROM AUTHOR]

Background: Clinically effective and cost-effective methods for managing problematic sexual behaviour in adolescents are urgently needed. Adolescents who show problematic sexual behaviour have a range of negative psychosocial outcomes, and they and their parents can experience stigma, hostility and rejection from their community. Multisystemic therapy (MST) shows some evidence for helping to reduce adolescent sexual reoffending and is one of the few promising interventions available to young people who show problematic sexual behaviour. This paper describes the protocol for Services for Teens Engaging in Problem Sexual Behaviour (STEPS-B), a feasibility trial of MST for problem sexual behaviour (MST-PSB) in antisocial adolescents at high risk of out-of-home placement due to problematic sexual behaviour.Methods/design: Eighty participants and their families recruited from five London boroughs will be randomized to MST-PSB or management as usual with follow-up to 20 months post-randomization. The primary outcome is out-of-home placement at 20 months. Secondary outcomes include sexual and non-sexual offending rates and antisocial behaviours, participant well-being, educational outcomes and total service and criminal justice sector costs. Feasibility outcomes include mapping the clinical service pathways needed to recruit adolescents displaying problematic sexual behaviour, acceptability of a randomized controlled trial to the key systems involved in managing these adolescents, and acceptability of the research protocol to young people and their families. Data will be gathered from police computer records, the National Pupil Database and interviews and self-report measures administered to adolescents and parents and will be analysed on an intention-to-treat basis.Discussion: The STEPS-B feasibility trial aims to inform policymakers, commissioners of services and professionals about the potential for implementing MST-PSB as an intervention for adolescents showing problem sexual behaviour. Should MST-PSB show potential, STEPS-B will determine what would be necessary to implement the programme more fully and at a scale that would warrant a full trial.Trial Registration: ISRCTN28441235 (registered 25 January 2012). [ABSTRACT FROM AUTHOR]

Background: There are 600 million girls in low and middle income countries (LMICs), many of whom are at great risk for poor health and education. There is thus great need for programs that can effectively improve wellbeing for these girls. Although many interventions have been developed to address these issues, most focus on health and education without integrating attention to social and emotional factors. This omission is unfortunate, as nascent evidence indicates that these factors are closely related to health and education. This paper describes the methods of a 4-arm randomized controlled trial among 3,560 adolescent girls in rural Bihar, India that tested whether adding an intervention targeting social-emotional issues (based on a "resilience framework") to an adolescent health intervention would improve emotional, social, physical, and educational wellbeing to a greater extent than its components and a control group. Study arms were: (1) Girls First, a combination of the Girls First Resilience Curriculum (RC) and the Girls First Health Curriculum (HC); (2) Girls First Resilience Curriculum (RC) alone; (3) Girls First Health Curriculum (HC) alone; and (4) a school-as-usual control group (SC).Methods: Seventy-six schools were randomized (19 per condition) and 74 local women with a tenth grade education were trained and monitored to facilitate the program. Quantitative data were collected from 3,560 girls over 4 assessment points with very low rates of participant attrition. Qualitative assessments were conducted with a subset of 99 girls and 27 facilitators.Results and Conclusions: In this article, we discuss guiding principles that facilitated trial implementation, including integrating diverse local and non-local sources of knowledge, focusing on flexibility of planning and implementation, prioritizing systematic measurement selection, and striking a balance between scientific rigor and real-world feasibility.Trial Registration: Clinicaltrials.gov NCT02429661 . Registered 24 April 2015. [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials (RCTs) of social interventions are often criticised as failing to open the 'black box' whereby they only address questions about 'what works' without explaining the underlying processes of implementation and mechanisms of action, and how these vary by contextual characteristics of person and place. Realist RCTs are proposed as an approach to evaluation science that addresses these gaps while preserving the strengths of RCTs in providing evidence with strong internal validity in estimating effects.Methods: In the context of growing interest in designing and conducting realist trials, there is an urgent need to offer a worked example to provide guidance on how such an approach might be practically taken forward. The aim of this paper is to outline a three-staged theoretical and methodological process of undertaking a realist RCT using the example of the evaluation of a whole-school restorative intervention aiming to reduce aggression and bullying in English secondary schools.Discussion: First, informed by the findings of our initial pilot trial and sociological theory, we elaborate our theory of change and specific a priori hypotheses about how intervention mechanisms interact with context to produce outcomes. Second, we describe how we will use emerging findings from the integral process evaluation within the RCT to refine, and add to, these a priori hypotheses before the collection of quantitative, follow-up data. Third, we will test our hypotheses using a combination of process and outcome data via quantitative analyses of effect mediation (examining mechanisms) and moderation (examining contextual contingencies). The results are then used to refine and further develop the theory of change.Conclusion: The aim of the realist RCT approach is thus not merely to assess whether the intervention is effective or not, but to develop empirically informed mid-range theory through a three-stage process. There are important implications for those involved with reporting and reviewing RCTs, including the use of new, iterative protocols.Trial Registration: Current Controlled Trials ISRCTN10751359 (Registered 11 March 2014). [ABSTRACT FROM AUTHOR]

Background: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.Results: We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.Conclusion: This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.Trial Registration: ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010). [ABSTRACT FROM AUTHOR]

Background: The prevention of obesity and improvement of academic achievement in children are concerns of industrialized societies. Obesity has been associated with psychological disorders, including attention deficit hyperactivity disorder, whose prevalence has been estimated at 6.8 % in Spanish children and adolescents. It is known that physical activity is positively related to academic achievement and negatively related to the risk of obesity in children. However, studies to test the effectiveness of physical activity interventions in improving academic achievement in preschool children are scarce and have some weaknesses that threaten their validity. Moreover, very few studies have examined their effectiveness in improving symptoms of attention deficit hyperactivity disorder. This paper outlines a two-year multidimensional preschool intervention (Movi-Kids) aimed at preventing obesity and improving academic achievement in children with or without attention deficit hyperactivity disorder.Methods/design: Twenty-one schools from Ciudad Real and Cuenca, Spain, were randomized to intervention and control groups. In the first academic year, children in the third grade of preschool and the first grade of primary school in the intervention group received the Movi-Kids intervention. In the second academic year, schools were crossed over to the other group. The intervention included children, parents and teachers, and the school environment, and consisted of: (i) three hour-long sessions of recreational non-competitive physical activity after school, weekly, (ii) educational materials for parents and teachers addressing sedentary lifestyle risks and (iii) playground modifications to promote physical activity during breaks. Primary outcome measures of this study were academic achievement (intelligence, cognition, memory, attention and perception), assessed by the Battery of General and Differential Aptitudes, and adiposity measures (body mass index, waist circumference, triceps skinfold thickness and body fat percentage). Secondary outcome measures were: attention deficit hyperactivity disorder risk, motor skills, health-related quality of life and sleep quality. These variables will all be measured in both groups at baseline and at the end of the first and second academic years.Discussion: It seems reasonable that an intervention to promote physical activity based on playground games will be useful for simultaneously improving academic achievement and controlling obesity.Trial Registration: ClinicalTrials.gov NCT01971827 . [ABSTRACT FROM AUTHOR]

Background: Pragmatic randomised controlled trials (PRCTs) aim to assess intervention effectiveness by accounting for 'real life' implementation challenges in routine practice. The methodological challenges of PRCT implementation, particularly in primary care, are not well understood. The Kanyini Guidelines Adherence to Polypill study (Kanyini GAP) was a recent primary care PRCT involving multiple private general practices, Indigenous community controlled health services and private community pharmacies. Through the experiences of Kanyini GAP participants, and using data from study materials, this paper identifies the critical enablers and barriers to implementing a PRCT across diverse practice settings and makes recommendations for future PRCT implementation.Methods: Qualitative data from 94 semi-structured interviews (47 healthcare providers (pharmacists, general practitioners, Aboriginal health workers; 47 patients) conducted for the process evaluation of Kanyini GAP was used. Data coded to 'trial impact', 'research motivation' and 'real world' were explored and triangulated with data extracted from study materials (e.g. Emails, memoranda of understanding and financial statements).Results: PRCT implementation was facilitated by an extensive process of relationship building at the trial outset including building on existing relationships between core investigators and service providers. Health providers' and participants' altruism, increased professional satisfaction, collaboration, research capacity and opportunities for improved patient care enabled implementation. Inadequate research infrastructure, excessive administrative demands, insufficient numbers of adequately trained staff and the potential financial impact on private practice were considered implementation barriers. These were largely related to this being the first experience of trial involvement for many sites. The significant costs of addressing these barriers drew study resources from the task of achieving recruitment targets.Conclusions: Conducting PRCTs is crucial to generating credible evidence of intervention effectiveness in routine practice. PRCT implementation needs to account for the particular challenges of implementing collaborative research across diverse stakeholder organisations. Reliance on goodwill to participate is crucial at the outset. However, participation costs, particularly for organisations with little or no research experience, can be substantial and should be factored into PRCT funding models. Investment in a pool to fund infrastructure in the form of primary health research networks will offset some of these costs, enabling future studies to be implemented more cost-effectively.Trial Registration: ACTRN126080005833347. [ABSTRACT FROM AUTHOR]

Background: Cognitive behaviour therapy (CBT) is recommended for the treatment of psychosis; however, only a small proportion of service users have access to this intervention. Smartphone technology using software applications (apps) could increase access to psychological approaches for psychosis. This paper reports the protocol development for a clinical trial of smartphone-based CBT.Methods/design: We present a study protocol that describes a single-blind randomised controlled trial comparing a cognitive behaviour therapy-informed software application (Actissist) plus Treatment As Usual (TAU) with a symptom monitoring software application (ClinTouch) plus TAU in early psychosis. The study consists of a 12-week intervention period. We aim to recruit and randomly assign 36 participants registered with early intervention services (EIS) across the North West of England, UK in a 2:1 ratio to each arm of the trial. Our primary objective is to determine whether in people with early psychosis the Actissist app is feasible to deliver and acceptable to use. Secondary aims are to determine whether Actissist impacts on predictors of first episode psychosis (FEP) relapse and enhances user empowerment, functioning and quality of life. Assessments will take place at baseline, 12 weeks (post-treatment) and 22-weeks (10 weeks post-treatment) by assessors blind to treatment condition. The trial will report on the feasibility and acceptability of Actissist and compare outcomes between the randomised arms. The study also incorporates semi-structured interviews about the experience of participating in the Actissist trial that will be qualitatively analysed to inform future developments of the Actissist protocol and app.Discussion: To our knowledge, this is the first controlled trial to test the feasibility, acceptability, uptake, attrition and potential efficacy of a CBT-informed smartphone app for early psychosis. Mobile applications designed to deliver a psychologically-informed intervention offer new possibilities to extend the reach of traditional mental health service delivery across a range of serious mental health problems and provide choice about available care.Trial Registration: ISRCTN34966555. Date of first registration: 12 June 2014. [ABSTRACT FROM AUTHOR]

Background: Attrition is problematic in trials, and may be exacerbated in longer studies, telehealth trials and participants with depression - three features of The Healthlines Study. Advance notification, including a photograph and using action-oriented email subject lines might increase response rates, but require further investigation. We examined the effectiveness of these interventions in three embedded Healthlines studies.Methods: Based in different trial sites, participants with depression were alternately allocated to be pre-called or not ahead of the 8-month follow-up questionnaire (Study 1), randomized to receive a research team photograph or not with their 12-month questionnaire (Study 2), and randomized to receive an action-oriented ('ACTION REQUIRED') or standard ('Questionnaire reminder') 12-month email reminder (Study 3). Participants could complete online or postal questionnaires, and received up to five questionnaire reminders. The primary outcome was completion of the Patient Health Questionnaire (PHQ-9). Secondary outcome measures were the number of reminders and time to questionnaire completion.Results: Of a total of 609 Healthlines depression participants, 190, 251 and 231 participants were included in Studies 1-3 (intervention: 95, 126 and 115), respectively. Outcome completion was ≥90 % across studies, with no differences between trial arms (Study 1: OR 0.38, 95 % CI 0.07-2.10; Study 2: OR 0.84, 95 % CI 0.26-2.66; Study 3: OR 0.53 95 % CI 0.19-1.49). Pre-called participants were less likely to require a reminder (48.4 % vs 62.1 %, OR 0.41, 95 % CI 0.21-0.78), required fewer reminders (adjusted difference in means -0.67, 95 % CI -1.13 to -0.20), and completed follow-up quicker (median 8 vs 15 days, HR 1.35, 95 % CI 1.00-1.82) than control subjects. There were no significant between-group differences in Studies 2 or 3.Conclusions: Eventual response rates in this trial were high, with no further improvement from these interventions. While the photograph and email interventions were ineffective, pre-calling participants reduced time to completion. This strategy might be helpful when the timing of study completion is important. Researchers perceived a substantial benefit from the reduction in reminders with pre-calling, despite no overall decrease in net effort after accounting for pre-notification.Trial Registration: Current Clinical Trials ISRCTN14172341. [ABSTRACT FROM AUTHOR]

Background: Approximately one fifth of Australian males aged 16+ experience mood, anxiety or substance use disorders in a given year, and suicide by males accounts for three quarters of all suicides annually. However, males with mental health problems are less likely to seek and receive help than their female counterparts. Media campaigns with videos at their core are gaining popularity as a means of promoting help-seeking for mental health difficulties, but few studies have rigorously tested the impact of such videos. This randomised controlled trial tests the effectiveness of a short video promoting help-seeking by Australian men.Methods: This study is an online randomised controlled trial (RCT). Participants will attend an online group orientation session, where they will provide consent to participate and complete a baseline questionnaire (T1). After completion of the T1 questionnaire, participants will be randomised to watch either the intervention or control video on a 1:1 basis. After randomisation, participants will be able to access their allocated video for 1 week. Seven days after T1, participants will again be sent links to the video and to the post-exposure questionnaire (T2). One month after T2, participants will be emailed the follow-up questionnaire (T3). The primary outcome will be change in help-seeking intentions from T1 to T2. Secondary outcomes will be changes in help-seeking intentions from T1 to T3, changes in intentions to encourage other males to seek help, self-reliance, and male depression symptoms from T1 to T2 and from T1 to T3. The cost-effectiveness of the intervention will be evaluated. Participants will also complete questions about their opinions of the video and its effects at T2 and T3.Discussion: Our video-based intervention is designed to promote help-seeking for mental health difficulties among Australian men. If a lack of net harm is shown to be associated with viewing the intervention video, the video will be publicly released and could have broad impacts on individual and community attitudes towards help-seeking for mental health difficulties, and ultimately enhance men's mental health and wellbeing. An evaluation of the effectiveness of the intervention is essential to ensure the intervention is achieving its objectives.Trial Registration: anzctr.org.au 12621001008819. [ABSTRACT FROM AUTHOR]

Background: Uptake matters for evaluating the health impact of water, sanitation and hygiene (WASH) interventions. Many large-scale WASH interventions have been plagued by low uptake. For the WASH Benefits Bangladesh efficacy trial, high uptake was a prerequisite. We assessed the degree of technology and behavioral uptake among participants in the trial, as part of a three-paper series on WASH Benefits Intervention Delivery and Performance.Methods: This study is a cluster randomized trial comprised of geographically matched clusters among four districts in rural Bangladesh. We randomly allocated 720 clusters of 5551 pregnant women to individual or combined water, sanitation, handwashing, and nutrition interventions, or a control group. Behavioral objectives included; drinking chlorine-treated, safely stored water; use of a hygienic latrine and safe feces disposal at the compound level; handwashing with soap at key times; and age-appropriate nutrition behaviors (pregnancy to 24 months) including a lipid-based nutrition supplement (LNS). Enabling technologies and behavior change were promoted by trained local community health workers through periodic household visits. To monitor technology and behavioral uptake, we conducted surveys and spot checks in 30-35 households per intervention arm per month, over a 20-month period, and structured observations in 324 intervention and 108 control households, approximately 15 months after interventions commenced.Results: In the sanitation arms, observed adult use of a hygienic latrine was high (94-97% of events) while child sanitation practices were moderate (37-54%). In the handwashing arms, handwashing with soap was more common after toilet use (67-74%) than nonintervention arms (18-40%), and after cleaning a child's anus (61-72%), but was still low before food handling. In the water intervention arms, more than 65% of mothers and index children were observed drinking chlorine-treated water from a safe container. Reported LNS feeding was > 80% in nutrition arms. There was little difference in uptake between single and combined intervention arms.Conclusions: Rigorous implementation of interventions deployed at large scale in the context of an efficacy trial achieved high levels of technology and behavioral uptake in individual and combined WASH and nutrition intervention households. Further work should assess how to achieve similar uptake levels under programmatic conditions.Trial Registration: WASH Benefits Bangladesh: ClinicalTrials.gov, identifier: NCT01590095 . Registered on April 30, 2012. [ABSTRACT FROM AUTHOR]

Objective: Although crossover trials enjoy wide use, standards for analysis and reporting have not been established. We reviewed methodological aspects and quality of reporting in a representative sample of published crossover trials. Methods: We searched MEDLINE for December 2000 and identified all randomized crossover trials. We abstracted data independently, in duplicate, on 14 design criteria, 13 analysis criteria, and 14 criteria assessing the data presentation. Results: We identified 526 randomized controlled trials, of which 116 were crossover trials. Trials were drug efficacy (48%), pharmacokinetic (28%), and nonpharmacologic (30%). The median sample size was 15 (interquartile range 8-38). Most (72%) trials used 2 treatments and had 2 periods (64%). Few trials reported allocation concealment (17%) or sequence generation (7%). Only 20% of trials reported a sample size calculation and only 31% of these considered pairing of data in the calculation. Carry-over issues were addressed in 29% of trial's methods. Most trials reported and defended a washout period (70%). Almost all trials (93%) tested for treatment effects using paired data and also presented details on by-group results (95%). Only 29% presented CIs or SE so that data could be entered into a meta-analysis. Conclusion: Reports of crossover trials frequently omit important methodological issues in design, analysis, and presentation. Guidelines for the conduct and reporting of crossover trials might improve the conduct and reporting of studies using this important trial design. [ABSTRACT FROM AUTHOR]

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

Background: Enhanced parenting self-efficacy (PSE) contributes to positive parenting and future parental-child health. First-time parents, in particular, are in need of support since the pregnancy until post-delivery to strengthen their early PSE. However, there is a lack of effective and sustainable relevant programmes in the community. The Community-enabled Readiness for first 1000 Days Learning Ecosystem (CRADLE) aims to develop a self-learning eco-community throughout the pregnancy and early childhood to promote PSE among first-time parents. We apply choice architecture strategy using behavioural nudges and midwife-led continuity care during the first 1000 days, and test their effects on PSE and mother-child health for first-time families in Singapore.Methods: This three-arm randomised controlled trial will recruit up to 750 pregnant women from the KK Women's and Children's Hospital, Singapore. Participants will be randomly assigned to receive: (1) standard routine care; (2) behavioural nudges (text messages) along with the use of a social media platform; or (3) midwife-led continuity care involving individualised teleconferencing sessions, during pregnancy and post-delivery. Using web-based questionnaires, participants will be assessed for baseline socio-demography and health status in the first visit, with follow-up assessments in the third trimester, at birth, 6-week (primary end-point), 6-, 12-, 18- and 24-month post-delivery. The primary outcome is PSE. Secondary outcomes include health and birth experience, mental wellness, feeding practice, maternal and child nutritional status. Intention-to-treat and per-protocol analyses will be performed using general linear models to test the effects of interventions across three arms. Recruitment has begun in June 2020 and is estimated to complete in September 2022.Discussion: This study may identify a sustainable effective strategy in the community by helping first-time parents to have a positive experience during the pregnancy, childbirth and parenthood, leading to an enhanced PSE and health outcomes for both mother and child. Findings from this study will provide insight into the implementation of early parenting and mother-child care programmes.Trial Registration: ClinicalTrials.gov NCT04275765 . Registered on 19 February 2020. [ABSTRACT FROM AUTHOR]

Background: Perceived high chronic stress is twice as prevalent among German general practitioners (GPs) and non-physician medical staff compared to the general population. The reasons are multi-factorial and include patient, practice, healthcare system and societal factors, such as multi-morbidity, the diversity of populations and innovations in medical care. Also, practice-related factors, like stressful patient-staff interactions, poor process management of waiting times and lack of leadership, play a role. This publicly funded study evaluates the effectiveness of the newly developed participatory, interdisciplinary, and multimodal IMPROVEjob intervention on improving job satisfaction among general practice personnel. The intervention aims at structural stress prevention with regard to working conditions and behavioural stress prevention for leaders and other practice personnel.Methods: In this cluster-randomised controlled trial, a total of 56 general practices will be assigned to either (1) participation in the IMPROVEjob intervention or (2) the waiting-list control group. The IMPROVEjob intervention consists of the following elements: three workshops, a toolbox with supplemental material and an implementation period with regular contact to so-called IMPROVEjob facilitators. The first workshop, addressing leadership issues, is designed for physicians with leadership responsibilities only. The two subsequent workshops target all GP and non-physician personnel; they address issues of communication (with patients and within the team), self-care and team-care and practice organisation. During the 9-month implementation period, practices will be contacted by IMPROVEjob facilitators to enhance motivation. Additionally, the practices will have access to the toolbox materials online. All participants will complete questionnaires at baseline and follow up. The primary outcome is the change in job satisfaction as measured by the respective scale of the validated German version of the Copenhagen Psychosocial Questionnaire (COPSOQ, version 2018). Secondary outcomes obtained by questionnaires and - qualitatively - by facilitators comprise psychosocial working conditions including leadership aspects, expectations and experiences of the workshops, team and individual efforts and organisational changes.Discussion: It is hypothesised that participation in the IMPROVEjob intervention will improve job satisfaction and thus constitute a structural and behavioural prevention strategy for the promotion of psychological wellbeing of personnel in general practices and prospectively in other small and medium sized enterprises.Trial Registration: German Clinical Trials Register: DRKS00012677. Registered on 16 October 2019. Retrospectively, https://www.drks.de/drks_web/navigate.do?navigationId=trial. HTML&TRIAL_ID = DRKS00012677. [ABSTRACT FROM AUTHOR]

Background: A wound that does not heal in the orderly stages of the healing process or does not heal within 3 months is considered a chronic wound. Wound healing is impaired when the wound remains in the inflammatory stage for too long. A range of factors can delay the healing process: imbalance between proteases and protease inhibitors in the wound bed; bacterial colonization and the presence of biofilm; and oxidative stress. Recently, wound management has improved significantly. A new antioxidant dressing has been developed, which combines an absorbent matrix obtained from locust bean gum galactomannan and a hydration solution with curcumin and N-acetylcysteine. This dressing combines the advantages of moist healing in exudate management and free radical neutralization, achieving wound reactivation. The primary aim of this study is to compare the effect of the antioxidant dressing on chronic wound healing against the use of a standard wound dressing in patients with hard-to-heal wounds.Methods: We will conduct a multicentre, single-blind, randomized controlled trial with parallel groups. Participants will be selected from three primary public health care centres located in Andalucía (southern Spain). Patients will be randomized into an intervention group (antioxidant dressing) or a control group (standard wound dressing). Assessments will be carried out at weeks 2, 4, 6 and 8. Follow-up will be for a period of 8 weeks or until complete healing if this occurs earlier.Discussion: The findings from this study should provide scientific evidence on the efficacy of the antioxidant dressing as an alternative for the treatment of chronic wounds. This study fills some of the gaps in the existing knowledge about patients with hard-to-heal wounds.Trial Registration: ClinicalTrials.gov: NCT03934671. Registered on 2 May 2019. [ABSTRACT FROM AUTHOR]

Background: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood-brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia.Methods/design: In total, 90 subjects aged 18-70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted.Discussion: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo.Trial Registration: ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014-000520-14 and 2017-000163-32. [ABSTRACT FROM AUTHOR]

Background: Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan.Methods: APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial.Discussion: This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP.Trial Registration: ISCRTN, ISCRTN13127147. Registered on 1 August 2016. EudraCT Number 2015-003600-23. Registered on 1 April 2016. [ABSTRACT FROM AUTHOR]

Background: Biomass fuel smoke is a leading risk factor for the burden of disease worldwide. International campaigns are promoting the widespread adoption of liquefied petroleum gas (LPG) in resource-limited settings. However, it is unclear if the introduction and use of LPG stoves, in settings where biomass fuels are used daily, reduces pollution concentration exposure, improves health outcomes, or how cultural and social barriers influence the exclusive adoption of LPG stoves.Methods: We will conduct a randomized controlled, field intervention trial of LPG stoves and fuel distribution in rural Puno, Peru, in which we will enroll 180 female participants aged 25-64 years and follow them for 2 years. After enrollment, we will collect information on sociodemographic characteristics, household characteristics, and cooking practices. During the first year of the study, LPG stoves and fuel tanks will be delivered to the homes of 90 intervention participants. During the second year, participants in the intervention arm will keep their LPG stoves, but the gas supply will stop. Control participants will receive LPG stoves and vouchers to obtain free fuel from distributors at the beginning of the second year, but gas will not be delivered. Starting at baseline, we will collect longitudinal measurements of respiratory symptoms, pulmonary function, blood pressure, endothelial function, carotid artery intima-media thickness, 24-h dietary recalls, exhaled carbon monoxide, quality-of-life indicators, and stove-use behaviors. Environmental exposure assessments will occur six times over the 2-year follow-up period, consisting of 48-h personal exposure and kitchen concentration measurements of fine particulate matter and carbon monoxide, and 48-h kitchen concentrations of nitrogen dioxide for a subset of 100 participants.Discussion: Findings from this study will allow us to better understand behavioral patterns, environmental exposures, and cardiovascular and pulmonary outcomes resulting from the adoption of LPG stoves. If this trial indicates that LPG stoves are a feasible and effective way to reduce household air pollution and improve health, it will provide important information to support widespread adoption of LPG fuel as a strategy to reduce the global burden of disease.Trial Registration: ClinicalTrials.gov, ID: NCT02994680 , Cardiopulmonary Outcomes and Household Air Pollution (CHAP) Trial. Registered on 28 November 2016. [ABSTRACT FROM AUTHOR]

Background: Analyses of multicenter studies often need to account for center clustering to ensure valid inference. For binary outcomes, it is particularly challenging to properly adjust for center when the number of centers or total sample size is small, or when there are few events per center. Our objective was to evaluate the performance of generalized estimating equation (GEE) log-binomial and Poisson models, generalized linear mixed models (GLMMs) assuming binomial and Poisson distributions, and a Bayesian binomial GLMM to account for center effect in these scenarios.Methods: We conducted a simulation study with few centers (≤30) and 50 or fewer subjects per center, using both a randomized controlled trial and an observational study design to estimate relative risk. We compared the GEE and GLMM models with a log-binomial model without adjustment for clustering in terms of bias, root mean square error (RMSE), and coverage. For the Bayesian GLMM, we used informative neutral priors that are skeptical of large treatment effects that are almost never observed in studies of medical interventions.Results: All frequentist methods exhibited little bias, and the RMSE was very similar across the models. The binomial GLMM had poor convergence rates, ranging from 27% to 85%, but performed well otherwise. The results show that both GEE models need to use small sample corrections for robust SEs to achieve proper coverage of 95% CIs. The Bayesian GLMM had similar convergence rates but resulted in slightly more biased estimates for the smallest sample sizes. However, it had the smallest RMSE and good coverage across all scenarios. These results were very similar for both study designs.Conclusions: For the analyses of multicenter studies with a binary outcome and few centers, we recommend adjustment for center with either a GEE log-binomial or Poisson model with appropriate small sample corrections or a Bayesian binomial GLMM with informative priors. [ABSTRACT FROM AUTHOR]

Background: Arterial carbon dioxide tension (PaCO2), oxygen tension (PaO2), and mean arterial pressure (MAP) are modifiable factors that affect cerebral blood flow (CBF), cerebral oxygen delivery, and potentially the course of brain injury after cardiac arrest. No evidence regarding optimal treatment targets exists.Methods: The Carbon dioxide, Oxygen, and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial is a pilot multi-center randomized controlled trial (RCT) assessing the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP in comatose, mechanically ventilated patients after out-of-hospital cardiac arrest (OHCA), as well as its effect on brain injury markers. Using a 23 factorial design, participants are randomized upon admission to an intensive care unit into one of eight groups with various combinations of PaCO2, PaO2, and MAP target levels for 36 h after admission. The primary outcome is neuron-specific enolase (NSE) serum concentration at 48 h after cardiac arrest. The main feasibility outcome is the between-group differences in PaCO2, PaO2, and MAP during the 36 h after ICU admission. Secondary outcomes include serum concentrations of NSE, S100 protein, and cardiac troponin at 24, 48, and 72 h after cardiac arrest; cerebral oxygenation, measured with near-infrared spectroscopy (NIRS); potential differences in epileptic activity, monitored via continuous electroencephalogram (EEG); and neurological outcomes at six months after cardiac arrest.Discussion: The trial began in March 2016 and participant recruitment has begun in all seven study sites as of March 2017. Currently, 115 of the total of 120 patients have been included. When completed, the results of this trial will provide preliminary clinical evidence regarding the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP values and its effect on developing brain injury, brain oxygenation, and epileptic seizures after cardiac arrest. The results of this trial will be used to evaluate whether a larger RCT on this subject is justified.Trial Registration: ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016. [ABSTRACT FROM AUTHOR]

Background: Meta-analyses of randomized controlled trials (RCTs) have shown that exercise has beneficial effects on quality of life (QoL) in patients with breast cancer. However, these effects were often small. Blinding in an exercise trial is not possible, which has the possible disadvantage of difficult accrual, drop-out after randomization to control and contamination between study groups (controls adopting the behaviour of the intervention group). The cohort multiple randomized controlled trial (cmRCT) is an alternative for conventional RCTs and has the potential to overcome these disadvantages.Methods: This cmRCT will be performed within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA). Patients with breast cancer who visit the radiotherapy department of the University Medical Center Utrecht are asked to participate in UMBRELLA. Patients give consent for collection of medical information, providing patient-reported outcomes through regular questionnaires and randomization into future intervention studies. Patients who fulfill the UMBRELLA Fit study eligibility criteria (12 to 18 months post inclusion in UMBRELLA, low physical activity level) will be randomly allocated to the intervention or control group (1:1 ratio). Patients randomized to the intervention group will be offered a 12-week exercise programme. The control group will not be informed. Regular cohort measurements will be used for outcome assessment. Feasiblity (including participation, contamination, generalizability and retention) of the cmRCT design and effects of the intervention on QoL will be evaluated.Discussion: We will examine the feasibility of the cmRCT design in exercise-oncology research and compare this with conventional RCTs. Furthermore, the effectiveness of an exercise intervention on the QoL of patients with breast cancer in the short term (6 months) and long term (24 months) will be studied.Trial Registration: Netherlands Trial Register, NTR5482/NL.52062.041.15 . Retrospectively registered on 7 December 2015. [ABSTRACT FROM AUTHOR]

Background: Intellectual disability (ID) is characterized by limitations in intellectual functioning and adaptive behavior. Adults with ID exhibit higher rates of obesity and poorer health status compared to the general population. Continuity of care and barriers to health-related activities may contribute to the poorer health status observed in this population. To address this problem, a tailored weight management online health information and communication technology platform, known as POWERSforID, was developed and is being tested to determine if this delivery mechanism can improve weight maintenance/weight loss in adults with ID.Methods: Obese adults with mild-to-moderate ID (n = 70) are randomized to the POWERS forID intervention or control group for a 24-week trial. Each group undergoes an assessment that includes body weight, waist circumference, and percent body fat at baseline and at weeks 6, 12, and 24. Physical activity barriers, healthy eating barriers, food frequency, and psychosocial wellbeing are measured at baseline and at weeks 12 and 24. Blood lipids are assessed at baseline and 24 weeks. Participants randomized to POWERS forID receive access to the POWERS forID website and calls from a health coach (weekly during weeks 1-12, biweekly during weeks 13-24). The health coach employs motivational interviewing techniques adapted for individuals with ID to promote behavior change. Participants randomized to the control group receive standard clinical weight-loss care. Differences in weight, waist circumference, blood lipids, percent body fat, and psychosocial self-report will be assessed. Barriers and facilitators of implementation as well as perception of study outcomes will be conducted via qualitative analysis.Discussion: POWERS forID is a novel information and communication technology platform designed to address health needs for adults with ID. This article describes the development and components of POWERS forID. The overall aim is to assess usability and feasibility of POWERS forID for promoting weight loss for obese adults with ID over the course of a 24-week randomized control trial.Trial Registration: Clinicaltrials.gov, NCT03139760 . Registered on XXX. [ABSTRACT FROM AUTHOR]

Background: Loneliness is associated with poor health outcomes at all ages, including shorter life expectancy and greater risk of developing depression. People with mental health problems are particularly vulnerable to loneliness and, for those with anxiety or depression, loneliness is associated with poorer outcomes. Interventions which support people to utilise existing networks and access new social contact are advocated in policy but there is little evidence regarding their effectiveness. People with mental health problems have potential to benefit from interventions to reduce loneliness, but evidence is needed regarding their feasibility, acceptability and outcomes. An intervention to reduce loneliness for people with anxiety or depression treated in secondary mental health services was developed for this study, which will test the feasibility and acceptability of delivering and evaluating it through a randomised controlled trial.Methods: In this feasibility trial, 40 participants with anxiety or depression will be recruited through two secondary mental health services in London and randomised to an intervention (n = 30) or control group (n = 10). The control group will receive standard care and written information about local community resources. The coproduced intervention, developed in this study, includes up to ten sessions with a 'Community Navigator' over a 6-month period. Community Navigators will work with people individually to increase involvement in social activities, with the aim of reducing feelings of loneliness. Data will be collected at baseline and at 6-month follow-up - the end of the intervention period. The acceptability of the intervention and feasibility of participant recruitment and retention will be assessed. Potential primary and secondary outcomes for a future definitive trial will be completed to assess response and completeness, including measures of loneliness, depression and anxiety. Qualitative interviews with participants, staff and other stakeholders will explore experiences of Community Navigator support, the mechanisms by which it may have its effects and suggestions for improving the programme.Discussion: Our trial will provide preliminary evidence of the feasibility and acceptability of Community Navigator support and of trial procedures for testing this. The results will inform a future definitive randomised controlled trial of this intervention.Trial Registration: ISRCTN10771821 . Registered on 3 April 2017. [ABSTRACT FROM AUTHOR]

Background: Interventional radiology includes a range of minimally invasive image-guided diagnostic and therapeutic procedures that have become routine clinical practice. Each procedure involves a percutaneous needle insertion, often guided using computed tomography (CT) because of its availability and usability. However, procedures remain complicated, in particular when an obstacle must be avoided, meaning that an oblique trajectory is required. Navigation systems track the operator's instruments, meaning the position and progression of the instruments are visualised in real time on the patient's images. A novel electromagnetic navigation system for CT-guided interventional procedures (IMACTIS-CT®) has been developed, and a previous clinical trial demonstrated improved needle placement accuracy in navigation-assisted procedures. In the present trial, we are evaluating the clinical benefit of the navigation system during the needle insertion step of CT-guided procedures in the thoraco-abdominal region.Methods/design: This study is designed as an open, multicentre, prospective, randomised, controlled interventional clinical trial and is structured as a standard two-arm, parallel-design, individually randomised trial. A maximum of 500 patients will be enrolled. In the experimental arm (navigation system), the procedures are carried out using navigation assistance, and in the active comparator arm (CT), the procedures are carried out with conventional CT guidance. The randomisation is stratified by centre and by the expected difficulty of the procedure. The primary outcome of the trial is a combined criterion to assess the safety (number of serious adverse events), efficacy (number of targets reached) and performance (number of control scans acquired) of navigation-assisted, CT-guided procedures as evaluated by a blinded radiologist and confirmed by an expert committee in case of discordance. The secondary outcomes are (1) the duration of the procedure, (2) the satisfaction of the operator and (3) the irradiation dose delivered, with (4) subgroup analysis according to the expected difficulty of the procedure, as well as an evaluation of (5) the usability of the device.Discussion: This trial addresses the lack of published high-level evidence studies in which navigation-assisted CT-guided interventional procedures are evaluated. This trial is important because it addresses the problems associated with conventional CT guidance and is particularly relevant because the number of interventional radiology procedures carried out in routine clinical practice is increasing.Trial Registration: ClinicalTrials.gov identifier: NCT01896219 . Registered on 5 July 2013. [ABSTRACT FROM AUTHOR]

Background: Postpartum haemorrhage complicates approximately 10% of all deliveries and contributes to at least a quarter of all maternal deaths worldwide. The competency-based Helping Mothers Survive Bleeding after Birth (HMS BAB) training was developed to support evidence-based management of postpartum haemorrhage. This one-day training includes low-cost MamaNatalie® birthing simulators and addresses both prevention and first-line treatment of haemorrhage. While evidence is accumulating that the training improves health provider's knowledge, skills and confidence, evidence is missing as to whether this translates into improved practices and reduced maternal morbidity and mortality. This cluster-randomised trial aims to assess whether this training package - involving a one-day competency-based HMS BAB in-facility training provided by certified trainers followed by 8 weeks of in-service peer-based practice - has an effect on the occurrence of haemorrhage-related morbidity and mortality.Methods/design: In Tanzania and Uganda we randomise 20 and 18 districts (clusters) respectively, with half receiving the training intervention. We use unblinded matched-pair randomisation to balance district health system characteristics and the main outcome, which is in-facility severe morbidity due to haemorrhage defined by the World Health Organizationation-promoted disease and management-based near-miss criteria. Data are collected continuously in the intervention and comparison districts throughout the 6-month baseline and the 9-month intervention phase, which commences after the training intervention. Trained facility midwives or clinicians review severe maternal complications to identify near misses on a daily basis. They abstract the case information from case notes and enter it onto programmed tablets where it is uploaded. Intention-to-treat analysis will be used, taking the matched design into consideration using paired t test statistics to compare the outcomes between the intervention and comparison districts. We also assess the impact pathway from the effects of the training on the health provider's skills, care and interventions and health system readiness.Discussion: This trial aims to generate evidence on the effect and limitations of this well-designed training package supported by birthing simulations. While the lack of blinding of participants and data collectors provides an inevitable limitation of this trial, the additional evaluation along the pathway of implementation will provide solid evidence on the effects of this HMS BAB training package.Trial Registration: Pan African Clinical Trials Registry, PACTR201604001582128 . Registered on 12 April 2016. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality worldwide. It is often undiagnosed and insufficiently managed. Effective forms of continuing medical education (CME) for primary care physicians (PCPs) are necessary to ensure the implementation of guidelines in clinical practice and, thus, improve patients' health.Methods: In this study, we will measure the effects of CME by Case Method and compare them against those of traditional lectures and no CME at all through an unblinded, cluster randomised controlled trial (CRCT). Thirty-three primary health care centres (PHCCs) in Stockholm, Sweden, with a total of 180 PCPs will be involved. Twenty-two primary PHCCs, will be cluster-randomised into: an intervention group who will receive CME by Case Method (n = 11) and a control group who will receive traditional lectures (n = 11). The remaining PHCCs (n = 11) will be a reference group and will receive no CME. From the intervention and control groups, 460 randomly selected patients with COPD in GOLD stages 2 and 3 will participate, while no patients will be recruited from the reference group. For the patients, smoking status, actual treatment and urgent visits to a health provider due to airway problems will be registered. For the PCPs, professional competence (i.e. knowledge and management skills) in COPD, will be measured using a questionnaire based on current guidelines and guideline implementation problems in clinical practice which has previously been described by the authors. Data will be collected at baseline and at follow-up, which will be after 1.5 years for the patients, and 1 year for the PCPs. Statistical methods for individual-level and cluster-level analyses will be used.Discussion: COPD is considered a particularly complex clinical challenge involving managing multimorbidity, symptom adaptation, and lifestyle problematisation. Case Method in CME for PCPs may contribute to a better understanding of the impact of COPD on patients' lives and, thus, improve their management of it. The present study is expected to contribute scientific knowledge about indicators for an effective CME in COPD that is tailor-made to primary care physicians.Trial Registration: ClinicalTrials.gov, identifier: NCT02213809 . Registered on 10 August 2014. Protocol version: Issue date: May 2014. [ABSTRACT FROM AUTHOR]

Background: Mindfulness-based approaches for adults are effective at enhancing mental health, but few controlled trials have evaluated their effectiveness or cost-effectiveness for young people. The primary aim of this trial is to evaluate the effectiveness and cost-effectiveness of a mindfulness training (MT) programme to enhance mental health, wellbeing and social-emotional behavioural functioning in adolescence.Methods/design: To address this aim, the design will be a superiority, cluster randomised controlled, parallel-group trial in which schools offering social and emotional provision in line with good practice (Formby et al., Personal, Social, Health and Economic (PSHE) Education: A mapping study of the prevalent models of delivery and their effectiveness, 2010; OFSTED, Not Yet Good Enough: Personal, Social, Health and Economic Education in schools, 2013) will be randomised to either continue this provision (control) or include MT in this provision (intervention). The study will recruit and randomise 76 schools (clusters) and 5700 school students aged 12 to 14 years, followed up for 2 years.Discussion: The study will contribute to establishing if MT is an effective and cost-effective approach to promoting mental health in adolescence.Trials Registration: International Standard Randomised Controlled Trials, identifier: ISRCTN86619085 . Registered on 3 June 2016. [ABSTRACT FROM AUTHOR]

Background: The impact of humanitarian disasters upon mental health is well recognised. The evidence for psychological interventions for mental health is mounting, but few interventions have been rigorously tested in humanitarian settings. To be sustainable in humanitarian settings interventions need to be short, simple, deliverable by nonspecialists under supervision, and adopt a transdiagnostic approach where an array of mental health outcomes are addressed simultaneously. These elements have been incorporated into the newly developed WHO Problem Management Plus (PM+) Group intervention. The aim of this trial is to evaluate the locally adapted PM+ Group intervention for women in Swat, Pakistan.Methods: This PM+ Group trial is a two-arm, single-blind, cluster randomised controlled trial conducted in a community-based setting with women in rural Pakistan. PM+ is delivered in partnership with the Lady Health Worker (LHW) Programme which provides community-based health care to women in Pakistan. Thirty-four LHW clusters will be randomised in a 1:1 allocation ratio using a permuted-block randomisation method. Participants screened and found to meet the inclusion criteria will be allocated to either the PM+ intervention group (n = 306), or the control arm (n = 306). The manualised PM+ intervention involves five sessions, each lasting 3 h, and introduces four strategies applied by participants to problems that they are facing. It is delivered by local female facilitators with a minimum of 16 years of education who are provided with targeted training and supervision. The primary outcome is individual psychological distress, measured by levels of anxiety and depression on the Hospital Anxiety and Depression Scale at 20 weeks after baseline. Secondary outcomes include major depression, post-traumatic stress disorder, levels of social support, levels of functioning, and economic effectiveness. Intervention acceptability will be explored through an embedded qualitative study.Discussion: The PM+ Group trial will provide important evidence on the effectiveness of an empirically supported psychological treatment delivered by nonspecialists in a humanitarian setting. If proven effective, the qualitative component will inform strategies for PM+ Group scale-up in health systems in other humanitarian settings.Trial Registration: Australian New Zealand Clinical Trials Registry, identifier: ACTRN12616000037404. Registered on 19 January 2016; WHO Protocol ID RPC705, v.4, 2 November 2015. [ABSTRACT FROM AUTHOR]

Background: Intravenous administration of fluids is an essential part of critical care. While some fluid administration is likely beneficial, there is increasing observational evidence that the development of fluid overload is associated with increased mortality. There are no randomised trials to confirm this association in patients with acute kidney injury. We aim to perform a pilot trial to test the feasibility of forced fluid removal compared to standard care in patients with acute kidney injury and severe fluid overload, the FFAKI trial.Methods: Then FFAKI trial is a pilot, multicentre, randomised clinical trial recruiting adult intensive care patients with acute kidney injury and fluid overload, defined as more than 10% of ideal bodyweight. Patients are randomised with concealed allocation to either standard care or forced fluid removal with a therapeutic target of negative net fluid balance ≥1 mL/kg/h. The safety of fluid removal is continually evaluated according to predefined criteria of hypoperfusion: lactate ≥4 mmol/L, mean arterial pressure <50 mmHg or mottling beyond the edge of the kneecaps. If patients fulfil one of these criteria, fluid removal is suspended until hypoperfusion has resolved. The primary outcome measure is fluid balance at 5 days after randomisation and secondary outcomes include mean daily fluid balance, fluid balance at discharge from the intensive care unit, time to neutral fluid balance, number of serious adverse reactions and number of protocol violations. All patients are followed for 90 days.Discussion: The FFAKI trial started in October 2015 and, when completed, will provide data to evaluate whether a large trial of forced fluid removal in critically ill patients is feasible. Our primary outcome will show if the experimental intervention leads to a clinically relevant difference in fluid balance, which could prove beneficial in intensive care patients with acute kidney injury.Trial Registration: EudraCT, identifier: 2015-001701-13. Registered on 19 September 2015; ClinicalTrials.gov, identifier: NCT02458157 . Registered on 21 May 2015; Danish Ethics Committee, identifier: H-15009589H. Registered on 22 September 2015; Danish Health and Medicines Authority, identifier: 2015070013. Registered on 11 August 2015. [ABSTRACT FROM AUTHOR]

Background: Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal.Methods/design: We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6-11 months old (length for age less than -1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study.Discussion: If vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide.Trial Registrations: ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014. [ABSTRACT FROM AUTHOR]

Background: Lower back pain is a global health issue affecting approximately 80% of people at some stage in their life. The current literature suggests that any exercise is beneficial for reducing back pain. However, as pain is a subjective evaluation and physical deficits are evident in low back pain, using it as the sole outcome measure to evaluate superiority of an exercise protocol for low back pain treatment is insufficient. The overarching goal of the current clinical trial is to implement two common, conservative intervention approaches and examine their impact on deficits in chronic low back pain.Methods/design: Forty participants, 25-45 years old with chronic (>3 months), non-specific low back pain will be recruited. Participants will be randomised to receive either motor control and manual therapy (n = 20) or general strength and conditioning (n = 20) exercise treatments for 6 months. The motor control/manual therapy group will receive twelve 30-min sessions, ten in the first 3 months (one or two per week) and two in the last 3 months. The general exercise group will attend two 1-hour sessions weekly for 3 months, and one or two a week for the following 3 months. Primary outcome measures are average lumbar spine intervertebral disc T2 relaxation time and changes in thickness of the transversus abdominis muscle on a leg lift using magnetic resonance imaging (MRI). Secondary outcomes include muscle size and fat content, vertebral body fat content, intervertebral disc morphology and water diffusion measured by MRI, body composition using dual energy X-ray absorptiometry, physical function through functional tests, changes in corticospinal excitability and cortical motor representation of the spinal muscles using transcranial magnetic stimulation and self-reported measure of pain symptoms, health and disability. Outcome measures will be conducted at baseline, at the 3-month follow-up and at 6 months at the end of intervention. Pain, depressive symptomology and emotions will be captured fortnightly by questionnaires.Discussion: Chronic low back pain is ranked the highest disabling disorder in Australia. The findings of this study will inform clinical practice guidelines to assist with decision-making approaches where outcomes beyond pain are sought for adults with chronic low back pain.Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12615001270505 . Registered on 20 November 2015. [ABSTRACT FROM AUTHOR]

Background: IgA nephropathy (IgAN) is one of the most common primary glomerular diseases worldwide, but effective therapy remains limited and many patients progress to end-stage renal disease (ESRD). Only angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin-receptor blockers (ARB) show a high level of evidence (1B level) of being of value in the treatment for IgAN according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. However, traditional Chinese medicine has raised attention in kidney disease research. Abelmoschus manihot, a single medicament of traditional Chinese medicine has shown therapeutic effects in primary glomerular disease according to the randomized controlled clinical trial that we have completed. Here, we conduct a new study to assess the efficacy and safety of Abelmoschus manihot in IgAN. Also, this study is currently the largest double-blind, randomized controlled registered clinical research for the treatment of IgAN.Methods: We will conduct a multicenter, prospective, double-blind, double-dummy randomized controlled study. The study is designed as a noninferiority clinical trial. Approximately 1600 biopsy-proven IgAN patients will be enrolled at 100 centers in China and followed up for as long as 48 weeks. IgAN patients will be randomized assigned to the Abelmoschus manihot group (in the form of a huangkui capsule, 2.5 g, three times per day) and the losartan potassium group (losartan potassium, 100 mg/d). The primary outcome is the change in 24-h proteinuria from baseline after 48 weeks of treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after 48 weeks of treatment, the incidence of endpoint events (proteinuria ≥3.5 g/24 h, the doubling of serum creatinine, or receiving blood purification treatment) are the secondary outcomes. Twenty-four-hour proteinuria and eGFR are measured at 0, 4, 12, 24, 36 and 48 weeks.Discussion: This study will be of sufficient size and scope to evaluate the efficacy and safety of Abelmoschus manihot compared to losartan potassium in treating patients with IgAN. The results of this study may provide a new, effective and safe treatment strategy for IgAN.Trial Registration: ClinicalTrials.gov, identifier: NCT02231125 . Registered on 30 August 2014. [ABSTRACT FROM AUTHOR]

Background: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. No 'gold standard' exists after total hip arthroplasty (THA) and combinations of different nonopioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen alone and in combination in different dosages after THA.Methods: PANSAID is a placebo-controlled, parallel four-group, multicentre trial with centralised computer-generated allocation sequence and allocation concealment and with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients and statisticians. Patients are randomised to four groups: (A) paracetamol 1 g × 4 and ibuprofen 400 mg × 4, (B) paracetamol 1 g × 4 and placebo, (C) placebo and ibuprofen 400 mg × 4 and (D) paracetamol 0.5 g × 4 and ibuprofen 200 mg. The two co-primary outcomes are 24-h consumption of morphine and number of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and number of patients with one or more adverse events within 24 h postoperatively. Inclusion criteria are patients scheduled for unilateral, primary THA; age above 18 years; ASA status 1-3; BMI >18 and <40 kg/m2; women must not be pregnant; and provision of informed consent. Exclusion criteria are patients who cannot cooperate with the trial; participation in another trial; patients who cannot understand/speak Danish; daily use of strong opioids; allergy against trial medication; contraindications against ibuprofen; alcohol and/or drug abuse. A total of 556 eligible patients are needed to detect a difference of 10 mg morphine i.v. the first 24 h postoperatively with a standard deviation of 20 mg and a family wise type 1 error rate of 0.025 (two-sided) and a type 2 error rate of 0.10 for the six possible comparisons of the four intervention groups.Discussion: We started recruiting patients in December 2015 and expect to finish in September 2017. Data analysis will be from September 2017 to October 2017 and manuscript submission ultimo 2017.Trial Registration: EudraCT: 2015-002239-16 (12/8-15); ClinicalTrials.gov: NCT02571361 . Registered on 7 October 2015. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in the medical and surgical fields, complications such as infection, pneumonia, or brain swelling may occur after a craniotomy. In some patients, perioperative antibiotic prophylaxis causes adverse effects such as itching, rash, or digestive conditions. Certain patients still develop infections severe enough to require a repeat operation despite antibiotic prophylaxis. Acupuncture has been used to treat inflammatory conditions, and many basic and clinical studies have provided evidence of its anti-inflammatory and immune regulatory effects. The aim of this study is to explore the effects of acupuncture on inflammation and immune function after craniotomy.Methods: This trial will be a single-center, parallel-group clinical trial. Forty patients who underwent craniotomy for an unruptured aneurysm, facial spasm, or a brain tumor will be allocated to either the study or the control group. The study group will receive conventional management as well as acupuncture, electroacupuncture, and intradermal acupuncture, which will start within 48 h of the craniotomy. The patients will receive a total of six sessions within 8 days. The control group will only receive conventional management. The primary outcome measure will be the C-reactive protein levels, while the secondary outcomes will be the serum erythrocyte sedimentation rate and the tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels measured at four different time points: within 48 h prior to the craniotomy and on days 2, 4, and 7 after surgery. The presence of fever and infection, the use of additional antibiotics, the presence of infection, including pneumonia or urinary tract infection, and safety will also be investigated.Discussion: In this trial, we will observe whether acupuncture has anti-inflammatory and immune regulatory effects after a craniotomy. If our study yields positive results and a placebo-controlled study also finds favorable results following our study, acupuncture could be recommended as an adjunctive therapy after a craniotomy.Trial Registration: ClinicalTrials.gov: NCT02761096 . Registered on 27 April 2016. [ABSTRACT FROM AUTHOR]

Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol 'as needed' in response to symptoms may represent an alternative treatment option for patients with mild asthma.Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors.Discussion: Given the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017.Trial Registration: ClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively. [ABSTRACT FROM AUTHOR]

Background: The interpretation of trial results can be helped by understanding how generalisable they are to the target population for which inferences are intended. INTERVAL, a large pragmatic randomised trial of blood donors in England, is assessing the effectiveness and safety of reducing inter-donation intervals. The trial recruited mainly from the blood service's static centres, which collect only about 10 % of whole-blood donations. Hence, the extent to which the trial's participants are representative of the general blood donor population is uncertain. We compare these groups in detail.Methods: We present the CONSORT flowchart from participant invitation to randomisation in INTERVAL. We compare the characteristics of those eligible and consenting to participate in INTERVAL with the general donor population, using the national blood supply 'PULSE' database for the period of recruitment. We compare the characteristics of specific groups of trial participants recruited from different sources, as well as those who were randomised versus those not randomised.Results: From a total of 540,459 invitations, 48,725 donors were eligible and consented to participate in INTERVAL. The proportion of such donors varied from 1-22 % depending on the source of recruitment. The characteristics of those consenting were similar to those of the general population of 1.3 million donors in terms of ethnicity, blood group distribution and recent deferral rates from blood donation due to low haemoglobin. However, INTERVAL participants included more men (50 % versus 44 %), were slightly older (mean age 43.1 versus 42.3 years), included fewer new donors (3 % versus 22 %) and had given more donations over the previous 2 years (mean 3.3 versus 2.2) than the general donor population. Of the consenting participants, 45,263 (93 %) donors were randomised. Compared to those not randomised, the randomised donors showed qualitatively similar differences to those described above.Conclusions: There was broad similarity of participants in INTERVAL with the general blood donor population of England, notwithstanding some differences in age, sex and donation history. Any heterogeneity of the trial's results according to these characteristics will need to be studied to ensure its generalisability to the general donor population.Trial Registration: Current Controlled Trials ISRCTN24760606 . Registered on 25 January 2012. [ABSTRACT FROM AUTHOR]