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Background: Attenuating the neurological damage occurring after out-of-hospital cardiac arrest is an ongoing research effort. This dual-centre study investigates the neuroprotective effects of the glucagon-like-peptide-1 analogue Exenatide administered within 4 hours from the return of spontaneous circulation to comatose patients resuscitated from out-of-hospital cardiac arrest.Methods/design: This pilot study will randomize a total of 120 unconscious patients with sustained return of spontaneous circulation after out-of-hospital cardiac arrest undergoing targeted temperature management in a blinded one-to-one fashion to a 6-hour and 15-minute infusion of either Exenatide or placebo. Patients are eligible for inclusion if resuscitated from cardiac arrest with randomization from 20 minutes to 240 minutes after return of spontaneous circulation. The co-primary endpoint is feasibility, defined as the initiation of treatment within the inclusion window in more than 90 % of participants, and efficacy, defined as the area under the neuron-specific enolase curve from 0 to 72 hours after admission. Secondary endpoints include all-cause mortality at 30 days and Cerebral Performance Category as well as a modified Rankin Score at 180 days. The study has been approved by the Danish National Board of Health and the local Ethics Committee and is monitored by Good Clinical Practice units. The study is currently enrolling.Discussion: This paper presents the methods and planned statistical analyses used in the GLP-1 trial and aims to minimize bias and data-driven reporting of results.Trial Registration: 1) Danish National Board of Health, EudraCT 2013-004311-45. Registered on 25 March 2014. 2) Videnskabsetisk komité C, Region Hovedstaden, No. 45728. Registered on 29 January 2014. 3) Clinicaltrial.gov, NCT02442791 . Registered on 25 of January 2015. [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: International recommendations suggest exercise and self-management programs, including non-pharmacological treatments, for knee osteoarthritis (KOA) because they can benefit pain relief and improve function and exercise adherence. The implementation of a combined self-management and exercise program termed PLE(2)NO may be a good method for controlling KOA symptoms because it encourages the development of self-efficacy to manage the pathology. This study will assess the effects of a self-management and exercise program in comparison to an educational intervention (control program) on symptoms, physical fitness, health-related quality of life, self-management behaviors, self-efficacy, physical activity level and coping strategies.Methods/design: This PLE(2)NO study is a single-blinded, randomized controlled trial of elderly (aged above 60 yrs old) patients with clinical and radiographic KOA. The patients will be allocated into either an educational group (control) or a self-management and exercise group (experimental). All participants will receive a supplement of chondroitin and glucosamine sulfates. This paper describes the protocol that will be used in the PLE(2)NO program.Discussion: This program has several strengths. First, it involves a combination of self-management and exercise approaches, is available in close proximity to the patients and occurs over a short period of time. The latter two characteristics are crucial for maintaining participant adherence. Exercise components will be implemented using low-cost resources that permit their widespread application. Moreover, the program will provide guidance regarding the effectiveness of using a self-management and exercise program to control KOA symptoms and improve self-efficacy and health-related quality of life.Trial Registration: NCT02562833 (09/23/2015). [ABSTRACT FROM AUTHOR]

Background: Cervicogenic headache is a prevalent and costly pain condition commonly treated by chiropractors. There is evidence to support the effectiveness for spinal manipulation, but the dose of treatment required to achieve maximal relief remains unknown. The purpose of this paper is to describe the methodology for a randomized controlled trial evaluating the dose--response of spinal manipulation for chronic cervicogenic headache in an adult population. Methods/Design: This is a mixed-methods, two-site, prospective, parallel groups, observer-blind, randomized controlled trial conducted at university-affiliated research clinics in the Portland, OR and Minneapolis, MN areas. The primary outcome is patient reported headache frequency. Other outcomes include self-reported headache intensity, disability, quality of life, improvement, neck pain intensity and frequency, satisfaction, medication use, outside care, cervical motion, pain pressure thresholds, health care utilization, health care costs, and lost productivity. Qualitative interviews are also conducted to evaluate patients' expectations of treatment. Discussion: With growing concerns regarding the costs and side effects of commonly used conventional treatments, greater numbers of headache sufferers are seeking other approaches to care. This is the first full-scale randomized controlled trial assessing the dose--response of spinal manipulation therapy on outcomes for cervicogenic headache. The results of this study will provide important evidence for the management of cervicogenic headache in adults. Trial registration: ClinicalTrials.gov (Identifier: NCT01530321) [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: The quality of the home learning environment has a significant influence on children's language and communication skills during the early years with children from disadvantaged families disproportionately affected. This paper describes the protocol and participant baseline characteristics of a community-based effectiveness study. It evaluates the effects of 'smalltalk', a brief group parenting intervention (with or without home coaching) on the quality of the early childhood home learning environment.Methods/design: The study comprises two cluster randomised controlled superiority trials (one for infants and one for toddlers) designed and conducted in parallel. In 20 local government areas (LGAs) in Victoria, Australia, six locations (clusters) were randomised to one of three conditions: standard care (control); smalltalk group-only program; or smalltalk plus (group program plus home coaching). Programs were delivered to parents experiencing socioeconomic disadvantage through two existing age-based services, the maternal and child health service (infant program, ages 6-12 months), and facilitated playgroups (toddler program, ages 12-36 months). Outcomes were assessed by parent report and direct observation at baseline (0 weeks), post-intervention (12 weeks) and follow-up (32 weeks). Primary outcomes were parent verbal responsivity and home activities with child at 32 weeks. Secondary outcomes included parenting confidence, parent wellbeing and children's communication, socio-emotional and general development skills. Analyses will use intention-to-treat random effects ("multilevel") models to account for clustering.Recruitment and Baseline Data: Across the 20 LGAs, 986 parents of infants and 1200 parents of toddlers enrolled and completed baseline measures. Eighty four percent of families demonstrated one or more of the targeted risk factors for poor child development (low income; receives government benefits; single, socially isolated or young parent; culturally or linguistically diverse background).Discussion: This study will provide unique data on the effectiveness of a brief group parenting intervention for enhancing the early home learning environment of young children from disadvantaged families. It will also provide evidence of the extent to which additional one-on-one support is required to achieve change and whether there are greater benefits when delivered in the 1st year of life or later. The program has been designed for scale-up across existing early childhood services if proven effective.Trial Registration: 8 September 2011; ACTRN12611000965909 . [ABSTRACT FROM AUTHOR]

Background: Upper limb orthoses are frequently prescribed for children with cerebral palsy (CP) who have muscle overactivity predominantly due to spasticity, with little evidence of long-term effectiveness. Clinical consensus is that orthoses help to preserve range of movement: nevertheless, they can be complex to construct, expensive, uncomfortable and require commitment from parents and children to wear. This protocol paper describes a randomised controlled trial to evaluate whether long-term use of rigid wrist/hand orthoses (WHO) in children with CP, combined with usual multidisciplinary care, can prevent or reduce musculoskeletal impairments, including muscle stiffness/tone and loss of movement range, compared to usual multidisciplinary care alone.Methods/design: This pragmatic, multicentre, assessor-blinded randomised controlled trial with economic analysis will recruit 194 children with CP, aged 5-15 years, who present with flexor muscle stiffness of the wrist and/or fingers/thumb (Modified Ashworth Scale score ≥1). Children, recruited from treatment centres in Victoria, New South Wales and Western Australia, will be randomised to groups (1:1 allocation) using concealed procedures. All children will receive care typically provided by their treating organisation. The treatment group will receive a custom-made serially adjustable rigid WHO, prescribed for 6 h nightly (or daily) to wear for 3 years. An application developed for mobile devices will monitor WHO wearing time and adverse events. The control group will not receive a WHO, and will cease wearing one if previously prescribed. Outcomes will be measured 6 monthly over a period of 3 years. The primary outcome is passive range of wrist extension, measured with fingers extended using a goniometer at 3 years. Secondary outcomes include muscle stiffness, spasticity, pain, grip strength and hand deformity. Activity, participation, quality of life, cost and cost-effectiveness will also be assessed.Discussion: This study will provide evidence to inform clinicians, services, funding agencies and parents/carers of children with CP whether the provision of a rigid WHO to reduce upper limb impairment, in combination with usual multidisciplinary care, is worth the effort and costs.Trial Registration: ANZ Clinical Trials Registry: U1111-1164-0572 . [ABSTRACT FROM AUTHOR]

Background: Process evaluation studies are recommended to improve our understanding of underlying mechanisms related to clinicians, patients, context and intervention delivery that may impact on trial or program results and on their potential transferability to practice. This paper aims to document the translation of a type-2 diabetes (T2D) prevention program into the routine context of several primary care centers, assessing process indicators related to clinician adoption, patient recruitment, exposure to the intervention components and baseline characteristics.Methods: An observational descriptive process evaluation study was conducted of the 2.5-year implementation of the Prevention of Diabetes in Euskadi cluster randomized trial in 14 primary care centers of the Basque Health Service (Osakidetza). The clinical intervention consisted of three components: (1) risk screening, (2) an educational intervention promoting healthy lifestyles, and (3) remote support (follow-up). A passive dissemination strategy of providing training and materials was used to translate the intervention into practice. All non-diabetic patients aged 45 to 70 years who were identified as being at high risk of developing T2D were eligible for study inclusion. The RE-AIM framework guided the process evaluation.Results: Overall, 31.4 % of family physicians and 57.6 % of nurses participated in the study, while 4170 out of 67,293 (6.2 %) targeted patients who attended the centers during the implementation period were reached through the screening. Around half of the screened patients were identified as being at high risk of developing T2D (FINDRISC score ≥14). The rate of refusal to participate and the proportion of women were higher in the intervention group. Finally, 634 and 454 non-diabetic 45- to 70-year-old patients who were at high risk of T2D were included in the control and intervention group centers (intervention reach = 48 %). Significant variability in most process indicators was observed at center level.Conclusion: The passive dissemination strategy has produced modest process indicators related to the adoption, reach and implementation of the intervention program, and reduced the possibility of its standardized application in heterogeneous contexts. The resulting different procedures and strategies used by the centers were associated with process outcomes. Context-specific variability and possible confounding will require rigorous procedures for analysis of the intervention effects.Trial Registration: The trial was registered in ClinicalTrials.gov (identifier: NCT01365013 ). Registered on June 2011. [ABSTRACT FROM AUTHOR]

Background: Many older adults with mobility limitations use assistive technology to help them perform daily activities. However, little attention has been paid to the impact on their family caregivers. This neglect produces an incomplete portrayal of the outcomes of assistive technology provision. This paper describes the protocol for a study that examines the impact of a tailored assistive technology intervention that is inclusive of assistance users and their family caregivers.Methods/design: This research will use a combination of quantitative and qualitative methods. The quantitative portion will be an experimental, single-blinded study in which participants are randomly assigned to either an experimental assistive technology intervention or a standard care group. We will enroll 240 participants (120 dyads) into the study from three Canadian sites. Participants will include older adults (>55) and family caregivers who provide ≥4 h per week of assistance with daily activities and social participation. The primary outcome measure for the older adults will be the Functional Autonomy Measurement System, and the primary outcome measure for the caregivers will be the Caregiver Assistive Technology Outcomes Measure. Qualitative data will be collected through detailed records of the therapists' interventions, as well as through interviews with dyads and therapists following the interventions. Data collection will occur at baseline (T0) with follow-ups at 6 weeks (T1), 22 weeks (T2), and 58 weeks (T3) after baseline evaluation.Discussion: The findings from this study will help service providers and clinicians to move forward with assistive technology recommendations that are more attuned to the needs of both older adults with mobility limitations and their family caregivers. Additionally, the study's findings will enhance our conceptual understanding of the spectrum of assistive technology outcomes and set the stage for econometric studies assessing cost-effectiveness.Trial Registration: ClinicalTrials.gov Identifier: NCT01640470 . Registered 11/21/2011. [ABSTRACT FROM AUTHOR]

Background: Approximately 20 % of children and adolescents who have sustained mild traumatic brain injuries may experience long-term consequences, including cognitive problems, post-traumatic stress symptoms and reduced load-bearing capacity. The underestimation and belated recognition of these long-term consequences may lead to chronic and disruptive problems, such as participation problems in school and in social relationships. The aim of this study is to examine the level of activities and participation of children and adolescents up to 6 months after a mild traumatic brain injury and to identify possible outcome predictors. Another aim is to investigate the effectiveness of an early psychoeducational intervention and compare the results with those obtained with usual care.Methods/design: This paper presents the Brains Ahead! study design, a randomised controlled trial nested within a multicentre, longitudinal, prospective cohort study. The eligible participants include children and adolescents between 6 and 18 years of age who have experienced a mild traumatic brain injury within the last 2 weeks. The cohort study will include 500 children and adolescents with a mild traumatic brain injury and their caregivers. A subset of 140 participants and their caregivers will be included in the randomised controlled trial. Participants in the randomised controlled trial will be randomly assigned to either the psychoeducational intervention group or the usual care control group. The psychoeducational intervention involves one face-to-face contact and one phone contact with the interventionist, during which the consequences of mild traumatic brain injury and advice for coping with these consequences to prevent long-term problems will be discussed. Information will be provided both verbally and in a booklet. The primary outcome domain is activities and participation, which will be evaluated using the Child and Adolescent Scale of Participation. Participants are evaluated 2 weeks, 3 months and 6 months after the mild traumatic brain injury.Discussion: The results of this study will provide insight into which children with mild traumatic brain injury are at risk for long-term participation problems and may benefit from a psychoeducational intervention.Trial Registration: Netherlands Trial Register identifier NTR5153 . Registered on 17 Apr 2015. [ABSTRACT FROM AUTHOR]

Background: A personal health record (PHR) is an online application through which individuals can access, manage, and share their health information in a private, secure, and confidential environment. Personal health records empower patients, facilitate collaboration among healthcare professionals, and improve health outcomes. Given these anticipated positive effects, we want to implement a PHR, named MyPregn@ncy, in a Dutch maternity care setting and to evaluate its effects in routine care. This paper presents the study protocol.Methods/design: The effects of implementing a PHR in maternity care on patients and professionals will be identified in a stepped-wedge, cluster-randomised, controlled trial. The study will be performed in the region of Nijmegen, a Dutch area with an average of 4,500 births a year and more than 230 healthcare professionals involved in maternity care. Data analyses will describe the effects of MyPregn@ncy on health outcomes in maternity care, quality of care from the patients' perspectives, and collaboration among healthcare professionals. Additionally, a process evaluation of the implementation of MyPregn@ncy will be performed. Data will be collected using data from the Dutch perinatal registry, questionnaires, interviews, and log data.Discussion: The study is expected to yield new information about the effects, strengths, possibilities, and challenges to the implementation and usage of a PHR in routine maternal care settings. Results may lead to new insights and improvements in the quality of maternal and perinatal care.Trial Registration: Netherlands Trial Register: NTR4063. [ABSTRACT FROM AUTHOR]

Background: Integration of physical activity (PA) into the classroom may be an effective way of promoting the learning and academic achievement of children at elementary school. This paper describes the research design and methodology of an intervention study examining the effect of classroom-based PA on mathematical achievement, creativity, executive function, body mass index and aerobic fitness.Methods: The study was designed as a school-based cluster-randomized controlled trial targeting schoolchildren in 1st grade, and was carried out between August 2012 and June 2013. Eligible schools in two municipalities in the Region of Southern Denmark were invited to participate in the study. After stratification by municipality, twelve schools were randomized to either an intervention group or a control group, comprising a total of 505 children with mean age 7.2 ± 0.3 years. The intervention was a 9-month classroom-based PA program that involved integration of PA into the math lessons delivered by the schools' math teachers. The primary study outcome was change in math achievement, measured by a 45-minute standardized math test. Secondary outcomes were change in executive function (using a modified Eriksen flanker task and the Behavior Rating Inventory of Executive Function (BRIEF) questionnaire filled out by the parents), creativity (using the Torrance Tests of Creative Thinking, TTCT), aerobic fitness (by the Andersen intermittent shuttle-run test) and body mass index. PA during math lessons and total PA (including time spent outside school) were assessed using accelerometry. Math teachers used Short Message Service (SMS)-tracking to report on compliance with the PA intervention and on their motivation for implementing PA in math lessons. Parents used SMS-tracking to register their children's PA behavior in leisure time.Discussion: The results of this randomized controlled trial are expected to provide schools and policy-makers with significant new insights into the potential of classroom-based PA to improve cognition and academic achievement in children.Trial Registration: Clinicaltrials.gov: NCT02488460 (06/29/2015). [ABSTRACT FROM AUTHOR]

Background: With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 μm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD.Methods/design: This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 μm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment.Discussion: This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol.Trial Registration: Trial Registration Number: NCT01972789. Date of registration: 24th October 2013. [ABSTRACT FROM AUTHOR]

Background: In 2009, we began recruiting dental practitioners across Germany to participate in a clinical trial to evaluate the clinical performance of EQUIA, a new glass ionomer restoration material. The aim of this paper is to discuss the outcomes of the dental practitioner recruitment and outline the process of establishing a practice-based research network.Methods: Study proposals were sent to randomly selected dental offices in 29 cities in Germany. The proposals were sent until a minimum of 10 clinics in each city declared participation. Later on, briefing lectures informed the participating practitioners about the design, methods, and material application procedure. Participants were familiarized with the guidelines of Good Manufacturing Practice (GMP) and Good Epidemiological Practice (GEP). A questionnaire describing the characteristics of each dental office was filled out by the participating practitioner. Additionally, participation levels were characterized according to the socioeconomic status and geographic districts of residence in Germany (Regions 0 to 9). The associations between the characteristics were tested by the Kruskal-Wallis Test and Chi-squared test (P < 0.05).Results: A total of 3194 private dental clinics were invited, 1712 clinics refused to participate, 1195 did not respond to the invitation, and 323 agreed to participate. Only 144 clinics participated in the lectures held in their cities and signed the participation agreement. Based on their geographic location, the highest participation was in Region 2 with a participation rate of 14.3%, and the lowest participation was in Region 6 with a participation rate of 1.7%. Regions with the lowest rate of unemployment and relatively higher rates of income (Regions 7 and 8) had the highest rate of refusals (86%).Conclusion: The initial results of the dental practitioner recruitment in this study suggest that the recruitment and pre-randomization design were successful, and by reaching out to a considerable number of private dental clinics to participate, we were able to recruit a smaller number of highly motivated dentists in this clinical study. Regional differences in socioeconomic status, practitioner specialization, and differences in patient health care insurance have to be considered when recruiting dental practitioners for clinical trials.Trial Registration: The trial has been registered at Deutsches Register Klinischer Studien (German register of clinical trials) on 6 September 2012 under DRKS-ID: DRKS00004220. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited.Methods: We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week(-1) via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention's effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFβ, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFβ, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes.Results: The accrual target was met after screening 101 cases (enrollment rate: 39.6%). Other outcomes included a retention rate of 85%, excellent adherence (95%), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were "too busy" (30%), medical exclusions (21%), and "distance" (16%).Conclusions: Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets.Trial Registration: NCT01886677. [ABSTRACT FROM AUTHOR]

Background: People with depression are usually managed in primary care and antidepressants are often the first-line treatment, but only one third of patients respond fully to a single antidepressant. This paper describes the protocol for a randomised controlled trial (MIR) to investigate the extent to which the addition of the antidepressant mirtazapine is effective in reducing the symptoms of depression compared with placebo in patients who are still depressed after they have been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 6 weeks in primary care.Methods/design: MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual. Eligible participants are those who: are aged 18 years or older; are currently taking an SSRI/SNRI antidepressant (for at least 6 weeks at an adequate dose); score ≥ 14 on the Beck Depression Inventory (BDI-II); have adhered to their medication; and meet ICD-10 criteria for depression (assessed using the Clinical Interview Schedule-Revised version). Participants who give written, informed consent, will be randomised to receive either oral mirtazapine or matched placebo, starting at 15 mg daily for 2 weeks and increasing to 30 mg daily thereafter, for up to 12 months (to be taken in addition to their usual antidepressant). Participants, their GPs, and the research team will all be blind to the allocation. The primary outcome will be depression symptoms at 12 weeks post randomisation, measured as a continuous variable using the BDI-II. Secondary outcomes (measured at 12, 24 and 52 weeks) include: response (reduction in depressive symptoms (BDI-II score) of at least 50% compared to baseline); remission of depression symptoms (BDI-II <10); change in anxiety symptoms; adverse effects; quality of life; adherence to antidepressant medication; health and social care use, time off work and cost-effectiveness. All outcomes will be analysed on an intention-to-treat basis. A qualitative study will explore patients' views and experiences of either taking two antidepressants, or an antidepressant and a placebo; and GPs' views on prescribing a second antidepressant in this patient group.Discussion: The MIR trial will provide evidence on the clinical and cost-effectiveness of mirtazapine as an adjunct to SSRI/SNRI antidepressants for patients in primary care who have not responded to monotherapy.Trial Registration: EudraCT Number: 2012-000090-23 (Registered January 2012); ISRCTN06653773 (Registered September 2012). [ABSTRACT FROM AUTHOR]

Background: Masticatory functioning alters with age. However, mastication has been found to be related to, for example, cognitive functioning, food intake, and some aspects of activities of daily living. Since cognitive functioning and activities of daily living show a decline in older adults with dementia, improving masticatory functioning may be of relevance to them. A possible way to improve mastication may be showing videos of people who are chewing. Observing chewing movements may activate the mirror neuron system, which becomes also activated during the execution of that same movement. The primary hypothesis is that the observation of chewing has a beneficial effect on masticatory functioning, or, more specifically, masticatory ability of older adults with dementia. Secondary, the intervention is hypothesized to have beneficial effects on food intake, cognition, activities of daily living, depression, and quality of life.Methods/design: An adjusted parallel randomized controlled trial is being performed in dining rooms of residential care settings. Older adults with dementia, for whom also additional eligibility criteria apply, are randomly assigned to the experimental (videos of chewing people) or control condition (videos of nature and buildings), by drawing folded pieces of paper. Participants who are able to watch each other's videos are assigned to the same study condition. The intervention takes place during lunchtime, from Monday to Friday, for 3 months. During four moments of measurement, masticatory ability, food intake, cognitive functioning, activities of daily living, depression, and quality of life are assessed. Tests administrators blind to the group allocation administer the tests to participants.Discussion: The goal of this study is to examine the effects of video observation of chewing on masticatory ability and several secondary outcome measures. In this study, the observation of chewing is added to the execution of the same action (i.e., during eating). Beneficial effects on masticatory ability, and consequently on the other outcome measures are hypothesized. The intervention may be easily integrated into daily care, and might add to the lives of the increasing number of older adults with dementia by beneficially influencing multiple daily life functions.Trial Registration: NTR5124. Registration date: 30 March 2015. [ABSTRACT FROM AUTHOR]

Background: Bullying refers to verbal, physical or psychological aggression repeated over time that is intended to cause harm or distress to the victims who are unable to defend themselves. It is a key public health priority owing to its widespread prevalence in schools and harmful short- and long-term effects on victims' well-being. There is a need to strengthen the evidence base by testing innovative approaches to preventing bullying. KiVa is a school-based bullying prevention programme with universal and indicated elements and an emphasis on changing bystander behaviour. It achieved promising results in a large trial in Finland, and now requires testing in other countries. This paper describes the protocol for a cluster randomised controlled trial (RCT) of KiVa in Wales.Methods/design: The study uses a two-arm waitlist control pragmatic definitive parallel group cluster RCT design with an embedded process evaluation and calculation of unit cost. Participating schools will be randomised a using a 1:1 ratio to KiVa plus usual provision (intervention group) or usual provision only (control group). The trial has one primary outcome, child self-reported victimisation from bullying, dichotomised as 'victimised' (bullied at least twice a month in the last couple of months) versus 'not victimised'. Secondary outcomes are: bullying perpetration; aspects of child social and emotional well-being (including emotional problems, conduct, peer relations, prosocial behaviour); and school attendance. Follow-up is at 12 months post-baseline. Implementation fidelity is measured through teacher-completed lesson records and independent school-wide observation. A micro-costing analysis will determine the costs of implementing KiVa, including recurrent and non-recurrent unit costs. Factors related to the scalability of the programme will be examined in interviews with head teachers and focus groups with key stakeholders in the implementation of school-based bullying interventions.Discussion: The results from this trial will provide evidence on whether the KiVa programme is transportable from Finland to Wales in terms of effectiveness and implementation. It will provide information about the costs of delivery and generate insights into factors related to the scalability of the programme.Trial Registration: Current Controlled Trials ISRCTN23999021 Date 10-6-13. [ABSTRACT FROM AUTHOR]

Background: Screening with the guaiac faecal occult blood test (gFOBt) is associated with improved colorectal cancer (CRC) survival, and is offered biennially to men and women aged 60-74 years in England's national Bowel Cancer Screening Programme (BCSP). Uptake of the gFOBt is low, with only 54 % of the eligible population completing the test. Text-message reminders could improve uptake of gFOBt.Methods/design: This paper describes the protocol for a randomised controlled trial, which will examine the effectiveness of a text-message reminder to promote uptake of gFOBt screening in the BCSP. Individual mobile telephone data from 180 general practices in London with existing mobile-health services will be linked to the national BCSP information system via a secure on-line network. All screening-eligible adults registered with a participating practice will be randomised, to receive either usual care (N = 1600) or usual care plus a text-message reminder to self-complete and return their kit eight weeks after their initial invitation (N = 1600). The primary outcome will be the proportion of individuals who return an adequately completed gFOBt kit within 18 weeks of the initial invitation. Differences in uptake between groups will be evaluated using a logistic regression analysis, adjusting for individual-level and area-level socio-demographic variables.Discussion: This will be the first large-scale randomised trial of a text-message reminder in a national screening programme for CRC. If effective, this study provides a cost-effective means to promote uptake of CRC screening in an organised programme.Trial Registration: Current Controlled Trials ISRCTN70904476 (18/09/2015). [ABSTRACT FROM AUTHOR]

Background: With ongoing concerns about the sexual health and wellbeing of young people, there is increasing need to innovate intervention approaches. Engaging parents as agents to support their children, alongside capitalising on increasingly sophisticated technological options could jointly enhance support. Converting existing programmes into interactive game based options has the potential to broaden learning access whilst preserving behaviour change technique fidelity. However the acceptability of this approach and viability of adapting resources in this way is yet to be established. This paper reports on the process of converting an existing group programme ("What Should We Tell the Children?") and tests the acceptability within a community setting.Methods: Translation of the original programme included selecting exercises and gathering user feedback on character and message framing preferences. For acceptability testing, parents were randomised to either the game (n = 106) or a control (non-interactive webpage) condition (n = 76). At time 1 all participants completed a survey on demographics, computer literacy and Theory of Planned Behaviour (TPB) items. Post intervention (time 2) users repeated the TPB questions in addition to acceptability items. Interviews (n = 17) were conducted 3 months post intervention to gather qualitative feedback on transfer of learning into real life.Results: The process of conversion identified clear preferences for first person role play, home setting and realistic characters alongside positively phrased feedback. Evaluation results show that the game was acceptable to parents on cognitive and emotional dimensions, particularly for parents of younger children. Acceptability was not influenced by baseline demographics, computer skills or baseline TPB variables. MANOVA analysis and qualitative feedback suggest potential for effective translation of learning into real life. However attrition was more likely in the game condition, potentially due to feedback text volume.Conclusions: A manualised group programme can be viably converted into a serious game format which is both cognitively and emotionally acceptable. The intervention may be more effectively targeted at parents with younger children, and further game developments must particularly address information dosing. Establishing the viability of digitally converting a group programme is a significant step forward for implementation focused research. [ABSTRACT FROM AUTHOR]

Background: This paper reports on the feasibility and initial efficacy of a culturally sensitive, comprehensive women-centered substance use intervention for women who inject drugs in Georgia in terms of the primary and secondary sex risk outcomes. The hypothesis under examination was that, relative to case management participants, participants in a culturally sensitive, comprehensive women-specific and -centered intervention would, on average, show significant decreases in past-30-day frequency of unprotected sex, unprotected sex at the last sexual encounter, and increases in condom use and safer sex actions.Methods: The study was a two-arm randomized trial, in which 173 potentially eligible women were screened, and those 128 women determined to be eligible were assigned at random to either Reinforcement-based Treatment plus Women's Co-Op (RBT + WC) or case management (CM). RBT + WC participants received 12 sessions of a structured intervention with the goal of reducing risky sex and substance use and improving physical and mental health. CM participants received 12 sessions of case management and informational brochures that focused on the same issues on which RBT + WC focused. Participants were assessed at baseline, post-treatment, and 3 months following treatment enrollment.Results: Analyses revealed case management having significantly overall higher Safer Sex action scores than RBT + WC, and a significant decrease over time for past 30-day number of unprotected sex acts. Unprotected sex at the last encounter and Condom Use action scores were nonsignificant.Conclusions: Women who inject drugs in Georgia are engaging in risky sexual practices, and are in need of an intervention that addresses these risky behaviors. Reasons for the failure to find differences between a culturally sensitive, comprehensive women-centered intervention and case management tailored to the needs of women who inject drugs in Georgia may have been the result of inadequate power to detect an effect in a sample whose drug use was not as serious as warranted by the intervention. (ClinicalTrials.gov Identifier: NCT01331460 ). [ABSTRACT FROM AUTHOR]

Background: Interventions on adolescents' lifestyle are important, but the main mechanisms that explain the changes (mediating variables) on lifestyle are unclear. This paper presents the rationale and methods of an intervention program focused on promoting active and healthy lifestyles (especially physical activity [PA] practice and reducing screen time) among Brazilian students-the Fortaleça sua Saúde program (Portuguese for "strengthen your health").Methods/design: This is a school-based cluster-randomized controlled trial. Three intervention and three control (no intervention) full-time public schools were randomly selected in Fortaleza, northeastern Brazil. Students (n = 1,272) from classes in Grades 7-9 were eligible, and 1,085 (548 in the intervention and 537 in control schools) completed the baseline and follow-up measures. The program duration was approximately four months and took place in 2014. Intervention strategies focused on teacher training, activities on health in the curriculum, active opportunities in the school environment (the availability of equipment for PA), and health education (health materials for students and parents). Data collection was undertaken before and immediately after the intervention. The primary variables included the practice of PA (weekly PA volume, PA behavior change stage and preference for PA during leisure-time) and screen time (TV and computer/video games). Potential intrapersonal, interpersonal and environmental mediators of PA and screen time were evaluated by a standardized questionnaire. Other lifestyle components (e.g., eating habits, substance use), psychological (e.g., self-rated health, body satisfaction) and biological (general and abdominal obesity) aspects, as well as academic performance were also evaluated in the total sample. Depressive symptoms, eating disorders, sleep quality, objectively-measured PA, and sedentary time were evaluated in obese students.Discussion: If effective, this program will contribute to the development of public policies for the promotion of active and healthy lifestyles in youth, especially those from low- and middle-income countries. The main intrapersonal, interpersonal and/or environmental mediators of PA and screen time may also be indicated. Finally, we anticipate that the proposed strategies may be adaptable to public schools and may even be extended to the entire school system.Trial Registration: ClinicalTrials.Gov: NCT02439827 . Registration date: May 3, 2015. [ABSTRACT FROM AUTHOR]

Background: With regard to the global childhood obesity epidemic, it is imperative that effective lifestyle interventions are devised to combat childhood obesity. This paper describes the development and implementation of a comprehensive (a combination of diet and physical activity (PA)), social cognitive behaviour modification intervention using accelerometry and a dietary diary to tackle child overweight and obesity. The comprehensive intervention effect was evaluated in a comparison with diet only, PA only and a no-treatment control group.Methods: A pilot study was conducted with a non-randomized cluster design. Four hundred thirty-eight overweight and obese children aged 7-12 years from ten primary schools in Beijing were recruited to receive a one-year intervention. Participants were allocated into one of four groups: the comprehensive intervention group; the PA only group (Happy 10 program); the diet only group (nutrition education program); and a control group. The effects of intervention on adiposity, blood pressure, and biochemical indicators were assessed by examining 2-way interactions (time × intervention) in linear mixed models. Means and 95 % confidence intervals (CI) for the adjusted changes between post-intervention and baseline relative to changes in the control group were calculated and reported as effect sizes.Results: The percentage of body fat in the comprehensive intervention group showed a significant relative decrease (adjusted change: -1.01 %, 95 % CI: (-1.81, -0.20) %) compared with the PA only, diet only or control groups (P < 0.001). Systolic blood pressure significantly decreased in the comprehensive intervention group (adjusted change: -4.37 mmHg, 95 % CI: (-8.42, -0.33) mmHg), as did diastolic blood pressure (adjusted change: -5.50 mmHg, 95 % CI (-8.81, -2.19) mmHg) (P < 0.05). Compared with the other two intervention groups and the control group, positive adjusted changes in fasting glucose in the comprehensive group were found, although not for the biochemical lipid metabolism indicators. Positive but non-significant adjusted changes in body mass index and waist circumference were observed.Conclusions: Compared with the diet or PA only intervention groups, the current comprehensive program had superior positive effects on body fat percentage and blood pressure but not on the biochemical lipid metabolism indicators in Chinese overweight and obese children. Future randomized controlled trials and long-term follow-up studies are required to elaborate the findings of the current intervention.Trial Registration: ClinicalTrials.gov identifier: NCT02228434. [ABSTRACT FROM AUTHOR]

Background: Surveys are commonly used in health research to assess patient satisfaction with hospital care. Achieving an adequate response rate, in the face of declining trends over time, threatens the quality and reliability of survey results. This paper evaluates a strategy to increase the response rate in a postal satisfaction survey with women who had recently given birth.Methods: A sample of 2048 Australian women who had recently given birth at seven maternity units in New South Wales were invited to participate in a postal survey about their recent experiences with maternity care. The study design included a randomised controlled trial that tested two types of pre-notification letter (with or without the option of opting out of the survey). The study also explored the acceptability of a request for consent to link survey data with existing routinely collected health data (omitting the latter data items from the survey reduced survey length and participant burden). This consent was requested of all women.Results: The survey had an overall response rate of 46% (913 completed surveys returned, total sample 1989). Women receiving the pre-notification letter with the option of opting out of the survey were more likely to actively decline to participate than women receiving the letter without this option, although the overall numbers of women declining were small (27 versus 12). Letter type was not significantly associated with the return of a completed survey. Among women who completed the survey, 97% gave consent to link their survey data with existing health data.Conclusions: The two types of pre-notification letters used in our study did not influence the survey response rate. However, seeking consent for record linkage was highly acceptable to women who completed the survey, and represents an important strategy to add to the arsenal for designing and implementing effective surveys. In addition to aspects of survey design, future research should explore how to more effectively influence personal constructs that contribute to the decision to participate in surveys. [ABSTRACT FROM AUTHOR]

Background: Research indicates that exercise can have a positive effect on both physical and mental health in nursing home patients with dementia, however the lasting effect is rarely studied. In a previously published article we investigated the immediate effect of a 12 weeks functional exercise program on physical function and mental health in nursing home residents with dementia. In this paper we studied the long-term effect of this exercise program. We explored the differences between the exercise and control group from baseline to 6 months follow-up and during the detraining period from month 3 to 6.Methods: A single blind, randomized controlled trial was conducted and a total of 170 nursing home residents with dementia were included. The participants were randomly allocated to an intervention (n = 87) or a control group (n = 83). The intervention consisted of intensive strengthening and balance exercises in small groups twice a week for 12 weeks. The control condition was leisure activities. Thirty participants were lost between baseline and six-month follow-up. Linear mixed model analyses for repeated measurements were used to investigate the effect of exercise after detraining period.Results: The exercise group improved their scores on Berg Balance Scale from baseline to 6 months follow-up by 2.7 points in average. The control group deteriorated in the same period and the difference between groups was statistically significant (p = 0.031). The exercise group also scored better on NPI agitation sub-score after 6 months (p = 0.045).Conclusion: The results demonstrate long-time positive effects of a high intensity functional exercise program on balance and indicate a positive effect on agitation, after an intervention period of 12 weeks followed by a detraining period of 12 weeks. Identifier at ClinicalTrials.gov: NCT02262104. [ABSTRACT FROM AUTHOR]

Background: Rates of perinatal depression (antenatal and postnatal depression) in South Asia are among the highest in the world. The delivery of effective psychological treatments for perinatal depression through existing health systems is a challenge due to a lack of human resources. This paper reports on a trial protocol that aims to evaluate the effectiveness and cost-effectiveness of the Thinking Healthy Programme delivered by peers (Thinking Healthy Programme Peer-delivered; THPP), for women with moderate to severe perinatal depression in rural and urban settings in Pakistan and India.Methods/design: THPP is evaluated with two randomised controlled trials: a cluster trial in Rawalpindi, Pakistan, and an individually randomised trial in Goa, India. Trial participants are pregnant women who are registered with the lady health workers in the study area in Pakistan and pregnant women attending outpatient antenatal clinics in India. They will be screened using the patient health questionnaire-9 (PHQ-9) for depression symptoms and will be eligible if their PHQ-9 is equal to or greater than 10 (PHQ-9 ≥ 10). The sample size will be 560 and 280 women in Pakistan and India, respectively. Women in the intervention arm (THPP) will be offered ten individual and four group sessions (Pakistan) or 6-14 individual sessions (India) delivered by a peer (defined as a mother from the same community who is trained and supervised in delivering the intervention). Women in the control arm (enhanced usual care) will receive health care as usual, enhanced by providing the gynaecologist or primary-health facilities with adapted WHO mhGAP guidelines for depression treatment, and providing the woman with her diagnosis and information on how to seek help for herself. The primary outcomes are remission and severity of depression symptoms at the 6-month postnatal follow-up. Secondary outcomes include remission and severity of depression symptoms at the 3-month postnatal follow-up, functional disability, perceived social support, breastfeeding rates, infant height and weight, and costs of health care at the 3- and 6-month postnatal follow-ups. The primary analysis will be intention-to-treat.Discussion: The trials have the potential to strengthen the evidence on the effectiveness and cost-effectiveness of an evidence-based psychological treatment recommended by the World Health Organisation and delivered by peers for perinatal depression. The trials have the unique opportunity to overcome the shortage of human resources in global mental health and may advance our understanding about the use of peers who work in partnership with the existing health systems in low-resource settings.Trial Registration: Pakistan Trial: ClinicalTrials.gov Identifier: NCT02111915 (9 April 2014) India Trial: ClinicalTrials.gov Identifier: NCT02104232 (1 April 2014). [ABSTRACT FROM AUTHOR]

Background: Using patient-reported outcome measures (PROMs) to assess Quality of Life (QoL) is well established, but commonly-used PROM item-sets do not necessarily capture what all respondents consider important. Measuring complex constructs is particularly difficult in randomised controlled trials (RCTs). The Mother-Generated Index (MGI) is a validated antenatal and postnatal QoL instrument in which the variables and scores are completely respondent-driven. This paper reports on the feasibility and acceptability of the MGI in an RCT, and compares the resulting variables and QoL scores with more commonly used instruments.Methods: The single-page MGI was included at the end of a ten page questionnaire pack and posted to the RCT participants at baseline (28-32 weeks' gestation) and follow-up (six weeks postnatal). Feasibility and acceptability were assessed by ease of administration, data entry and completion rates. Variables cited by women were analysed thematically. MGI QoL scores were compared with outcomes from the EQ-5D-3 L; Edinburgh Postnatal Depression Scale; Satisfaction With Life Scale; and State Trait Anxiety Inventory.Results: Six hundred and seventy eight pregnant women returned the pack at baseline; 668 completed the MGI (98.5%); 383/400 returns at follow up included a completed MGI (95.7%). Quantitative data were scanned into SPSS using a standard data scanning system, and were largely error-free; qualitative data were entered manually. The variables recorded by participants on the MGI forms incorporated many of those in the comparison instruments, and other outcomes commonly used in intrapartum trials, but they also revealed a wider range of issues affecting their quality of life. These included financial and work-related worries; moving house; and concerns over family illness and pets. The MGI scores demonstrated low-to-moderate correlation with other tools (all r values p < .01).Conclusions: Without face-to-face explanation and at the end of a long questionnaire, the MGI was feasible to use, and acceptable to RCT participants. It allowed individual participants to include issues that were important to them, but which are not well captured by existing tools. The MGI unites the explanatory power of qualitative research with the comparative power of quantitative designs, is inexpensive to administer, and requires minimal linguistic and conceptual translation.Trial Registration: ISRCTN27575146 (date assigned 23 March 2011). [ABSTRACT FROM AUTHOR]

Background: Cancer-related fatigue is a distressing symptom experienced by many after cancer treatment. An exploratory randomised controlled trial was conducted to test proof of concept of RESTORE: a web-based tool to enhance self-efficacy to manage cancer-related fatigue. This paper reports findings from a qualitative process evaluation to determine feasibility and acceptability of the intervention and trial processes.Method: Qualitative process evaluation carried out at the end of the trial to explore participants' experiences using semi-structured telephone interviews with a purposive sample of participants from both trial arms. Normalisation Process Theory informed data collection and analysis. Analysis involved directed content analysis within a Framework Approach.Results: Nineteen participants took part. They understood the purpose and requirements of the trial and identified beneficial outcomes from taking part. For the majority, the work of the trial was easily accommodated into daily routines and did not require new skills. There were mixed views about the value of the information provided by RESTORE, depending on time since diagnosis and treatment. Personal factors, constraints of the intervention, and environmental context inhibited the integration and embedding of RESTORE into everyday life. Access to the intervention at an early stage in the treatment trajectory was important to effective utilisation, as were individual preferences for delivery of information.Conclusion: The theoretical foundations of the intervention were sound. Participants derived benefits from the intervention but barriers to implementation and integration suggest that RESTORE and the trial processes require some modification before testing in a full trial.Trial Registration: ISRCTN67521059 (10(th) October 2012). [ABSTRACT FROM AUTHOR]

Background: The LiGHT trial (Laser-1st versus Drops-1st for Glaucoma and Ocular Hypertension Trial) is a multicentre randomised controlled trial of two treatment pathways for patients who are newly diagnosed with open-angle glaucoma (OAG) and ocular hypertension (OHT). The main hypothesis for the trial is that lowering intraocular pressure (IOP) with selective laser trabeculoplasty (SLT) as the primary treatment ('Laser-1st') leads to a better health-related quality of life than for those started on IOP-lowering drops as their primary treatment ('Medicine-1st') and that this is associated with reduced costs and improved tolerability of treatment. This paper describes the statistical analysis plan for the study.Methods/design: The LiGHT trial is an unmasked, multi-centre randomised controlled trial. A total of 718 patients (359 per arm) are being randomised to two groups: medicine-first or laser-first treatment. Outcomes are recorded at baseline and at 6-month intervals up to 36 months. The primary outcome measure is health-related quality of life (HRQL) at 36 months measured using the EQ-5D-5L. The main secondary outcome is the Glaucoma Utility Index. We plan to analyse the patient outcome data according to the group to which the patient was originally assigned. Methods of statistical analysis are described, including the handling of missing data, the covariates used in the adjusted analyses and the planned sensitivity analyses.Trial Registration: The trial was registered with the ISRCTN register on 23/07/2012, number ISRCTN32038223 . [ABSTRACT FROM AUTHOR]

Background: International epidemiological research into violence against children is increasing in scope and frequency, but little has been written about practical management of the ethical aspects of conducting such research in low and middle-income countries. In this paper, we describe our study procedures and reflect on our experiences conducting a survey of more than 3,700 primary school children in Uganda as part of the Good Schools Study, a cluster randomised controlled trial of a school-based violence prevention intervention. Children were questioned extensively about their experiences of physical, sexual, and emotional violence from a range of different perpetrators. We describe our sensitisation and consent procedures, developed based on our previous research experience and requirements for our study setting. To respond to disclosures of abuse that occurred during our survey, we describe a referral algorithm developed in conjunction with local services. We then describe our experience of actually implementing these procedures in our 2012 survey, based on reflections of the research team. Drawing on 40 qualitative interviews, we describe children's experiences of participating in the survey and of being referred to local child protection services.Results: Although we were able to implement much of our protocol in a straightforward manner, we also encountered major challenges in relation to the response of local services to children's disclosures of violence. The research team had to intervene to ensure that children were provided with appropriate support and that our ethical obligations were met.Conclusions: In resource poor settings, finding local services that can provide appropriate support for children may be challenging, and researchers need to have concrete plans and back-up plans in place to ensure that obligations can be met. The merits of mandatory reporting of children's disclosures to local services need to be considered on a case by case basis-in some places this has the potential to do harm. Research teams also must agree on what level of ancillary care will be provided, and budget accordingly. Further practical examples of how to address the challenges encountered in this work are needed, in order to build a consensus on best practices.Trial Registration: NCT01678846 (clinicaltrials.gov), August 24, 2012. [ABSTRACT FROM AUTHOR]

Background: A common complication after stroke is development of cognitive impairment and dementia. However, effective strategies for reducing the risk of developing these problems remain undefined. Potential strategies include intensive lowering of blood pressure (BP) and/or lipids. This paper summarises the baseline characteristics, statistical analysis plan and feasibility of a randomised control trial of blood pressure and lipid lowering in patients post-stroke with the primary objective of reducing cognitive impairment and dementia.Methods: The Prevention Of Decline in Cognition After Stroke Trial (PODCAST) was a multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial internal pilot trial running in secondary and primary care. Participants without dementia were enrolled 3-7 months post ischaemic stroke or spontaneous intracerebral haemorrhage, and randomised to intensive versus guideline BP lowering (target systolic BP <125 mmHg versus <140 mmHg); patients with ischaemic stroke were also randomised to intensive or guideline lipid lowering (target LDL cholesterol <1.4 mmol/L versus <3 mmol/L). The primary outcome was the Addenbrooke's Cognitive Examination-Revised; a key secondary outcome was to assess feasibility of performing a large trial of one or both interventions. Data are number (%) or mean (standard deviation). The trial was planned to last for 8 years with follow-up between 1 and 8 years. The plan for reporting the main results is included as Additional file 2.Results: 83 patients (of a planned 600) were recruited from 19 UK sites between 7 October 2010 and 31 January 2014. Delays, due to difficulties in the provision of excess treatment costs and to complexity of follow-up, led to few centres taking part and a much lower recruitment rate than planned. Patient characteristics at baseline were: age 74 (SD 7) years, male 64 (77 %), index stroke ischaemic 77 (93 %), stroke onset to randomisation 4.5 [SD 1.3] months, Addenbrooke's Cognitive Examination-Revised 86 (of 100, SD 8), Montreal Cognitive Assessment 24 (of 30, SD 3), BP 147/82 (SD 19/11) mmHg, total cholesterol 4.0 (SD 0.8) mmol/L and LDL cholesterol 2.0 (SD 0.7) mmol/L, modified Rankin Scale 1.1 (SD 0.8).Conclusion: Limited recruitment suggests that a large trial is not feasible using the current protocol. The effects of the interventions on BP, lipids, and cognition will be reported in the main publication.Trial Registration: ISRCTN85562386 registered on 23 September 2009. [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: Behavioral assessment has been acted as the gold standard for the diagnosis of disorders of consciousness (DOC) patients. The item "Functional Object Use" in the motor function sub-scale in the Coma Recovery Scale-Revised (CRS-R) is a key item in differentiating between minimally conscious state (MCS) and emergence from MCS (EMCS). However, previous studies suggested that certain specific stimuli, especially something self-relevant can affect DOC patients' scores of behavioral assessment scale. So, we attempted to find out if personalized objects can improve the diagnosis of EMCS in the assessment of Functional Object Use by comparing the use of patients' favorite objects and other common objects in MCS patients.Methods: Twenty-one post-comatose patients diagnosed as MCS were prospectively included. The item "Functional Object Use" was assessed by using personalized objects (e.g., cigarette, paper) and non-personalized objects, which were presented in a random order. The rest assessments were performed following the standard protocol of the CRS-R. The differences between functional uses of the two types of objects were analyzed by the McNemar test.Results: The incidence of Functional Object Use was significantly higher using personalized objects than non-personalized objects in the CRS-R. Five out of the 21 MCS studied patients, who were assessed with non-personalized objects, were re-diagnosed as EMCS with personalized objects (χ2 = 5, df = 1, p < 0.05).Conclusions: Personalized objects employed here seem to be more effective to elicit patients' responses as compared to non-personalized objects during the assessment of Functional Object Use in DOC patients.Trial Registration: Clinical Trials.gov: NCT02988206 ; Date of registration: 2016/12/12. [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: The present study protocol describes the evaluation of a comprehensive integrated care model implemented at two hospital sites at the University Hospital of North Norway (UNN). The PAtient Centred Team (PACT) model includes proactive, patient-centred interdisciplinary teams that aim to improve the continuum and quality of care of frail elderly patients and reduce health care costs. The main objectives of the evaluation are to analyse the effectiveness and cost effectiveness of using patient-centred teams as part of routine service provision for this patient group. The evaluation will analyse the effect on patient health and functional status, patient experiences and hospital utilisation, and it will conduct an economic evaluation. This paper describes the PACT model and the rationale for and design of the planned effectiveness and cost-effectiveness study.Methods/design: This is a prospective, non-randomised matched control before-and-after intervention study. Patients in the intervention group will be recruited from the hospital sites that have implemented the PACT model. The controls will be recruited from two hospitals without the model. The control patients and the index patients will be matched according to sex, age and number of long-term conditions. The study aims to include 600 patients in each group, which will provide sufficient power to detect a clinical change in the primary outcome. The primary outcome is the physical dimension of the Short Form Health Survey (SF-36). Secondary outcomes are the Patient Generated Index (PGI), the Patient Activation Measure (PAM), the Patient Assessment of Chronic Illness Care (PACIC), hospitalisation and length of stay. The cost-effectiveness study takes a health provider perspective and calculates the cost per quality-adjusted life-years (QALYs) gained. The data will be collected at baseline, 6 and 12 months. The data will be analysed using techniques and models that recognise the lack of randomisation and the correlation of cost and effect data.Discussion: The study results will provide knowledge about whether the integrated care model implemented at UNN improves the quality of care for the frail elderly with multiple conditions. The study will establish whether the PAC. T model improves health and functional status and is cost effective compared to the usual care for this patient group.Trial Registration: ClinicalTrials.gov: NCT02541474. [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: Nursing home patients have complex mental and physical health problems, disabilities and social needs, combined with widespread prescription of psychotropic drugs. Preservation of their quality of life is an important goal. This can only be achieved within nursing homes that offer competent clinical conditions of treatment and care. COmmunication, Systematic assessment and treatment of pain, Medication review, Occupational therapy, Safety (COSMOS) is an effectiveness-implementation hybrid trial that combines and implements organization of activities evidence-based interventions to improve staff competence and thereby the patients' quality of life, mental health and safety. The aim of this paper is to describe the development, content and implementation process of the COSMOS trial.Methods/design: COSMOS includes a 2-month pilot study with 128 participants distributed among nine Norwegian nursing homes, and a 4-month multicenter, cluster randomized effectiveness-implementation clinical hybrid trial with follow-up at month 9, including 571 patients from 67 nursing home units (one unit defined as one cluster). Clusters are randomized to COSMOS intervention or current best practice (control group). The intervention group will receive a 2-day education program including written guidelines, repeated theoretical and practical training (credited education of caregivers, physicians and nursing home managers), case discussions and role play. The 1-day midway evaluation, information and interviews of nursing staff and a telephone hotline all support the implementation process. Outcome measures include quality of life in late-stage dementia, neuropsychiatric symptoms, activities of daily living, pain, depression, sleep, medication, cost-utility analysis, hospital admission and mortality.Discussion: Despite complex medical and psychosocial challenges, nursing home patients are often treated by staff possessing low level skills, lacking education and in facilities with a high staff turnover. Implementation of a research-based multicomponent intervention may improve staff's knowledge and competence and consequently the quality of life of nursing home patients in general and people with dementia in particular.Trial Registration: ClinicalTrials.gov NCT02238652. [ABSTRACT FROM AUTHOR]

Background: Major depression is one of the most debilitating diseases in terms of quality of life. Less than half of patients suffering from depression can achieve remission after adequate antidepressant treatment. Another promising treatment option is cognitive-behavior therapy (CBT). However, the need for experienced therapists and substantive dedicated time prevent CBT from being widely disseminated. In the present study, we aim to examine the effectiveness of switching antidepressants and starting a smartphone-based CBT program at the same time, in comparison to switching antidepressants only, among patients still suffering from depression after adequate antidepressant treatment.Methods/design: A multi-center randomized trial is currently being conducted since September 2014. The smartphone-based CBT program, named the "Kokoro-App," for major depression has been developed and its feasibility has been confirmed in a previous open study. The program consists of an introduction, 6 sessions and an epilogue, and is expected to be completed within 9 weeks by patients. In the present trial, 164 patients with DSM-5 major depressive disorder and still suffering from depressive symptoms after adequate antidepressant treatment for more than 4 weeks will be allocated to the Kokoro-App plus switching antidepressant group or the switching antidepressant alone group. The participants allocated to the latter group will receive full components of the Kokoro-App after 9 weeks. The primary outcome is the change in the total score on the Patient Health Questionnaire through the 9 weeks of the program, as assessed at week 0, 1, 5 and 9 via telephone by blinded raters. The secondary outcomes include the change in the total score of the Beck Depression Inventory-II, change in side effects as assessed by the Frequency, Intensity and Burden of Side Effects Rating, and treatment satisfaction.Discussion: An effective and reachable intervention may not only lead to healthier mental status among depressed patients, but also to reduced social burden from this illness. This paper outlines the background and methods of a trial that evaluates the possible additive value of a smartphone-based CBT program for treatment-resistant depression.Trial Registration: UMIN-CTR: UMIN000013693 (registered on 1 June 2014). [ABSTRACT FROM AUTHOR]

Background: Systematic reviews suggest that multi-component interventions are effective in reducing bullying victimisation and perpetration. We are undertaking a phase III randomised trial of the INCLUSIVE multi-component intervention. This trial aims to assess the effectiveness and cost-effectiveness of the INCLUSIVE intervention in reducing aggression and bullying victimisation in English secondary schools. This paper updates the original trial protocol published in 2014 (Trials 15:381, 2014) and presents the changes in the process evaluation protocol and the secondary outcome data collection.Methods: The methods are summarised as follows.Design: cluster randomised trial.Participants: 40 state secondary schools. Outcomes assessed among the cohort of students at the end of year 7 (n = 6667) at baseline.Intervention: INCLUSIVE is a multi-component school intervention including a social and emotional learning curriculum, changes to school environment (an action group comprising staff and students reviews local data on needs to review rules and policies and determine other local actions) and staff training in restorative practice. The intervention will be delivered by schools supported in the first two years by educational facilitators independent of the research team, with a third intervention year involving no external facilitation but all other elements. Comparator: normal practice.Outcomes: Primary: Two primary outcomes at student level assessed at baseline and at 36 months: 1. Aggressive behaviours in school: Edinburgh Study of Youth Transitions and Crime school misbehaviour subscale (ESYTC) 2. Bullying and victimisation: Gatehouse Bullying Scale (GBS) Secondary outcomes assessed at baseline, 24 and 36 months will include measures relating to the economic evaluation, psychosocial outcomes in students and staff and school-level truancy and exclusion rates.Sample Size: 20 schools per arm will provide 90% power to identify an effect size of 0.25 SD with a 5% significance level. Randomisation: eligible consenting schools were randomised stratified for single-sex versus mixed-sex schools, school-level deprivation and measures of school attainment.Discussion: The trial involves independent research and intervention teams and is supervised by a Trial Steering Committee and a Data Monitoring Committee.Trial Registration: Current Controlled Trials, ISRCTN10751359 . Registered on 11 March 2014. [ABSTRACT FROM AUTHOR]

Background Secondary arm lymphoedema continues to affect at least 20% of women after treatment for breast cancer requiring lifelong professional treatment and self-management. The holistic practice of yoga may offer benefits as an adjunct self-management option. The aim of this small pilot trial was to gain preliminary data to determine the effect of yoga on women with stage one breast cancer-related lymphoedema (BCRL). This paper reports the results for the primary and secondary outcomes. Methods Participants were randomised, after baseline testing, to receive either an 8-week yoga intervention (n = 15), consisting of a weekly 90-minute teacher-led class and a 40-minute daily session delivered by DVD, or to a usual care wait-listed control group (n = 13). Primary outcome measures were: arm volume of lymphoedema measured by circumference and extracellular fluid measured by bioimpedance spectroscopy. Secondary outcome measures were: tissue induration measured by tonometry; levels of sensations, pain, fatigue, and their limiting effects all measured by a visual analogue scale (VAS) and quality of life based on the Lymphoedema Quality of Life Tool (LYMQOL). Measurements were conducted at baseline, week 8 (post-intervention) and week 12 (four weeks after cessation of the intervention). Results At week 8, the intervention group had a greater decrease in tissue induration of the affected upper arm compared to the control group (p = 0.050), as well as a greater reduction in the symptom sub-scale for QOL (p = 0.038). There was no difference in arm volume of lymphoedema or extra-cellular fluid between groups at week 8; however, at week 12, arm volume increased more for the intervention group than the control group (p = 0.032). Conclusions An 8-week yoga intervention reduced tissue induration of the affected upper arm and decreased the QOL sub-scale of symptoms. Arm volume of lymphoedema and extra-cellular fluid did not increase. These benefits did not last on cessation of the intervention when arm volume of lymphoedema increased. Further research trials with a longer duration, higher levels of lymphoedema and larger numbers are warranted before definitive conclusions can be made. [ABSTRACT FROM AUTHOR]

Background In a large randomised trial in patients with seasonal allergic rhinitis (SAR), acupuncture was superior compared to sham acupuncture and rescue medication. The aim of this paper is to describe the characteristics of the trial's participating physicians and to describe the trial intervention in accordance with the STRICTA (Standards for Reporting Interventions in Controlled Trials of Acupuncture) guidelines, to make details of the trial intervention more transparent to researchers and physicians. Methods ACUSAR (Acupuncture in Seasonal Allergic Rhinitis) was a three-armed, randomised, controlled multicentre trial. 422 SAR patients were randomised to semi-standardised acupuncture plus rescue medication (RM, cetirizine), sham acupuncture plus RM or RM alone. We sent a questionnaire to trial physicians in order to evaluate their characteristics regarding their education about and experience in providing acupuncture. During the trial, acupuncturists were asked to diagnose all of their patients according to Chinese Medicine (CM) as a basis for the semi-standardised, individualized intervention in the acupuncture group. Every acupuncture point used in this trial had to be documented after each session Results Acupuncture was administered in outpatient clinics by 46 (mean age 47 ± 10 years; 24 female/ 22 male) conventionally-trained medical doctors (67% with postgraduate specialization such as internal or family medicine) with additional extensive acupuncture training (median 500 hours (1st quartile 350, 3rd quartile 1000 hours with 73% presenting a B-diploma in acupuncture training (350 hours)) and experience (mean 14 years in practice). The most reported traditional CM diagnosis was 'wind-cold invading the lung' (37%) and 'wind-heat invading the lung' (37%), followed by 'lung and spleen qi deficiency' (9%). The total number of needles used was higher in the acupuncture group compared to the sham acupuncture group (15.7 ± 2.5 vs. 10.0 ± 1.6). Conclusions The trial interventions were provided by well educated and experienced acupuncturists. The different number of needles in both intervention groups could be possibly a reason for the better clinical effect in SAR patients. For future trials it might be more appropriate to ensure that acupuncture and sham acupuncture groups should each be treated by a similar number of needles. [ABSTRACT FROM AUTHOR]

Background: Patients with acute leukemia experience a substantial symptom burden and are at risk of developing infections throughout the course of repeated cycles of intensive chemotherapy. Physical activity in recent years has been a strategy for rehabilitation in cancer patients to remedy disease and treatment related symptoms and side effects. To date, there are no clinical practice exercise guidelines for patients with acute leukemia undergoing induction and consolidation chemotherapy. A randomized controlled trial is needed to determine if patients with acute leukemia can benefit by a structured and supervised counseling and exercise program.Methods/design: This paper presents the study protocol: Patient Activation through Counseling and Exercise--Acute Leukemia (PACE-AL) trial, a two center, randomized controlled trial of 70 patients with acute leukemia (35 patients/study arm) following induction chemotherapy in the outpatient setting. Eligible patients will be randomized to usual care or to the 12 week exercise and counseling program. The intervention includes 3 hours + 30 minutes per week of supervised and structured aerobic training (moderate to high intensity 70-80%) on an ergometer cycle, strength exercises using hand weights and relaxation exercise. Individual health counseling sessions include a self directed home walk program with a step counter. The primary endpoint is functional performance/exercise capacity (6 minute walk distance). The secondary endpoints are submaximal VO₂ max test, sit to stand and bicep curl test, physical activity levels, patient reported outcomes (quality of life, anxiety and depression, symptom prevalence, intensity and interference). Evaluation of clinical outcomes will be explored including incidence of infection, hospitalization days, body mass index, time to recurrence and survival. Qualitative exploration of patients' health behavior and experiences.Discussion: PACE-AL will provide evidence of the effect of exercise and health promotion counseling on functional and physical capacity, the symptom burden and quality of life in patients with acute leukemia during out patient management. The results will inform clinical practice exercise guidelines and rehabilitation programs for patients undergoing treatment for acute leukemia. Optimizing the treatment and care pathway may ease the transition for patients from illness to the resumption of everyday activities.Trial Registration: ClinicalTrials.gov Identifier: NCT01404520. [ABSTRACT FROM AUTHOR]

Background: It is estimated that 29% of deaths in Australia are caused by malignant disease each year and can be expected to increase with population ageing. In advanced cancer, the prevalence of fatigue is high at 70-90%, and can be related to the disease and/or the treatment. The negative impact of fatigue on function (physical, mental, social and spiritual) and quality of life is substantial for many palliative patients as well as their families/carers. Method/design: This paper describes the design of single patient trials (n-of-1 s or SPTs) of a psychostimulant, methylphenidate hydrochloride (MPH) (5 mg bd), compared to placebo as a treatment for fatigue, with a population estimate of the benefit by the aggregation of multiple SPTs. Forty patients who have advanced cancer will be enrolled through specialist palliative care services in Australia. Patients will complete up to 3 cycles of treatment. Each cycle is 6 days long and has 3 days treatment and 3 days placebo. The order of treatment and placebo is randomly allocated for each cycle. The primary outcome is a reduction in fatigue severity as measured by the Functional Assessment of Cancer Therapy-fatigue subscale (FACIT-F). Secondary outcomes include adverse events, quality of life, additional fatigue assessments, depression and Australian Karnovsky Performance Scale. Discussion: This study will provide high-level evidence using a novel methodological approach about the effectiveness of psychostimulants for cancer-related fatigue. If effective, the findings will guide clinical practice in reducing this prevalent condition to improve function and quality of life. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12609000794202. [ABSTRACT FROM AUTHOR]

Background: After the first six months of exclusive breastfeeding, children are introduced to liquids and semi-solid food, known as the complementary feeding phase. This phase is critical because it is often accompanied by improper feeding in children, which may lead to wasting and other nutrition problems. Fortified biscuits have been provided for wasting children as a nationwide programme. However, the ability of children to accept food supplementation remains questionable. This paper describes the protocol of a study investigating the efficacy of food supplementation (PMT biscuit) and nutrition education to improve the nutritional status of wasting children in Indonesia.Method: The efficacy of a government food supplementation programme will be examined using a randomized control trial design. Parents with wasting children aged 6-17 months will be recruited to participate in the study. After obtaining informed consent and pre-intervention measures, participants will be assigned into three arms of intervention with PMT biscuits and/or nutrition education only. The two primary outcomes for this study are the nutritional status of wasting children and PMT biscuit compliance. Characteristics of all subjects in each arm will be analysed and compared with each other to assess their comparability at the beginning. The data will be collected at pre-intervention, at 3 months of intervention, post-intervention, and at the 6- to 9-month follow up.Discussion: This paper aims to describe the study protocol of a randomized controlled trial investigating the effects of different PMT biscuit portion and nutrition education in two arms and nutrition education only in another arm. This study is important because it will provide evidence for the Indonesian government regarding the efficacy of food supplementation and/or food-based recommendations to improve the nutritional status of wasting children aged 6-23 months in Indonesia.Trial Registration: The study has been registered at clinicaltrials.gov, maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH), on April 26, 2018, and was last updated on April 30, 2018 (registration number: NCT03509155 ). [ABSTRACT FROM AUTHOR]

Background: To combat emerging drug resistance in the Greater Mekong Sub-region (GMS) the World Health Organization and GMS countries have committed to eliminating malaria in the region by 2030. The overall approach includes providing universal access to diagnosis and treatment of malaria, and sustainable preventive measures, including vector control. Topical repellents are an intervention that can be used to target residual malaria transmission not covered by long lasting insecticide nets and indoor residual spraying. Although there is strong evidence that topical repellents protect against mosquito bites, evidence is not well established for the effectiveness of repellents distributed as part of malaria control activities in protecting against episodes of malaria. A common approach to deliver malaria services is to assign Village Health Volunteers (VHVs) to villages, particularly where limited or no services exist. The proposed trial aims to provide evidence for the effectiveness of repellent distributed through VHVs in reducing malaria.Methods: The study is an open stepped-wedge cluster-randomised controlled trial randomised at the village level. Using this approach, repellent (N,N-diethyl-benzamide - 12% w/w, cream) is distributed by VHVs in villages sequentially throughout the malaria transmission season. Villages will be grouped into blocks, with blocks transitioned monthly from control (no repellent) to intervention states (to receive repellent) across 14 monthly intervals in random order). This follows a 4-week baseline period where all villages do not receive repellent. The primary endpoint is defined as the number of individuals positive for Plasmodium falciparum and Plasmodium vivax infections diagnosed by a rapid diagnostic test. Secondary endpoints include symptomatic malaria, Polymerase Chain Reaction (PCR)-detectable Plasmodium spp. infections, molecular markers of drug resistance and antibodies specific for Plasmodium spp. parasites.Discussion: This study has been approved by relevant institutional ethics committees in Myanmar and Australia. Results will be disseminated through workshops, conferences and peer-reviewed publications. Findings will contribute to a better understanding of the optimal distribution mechanisms of repellent, context specific effectiveness and inform policy makers and implementers of malaria elimination programs in the GMS.Trial Registration: Australian and New Zealand Clinical Trials Registry ( ACTRN12616001434482 ). Retrospectively registered 14th October 2016. [ABSTRACT FROM AUTHOR]

Background: Large multicentre trials are complex and expensive projects. A key factor for their successful planning and delivery is how well sites meet their targets in recruiting and retaining participants, and in collecting high-quality, complete data in a timely manner. Collecting and monitoring easily accessible data relevant to performance of sites has the potential to improve trial management efficiency. The aim of this systematic review was to identify metrics that have either been proposed or used for monitoring site performance in multicentre trials.Methods: We searched the Cochrane Library, five biomedical bibliographic databases (CINAHL, EMBASE, Medline, PsychINFO and SCOPUS) and Google Scholar for studies describing ways of monitoring or measuring individual site performance in multicentre randomised trials. Records identified were screened for eligibility. For included studies, data on study content were extracted independently by two reviewers, and disagreements resolved by discussion.Results: After removing duplicate citations, we identified 3188 records. Of these, 21 were eligible for inclusion and yielded 117 performance metrics. The median number of metrics reported per paper was 8, range 1-16. Metrics broadly fell into six categories: site potential; recruitment; retention; data collection; trial conduct and trial safety.Conclusions: This review identifies a list of metrics to monitor site performance within multicentre randomised trials. Those that would be easy to collect, and for which monitoring might trigger actions to mitigate problems at site level, merit further evaluation. [ABSTRACT FROM AUTHOR]

Background: Water, sanitation, and hygiene (WASH) efficacy trials deliver interventions to the target population under optimal conditions to estimate their effects on outcomes of interest, to inform subsequent selection for inclusion in routine programs. A systematic and intensive approach to intervention delivery is required to achieve the high-level uptake necessary to measure efficacy. We describe the intervention delivery system adopted in the WASH Benefits Bangladesh study, as part of a three-paper series on WASH Benefits Intervention Delivery and Performance.Methods: Community Health Workers (CHWs) delivered individual and combined WASH and nutrition interventions to 4169 enrolled households in geographically matched clusters. Households were provided with free enabling technologies and supplies, integrated with parallel behaviour-change promotion. Behavioural objectives were drinking treated, safely stored water, safe feces disposal, handwashing with soap at key times, and age-appropriate nutrition behaviours (birth to 24 months). The intervention delivery system built on lessons learned from prior WASH intervention effectiveness, implementation, and formative research studies. We recruited local CHWs, residents of the study villages, through transparent merit-based selection methods, and consultation with community leaders. CHW supervisors received training on direct intervention delivery, then trained their assigned CHWs. CHWs in turn used the technologies in their own homes. Each CHW counseled six to eight intervention households spread across a 0.2-2.2-km radius, with a 1:12 supervisor-to-CHW ratio. CHWs met monthly with supervisor-trainers to exchange experiences and adapt technology and behaviour-change approaches to evolving conditions. Intervention uptake was tracked through fidelity measures, with a priori benchmarks necessary for an efficacy study.Results: Sufficient levels of uptake were attained by the fourth intervention assessment month and sustained throughout the intervention period. Periodic internal CHW monitoring resulted in discontinuation of a small number of low performers.Conclusions: The intensive intervention delivery system required for an efficacy trial differs in many respects from the system for a routine program. To implement a routine program at scale requires further research on how to optimize the supervisor-to-CHW-to-intervention household ratios, as well as other program costs without compromising program effectiveness.Trial Registration: ClinicalTrials.gov, ID: NCC01590095 . Registered on 2 May 2012. [ABSTRACT FROM AUTHOR]

Background: Child maltreatment is a significant public health problem. Group Family Nurse Partnership (gFNP) is a new intervention for young, expectant mothers implemented successfully in pilot studies. This study was designed to determine the effectiveness and cost-effectiveness of gFNP in reducing risk factors for maltreatment with a potentially vulnerable population.Methods: A multi-site, randomized controlled, parallel-arm trial and prospective economic evaluation was conducted, with allocation via remote randomization (minimization by site, maternal age group) to gFNP or usual care. Participants were expectant mothers aged below 20 years with at least one live birth, or aged 20-24 years with no live births and with low educational qualifications. Data from maternal interviews at baseline and when infants were 2, 6 and 12 months, and video-recording at 12 months, were collected by researchers blind to allocation. Cost information came from weekly logs completed by gFNP family nurses and other service delivery data reported by participants. Primary outcomes measured at 12 months were parenting attitudes (Adult-Adolescent Parenting Index, AAPI-2) and maternal sensitivity (CARE Index). The economic evaluation was conducted from a UK NHS and personal social services perspective with cost-effectiveness expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The main analyses were intention-to-treat with additional complier average causal effects (CACE) analyses.Results: Between August 2013 and September 2014, 492 names of potential participants were received of whom 319 were eligible and 166 agreed to take part, 99 randomly assigned to receive gFNP and 67 to usual care. There were no between-arm differences in AAPI-2 total (7 · 5/10 in both, SE 0.1), difference adjusted for baseline, site and maternal age group 0 · 06 (95% CI - 0 · 15 to 0 · 28, p = 0 · 59) or CARE Index (intervention 4 · 0 (SE 0 · 3); control 4 · 7 (SE 0 · 4); difference adjusted for site and maternal age group - 0 · 68 (95% CI - 1 · 62 to 0 · 16, p = 0 · 25) scores. The probability that gFNP is cost-effective based on the QALY measure did not exceed 3%.Conclusions: The trial did not support gFNP as a means of reducing the risk of child maltreatment in this population but slow recruitment adversely affected group size and consequently delivery of the intervention.Trial Registration: ISRCTN78814904 . Registered on 17 May 2013. [ABSTRACT FROM AUTHOR]

Background: There are few published standards or methodological guidelines for integrating Data Quality Assurance (DQA) protocols into large-scale health systems research trials, especially in resource-limited settings. The BetterBirth Trial is a matched-pair, cluster-randomized controlled trial (RCT) of the BetterBirth Program, which seeks to improve quality of facility-based deliveries and reduce 7-day maternal and neonatal mortality and maternal morbidity in Uttar Pradesh, India. In the trial, over 6300 deliveries were observed and over 153,000 mother-baby pairs across 120 study sites were followed to assess health outcomes. We designed and implemented a robust and integrated DQA system to sustain high-quality data throughout the trial.Methods: We designed the Data Quality Monitoring and Improvement System (DQMIS) to reinforce six dimensions of data quality: accuracy, reliability, timeliness, completeness, precision, and integrity. The DQMIS was comprised of five functional components: 1) a monitoring and evaluation team to support the system; 2) a DQA protocol, including data collection audits and targets, rapid data feedback, and supportive supervision; 3) training; 4) standard operating procedures for data collection; and 5) an electronic data collection and reporting system. Routine audits by supervisors included double data entry, simultaneous delivery observations, and review of recorded calls to patients. Data feedback reports identified errors automatically, facilitating supportive supervision through a continuous quality improvement model.Results: The five functional components of the DQMIS successfully reinforced data reliability, timeliness, completeness, precision, and integrity. The DQMIS also resulted in 98.33% accuracy across all data collection activities in the trial. All data collection activities demonstrated improvement in accuracy throughout implementation. Data collectors demonstrated a statistically significant (p = 0.0004) increase in accuracy throughout consecutive audits. The DQMIS was successful, despite an increase from 20 to 130 data collectors.Conclusions: In the absence of widely disseminated data quality methods and standards for large RCT interventions in limited-resource settings, we developed an integrated DQA system, combining auditing, rapid data feedback, and supportive supervision, which ensured high-quality data and could serve as a model for future health systems research trials. Future efforts should focus on standardization of DQA processes for health systems research.Trial Registration: ClinicalTrials.gov identifier, NCT02148952 . Registered on 13 February 2014. [ABSTRACT FROM AUTHOR]

Background: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non-inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here.Methods/design: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8-10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator-determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper.Discussion: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias.Trial Registration: EU Clinical Trials Register (EudraCT number: 2016-001528-69). Registered on 5 April 2016. ClinicalTrials.gov, ID: NCT02922686 . Registered on 9 August 2016. [ABSTRACT FROM AUTHOR]