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BackgroundTraumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.ObjectiveTo study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.MethodsCIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.DiscussionWe expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients.Trial registrationClinicalTrials.govNCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58

Men's perpetration of intimate partner violence (IPV) limits gains in health and wellbeing for populations globally. Largely informal, rapidly expanding peri-urban settlements, with limited basic services such as electricity, have high prevalence rates of IPV. Evidence on how to reduce men's perpetration, change social norms and patriarchal attitudes within these settings is limited. Our cluster randomised controlled trial aimed to determine the effectiveness of the Sonke CHANGE intervention in reducing use of sexual and/or physical IPV and severity of perpetration by men aged 18-40 years over 2 years.The theory-based intervention delivered activities to bolster community action, including door-to-door discussions, workshops, drawing on the CHANGE curriculum, and deploying community action teams over 18 months. In 2016 and 2018, we collected data from a cohort of men, recruited from 18 clusters; nine were randomised to receive the intervention, while the nine control clusters received no intervention. A self-administered questionnaire, using audio-computer assisted software, asked about sociodemographics, gender attitudes, mental health, and the use and severity of IPV. We conducted an intention-to-treat analysis at the cluster level comparing the expected risk to observed risk of using IPV while controlling for baseline characteristics. A secondary analysis used latent classes (LCA) of men to see whether there were differential effects of the intervention for subgroups of men.Of 2406 men recruited, 1458 (63%) were followed to 2 years. Overall, we saw a reduction in men's reports of physical, sexual and severe IPV from baseline to endpoint (40.2% to 25.4%, 31.8% to 15.8%, and 33.4% to 18.2%, respectively). Intention-to-treat analysis showed no measurable differences between intervention and control clusters for primary IPV outcomes. Difference in the cluster-level proportion of physical IPV perpetration was 0.002 (95% confidence interval [CI] - 0.07 to 0.08). Similarly, differences between arms for sexual IPV was 0.01 (95% CI - 0.04 to 0.06), while severe IPV followed a similar pattern (Diff = 0.01; 95% CI - 0.05 to 0.07). A secondary analysis using LCA suggests that among the men living in intervention communities, there was a greater reduction in IPV among less violent and more law abiding men than among more highly violent men, although the differences did not reach statistical significance.The intervention, when implemented in a peri-urban settlement, had limited effect in reducing IPV perpetrated by male residents. Further analysis showed it was unable to transform entrenched gender attitudes and use of IPV by those men who use the most violence, but the intervention showed promise for men who use violence less.ClinicalTrials.gov, NCT02823288. Registered on 30 June 2016.

Background Knee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA. Methods/design We will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses. Discussion This study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016. Universal Trial Number (UTN) U1111–1181-7087.

Contains fulltext : 200404.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. However, persistent pain after cholecystectomy for symptomatic cholecystolithiasis is reported in up to 40% of patients. The aim of the SECURE trial is to compare the effectiveness of usual care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. The SECURE trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound-proven gallstones or sludge. Randomization was performed to either usual care (standard practice, according to the physician's knowledge and experience, and physician's and patient's preference) or a restrictive standardized strategy: treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy based on fulfilment of pre-specified criteria. This article presents in detail the statistical analysis plan (SAP) of this trial and was submitted before outcomes were available to the investigators. RESULTS: The primary end point of this trial is defined as the proportion of patients being pain-free at 12 months' follow-up. Pain will be assessed with the Izbicki Pain Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, quality of life, the association between the patients' symptoms and treatment, work performance, and cost-effectiveness. DISCUSSION: The data from the SECURE trial will provide evidence whether or not a restrictive strategy in patients with symptomatic cholecystolithiasis is associated with similar patient reported outcomes and a reduction in the number of cholecystectomies compared to usual care. The data from this trial will be analyzed according to this pre-specified SAP. TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022 . Registered on 5 June 2013.

Background A previous randomised controlled trial (RCT) of patients with chronic low back pain (LBP) and vertebral bone marrow (Modic) changes (MCs) on magnetic resonance imaging (MRI), reported that a 3-month, high-dose course of antibiotics had a better effect than placebo at 12 months’ follow-up. The present study examines the effects of antibiotic treatment in chronic LBP patients with MCs at the level of a lumbar disc herniation, similar to the previous study. It also aims to assess the cost-effectiveness of the treatment, refine the MRI assessment of MCs, and further evaluate the impact of the treatment and the pathogenesis of MCs by studying genetic variability and the gene and protein expression of inflammatory biomarkers. Methods/design A double-blinded RCT is conducted at six hospitals in Norway, comparing orally administered amoxicillin 750 mg, or placebo three times a day, over a period of 100 days in patients with chronic LBP and type I or II MCs at the level of a MRI-confirmed lumbar disc herniation within the preceding 2 years. The inclusion will be stopped when at least 80 patients are included in each of the two MC type groups. In each MC type group, the study is designed to detect (β = 0.1, α = 0.05) a mean difference of 4 (standard deviation 5) in the Roland Morris Disability Questionnaire score between the two treatment groups (amoxicillin or placebo) at 1-year follow-up. The study includes cost-effectiveness measures. Blood samples are assessed for security measures and for possible inflammatory mediators and biomarkers at different time points. MCs are evaluated on MRI at baseline and after 12 months. A blinded intention-to-treat analysis of treatment effects will be performed in the total sample and in each MC type group. Discussion To ensure the appropriate use of antibiotic treatment, its effect in chronic LBP patients with MCs should be re-assessed. This study will investigate the effects and cost-effectiveness of amoxicillin in patients with chronic LBP and MCs at the level of a disc herniation. The study may also help to refine imaging and characterise the biomarkers of MCs. © The Author(s). 2017O. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Background Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. Methods/design A prospective randomized placebo-controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12–23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (Δ%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in Δ%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. Discussion A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. Trial Registration Clinicaltrials.gov, NCT02925026. Registered on 4 October 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2278-8) contains supplementary material, which is available to authorized users.

Background Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a ‘good’ mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a ‘poor response’ identifies an adverse prognostic group which may benefit from additional pre-operative therapy. Methods/design TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. Discussion The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. Trial registration ClinicalTrials.gov, ID: NCT02704520. Registered on 5 February 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2085-2) contains supplementary material, which is available to authorized users.

Background The routine implementation of sternal precautions to prevent sternal complications that restrict the use of the upper limbs is currently worldwide practice following a median sternotomy. However, evidence is limited and drawn primarily from cadaver studies and orthopaedic research. Sternal precautions may delay recovery, prolong hospital discharge and be overly restrictive. Recent research has shown that upper limb exercise reduces post-operative sternal pain and results in minimal micromotion between the sternal edges as measured by ultrasound. The aims of this study are to evaluate the effects of modified sternal precautions on physical function, pain, recovery and health-related quality of life after cardiac surgery. Methods/design This study is a phase II, double-blind, randomised controlled trial with concealed allocation, blinding of patients and assessors, and intention-to-treat analysis. Patients (n = 72) will be recruited following cardiac surgery via a median sternotomy. Sample size calculations were based on the minimal important difference (two points) for the primary outcome: Short Physical Performance Battery. Thirty-six participants are required per group to counter dropout (20%). All participants will be randomised to receive either standard or modified sternal precautions. The intervention group will receive guidelines encouraging the safe use of the upper limbs. Secondary outcomes are upper limb function, pain, kinesiophobia and health-related quality of life. Descriptive statistics will be used to summarise data. The primary hypothesis will be examined by repeated-measures analysis of variance to evaluate the changes from baseline to 4 weeks post-operatively in the intervention arm compared with the usual-care arm. In all tests to be conducted, a p value

Background This randomised controlled study evaluated a computer-generated future self-image as a personalised, visual motivational tool for weight loss in adults. Methods One hundred and forty-five people (age 18–79 years) with a Body Mass Index (BMI) of at least 25 kg/m2 were randomised to receive a hard copy future self-image at recruitment (early image) or after 8 weeks (delayed image). Participants received general healthy lifestyle information at recruitment and were weighed at 4-weekly intervals for 24 weeks. The image was created using an iPad app called ‘Future Me’. A second randomisation at 16 weeks allocated either an additional future self-image or no additional image. Results Seventy-four participants were allocated to receive their image at commencement, and 71 to the delayed-image group. Regarding to weight loss, the delayed-image group did consistently better in all analyses. Twenty-four recruits were deemed non-starters, comprising 15 (21%) in the delayed-image group and 9 (12%) in the early-image group (χ2(1) = 2.1, p = 0.15). At 24 weeks there was a significant change in weight overall (p

Background Randomized trials are considered the gold standard for making inferences about the causal effects of treatments. However, when protocol deviations occur, the baseline randomization of the trial is no longer sufficient to ensure unbiased estimation of the per-protocol effect: post-randomization, time-varying confounders must be sufficiently measured and adjusted for in the analysis. Given the historical emphasis on intention-to-treat effects in randomized trials, measurement of post-randomization confounders is typically infrequent. This may induce bias in estimates of the per-protocol effect, even using methods such as inverse probability weighting, which appropriately account for time-varying confounders affected by past treatment. Methods/design In order to concretely illustrate the potential magnitude of bias due to infrequent measurement of time-varying covariates, we simulated data from a very large trial with a survival outcome and time-varying confounding affected by past treatment. We generated the data such that the true underlying per-protocol effect is null and under varying degrees of confounding (strong, moderate, weak). In the simulated data, we estimated per-protocol survival curves and associated contrasts using inverse probability weighting under monthly measurement of the time-varying covariates (which constituted complete measurement in our simulation), yearly measurement, as well as 3- and 6-month intervals. Results Using inverse probability weighting, we were able to recover the true null under the complete measurement scenario no matter the strength of confounding. Under yearly measurement intervals, the estimate of the per-protocol effect diverged from the null; inverse probability weighted estimates of the per-protocol 5-year risk ratio based on yearly measurement were 1.19, 1.12, and 1.03 under strong, moderate, and weak confounding, respectively. Bias decreased with measurement interval length. Under all scenarios, inverse probability weighted estimators were considerably less biased than a naive estimator that ignored time-varying confounding completely. Conclusions Bias that arises from interval measurement designs highlights the need for planning in the design of randomized trials for collection of time-varying covariate data. This may come from more frequent in-person measurement or external sources (e.g., electronic medical record data). Such planning will provide improved estimates of the per-protocol effect through the use of methods that appropriately adjust for time-varying confounders. Electronic supplementary material The online version of this article (10.1186/s13063-019-3577-z) contains supplementary material, which is available to authorized users.

Rationale Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH). Methods and design TICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat. Results This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year. Discussion The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy. Trial registration ISRCTN registry, ID: ISRCTN93732214. Registered on 17 January 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2341-5) contains supplementary material, which is available to authorized users.

Background There has been a recent steep growth in platelet-rich plasma (PRP) use for musculoskeletal conditions, but findings from high quality clinical trial data are lacking in the literature. Here, we describe the statistical analysis plan (SAP) for the Platelet-rich plasma in Achilles Tendon Healing 2 (PATH-2) trial. Methods PATH-2 is a pragmatic, parallel-group, multi-centre, double-blinded, randomised, placebo-controlled, superiority trial. The study aims to evaluate the clinical efficacy of PRP in acute Achilles tendon rupture in terms of muscle-tendon function. Patients are identified in the orthopaedic/trauma outpatient clinic. The primary outcome is muscle-tendon work capacity from the Heel Rise Endurance Test result, expressed as the Limb Symmetry Index (work, in joules), at 24 weeks post randomisation. Multivariate linear regression adjusting for the stratification factors (centre and age) and additional prognostic factors will be used to investigate the adjusted effect of the intervention. The analysis will be by modified intention-to-treat. Sensitivity analysis will assess the internal validity of the trial results by performing a per-protocol analysis. Safety will be summarised by treatment arm for all patients who started treatment. Secondary patient-reported outcome measures will be analysed using linear mixed effects models to allow all data collected at all follow-up points to be considered. Missing data will be summarised and reported by treatment arm. Missing data imputation will be performed, if appropriate. Discussion The PATH-2 trial will be reported in accordance with the CONSORT statement. This SAP publication will avoid bias arising from prior knowledge of the study results. Any changes or deviations from the current SAP will be described and justified in the final report. Trial registration ISRCTN registry: ISRCTN54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850. Electronic supplementary material The online version of this article (10.1186/s13063-018-2840-z) contains supplementary material, which is available to authorized users.

Background Neuropathic pain is difficult to treat, and the efficacy of recommended drugs remains limited. N-methyl-d-aspartate receptors are implicated, and antagonists are a pharmacological option. Ketamine is widely used in French pain clinics, but without consensus or recommendations. Furthermore, the association of ketamine with magnesium has been poorly studied. The aim of the present study is to evaluate the benefit of ketamine with or without magnesium in refractory neuropathic pain. Methods/design A randomized, double-blind, crossover, placebo-controlled study will be performed in Clermont-Ferrand University Hospital, Clermont-Ferrand, France. The aim is to evaluate the effect of ketamine with or without magnesium in 22 patients with neuropathic pain. Intravenous ketamine/placebo, ketamine/magnesium sulfate, or placebo/placebo will be administered consecutively to each patient, in random order, once at 5-week intervals. The primary endpoint is the AUC of pain intensity assessed on a 0–10 Numeric Pain Rating Scale for a 5-week period. Data analysis will be performed on an intention-to-treat basis, and all statistical tests (except primary analysis) will be performed with an α risk of 5% (two-sided). Discussion Considering the poor efficacy of the drugs available for neuropathic pain, ketamine with or without magnesium sulfate may be a valuable therapeutic option that needs to be standardized. Trial registration EudraCT number–2015-000142-29. Registered on April 9, 2015; version 1.4 Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2254-3) contains supplementary material, which is available to authorized users.

Background: Cooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial.Methods/design: The EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes).Discussion: Major adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size.Trial registration: Clinicaltrials.gov, identifier: NCT01833312. 4 April 2013.

Background Obstructive sleep apnea (OSA) occurs due to sleep-induced upper airway muscle relaxation resulting in increased pharyngeal collapsibility. Clinical trials have shown a favorable effect of exercise training on OSA severity in middle-aged adults. Aging is characterized by motor-unit loss. Force training may affect the whole body muscle tone. We hypothesize that interventions increasing muscle strength might propagate to motor units at the abductor pharyngeal muscles, reducing collapsibility and, hence, sleep apnea severity in elderly patients with obstructive sleep apnea. Methods/design This is a randomized clinical trial including patients between 65 and 80 years of age, with obstructive sleep apnea, and an apnea-hypopnea index (AHI) between 20 and 50 events/hour, diagnosed by out-of-center in-home type III polysomnography. Forty subjects will be included and randomly assigned to two equal sized groups. The participants allocated to the intervention group will attend two sessions per week of one-hour strength training for the legs, arms, chest, back, and abdomen and the controls will receive advice on lifestyle change. The primary outcome measure of the study will be the change in apnea-hypopnea index and the secondary outcomes will be the body composition, evaluated by anthropometric and bioelectrical impedance variables; maximum dynamic force, appraised by one-repetition maximum strength test; muscle quality and thickness by ultrasound; physical function assessed by sit-to-stand test, timed up and go test, handgrip strength test. The study duration will be 12 weeks. Intention-to-treat and per-protocol analyses will be performed. Discussion The high prevalence of obstructive sleep apnea in elderly people is a public health issue. OSA is a recognized cause of cardiovascular disease and reduces quality of life due to sleepiness and fatigue. Exercise is a low-cost intervention that could help to detain the trend towards age-dependent loss of pharyngeal motor units and progressive severity of obstructive sleep apnea. Home-based strength exercises may represent a more practical approach than aerobic exercise for elderly patients. If the results confirm our hypothesis, further research on the clinical application of our findings will be warranted. Trial registration ClinicalTrials.gov, NCT02742792. Registered on 1 April 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2238-3) contains supplementary material, which is available to authorized users.

Background Most patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in primary care are prescribed an antibiotic, which may not always be appropriate and may cause harm. C-reactive protein (CRP) is an acute-phase biomarker that can be rapidly measured at the point of care and may predict benefit from antibiotic treatment in AECOPD. It is not clear whether the addition of a CRP point-of-care test (POCT) to clinical assessment leads to a reduction in antibiotic consumption without having a negative impact on COPD health status. Methods/design This is a multicentre, individually randomised controlled trial (RCT) aiming to include 650 participants with a diagnosis of AECOPD in primary care. Participants will be randomised to be managed according to usual care (control) or with the addition of a CRP POCT to guide antibiotic prescribing. Antibiotic consumption for AECOPD within 4 weeks post randomisation and COPD health status (total score) measured by the Clinical COPD Questionnaire (CCQ) at 2 weeks post randomisation will be co-primary outcomes. Primary analysis (by intention-to-treat) will determine differences in antibiotic consumption for superiority and COPD health status for non-inferiority. Secondary outcomes include: COPD health status, CCQ domain scores, use of other COPD treatments (weeks 1, 2 and 4), EQ-5D utility scores (weeks 1, 2 and 4 and month 6), disease-specific, health-related quality of life (HRQoL) at 6 months, all-cause antibiotic consumption (antibiotic use for any condition) during first 4 weeks post randomisation, total antibiotic consumption (number of days during first 4 weeks of antibiotic consumed for AECOPD/any reason), antibiotic prescribing at the index consultation and during following 4 weeks, adverse effects over the first 4 weeks, incidence of pneumonia (weeks 4 and 6 months), health care resource use and cost comparison over the 6 months following randomisation. Prevalence and resistance profiles of bacteria will be assessed using throat and sputum samples collected at baseline and 4-week follow-up. A health economic evaluation and qualitative process evaluation will be carried out. Discussion If shown to be effective (i.e. leads to a reduction in antibiotic use with no worse COPD health status), the use of the CRP POCT could lead to better outcomes for patients with AECOPD and help reduce selective pressures driving the development of antimicrobial resistance. PACE will be one of the first studies to evaluate the cost-effectiveness of a POCT biomarker to guide clinical decision-making in primary care on patient-reported outcomes, antibiotic prescribing and antibiotic resistance for AECOPD. Trial registration ISRCTN registry, ID: ISRCTN24346473. Registered on 20 August 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2144-8) contains supplementary material, which is available to authorized users.

Background Although not always recognized as a pressing health care problem, wounds are a common, complex and costly condition. The burden of treating wounds is growing rapidly due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. The Integrated Client Care (ICC) Project was a multi-year initiative to develop and test a new, integrated model of wound care within the home care sector in Ontario, Canada to improve health outcomes for patients and decrease system costs. Methods Cluster randomized trial, with allocation of intervention randomized at the cluster level (14 home care centers) and analysis of outcomes based on individual-level data (patients). Primary analysis was an intention-to-treat (ITT) analysis. Two wound types, diabetic foot ulcers and pilonidal sinus, were selected as tracer conditions to assess the impact of the intervention on two different patient populations. Time to successful discharge from home care was analyzed using multivariable Cox proportional hazards regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. Results A total of 12,063 diabetic foot ulcer patients and 1954 pilonidal sinus patient records were available for analysis. No appreciable differences were observed between patients in the control and intervention arms for either of the primary or secondary analyses in either condition group. In the diabetic foot ulcer group, 72.7% patients in the control arm and 73.6% patients in the intervention arm were discharged in the follow-up period (HR 1.05; 95% CI 0.94 to 1.17). In the pilonidal sinus group, 91.0% patients in the control arm and 89.0% patients in the intervention arm were discharged in the follow-up period (HR 0.96; 95% CI 0.82 to 1.12). Conclusion As implemented, the ICC intervention was not effective, most likely due to failure of implementation, and is, therefore, not ready for widespread implementation in Ontario. Significant work remains to be done to correct the implementation process so that the concept of outcome-based health care can be properly evaluated. Trial registration ClinicalTrials.gov, ID: NCT01573832 . Registered on 12 January 2012.

Background South Africa recently phased out access to free formula milk in the public sector in support of breastfeeding for women living with HIV. Few women living with HIV in South Africa choose breastfeeding and among those who do, many stop breastfeeding early. We sought to explore the feasibility of using mobile phone text messaging coupled with motivational interviewing to enhance adherence to breastfeeding practices. Methods and design A randomized, parallel group, single-center pilot trial. Electronic sequence generation and random allocation will be done centrally. Women of low socioeconomic status, from Cape Town, South Africa will be randomly assigned within 24 h of giving birth at a primary healthcare clinic to a structured weekly text message plus motivational interviewing and usual standard of care, using a permutation of different block sizes. Criteria for feasibility success will include: five participants recruited per week (over 12 weeks), about 75% of all eligible participants consent for study participation, complete evaluation of outcomes in at least 70% of all recruited participants, breastfeeding adherence rates of at least 70% in the intervention group, six months after delivery. Participants will be evaluated soon after giving birth and post-delivery at weeks 2, 6, 10, and 24. Primary analysis will follow the “intention-to-treat” principle. Sub-group analysis will be used to assess sub-group effects. Discussion This pilot trial will evaluate the feasibility of conducting a larger trial on communication and support approaches to improve adherence to breastfeeding by HIV-infected women. Text messaging and motivational interviewing are simple interventions which may allow participants to access personalized adherence advice and support. Trial registration ClinicalTrials.gov: NCT02949713. Registered on 26 October 2016; Pan African Clinical Trial Registry PACTR201611001855404. Registered on 8 November 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2079-0) contains supplementary material, which is available to authorized users.

Background Attention has shifted to the use of non-pharmacological interventions to prevent cognitive decline as a preventive strategy, as well as for those at risk and those with mild cognitive impairment. Early introduction of psycho-social interventions can address cognitive decline and significantly impact quality of life and the wellbeing of elderly individuals. This pilot study explores the feasibility of using art therapy and music reminiscence activity to improve the cognition of community living elderly with mild cognitive impairment. Methods/Design This open-label, interventional study involves a parallel randomized controlled trial design with three arms (two intervention arms and a control group) over a nine-month period. Participants will be community-living elderly individuals aged 60–85 years, both genders, who meet predefined inclusion and exclusion criteria. In the initial three months, interventions will be provided weekly and for the remaining six months fortnightly. A sample size of 90 participants is targeted based on expected neuropsychological test performance, a primary outcome measure, and drop-out rates. The randomization procedure will be carried out via a web-based randomization system. Interventions will be provided by trained staff with a control group not receiving any intervention but continuing life as usual. Assessments will be done at baseline, three months, and nine months, and include neuroimaging to measure cerebral changes and neuropsychological tests to measure for changes in cognition. Secondary outcome measures will include mood changes in anxiety and depression and telomere lengths. Statistical analysis will be undertaken by statisticians; all efficacy analysis will be carried out on an intention-to-treat basis. Primary and secondary outcomes will be modeled using the linear mixed model for repeated measurements and further analysis may be undertaken to adjust for potential confounders. Discussion This will be the first study to compare the effectiveness of art therapy and music reminiscence activity in a randomized controlled trial. We expect that the trial will provide useful evidence for developing psychosocial interventions for the elderly with mild cognitive impairment. Trial registration The study was registered on 7 July 2016 at Clinical Trials.gov, a service of the US National Institute of Health (NCT02854085), retrospectively. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2080-7) contains supplementary material, which is available to authorized users.

Background Postoperative surgical site infection (SSI) is one of the most common hospital infections and contributes substantially to postoperative morbidity and mortality. In addition, SSIs dramatically increase the treatment cost and length of hospital stay. Following visceral surgery by laparotomy, SSI rates are especially high (14–25%). Therefore, measures to prevent SSI in this field are urgently needed. Prophylactic intraoperative wound irrigation (IOWI) of the subcutaneous soft tissue before skin closure hypothetically represents an easy and economical option to reduce SSI rates and is already frequently used in clinical practice. However, there are currently no definite recommendations on the use of IOWI since high-level evidence supporting its use is lacking. Consequently, clinical practice varies widely. Antiseptic polyhexanide (PHX)-based solutions are approved for soft-tissue wound irrigation in surgery but have not been specifically evaluated in randomized clinical trials for the prevention of SSI following laparotomy for visceral surgery. Methods/design The IOWISI trial is a multicentre, randomized, observer- and patient-blinded clinical trial with three parallel treatment groups, comparing IOWI with a 0.04% PHX solution to no irrigation (test 1) or saline (test 2) before skin closure after laparotomy for visceral surgery (contamination level II–IV). The primary endpoint of the trial is the SSI rate within 30 days postoperatively. Statistical analysis of the primary endpoint measure will be based on the intention-to-treat population. The global level of significance is set at 2.5% for test 1 and 5% for test 2 and the sample size (n = 540) is determined to assure a power of 94% (test 1) and 85% (test 2). Discussion The IOWISI trial will provide high-level evidence as a basis for clinical recommendations regarding the use of IOWI with PHX or saline and will potentially impact on future clinical guidelines and practice. The pragmatic trial design guarantees high external validity. Trial registration Registered at the German Clinical Trials Register, DRKS00012251. Registered on 3 July 2017. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2154-6) contains supplementary material, which is available to authorized users.

Background Postpartum haemorrhage complicates approximately 10% of all deliveries and contributes to at least a quarter of all maternal deaths worldwide. The competency-based Helping Mothers Survive Bleeding after Birth (HMS BAB) training was developed to support evidence-based management of postpartum haemorrhage. This one-day training includes low-cost MamaNatalie® birthing simulators and addresses both prevention and first-line treatment of haemorrhage. While evidence is accumulating that the training improves health provider’s knowledge, skills and confidence, evidence is missing as to whether this translates into improved practices and reduced maternal morbidity and mortality. This cluster-randomised trial aims to assess whether this training package — involving a one-day competency-based HMS BAB in-facility training provided by certified trainers followed by 8 weeks of in-service peer-based practice — has an effect on the occurrence of haemorrhage-related morbidity and mortality. Methods/design In Tanzania and Uganda we randomise 20 and 18 districts (clusters) respectively, with half receiving the training intervention. We use unblinded matched-pair randomisation to balance district health system characteristics and the main outcome, which is in-facility severe morbidity due to haemorrhage defined by the World Health Organizationation-promoted disease and management-based near-miss criteria. Data are collected continuously in the intervention and comparison districts throughout the 6-month baseline and the 9-month intervention phase, which commences after the training intervention. Trained facility midwives or clinicians review severe maternal complications to identify near misses on a daily basis. They abstract the case information from case notes and enter it onto programmed tablets where it is uploaded. Intention-to-treat analysis will be used, taking the matched design into consideration using paired t test statistics to compare the outcomes between the intervention and comparison districts. We also assess the impact pathway from the effects of the training on the health provider’s skills, care and interventions and health system readiness. Discussion This trial aims to generate evidence on the effect and limitations of this well-designed training package supported by birthing simulations. While the lack of blinding of participants and data collectors provides an inevitable limitation of this trial, the additional evaluation along the pathway of implementation will provide solid evidence on the effects of this HMS BAB training package. Trial registration Pan African Clinical Trials Registry, PACTR201604001582128. Registered on 12 April 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2056-7) contains supplementary material, which is available to authorized users.

Background Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. Methods/design This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. Discussion This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting. Trial registration ISRCTN identifier, ISRCTN22567894. Registered on 27 August 2015 EudraCT identifier, 2014-002188-13. Registered on 21 May 2014 NIHR HTA Grant: 12/127/134 Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2010-8) contains supplementary material, which is available to authorized users.

Background The at-risk mental state (ARMS) describes individuals at high risk of developing schizophrenia or psychosis. The use of antipsychotics in this population is not supported, because most individuals with ARMS are unlikely to develop psychosis. Anti-inflammatory treatments and polyunsaturated fatty acids (PUFAs) may have some beneficial effects in the treatment of ARMS. There have been no controlled clinical trials in which researchers have investigated the use of minocycline for ARMS and no trials involving PUFAs in combination with other proposed treatments. There is a need to find effective, tolerable and inexpensive interventions for individuals with ARMS that are available in high-, low- and middle-income countries. Methods/design A 6-month intervention study of minocycline and/or omega-3 fatty acids added to treatment as usual (TAU) in patients with ARMS will be conducted in Pakistan using a randomised, placebo-controlled, double-blind factorial design. A total of 320 consenting patients with capacity will be recruited from the community, general practitioner clinics and psychiatric units. Allowing for a 25% dropout rate, we will recruit 59 completing participants into each study arm, and in total 236 will complete the study. We will determine whether the addition of minocycline and/or omega-3 fatty acids to TAU attenuates the rate of transition from ARMS to first-episode psychosis and improves symptoms and/or level of functioning in ARMS. We will also investigate whether any candidate risk factors, such as negative symptoms, influence treatment response in the ARMS group. The primary efficacy endpoint is conversion to psychotic disorder at 12 months after study entry. Analysis will be done according to the intention to treat principle using analysis of variance, chi-square tests and adjusted ORs to assess between-group differences. Cox regression analysis will be used to evaluate potential between-group differences in time to onset of psychosis. Discussion The outcomes of this trial will provide evidence of the potential benefits of minocycline and PUFAs in the treatment of ARMS. Both minocycline and PUFAs are inexpensive, are readily available in low-/middle-income countries such as Pakistan, and if proven, may be safe and effective for treating individuals with ARMS. Trial registration ClinicalTrials.gov, NCT02569307. Registered on 3 October 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2275-y) contains supplementary material, which is available to authorized users.

Background NICE guidelines state cognitive behavioural therapy (CBT) is a front-line psychological treatment for people presenting with depression in primary care. Counselling for Depression (CfD), a form of Person-Centred Experiential therapy, is also offered within Improving Access to Psychological Therapies (IAPT) services for moderate depression but its effectiveness for severe depression has not been investigated. A full-scale randomised controlled trial to determine the efficacy and cost-effectiveness of CfD is required. Methods PRaCTICED is a two-arm, parallel group, non-inferiority randomised controlled trial comparing CfD against CBT. It is embedded within the local IAPT service using a stepped care service delivery model where CBT and CfD are routinely offered at step 3. Trial inclusion criteria comprise patients aged 18 years or over, wishing to work on their depression, judged to require a step 3 intervention, and meeting an ICD-10 diagnosis of moderate or severe depression. Patients are randomised using a centralised, web-based system to CfD or CBT with each treatment being delivered up to a maximum 20 sessions. Both interventions are manualised with treatment fidelity tested via supervision and random sampling of sessions using adherence/competency scales. The primary outcome measure is the Patient Health Questionnaire-9 collected at baseline, 6 and 12 months. Secondary outcome measures tap depression, generic psychological distress, anxiety, functioning and quality of life. Cost-effectiveness is determined by a patient service receipt questionnaire. Exit interviews are conducted with patients by research assessors blind to treatment allocation. The trial requires 500 patients (250 per arm) to test the non-inferiority hypothesis of −2 PHQ-9 points at the one-sided, 2.5% significance level with 90% power, assuming no underlying difference and a standard deviation of 6.9. The primary analysis will be undertaken on all patients randomised (intent to treat) alongside per-protocol and complier-average causal effect analyses as recommended by the extension to the CONSORT statement for non-inferiority trials. Discussion This large-scale trial utilises routinely collected outcome data as well as specific trial data to provide evidence of the comparative efficacy and cost-effectiveness of Counselling for Depression compared with Cognitive Behaviour Therapy as delivered within the UK government’s Improving Access to Psychological Therapies initiative. Trial registration Controlled Trials ISRCTN Registry, ISRCTN06461651. Registered on 14 September 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1834-6) contains supplementary material, which is available to authorized users.

Background Globally, 220 million women experience an unmet need for family planning. A newly designed female condom, the Woman’s Condom (WC), has been developed featuring an improved design. It is the first dual-protection, female-initiated contraceptive that is a premium, higher price point product. However, market availability alone will not increase uptake. In February 2016 the WC will be distributed with a strong media campaign and interpersonal communication (IPC) outreach intervention. The impact of these on knowledge, acceptability, and use of the WC will be measured. Methods/design A baseline survey of 2314 randomly selected 18- to 24-year-old sexually active men and women has been conducted. The WC and mass media will be introduced throughout 40 urban wards in and surrounding Lusaka, Zambia. The baseline survey will serve as a quasi-control arm to determine the impact of introducing the WC with mass media. Half of the wards will be randomly allocated to additionally receive the IPC intervention. A single-blind randomized controlled trial will determine the impact of the IPC intervention on knowledge, uptake, and use of the WC. After one year, another 2314 individuals will be randomly selected to participate in the endline survey. We hypothesize that (1) the distribution and media campaign of the WC will increase overall condom use in selected urban wards, and specifically use of the WC; (2) the IPC intervention will significantly impact knowledge, acceptability, and use of the WC. The primary outcome measures are use of the WC, use of any condom, and willingness to use the WC. Secondary outcomes include measures of knowledge, acceptability, and choice of contraception. Odds ratios will be estimated to measure the effect of the intervention on the outcomes with 95% confidence intervals. All analyses will be based on the intention-to-treat principle. Discussion Increasing uptake of dual prevention measures (such as the WC) may reduce incidence of sexually transmitted infections/HIV and unplanned pregnancies. It is important to ensure young, urban adults have access to new contraceptive methods; and, understanding how mass media and IPC impact contraceptive knowledge, acceptability, and use is critical to reduce unmet need. Trial registration AEARCTR-0000899. Registered on 26 October 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1681-x) contains supplementary material, which is available to authorized users.

Background Hazardous and harmful consumption of alcohol is a leading cause of preventable disease and premature deaths. Modifying the amount and pattern of risky alcohol consumption conveys substantial benefits to individuals and to society at large. Telephone helplines provide a feasible alternative to face-to-face counselling in order to increase the reach of brief interventions aiming at modifying the hazardous and harmful use of alcohol. However, there is a lack of studies on the implementation and evaluation of population-based telephone services for the prevention and treatment of alcohol misuse. Methods/design A randomised controlled trial was designed to compare a brief, structured intervention to usual care within the Swedish National Alcohol Helpline (SAH), concerning their effectiveness on decreasing the hazardous use of alcohol. Between May 2015 and December 2017, about 300 callers are to be individually randomised with a 1:1 ratio to a brief, structured intervention (n = 150) or to usual care (n = 150). The brief, structured intervention consists of the delivery of a self-help booklet followed by one proactive call from SAH counsellors to monitor and give feedback about the client’s progression. Callers assigned to usual care receive telephone counselling according to existing practice, i.e., motivational interviewing in a tailored and client-driven combination of proactive and reactive calls. The primary outcome is defined as a change from a higher to a lower AUDIT risk-level category between baseline and follow-up. General linear modeling will be used to calculate risk ratios of the outcome events. The primary analysis will follow an intention-to-treat (ITT) approach. Discussion The trial is designed to evaluate the effectiveness in decreasing the hazardous and harmful consumption of alcohol of a brief, structured intervention compared to usual care when delivered at the SAH. The results of the study will be used locally to improve the effectiveness of the service provided at the SAH. Additionally, they will expand the evidence base about optimal counselling models in population-based telephone services for alcohol misuse prevention and treatment. Trial registration ISRCNT.com, ID: ISRCTN13160878. Retrospectively registered on 18 January 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2005-5) contains supplementary material, which is available to authorized users.

Background Knee osteoarthritis (KOA) is a leading cause of public disability. Neuromuscular function contributes to the development and/or progression of KOA. Whole body vibration (WBV) exercise improve the neuromuscular function of patients with neurological disorders and even that of older patients with limited exercise options. Therefore, WBV exercise may offer an efficient and alternative treatment for individuals with KOA. However, the effects of WBV training on the neuromuscular function of individuals with KOA remain unclear. Therefore, this study attempts to investigate the effect of a 12-week WBV exercise on the neuromuscular function of individuals with KOA. Methods/design We will conduct a prospective, single-blind randomized controlled trial on 180 KOA patients. Participants will be randomly assigned to the WBV exercise, lower extremity resistance training, and health education groups. The WBV exercise group will participate in a 12-week WBV training. The lower extremity resistance training group will undergo a 12-week lower extremity resistance training of both lower limbs. The control group will receive health education for 12 weeks. After the intervention, the participants will be followed up for 3 months with no active intervention. Primary outcome measures will include anthropometric measurements, gait analysis during walking and stair climbing, muscle strength test of the knee and ankle, proprioception test of the knee and ankle, and neuromuscular response of the leg muscles. Secondary outcome measures will include self-reported pain and physical functional capacity, and physical performance measures. Furthermore, adverse events will be recorded and analyzed. If any participant withdraws from the trial, intention-to-treat analysis will be performed. Discussion Important features of this trial mainly include intervention setting, outcome measure selection, and study duration. This study is intended for estimating the effect of WBV intervention on neuromuscular control outcomes. Study results may provide evidence to support the beneficial effects of WBV exercise on the physical performance and neuromuscular control of individuals with KOA to fill the research gap on the efficacy of WBV. Trial registration Chinese Clinical Trial Registry, ID: ChiCTR-IOR-16009234. Registered on 21 September 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2170-6) contains supplementary material, which is available to authorized users.

The negative effects of perinatal depression on the mother and child start early and persist throughout the lifecourse (Lancet 369(9556):145–57, 2007; Am J Psychiatry 159(1):43-7, 2002; Arch Dis Child 77(2):99–101, 1997; J Pak Med Assoc 60(4):329; J Psychosoma Res 49(3):207–16, 2000; Clin Child Fam Psychol Rev 14(1):1–27, 2011). Given that 10–35% of children worldwide are exposed to perinatal depression in their first year of life (Int Rev Psychiatry 8(1):37–54, 1996), mitigating this intergenerational risk is a global public health priority (Perspect Public Health 129(5):221–7, 2009; Trop Med Int Health 13(4):579–83, 2008; Br Med Bull 101(1):57–79, 2012). However, it is not clear whether intervention with depressed women can have long-term benefits for the mother and/or her child. We describe a study of the effectiveness of a peer-delivered depression intervention delivered through 36 postnatal months, the Thinking Healthy Program Peer-delivered PLUS (THPP+) for women and their children in rural Pakistan. The THPP+ study aims are: (1) to evaluate the effects of an extended 36-month perinatal depression intervention on maternal and index child outcomes using a cluster randomized controlled trial (c-RCT) and (2) to determine whether outcomes among index children of perinatally depressed women in the intervention arm converge with those of index children born to perinatally nondepressed women. The trial is designed to recruit 560 pregnant women who screened positive for perinatal depression (PHQ-9 score ≥10) from 40 village clusters, of which 20 receive the THPP+ intervention. An additional reference group consists of 560 perinatally nondepressed women from the same 40 clusters as the THPP+ trial. The women in the nondepressed group are not targeted to receive the THPP+ intervention; but, by recruiting pregnant women from both intervention and control clusters, we are able to evaluate any carryover effects of the THPP+ intervention on the women and their children. Perinatally depressed women in the THPP+ intervention arm receive bimonthly group-based sessions. Primary outcomes are 3-year maternal depression and 3-year child development indicators. Analyses are intention-to-treat and account for the clustered design. This trial, together with the reference group, has the potential to further our understanding of the early developmental lifecourse of children of both perinatally depressed and perinatally nondepressed women in rural Pakistan and to determine whether intervening with women’s depression in the perinatal period can mitigate the negative effects of maternal depression on 36-month child development. THPP-P ClinicalTrials.gov Identifier: NCT02111915 (registered on 9 April 2014). THPP+ ClinicalTrials.gov Identifier: NCT02658994 (registered on 21 January 2016). Sponsor: Human Development Research Foundation (HDRF).

Background Small fiber neuropathy is the most common cause of neuropathic pain in peripheral neuropathies, with a minimum prevalence of 53/100,000. Patients experience excruciating pain, and currently available anti-neuropathic and other pain drugs do not relieve the pain substantially. Several open-label studies have suggested an immunological basis in small fiber neuropathy and have reported efficacy of treatment with intravenous immunoglobulin. Therefore, immunological mechanisms conceivably may play a role in small fiber neuropathy. To date, no randomized controlled study with intravenous immunoglobulin in patients with small fiber neuropathy has been performed. Methods/design This study is a randomized, double-blind, placebo-controlled, clinical trial in patients with idiopathic small fiber neuropathy. The primary objective is to investigate the efficacy of intravenous immunoglobulin versus placebo on pain alleviation. A 1-point change in the PI-NRS compared to baseline is considered the minimum clinically important difference. In the IVIg-treated group, we assume a response rate of approximately 60 % based on the criteria composed by the IMMPACT group for measurement of pain. Based on this, a sample size of 60 patients is needed. Eligible patients fulfilling the inclusion/exclusion criteria will be randomized to receive either intravenous immunoglobulin or placebo (0.9 % saline). The treatment regimen will start with a loading dose of 2 g/kg body weight over 2–4 consecutive days, followed by a maintenance dose of 1 g/kg body weight over 1–2 consecutive days given three times at a 3-week interval. The primary endpoint is the comparison of the percentage of responder subjects between the two treatment groups from the first randomization during the 12 weeks of treatment. A responder is defined as ≥ 1-point Pain Intensity Numerical Rating Scale improvement on the mean weekly peak pain relative to baseline. The secondary outcomes are pain intensity, pain qualities, other small fiber neuropathy-related complaints, daily and social functioning, as well as quality of life. In addition, safety assessments will be performed for adverse events, vital signs, and laboratory values outside the normal range. Responders during the 12-week treatment period will be followed during a 3-month extension phase. Discussion This is the first randomized, double-blind, placebo-controlled clinical trial with intravenous immunoglobulin in patients with idiopathic small fiber neuropathy. Positive findings will result in a new treatment option for small fiber neuropathy and support an immunological role in this condition. Trial registration ClinicalTrials.gov, NCT02637700. Registered on 16 December 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1450-x) contains supplementary material, which is available to authorized users.

Background Neurocognitive disorders are an important societal challenge and the need for early prevention is increasingly recognized. Meta-analyses show beneficial effects of cognitive activities on cognition. However, high financial costs, low intrinsic motivation, logistic challenges of group-based activities, or the need to operate digital devices prevent their widespread application in clinical practice. Solving jigsaw puzzles is a cognitive activity without these hindering characteristics, but cognitive effects have not been investigated yet. With this study, we aim to evaluate the effect of solving jigsaw puzzles on visuospatial cognition, daily functioning, and psychological outcomes. Methods The pre-posttest, assessor-blinded study will include 100 cognitively healthy adults 50 years of age or older, who will be randomly assigned to a jigsaw puzzle group or a cognitive health counseling group. Within the 5-week intervention period, participants in the jigsaw puzzle group will engage in 30 days of solving jigsaw puzzles for at least 1 h per day and additionally receive cognitive health counseling. The cognitive health counseling group will receive the same counseling intervention but no jigsaw puzzles. The primary outcome, global visuospatial cognition, will depict the average of the z-standardized performance scores in visuospatial tests of perception, constructional praxis, mental rotation, processing speed, flexibility, working memory, reasoning, and episodic memory. As secondary outcomes, we will assess the eight cognitive abilities, objective and subjective visuospatial daily functioning, psychological well-being, general self-efficacy, and perceived stress. The primary data analysis will be based on mixed-effects models in an intention-to-treat approach. Discussion Solving jigsaw puzzles is a low-cost, intrinsically motivating, cognitive leisure activity, which can be executed alone or with others and without the need to operate a digital device. In the case of positive results, these characteristics allow an easy implementation of solving jigsaw puzzles in clinical practice as a way to improve visuospatial functioning. Whether cognitive impairment and loss of independence in everyday functioning might be prevented or delayed in the long run has to be examined in future studies. Trial registration ClinicalTrials.gov, NCT02667314. Registered on 27 January 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2151-9) contains supplementary material, which is available to authorized users.

Background Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations. Methods A systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals. Results A total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2–53 % and were above 30 % in 9 trials, 20–30 % in 11 trials, 10–20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines. Conclusions This review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant’s flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1402-5) contains supplementary material, which is available to authorized users.

Acute kidney injury remains a common complication in critically ill patients and despite multiple trials and observational studies, the optimal timing for initiation of renal replacement therapy is still unclear. The early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury (ELAIN) study is a randomized, single-center, prospective, two-arm, parallel group trial to reduce mortality in patients with severe acute kidney injury. We describe the study design and discuss aspects of the need for a trial in this patient cohort.Our plan is to randomize critically ill patients with acute kidney injury to 'early' or 'late' initiation of renal replacement therapy according to stage 2 and 3 of the KDIGO classification using a specific trial protocol. We plan to guide data collection and analysis using pre-existing definitions and testing. The primary endpoint is overall survival in a 90-day follow-up period. Secondary endpoints include 28-day, 60-day, 90-day and 1-year all-cause mortality, recovery of renal function, ICU and hospital length-of-stay. The primary analysis will be an intention-to-treat analysis; secondary analyses include treated analyses. We will also specify rules for handling data and determining outcome.Several challenges for study design and execution can be seen in our trial, and it should generate results that will inform and influence the practice of renal replacement therapy in critically ill patients with acute kidney injury.German Clinical Trials Register: DRKS00004367 ( www.germanctr.de ); 28 May 2013.

Background Many people with multiple sclerosis experience problems with walking, which can make daily activities difficult and often leads to falls. Foot sensation plays an important role in keeping the body balanced whilst walking; however, people with multiple sclerosis often have poor sensation on the soles of their feet. Wearing a specially designed shoe insole, which enhances plantar sensory information, could help people with multiple sclerosis to walk better. This study will explore whether long-term wear of a textured insole can improve walking in people with multiple sclerosis. Methods A prospective randomised controlled trial with two parallel groups will be conducted aiming to recruit 176 people with multiple sclerosis living in the community (Brisbane, Australia). Adults with a clinical diagnosis of multiple sclerosis, Disease Steps score 1–4, who are ambulant over 100 m and who meet specific inclusion criteria will be recruited. Participants will be randomised to a smooth control insole (n = 88) or textured insole (n = 88) group. The allocated insole will be worn for 12-weeks within participants’ own footwear, with self-report wear diaries and falls calendars being completed over this period. Blinded assessors will conduct two baseline assessments and one post-intervention assessment. Gait tasks will be completed barefoot, wearing standardised footwear only, and wearing standardised footwear with smooth and textured insoles. The primary outcome measure will be mediolateral base of support when walking over even and uneven surfaces. Secondary measures include spatiotemporal gait parameters (stride length, stride time variability, double-limb support time, velocity), gait kinematics (hip, knee, and ankle joint angles, toe clearance, trunk inclination, arm swing, mediolateral pelvis/head displacement), foot sensation (light touch-pressure, vibration, two-point discrimination) and proprioception (ankle joint position sense). Group allocation will be concealed and all analyses will be based on an intention-to-treat principle. Discussion This study will explore the effects of wearing textured insoles over 12-weeks on gait, foot sensation and proprioception in people with multiple sclerosis. The study has the potential to identify a new, evidence-based footwear intervention which has the capacity to enhance mobility and independent living in people with multiple sclerosis. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12615000421538. Registered 4 May 2015.

Background This study protocol evaluates the effectiveness of adjuvant electroacupuncture (EA) for urinary retention in poststroke patients undergoing conventional treatments, in comparison with that of a sham control. Methods/design A multicenter, blinded, randomized controlled trial will be conducted in three hospitals in the Republic of Korea. We are recruiting 54 stroke survivors (aged >19 years), who were diagnosed with urinary retention based on the results of two consecutive post-void residual (PVR) tests, and dividing them randomly into two arms: the EA and Park-sham control groups. They will receive ten sessions of EA or sham treatment for 2 weeks. The participants will be blinded with non-penetrating needles and fake sounds of EA stimulators. The daily PVR ratio will be primarily measured at baseline and at the end of the study to statistically test the effectiveness of EA for poststroke urinary retention. Then, the Korean version of the Qualiveen Questionnaire, the Korean version of the International Prostate Symptom Score, and the blinding index will be assessed. After each EA session or sham EA, adverse events will be reported to evaluate the safety of EA. Results will be analyzed by using the independent t-test or Mann-Whitney U test, based on both intention-to-treat and per-protocol principles. Discussion The findings will provide clinical evidence for the effectiveness of EA treatment to improve urinary retention in stroke survivors. Trial Registration This study protocol was registered in ClinicalTrials.gov (NCT02472288) on 10 June 2015.

Despite successes in preventing and treating HIV, Indigenous people in Canada continue to face disproportionately high rates of HIV infection. Programs that support healing from lifetime trauma, support connection to culture, and reduce drug-related harms are critical to preventing HIV among young Indigenous people who use drugs. The Cedar Project WelTel mHealth intervention proposed here is a structured mobile-phone initiative to connect young Indigenous people who use drugs with Cedar Case Managers in a community-based setting. The intervention consists of a package of supports, including a mobile phone and cellular plan, weekly two-way text messaging, and support from Cedar Case Managers. The Cedar Project WelTel mHealth study is a multi-site Zelen pre-randomized trial to measure the effect of a two-way supportive text-message intervention to reduce HIV vulnerability among young Indigenous people who use illicit drugs in two Canadian cities. The trial is nested within the Cedar Project, an ongoing cohort study addressing HIV and hepatitis C vulnerability among young Indigenous people who use drugs in Vancouver and Prince George, British Columbia. The Cedar Project Partnership, an independent body of Indigenous Elders, leaders, and health/social service experts, governs all aspects of the study. Two hundred participants will be followed over a 16-month period, with HIV propensity score at 6 months as the primary outcome. Secondary outcomes include HIV propensity at 1 year, HIV risk, resilience, psychological distress, access to drug-related services, and connection to culture measured at 6 months and 1 year. Primary analysis is by intention to treat. Culturally safe interventions that address barriers to HIV prevention while supporting the strength of young Indigenous people who use drugs are urgently needed. Despite presenting a tremendous opportunity to connect young, highly transient Indigenous people who use drugs to prevention services, supportive two-way mHealth programs have yet to be tested for HIV prevention in a community-based setting with this population. ClinicalTrials.gov NCT02437123 https://clinicaltrials.gov/show/NCT02437123 (registered 4 May 2015). Protocol version: 24 July 2015.

Background Sedation prior to esophagogastroduodenoscopy is widespread and increases patient comfort. However, it demands additional trained personnel, accounts for up to 40 % of total endoscopy costs and impedes rapid hospital discharge. Most patients lose at least one day of work. 98 % of all serious adverse events occurring during esophagogastroduodenoscopy are ascribed to sedation. Acupuncture is reported to be effective as a supportive intervention for gastrointestinal endoscopy, similar to conventional premedication. We investigated whether acupuncture during elective diagnostic esophagogastroduodenoscopy could increase the comfort of patients refusing systemic sedation. Methods We performed a single-center, double-blinded, placebo-controlled superiority trial to compare the success rates of elective diagnostic esophagogastroduodenoscopies using real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic esophagogastroduodenoscopy who refused systemic sedation were eligible; 354 patients were randomized. The primary endpoint measure was the rate of successful esophagogastroduodenoscopies. The intervention was real or placebo acupuncture before and during esophagogastroduodenoscopy. Successful esophagogastroduodenoscopy was based on a composite score of patient satisfaction with the procedure on a Likert scale as well as quality of examination, as assessed by the examiner. Results From February 2010 to July 2012, 678 patients were screened; 354 were included in the study. Baseline characteristics of the two groups showed a similar distribution in all but one parameter: more current smokers were allocated to the placebo group. The intention-to-treat analysis included 177 randomized patients in each group. Endoscopy could successfully be performed in 130 patients (73.5 %) in the real acupuncture group and 129 patients (72.9 %) in the placebo group. Willingness to repeat the procedure under the same conditions was 86.9 % in the real acupuncture group and 87.6 % in the placebo acupuncture group. Conclusions Esophagogastroduodenoscopy without sedation is safe and can successfully be performed in two-thirds of patients. Patients planned for elective esophagogastroduodenoscopy without sedation do not benefit from acupuncture of the Sinarteria respondens (Rs) 24 Chengjiang middle line, Pericard (Pc) 6 Neiguan bilateral, or Dickdarm (IC) 4 Hegu bilateral, according to traditional Chinese medicine meridian theory. Trial registration DRKS00000164. Registered on 10 December 2009.

Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.

This randomised controlled trial (RCT) with two parallel arms will evaluate the efficacy of an internet-delivered six-lesson 10-week cognitive behavioural therapy (iCBT) intervention for posttraumatic stress disorder (PTSD). It will also investigate the association between changes in PTSD symptoms, intolerance of uncertainty (IU) and emotion regulation. Patients with PTSD will be recruited via the research arm of a not-for-profit clinical and research unit in Australia and randomised to a treatment group or waitlist control group. The minimum sample size for each group (alpha 0.05, power 0.80 for a g of 0.47) was identified as 72, but 10 % more will be recruited to hedge against expected attrition. PTSD diagnosis will be determined using the PTSD module from the Mini International Neuropsychiatric Interview version 5.0.0. The PTSD Checklist – Civilian version (PCL-C) will be used to measure PTSD symptoms (the primary outcome measure), with the Intolerance of Uncertainty Scale 12-item version (IUS-12) and the Emotion Regulation Questionnaire (ERQ) used to measure intolerance of uncertainty and emotion regulation, respectively. The PCL-C will be administered to the treatment group before each lesson of the PTSD program and at 3-month follow-up. The IUS-12 and ERQ will be administered before lessons 1 and 4, at post-treatment and at 3-month follow-up. The waitlist control group will complete these measures at week 1, week 5 and week 11 of the waitlist period. PTSD program efficacy will be determined using intent-to-treat mixed models. Maintenance of gains will be assessed at 3-month follow-up. Mediation analyses using PROCESS will be used to examine the association between change in PTSD symptoms over treatment and change in each of IU and emotion regulation ability in separate analyses. The current RCT seeks to replicate previous efficacy findings of iCBT for PTSD in a formally assessed PTSD sample from the general population. Findings may point to future lines of enquiry for the role of IU and emotion regulation in the mechanism of PTSD symptom change during CBT. Australian New Zealand Clinical Trials Registry: ACTRN12614001213639 , registered 18 November 2014. This trial protocol is written in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.

This paper reports the results of a repeat trial assessing the effectiveness of an online theory-based intervention to promote healthy lifestyle behaviours in new university students. The original trial found that the intervention reduced the number of smokers at 6-month follow-up compared with the control condition, but had non-significant effects on the other targeted health behaviours. However, the original trial suffered from low levels of engagement, which the repeat trial sought to rectify. Three weeks before staring university, all incoming undergraduate students at a large university in the UK were sent an email inviting them to participate in the study. After completing a baseline questionnaire, participants were randomly allocated to intervention or control conditions. The intervention consisted of a self-affirmation manipulation, health messages based on the theory of planned behaviour and implementation intention tasks. Participants were followed-up 1 and 6 months after starting university. The primary outcome measures were portions of fruit and vegetables consumed, physical activity levels, units of alcohol consumed and smoking status at 6-month follow-up. The study recruited 2,621 students (intervention n = 1346, control n = 1275), of whom 1495 completed at least one follow-up (intervention n = 696, control n = 799). Intention-to-treat analyses indicated that the intervention had a non-significant effect on the primary outcomes, although the effect of the intervention on fruit and vegetable intake was significant in the per-protocol analyses. Secondary analyses revealed that the intervention had significant effects on having smoked at university (self-report) and on a biochemical marker of alcohol use. Despite successfully increasing levels of engagement, the intervention did not have a significant effect on the primary outcome measures. The relatively weak effects of the intervention, found in both the original and repeat trials, may be due to the focus on multiple versus single health behaviours. Future interventions targeting the health behaviour of new university students should therefore focus on single health behaviours. Current Controlled Trials ISRCTN07407344 .

Osteoarthritis (OA) is a major clinical and public health problem, with no current medications approved as having disease modifying effects. HMG-CoA reductase inhibitors, or “statins”, a drug class widely used to prevent cardiovascular events, could potentially affect OA progression via a number of mechanisms including their effects on lipid metabolism and inflammation. The aim of this multicentre, randomised, double-blind, placebo-controlled trial is to determine whether atorvastatin reduces the progression of knee structural changes and symptoms over 2 years in patients with symptomatic knee OA. 350 patients with symptomatic knee OA will be recruited through the OA Clinical Trial Network (in Melbourne, Hobart and Adelaide). They will be randomly allocated to the two arms of the study, receiving either 40 mg of atorvastatin or identical placebo once daily for 2 years. Magnetic resonance imaging of the knee will be performed at baseline and 2 years later. Knee structure, symptoms and function will be assessed using validated methods. The primary outcome is annual percentage change in knee cartilage volume. Secondary outcomes include progression of cartilage defects, bone marrow lesions, knee pain and function. The primary analysis will be by intention to treat, but per protocol analyses will also be performed. The study will provide high-quality evidence to address whether atorvastatin has a novel disease modifying effect in OA by delaying the structural and symptomatic progression of knee OA. Thus, the trial has major public health and clinical importance, as if found to be beneficial, atorvastatin could produce substantial cost savings by delaying and possibly reducing the need for joint replacement surgery, and provide marked improvements in quality of life for people with OA. Australian New Zealand Clinical Trials Registry: ACTRN12613000190707 , registered on 18 February 2013.

Background Acupuncture is considered to be an effective and safe treatment for obese and overweight patients, although high-quality evidence regarding the effects of acupuncture on obesity are not conclusive. The aim of the current study is to investigate the effectiveness of electro-acupuncture plus lifestyle modification for treating obese and overweight patients, in comparison with lifestyle modification alone in China. Methods/Design To compare the effectiveness of acupuncture plus lifestyle modification, a 2-armed, controlled trial with randomization using minimization will be conducted on 150 simple obesity and overweight patients, aged 18–50 years, for a 36-week study duration. All patients will be randomly assigned to one of two groups and will receive either acupuncture plus lifestyle modification or lifestyle modification alone. Outcomes will be evaluated at baseline and at 4 weeks, 8 weeks, and 12 weeks during treatment as well as at 6-week, 12-week, and 24-week follow-up. The primary endpoint is change of body mass index (BMI) during the 12th week. Secondary endpoints are body weight; waist-to-hip ratio; biochemical tests including serum cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL) levels; and answers to the Short Form 36 (SF-36) and the Impact of Weight on Quality of Life Questionnaire-Lite Version (IWQOL-Lite). Statistical analyses will be based on the intention-to-treat (ITT) principle. The main endpoint will be analyzed by analysis of covariance (ANCOVA), and the objective outcome results will be analyzed by logistic regression analysis. To avoid potential confounding factors, additional sensitivity analyses will be conducted following these statistical analyses. Discussion This trial is the first to compare the effectiveness of acupuncture plus lifestyle modification for treating obesity relative to lifestyle modification treatment alone by using a pragmatic study design. We hope that the results of this study will contribute to advancing the current methodology of acupuncture trials for obesity and will facilitate the application of useful acupuncture strategies in real-world clinical settings. Trial registration ChiCTR-TRC-12002762. The date of registration is 31 October 2012.

Background Noncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs). Intention to treat (ITT) is generally considered the best method for addressing noncompliance in RCTs. Alternatives to ITT exist, including per protocol (PP), as treated (AT), and instrumental variables (IV). These three methods define participant compliance dichotomously, but partial compliance is a common occurrence in RCTs. By defining a threshold, above which a participant is called a complier, PP, AT and IV can be used, but the resulting loss of information may affect their performance. Trials with factorial designs may experience higher rates of noncompliance due to the heavier burden that participants experience by being assigned to multiple experimental treatments. Methods Using simulations, we assessed the performance of ITT, PP, AT, and IV in both the partial compliance setting and in a 2-by-2 factorial design with increased participant burden for those randomized to both active treatments. Results The bias, mean squared error, and type I error rates of the IV method after dichotomizing partial compliance were heavily inflated. The performance of all four methods depended on the level of noncompliance present, with higher average noncompliance leading to poorer performance. PP and AT showed improved bias and power relative to ITT without inflating the type I error beyond acceptable limits. However, the PP and AT heavily inflated the type I error rates when participant compliance was affected by the participants’ general health. Conclusions There are consequences for dichotomizing compliance information to make it fit into well-known methods. The results suggest the need for a method of estimating treatment effects that can utilize partial compliance information. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1044-z) contains supplementary material, which is available to authorized users.