The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

INTRODUCTION Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. METHODS The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. ETHICS AND DISSEMINATION The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. REGISTRATION DETAILS The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). TRIAL REGISTRATION NUMBER NCT01690988 (last updated December 2013).

Blind intubation of anaesthetised children with supraglottic airway devices AmbuAura-i and Air-Q cannot be recommended: A randomised controlled trial.

BACKGROUND Paediatric supraglottic airway devices AmbuAura-i and Air-Q were designed as conduits for tracheal intubation. Although fibreoptic-guided intubation has proved successful, blind intubation as a rescue technique has never been evaluated. OBJECTIVE Evaluation of blind intubation through AmbuAura-i and Air-Q. On the basis of fibreoptic view data, we hypothesised that the success rate with the AmbuAura-i would be higher than with the Air-Q. DESIGN A prospective, randomised controlled trial with institutional review board (IRB) approval and written informed consent. SETTING University Childrens' Hospital; September 2012 to July 2014. PATIENTS Eighty children, American Society of Anesthesiologists (ASA) class I to III, weight 5 to 50 kg. INTERVENTIONS Tracheal intubation was performed through the randomised device with the tip of a fibrescope placed inside and proximal to the tip of the tracheal tube. This permitted sight of tube advancement, but without fibreoptic guidance (visualised blind intubation). MAIN OUTCOME MEASURES Primary outcome was successfully visualised blind intubation; secondary outcomes included supraglottic airway device success, insertion times, airway leak pressure, fibreoptic view and adverse events. RESULTS Personal data did not differ between groups. In contrast to our hypothesis, blind intubation was possible in 15% with the Air-Q and in 3% with the AmbuAura-i [95% confidence interval (95% CI) 6 to 31 vs. 0 to 13%; P = 0.057]. First attempt supraglottic airway device insertion success rates were 95% (Air-Q) and 100% (AmbuAura-i; 95% CI 83 to 99 vs. 91 to 100; P = 0.49). Median leak pressures were 18 cmH2O (Air-Q) and 17 cmH2O [AmbuAura-i; interquartile range (IQR) 14 to 18 vs. 14 to 19 cmH2O; P = 0.66]. Air-Q insertion was slower (27 vs. 19 s, P < 0.001). There was no difference in fibreoptic view, or adverse events (P > 0.05). In one child (Air-Q size 1.5, tube size 3.5), the tube dislocated during device removal. CONCLUSION Ventilation with both devices is reliable, but success of blind intubation is unacceptably low and cannot be recommended for elective or rescue purposes. If intubation through a paediatric supraglottic airway device is desired, we suggest that fibreoptic guidance is used. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01692522.

DESyne novolimus-eluting coronary stent is superior to Endeavor zotarolimus-eluting coronary stent at five-year follow-up: final results of the multicentre EXCELLA II randomised controlled trial

AIMS Newer-generation drug-eluting stents (DES) have been shown to be superior to first-generation DES. Current-generation DES have zotarolimus, everolimus or biolimus as antiproliferative drugs. Novolimus, a metabolite of sirolimus, has been specifically developed to provide efficacy similar to currently available agents at a lower dose and thus requires a lower polymer load. We report the final five-year outcomes of the EXCELLA II trial comparing a zotarolimus-eluting stent (ZES) with a novolimus-eluting stent (NES). METHODS AND RESULTS EXCELLA II is a prospective, multicentre, single-blind, non-inferiority clinical trial. Patients (n=210) with a maximum of two de novo lesions in two different epicardial vessels were randomised (2:1) to treatment with either NES (n=139) or ZES (n=71). At five-year follow-up, patients in the NES group had a significantly lower incidence of the patient-oriented (HR 0.53, 95% CI: 0.32-0.87, p=0.013) and device-oriented (HR 0.38, 95% CI: 0.17-0.83, p=0.011) composite endpoints. There was no difference in cardiac death and definite/probable stent thrombosis between the two groups; however, there was a trend towards reduction in myocardial infarction and repeat revascularisation in the NES group at five-year follow-up. CONCLUSIONS At five-year follow-up, the incidence of device- and patient-oriented events was significantly lower in the NES group. Further studies, adequately powered for clinical outcomes, are warranted. TRIAL REGISTRATION ClinicalTrials.gov number NCT00792753.

A randomised controlled trial: can acupuncture reduce drug requirement during analgosedation with propofol and alfentanil for colonoscopy? A study protocol.

BACKGROUND The number of colonoscopies tremendously increased in recent years and will further rise in the near future. Because of patients' growing expectation on comfort during medical procedures, it is not surprising that the demand for sedation also expands. Propofol in combination with alfentanil is known to provide excellent analgosedation, however, its use is associated with respiratory and cardiovascular depression. Acupuncture could be a technique to reduce drug requirement while providing the same level of sedation and analgesia. METHODS/DESIGN The study will be performed as a single centre, randomised, placebo controlled trial. 153 patients scheduled for propofol/alfentanil sedation during colonoscopy will be randomly assigned to receive electroacupuncture (P6, ST36, LI4), sham acupuncture, or placebo acupuncture. Following endoscopy patients and gastroenterologists have to fill in questionnaires about their sedation experiences. Additionally, patients have to accomplish the Trieger test before and after the procedure. Patient monitoring includes time adapted HR, SpO2, ECG, NIBP, exCO2, OAA/S, and the Aldrete score. The primary outcome parameter is the dosage of propofol necessary for an adequate level of sedation to tolerate the procedure (OAA/S < 4). Effectiveness of sedation, classified by satisfaction levels measured by questionnaires is the secondary outcome parameter. DISCUSSION Moderate to deep sedation using propofol is increasingly applied during colonoscopies with a high satisfaction level among patients despite well-known hemodynamic and respiratory side effects of this hypnotic agent. Acupuncture is known to attenuate gastrointestinal discomfort and pain. We hypothesize that the combination of conventional sedation techniques with acupuncture may result in equally satisfied patients with a lower risk of respiratory and hemodynamic events during colonoscopies. TRIAL REGISTRATION This trial is registered in the Nederland's Trial Register NTR 4325 . The first patient was randomized on 13 February 2014.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc.

Anaesthetic induction with etomidate in cardiac surgery: A randomised controlled trial.

BACKGROUND Etomidate is perceived as preserving haemodynamic stability during induction of anaesthesia. It is also associated with adrenocortical dysfunction. The risk/benefit relationship is controversial. OBJECTIVES We tested the hypotheses that single-dose etomidate increases cumulative vasopressor requirement, time to extubation and length of stay in the ICU. DESIGN Double-blind randomised controlled trial. SETTING Bern University Hospital, Switzerland, from November 2006 to December 2009. PATIENTS There were 90 patients undergoing coronary artery bypass grafts (CABG) and 40 patients undergoing mitral valve surgery (MVS). Reasons for noninclusion were known adrenocortical insufficiency, use of etomidate or propofol within 1 week preoperatively, use of glucocorticoids within 6 months preoperatively, severe renal or liver dysfunction, or carotid stenosis. INTERVENTIONS CABG patients were allocated randomly to receive either etomidate 0.15 mg kg with placebo, propofol 1.5 mg kg with placebo or etomidate 0.15 mg kg with hydrocortisone (n = 30 in each arm). Risk stratification (low vs. high) was achieved by block randomisation. MVS patients received either etomidate 0.15 mg kg or propofol 1.5 mg kg (n = 20 in each arm). MAIN OUTCOME MEASURES Cumulative vasopressor requirements, incidence of adrenocortical insufficiency, length of time to extubation and length of stay in ICU. RESULTS Cumulative vasopressor requirements 24 h after induction did not differ between treatments in patients who underwent CABG, whereas more noradrenaline was used in MVS patients following propofol induction (absolute mean difference 5.86 μg kg over 24 h P = 0.047). The incidence of relative adrenocortical insufficiency was higher after etomidate alone than propofol (CABG 83 vs. 37%, P < 0.001; MVS: 95 vs. 35%, P < 0.001). The time to extubation, length of stay in ICU and 30-day mortality did not differ among treatments. Within low and high-risk subgroups, no differences in vasopressor use or outcomes were found. CONCLUSION In elective cardiac surgery, laboratory indicators of etomidate-induced adrenal insufficiency do not translate into increased vasopressor requirement or inferior early outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT 00415701.

The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial.

BACKGROUND Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression-free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION ISRCTN71502099 on 19 May 2014.

Feasibility study of a single-blind randomised controlled trial of an occupational therapy intervention.

BACKGROUND Several factors facilitate or hinder efficacy research in occupational therapy. Strategies are needed, therefore, to support the successful implementation of trials. AIM To assess the feasibility of conducting a randomised controlled trial (RCT). The main feasibility objectives of this study were to assess the process, resources, management, and scientific basis of a trial RCT. MATERIAL AND METHODS A total of 10 occupational therapists, between the ages of 30 and 55 (M 43.4; SD 8.3) with seven to 26 years' (M 14.3; SD 6.1) experience, participated in this study. Qualitative data collected included minutes of meetings, reports, and field notes. The data were analysed based on the principles of content analysis, using feasibility objectives as the main categories. RESULTS Data analysis revealed strengths in relation to retention and inclusion criteria of participants, the study protocol, study organisation, and the competence of researchers. Weaknesses were found related to recruitment, randomisation, data collection, time for training and communication, commitment, and design. CONCLUSION The findings indicated that there are several factors which had a considerable impact on the implementation of an RCT in practice. However, it was useful to assess methods and procedures of the trial RCT as a basis to refine research plans.

Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

BACKGROUND The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. METHODS The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. DISCUSSION This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients. TRIAL REGISTRATION NCT01689077.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

The PRO-AGE study: an international randomised controlled study of health risk appraisal for older persons based in general practice

BACKGROUND: This paper describes the study protocol, the recruitment, and base-line data for evaluating the success of randomisation of the PRO-AGE (PRevention in Older people-Assessment in GEneralists' practices) project. METHODS/DESIGN: A group of general practitioners (GPs) in London (U.K.), Hamburg (Germany) and Solothurn (Switzerland) were trained in risk identification, health promotion, and prevention in older people. Their non-disabled older patients were invited to participate in a randomised controlled study. Participants allocated to the intervention group were offered the Health Risk Appraisal for Older Persons (HRA-O) instrument with a site-specific method for reinforcement (London: physician reminders in electronic medical record; Hamburg: one group session or two preventive home visits; Solothurn: six-monthly preventive home visits over a two-year period). Participants allocated to the control group received usual care. At each site, an additional group of GPs did not receive the training, and their eligible patients were invited to participate in a concurrent comparison group. Primary outcomes are self-reported health behaviour and preventative care use at one-year follow-up. In Solothurn, an additional follow-up was conducted at two years. The number of older persons agreeing to participate (% of eligible persons) in the randomised controlled study was 2503 (66.0%) in London, 2580 (53.6%) in Hamburg, and 2284 (67.5%) in Solothurn. Base-line findings confirm that randomisation of participants was successful, with comparable characteristics between intervention and control groups. The number of persons (% of eligible) enrolled in the concurrent comparison group was 636 (48.8%) in London, 746 (35.7%) in Hamburg, and 1171 (63.0%) in Solothurn. DISCUSSION: PRO-AGE is the first large-scale randomised controlled trial of health risk appraisal for older people in Europe. Its results will inform about the effects of implementing HRA-O with different methods of reinforcement.

Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Dyadic action control in overweight and obese couples: Effectiveness of a randomized controlled trial to promote physical activity.

BACKGROUND: Enhancing physical activity in overweight and obese individuals is an important means to promote health in this target population. The Health Action Process Approach (HAPA), which was the theoretical framework of this study, focuses on individual self-regulation variables for successful health behavior change. One key self-regulation variable of this model is action control with its three subfacets awareness of intentions, self-monitoring and regulatory effort. The social context of individuals, however, is usually neglected in common health behavior change theories. In order to integrate social influences into the HAPA, this randomized controlled trial investigated the effectiveness of a dyadic conceptualization of action control for promoting physical activity. METHODS/DESIGN: This protocol describes the design of a single-blind randomized controlled trial, which comprises four experimental groups: a dyadic action control group, an individual action control group and two control groups. Participants of this study are overweight or obese, heterosexual adult couples who intend to increase their physical activity. Blocking as means of a gender-balanced randomization is used to allocate couples to conditions and partners to either being the target person of the intervention or to the partner condition. The ecological momentary intervention takes place in the first 14 days after baseline assessment and is followed by another 14 days diary phase without intervention. Follow-ups are one month and six months later. Subsequent to the six-months follow-up another 14 days diary phase takes place.The main outcome measures are self-reported and accelerometer-assessed physical activity. Secondary outcome measures are Body Mass Index (BMI), aerobic fitness and habitual physical activity. DISCUSSION: This is the first study examining a dyadic action control intervention in comparison to an individual action control condition and two control groups applying a single-blind randomized control trial. Challenges with running couples studies as well as advantages and disadvantages of certain design-related decisions are discussed. This RCT was funded by the Swiss National Science Foundation (PP00P1_133632/1) and was registered on 27/04/2012 at http://www.isrctn.com/ISRCTN15705531.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications.

OBJECTIVE To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.