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1.  Thanks to all those who reviewed for Trials in 2014 
Trials  2015;16:55.
Contributing reviewers
A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editors-in-Chief and staff of the journal warmly thank the 610 reviewers whose comments helped to shape Trials, for their invaluable assistance with review of manuscripts for the journal in Volume 15 (2014).
PMCID: PMC4336513
3.  Effect of suture technique on the occurrence of incisional hernia after elective midline abdominal wall closure: study protocol for a randomized controlled trial 
Trials  2015;16:52.
Based on a recent meta-analysis, a continuous suture technique with a suture to wound length ratio of at least 4:1, using a slowly absorbable monofilament suture material, is recommended for primary median laparotomy closure. Incisional hernia, which develops in 9 to 20% of patients, remains the major complication of abdominal wall closure. Current clinical data indicate that the incidence of incisional hernias increases by 60% between the first and the third year after median laparotomy, implicating that a follow-up period of 1 year postoperatively is too short with regard to this common complication. Trauma to the abdominal wall can be reduced by improvements in suture technique as well as suture material. Several factors, such as stitch length, suture tension, elasticity, and tensile strength of the suture material are discussed and currently under investigation. A Swedish randomized controlled trial showed a significant reduction in the incisional hernia rate by shortening the stitch length. However, a non-elastic thread was used and follow-up ended after 12 months. Therefore, we designed a multicenter, international, double-blinded, randomized trial to analyze the influence of stitch length, using an elastic, extra-long term absorbable monofilament suture, on the long term clinical outcome of abdominal wall closure.
In total, 468 patients undergoing an elective, median laparotomy will be randomly allocated to either the short stitch or the long stitch suture technique for abdominal wall closure in a 1:1 ratio. Centers located in Germany and Austria will participate. The primary endpoint measure is the incisional hernia rate 1 year postoperatively, as verified by ultrasound. The frequency of short term and long term complications as well as costs, length of hospital stay and patients’ quality of life (EQ-5D-5 L) will be considered as secondary parameters. Following hospital discharge, patients will be examined after 30 days and 1, 3, and 5 years after surgery.
This study will provide further evidence on whether a short stitch suture technique in combination with an elastic, extra-long term absorbable monofilament suture can prevent incisional hernias in the long term, compared with the long stitch suture technique.
Trial registration
PMCID: PMC4336759
Abdominal wall closure; Incisional hernia; Laparotomy; Large bites; Small bites; Suture technique
4.  Effectiveness and cost-effectiveness of cognitive adaptation training as a nursing intervention in long-term residential patients with severe mental illness: study protocol for a randomized controlled trial 
Trials  2015;16:49.
Despite the well-known importance of cognitive deficits for everyday functioning in patients with severe mental illness (SMI), evidence-based interventions directed at these problems are especially scarce for SMI patients in long-term clinical facilities. Cognitive adaptation Training (CAT) is a compensatory approach that aims at creating new routines in patients’ living environments through the use of environmental supports. Previous studies on CAT showed that CAT is effective in improving everyday functioning in outpatients with schizophrenia. The aim of this study is to evaluate the effect of CAT as a nursing intervention in SMI patients who reside in long-term clinical facilities.
This is a multicenter cluster randomized controlled trial comparing CAT (intervention group) as a nursing intervention to treatment as usual (control group). The primary goal is to evaluate the effectiveness of CAT on everyday functioning. Secondary outcomes are quality of life, empowerment and apathy. Further, an economic evaluation will be performed. The study has a duration of one year, with four follow-up assessments at 15, 18, 21 and 24 months for the intervention group.
There is a need for evidence-based interventions that contribute to the improvement of the functional recovery of long-term residential patients. If our hypotheses are confirmed, it may be recommended to include CAT in the guidelines for SMI care and to implement the method in standardized care.
Trial registration
Nederlands Trial Register (identifier: NTR3308). Date registered: 12 February 2012.
PMCID: PMC4327948
Cognitive adaptation training; CAT; Functioning; Severe mental illness; Schizophrenia; Quality of life; Nursing intervention; Cognitive remediation
5.  The efficacy of indwelling pleural catheter placement versus placement plus talc sclerosant in patients with malignant pleural effusions managed exclusively as outpatients (IPC-PLUS): study protocol for a randomised controlled trial 
Trials  2015;16:48.
Malignant pleural effusions (MPEs) remain a common problem, with 40,000 new cases in the United Kingdom each year and up to 250,000 in the United States. Traditional management of MPE usually involves an inpatient stay with placement of a chest drain, followed by the instillation of a pleural sclerosing agent such as talc, which aims to minimise further fluid build-up. Despite a good success rate in studies, this approach can be expensive, time-consuming and inconvenient for patients. More recently, an alternative method has become available in the form of indwelling pleural catheters (IPCs), which can be inserted and managed in an outpatient setting. It is currently unknown whether combining talc pleurodesis with IPCs will provide improved pleural symphysis rates over those of IPCs alone.
IPC-PLUS is a patient-blind, multicentre randomised controlled trial (RCT) comparing the combination of talc with an IPC to the use of an IPC alone for inducing pleurodesis in MPEs. The primary outcome is successful pleurodesis at five weeks post-randomisation. This study will recruit 154 patients, with an interim analysis for efficacy after 100 patients, and aims to help to define the future gold standard for outpatient management of patients with symptomatic MPEs.
IPC-PLUS is the first RCT to examine the practicality and utility of talc administered via an IPC. The study remains in active recruitment and has the potential to significantly alter how patients requiring pleurodesis for MPE are approached in the future.
Trial registration
This trial was registered with Current Controlled Trials (identifier: ISRCTN73255764) on 23 August 2012.
PMCID: PMC4333179
Catheters; indwelling; Chest tubes; Outpatients; Pleural effusion; malignant; Pleurodesis; Sclerosing solutions; Talc; Randomised controlled trial
6.  Core outcome sets for use in effectiveness trials involving people with bipolar and schizophrenia in a community-based setting (PARTNERS2): study protocol for the development of two core outcome sets 
Trials  2015;16:47.
In the general population the prevalence of bipolar and schizophrenia is 0.24% and 1.4% respectively. People with schizophrenia and bipolar disorder have a significantly reduced life expectancy, increased rates of unemployment and a fear of stigma leading to reduced self-confidence. A core outcome set is a standardised collection of items that should be reported in all controlled trials within a research area. There are currently no core outcome sets available for use in effectiveness trials involving bipolar or schizophrenia service users managed in a community setting.
A three-step approach is to be used to concurrently develop two core outcome sets, one for bipolar and one for schizophrenia. First, a comprehensive list of outcomes will be compiled through qualitative research and systematic searching of trial databases. Focus groups and one-to-one interviews will be completed with service users, carers and healthcare professionals. Second, a Delphi study will be used to reduce the lists to a core set. The three-round Delphi study will ask service users to score the outcome list for relevance. In round two stakeholders will only see the results of their group, while in round three stakeholders will see the results of all stakeholder group by stakeholder group. Third, a consensus meeting with stakeholders will be used to confirm outcomes to be included in the core set. Following the development of the core set a systematic literature review of existing measures will allow recommendations for how the core outcomes should be measured and a stated preference survey will explore the strength of people’s preferences and estimate weights for the outcomes that comprise the core set.
A core outcome set represents the minimum measurement requirement for a research area. We aim to develop core outcome sets for use in research involving service users with schizophrenia or bipolar managed in a community setting. This will inform the wider PARTNERS2 study aims and objectives of developing an innovative primary care-based model of collaborative care for people with a diagnosis of bipolar or schizophrenia.
PMCID: PMC4334396
7.  Lactose-free milk for infants with acute gastroenteritis in a developing country: study protocol for a randomized controlled trial 
Trials  2015;16:46.
Acute gastroenteritis is a major cause of pediatric morbidity and mortality, accounting for 15% of all childhood deaths worldwide. In developing countries, diarrheal diseases continue to be a major public health burden. Evidence from developed countries suggests that intake of lactose-free milk during diarrheal episodes may reduce the duration of the illness in pediatric inpatients. It is unknown whether lactose-free milk reduces the severity or duration of acute gastroenteritis in infants treated in outpatient settings in developing countries where diarrhea is more severe, and results in higher morbidities and mortalities. We hypothesize that lactose-free milk intake during acute gastroenteritis would significantly decrease the duration and severity of diarrhea in infants presenting to the Emergency Department (ED), as compared with lactose-containing milk.
An open-label randomized clinical trial. Study population: 40 infants with acute gastroenteritis, age between 2 and 12 months, presenting to the ED, will be randomized to control or intervention group. Intervention: Lactose-free milk, whereas the control group will continue on regular infant formula for a total of 7 days. Infants will be followed up for 7 days. Outcome measures: Diarrhea duration, weight loss, illness clinic visits, hospitalization rate, parental satisfaction, and time to symptom resolution. Statistical analysis: Descriptive and regression analysis will be conducted under the intention-to-treat basis by using SPSS version 21.
Acute gastroenteritis is a public health burden for developing countries, with a significant impact on infant morbidity and mortality. Provision of infant formula that may reduce the duration and severity of diarrhea can decrease this burden in countries with limited healthcare resources, like Lebanon. The findings from this study are anticipated to provide evidence-based dietary recommendations for ambulatory infants with acute diarrhea in developing countries.
Trial registration NCT02246010; September 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0565-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4324790
Acute gastroenteritis; Lactose-free milk; Developing world
8.  Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial 
Trials  2015;16:39.
Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.
The erythropoietin in traumatic brain injury trial is a stratified prospective, multi-centre, randomised, blinded, parallel-group, placebo-controlled phase III trial. It aims to determine whether the administration of erythropoietin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at six months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe (Glasgow Coma Score: 3 to 8) or moderate (Glasgow Coma Score: 9 to 12) traumatic brain injury in Australia, New Zealand, Kingdom of Saudi Arabia, France, Finland, Germany and Ireland.
Trial patients will receive either subcutaneous erythropoietin or placebo within 24 hours of injury, and weekly thereafter for up to three doses during the intensive care unit admission. The primary outcome will be the combined proportion of unfavourable neurological outcomes at six months: severe disability or death. Secondary outcomes will include the rate of proximal deep venous thrombosis detected by compression Doppler ultrasound, six-month mortality, the proportion of patients with composite vascular events (deep venous thrombosis, pulmonary embolism, myocardial infarction, cardiac arrest and cerebrovascular events) at six months and quality of life with health economic evaluations.
When completed, the trial aims to provide evidence on the efficacy and safety of erythropoietin in traumatic brain injury patients, and to provide clear guidance for clinicians in their management of this devastating condition.
Trial registration
Australian New Zealand Clinical Trials registry: ACTRN12609000827235 (registered on 22 September 2009). NCT00987454 (registered on 29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (registered on 18 January 2012).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0528-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4326467
Traumatic brain injury; Erythropoietin; Outcome; Critical care; Randomised controlled trials
9.  The Community In-Reach and Care Transition (CIRACT) clinical and cost-effectiveness study: study protocol for a randomised controlled trial 
Trials  2015;16:41.
Older people represent a significant proportion of patients admitted to hospital. Their care compared to younger patients is more challenging, length of stay is longer, risk of hospital-acquired problems higher and the risk of being re-admitted within 28 days greater. This study aims to compare a Community In-Reach and Care Transition (CIRACT) service with Traditional Hospital Based rehabilitation (THB-Rehab) provided to the older person. The CIRACT service differs from the THB-rehab service in that they are able to provide more intensive hospital rehabilitation, visiting patients daily, and are able to continue with the patient’s rehabilitation following discharge allowing a seamless, integrated discharge working alongside community providers. A pilot comparing the two services showed that the CIRACT service demonstrated reduced length of stay and reduced re-admission rates when analysed over a four-month period.
This trial will evaluate the clinical and cost-effectiveness of the CIRACT service, conducted as a randomised controlled trial (RCT) with an integral qualitative mechanism and action study designed to provide the explanatory and theoretical components on how the CIRACT service compares to current practice. The RCT element consists of 240 patients over 70 years of age, being randomised to either the THB therapy group or the CIRACT service following an unplanned hospital admission. The primary outcome will be hospital length of stay from admission to discharge from the general medical elderly care ward. Additional outcome measures including the Barthel Index, Charlson Co-morbidity Scale, EuroQoL-5D and the modified Client Service Receipt Inventory will be assessed at the time of recruitment and repeated at 91 days post-discharge. The qualitative mechanism and action study will involve a systematic programme of organisational profiling, observations of work processes, interviews with key informants and care providers and tracking of participants. In addition, a within-trial economic evaluation will be undertaken comparing the CIRACT and THB-rehab services to determine cost-effectiveness.
The outcome of the study will inform clinical decision-making, with respect to allocation of resources linked to hospital discharge planning and re-admissions, in a resource intensive and growing group of patients.
Trial registration
Registered with the ISRCTN registry (ISCRCTN94393315) on 25 April 2013 (version 3.1, 11 September 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0551-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4327808
Rehabilitation; In-reach; Community; In-patients; Older people
10.  A mindfulness-based stress prevention training for medical students (MediMind): study protocol for a randomized controlled trial 
Trials  2015;16:40.
Medical training is very demanding and associated with a high prevalence of psychological distress. Compared to the general population, medical students are at a greater risk of developing a psychological disorder. Various attempts of stress management training in medical school have achieved positive results on minimizing psychological distress; however, there are often limitations. Therefore, the use of a rigorous scientific method is needed. The present study protocol describes a randomized controlled trial to examine the effectiveness of a specifically developed mindfulness-based stress prevention training for medical students that includes selected elements of cognitive behavioral strategies (MediMind).
This study protocol presents a prospective randomized controlled trial, involving four assessment time points: baseline, post-intervention, one-year follow-up and five-year follow-up. The aims include evaluating the effect on stress, coping, psychological morbidity and personality traits with validated measures. Participants are allocated randomly to one of three conditions: MediMind, Autogenic Training or control group. Eligible participants are medical or dental students in the second or eighth semester of a German university. They form a population of approximately 420 students in each academic term. A final total sample size of 126 (at five-year follow-up) is targeted. The trainings (MediMind and Autogenic Training) comprise five weekly sessions lasting 90 minutes each. MediMind will be offered to participants of the control group once the five-year follow-up is completed. The allotment is randomized with a stratified allocation ratio by course of studies, semester, and gender. After descriptive statistics have been evaluated, inferential statistical analysis will be carried out with a repeated measures ANOVA-design with interactions between time and group. Effect sizes will be calculated using partial η-square values.
Potential limitations of this study are voluntary participation and the risk of attrition, especially concerning participants that are allocated to the control group. Strengths are the study design, namely random allocation, follow-up assessment, the use of control groups and inclusion of participants at different stages of medical training with the possibility of differential analysis.
Trial registration
This trial is recorded at German Clinical Trials Register under the number DRKS00005354 (08 November 2013).
PMCID: PMC4328883
11.  Three donor site dressings in pediatric split-thickness skin grafts: study protocol for a randomised controlled trial 
Trials  2015;16:43.
For children requiring split-thickness skin grafting for burn injury, the optimum donor site dressing is an ongoing subject of debate. The most common dressings in use, both regionally and worldwide, are calcium alginates. We will compare an alginate with two other dressings, all of which are in current use in the Pegg Leditschke Paediatric Burns Centre (PLPBC), to determine which dressing performs the best.
This is a randomised, prospective single center parallel three-arm trial comparing three donor site wound (DSW) dressings: Algisite™ M, a calcium alginate dressing; Cuticerin™, a smooth acetate gauze impregnated with water-repellent ointment (petrolatum, paraffin and Eucerite®) and Sorbact®, a gauze mesh coated with a dialkylcarbamoyl chloride (DACC) and amorphous hydrogel.
Primary outcomes are days to complete DSW healing, and pain. Previously validated measures will be used for all outcomes. Secondary outcomes are: itch; scar appearance at three, six and 12 months; ease of dressing application and removal and dressing costs and utility. Results will be analysed on an intention-to-treat basis. Donor site thickness will be measured with a small biopsy from the center of the graft, to document the depth of the DSW across the groups.
This study will provide comprehensive short- and long-term data on DSW dressings in pediatric split-thickness skin grafting. The best-performing dressing will become the preferred dressing for the PLPBC. We will provide rigorous data against which other dressings can be compared in future, recognising that alginates are the most common DSW dressing currently in use. Our study design replicates a real-world scenario in order to identify clinically significant differences between the three dressings.
Trial registration
This trial was prospectively registered on 8 April 2014 with the Australia and New Zealand Clinical Trials Register (identifier: ACTRN12614000380695).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0557-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4335760
Pediatric; Burns; Split-thickness skin graft; Donor site; Dressing; Randomised controlled trial; Pain; Scar; Itch; Re-epithelialisation
12.  The efficacy of electroacupuncture for the treatment of simple female stress urinary incontinence - comparison with pelvic floor muscle training: study protocol for a multicenter randomized controlled trial 
Trials  2015;16:45.
Previous research has shown that electroacupuncture therapy has a potential therapeutic effect for simple female stress urinary incontinence. In this study, pelvic floor muscle training, the first-line treatment for stress urinary incontinence in women based on meta-analysis of numerous randomized control trials and recommended by international clinical practice, is used as a control group to demonstrate whether electroacupuncture therapy is a better method for female stress urinary incontinence.
A randomized controlled trial has been designed to evaluate the therapeutic benefit of electroacupuncture for female stress urinary incontinence compared with pelvic floor muscle training. The safety of electroacupuncture and patient compliance will also be evaluated. Untoward reaction to the electroacupuncture, including a broken needle, fainting on acupuncture, or pain during acupuncture, will be recorded and the therapy will be stopped if an untoward reaction occurs. After we have received full ethical approval and patient consent, participants will be randomized to receive a series of 24 electroacupuncture or pelvic floor muscle training interventions. The frequency and amount of leakage will be measured as the primary outcome parameters. Secondary outcome parameters include the 1-hour pad test, the short-form of the International Consultation on Incontinence Questionnaire, patient subjective effectiveness evaluation, weekly usage of pad, and usage of specialty therapy for female stress urinary incontinence.
This trial will help to determine whether electroacupuncture is a more effective treatment than pelvic floor muscle training for patients with female stress urinary incontinence.
Trial registration NCT01940432 (12 September 2013).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0560-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4336724
Electroacupuncture; Female stress urinary incontinence; Pelvic floor muscle training
13.  Update to the study protocol, including statistical analysis plan for a randomized clinical trial comparing comprehensive cardiac rehabilitation after heart valve surgery with control: the CopenHeartVR trial 
Trials  2015;16:38.
Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising because of an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post-surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesize that a comprehensive cardiac rehabilitation program can improve physical capacity and self-assessed mental health and reduce hospitalization and healthcare costs after heart valve surgery.
This randomized clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients 1:1 to an intervention or a control group, using central randomization, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise and a psycho-educational intervention comprising five consultations. The primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. The secondary outcome is self-assessed mental health measured by the standardized questionnaire Short Form-36. Long-term healthcare utilization and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design will be used to evaluate qualitative and quantitative findings, encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study.
This randomized clinical trial will contribute with evidence of whether cardiac rehabilitation should be provided after heart valve surgery. The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency ( 2007-58-0015).
Trial registration
Trial registered 16 March 2012; (NCT01558765).
PMCID: PMC4326522  PMID: 25652891
Heart valve surgery; Rehabilitation; Physical exercise; Psycho-education
14.  A mindfulness-based stress management program and treatment with omega-3 fatty acids to maintain a healthy mental state in hospital nurses (Happy Nurse Project): study protocol for a randomized controlled trial 
Trials  2015;16:36.
It is reported that nursing is one of the most vulnerable jobs for developing depression. While they may not be clinically diagnosed as depressed, nurses often suffer from depression and anxiety symptoms, which can lead to a low level of patient care. However, there is no rigorous evidence base for determining an effective prevention strategy for these symptoms in nurses. After reviewing previous literature, we chose a strategy of treatment with omega-3 fatty acids and a mindfulness-based stress management program for this purpose. We aim to explore the effectiveness of these intervention options for junior nurses working in hospital wards in Japan.
A factorial-design multi-center randomized trial is currently being conducted. A total of 120 nurses without a managerial position, who work for general hospitals and gave informed consent, have been randomly allocated to a stress management program or psychoeducation using a leaflet, and to omega-3 fatty acids or identical placebo pills. The stress management program has been developed according to mindfulness cognitive therapy and consists of four 30-minute individual sessions conducted using a detailed manual. These sessions are conducted by nurses with a managerial position. Participants allocated to the omega-3 fatty acid groups are provided with 1,200 mg/day of eicosapentaenoic acid and 600 mg/day of docosahexaenoic acid for 90 days.
The primary outcome is the change in the total score of the Hospital Anxiety and Depression Scale (HADS), determined by a blinded rater via the telephone at week 26. Secondary outcomes include the change in HADS score at 13 and 52 weeks; presence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism; utility scores and adverse events at 13, 26 and 52 weeks.
An effective preventive intervention may not only lead to the maintenance of a healthy mental state in nurses, but also to better quality of care for inpatients. This paper outlines the background and methods of a randomized trial that evaluates the possible additive value of omega-3 fatty acids and a mindfulness-based stress management program for reducing depression in nurses.
Trial registration NCT02151162 (registered on 27 May 2014).
PMCID: PMC4326519  PMID: 25636180
Anxiety; Behavior therapy; Depression; Fatty acids; Omega-3; Mindfulness; Prevention and control
15.  Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine: study protocol for a pragmatic randomized controlled trial (CYSCEtrial) 
Trials  2015;16:37.
Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine.
In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening.
Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression.
Trial registration NCT01778907; registration date: 22 January 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0561-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4328880  PMID: 25636328
CYP2D6; Pharmacogenetics; Depression; Nortriptyline; Venlafaxine
16.  A novel comparative effectiveness study of Tai Chi versus aerobic exercise for fibromyalgia: study protocol for a randomized controlled trial 
Trials  2015;16:34.
Fibromyalgia is a chronic musculoskeletal pain syndrome that causes substantial physical and psychological impairment and costs the US healthcare system over $25 billion annually. Current pharmacological therapies may cause serious adverse effects, are expensive, and fail to effectively improve pain and function. Finding new and effective non-pharmacological treatments for fibromyalgia patients is urgently needed. We are currently conducting the first comparative effectiveness randomized trial of Tai Chi versus aerobic exercise (a recommended component of the current standard of care) in a large fibromyalgia population. This article describes the design and conduct of this trial.
A single-center, 52-week, randomized controlled trial of Tai Chi versus aerobic exercise is being conducted at an urban tertiary medical center in Boston, Massachusetts. We plan to recruit 216 patients with fibromyalgia. The study population consists of adults ≥21 years of age with fibromyalgia who meet American College of Rheumatology 1990 and 2010 diagnostic criteria. Participants are randomized to one of four Tai Chi intervention groups: 12 or 24 weeks of supervised Tai Chi held once or twice per week, or a supervised aerobic exercise control held twice per week for 24 weeks. The primary outcome is the change in Revised Fibromyalgia Impact Questionnaire total score from baseline to 24 weeks. Secondary outcomes include measures of widespread pain, symptom severity, functional performance, balance, muscle strength and power, psychological functioning, sleep quality, self-efficacy, durability effects, and health-related quality of life at 12, 24, and 52 week follow-up.
This study is the first comparative effectiveness randomized trial of Tai Chi versus aerobic exercise in a large fibromyalgia population with long-term follow up. We present here a robust and well-designed trial to determine the optimal frequency and duration of a supervised Tai Chi intervention with regard to short- and long-term effectiveness. The trial also explores multiple outcomes to elucidate the potential mechanisms of Tai Chi and aerobic exercise and the generalizability of these interventions across instructors. Results of this study are expected to have important public health implications for patients with a major disabling disease that incurs substantial health burdens and economic costs.
Trial registration identifier: NCT01420640, registered 18 August 2011.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0548-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4323027  PMID: 25633475
Tai Chi; Aerobic exercise; Fibromyalgia; Randomized controlled trial; Comparative effectiveness research
17.  Couplelinks - an online intervention for young women with breast cancer and their male partners: study protocol for a randomized controlled trial 
Trials  2015;16:33.
Young breast cancer survivors (aged 50 years and under) and their partners are at an elevated risk for relationship distress and poor psychological adjustment relative to older age couples. Limited availability of time and resources and the distance to travel are major barriers to engaging in evidence-based psychosocial support programs. This paper describes the study protocol of a novel, manualized online intervention called Couplelinks that was developed to improve relationship adjustment and psychological wellbeing of young couples affected by breast cancer. Couplelinks is a custom-designed website offering a professionally facilitated, couple-centered intervention that entails informational, experiential, and interactive components.
A total of 80 heterosexual couples from across Canada in which the female partner has been diagnosed with a primary breast cancer will be recruited and randomized to a treatment or waitlist control group. Six dyadic learning modules form the core of the program and will be undertaken on a weekly basis. The manualized online intervention involves psycho-education and experiential exercises to enhance communication, coping ability, mutual empathy, and perspective-taking in relation to cancer. An online facilitator who is a trained mental health professional will guide and support couples throughout the process. Data collection will occur at baseline, at post-treatment or eight weeks into the waiting period, and at the three-month follow-up assessment. Primary outcome measures include the Revised Dyadic Adjustment Survey (RDAS) and Dyadic Coping Inventory (DCI) scores, and secondary outcome measures include the Hospital Anxiety and Depression Survey (HADS) score.
Couplelinks is one of the first internet-based psychological interventions to improve the psychosocial adjustment of couples coping with a life-threatening illness such as cancer. If successful, the design of this program as described in this paper makes a valuable contribution to the literature on the delivery of couple-focused psychosocial interventions, both within and outside of oncology.
Trial registration
This trial was registered with (identifier: NCT01089764) on 17 March 2010.
PMCID: PMC4336511  PMID: 25630357
Cancer; Breast; Couple; Online intervention; Internet; Psychosocial; Protocol; Randomized control trial
18.  “High or low Inferior Mesenteric Artery ligation in Laparoscopic low Anterior Resection: study protocol for a randomized controlled trial” (HIGHLOW trial) 
Trials  2015;16:21.
The position of arterial ligation during laparoscopic anterior rectal resection with total mesorectal excision can affect genito-urinary function, bowel function, oncological outcomes, and the incidence of anastomotic leakage. Ligation to the inferior mesenteric artery at the origin or preservation of the left colic artery are both widely performed in rectal surgery. The aim of this study is to compare the incidence of genito-urinary dysfunction, anastomotic leak and oncological outcomes in laparoscopic anterior rectal resection with total mesorectal excision with high or low ligation of the inferior mesenteric artery in a controlled randomized trial.
The HIGHLOW study is a multicenter randomized controlled trial in which patients are randomly assigned to high or low inferior mesenteric artery ligation during laparoscopic anterior rectal resection with total mesorectal excision for rectal cancer. Inclusion criteria are middle or low rectal cancer (0 to 12 cm from the anal verge), an American Society of Anesthesiologists score of I, II, or III, and a body mass index lower than 30. The primary end-point measure is the incidence of post-operative genito-urinary dysfunction. The secondary end-point measure is the incidence of anastomotic leakage in the two groups. A total of 200 patients (100 per arm) will reliably have 84.45 power in estimating a 20% difference in the incidence of genito-urinary dysfunctions. With a group size of 100 patients per arm it is possible to find a significant difference (α = 0.05, β = 0.1555). Allowing for an estimated dropout rate of 5%, the required sample size is 212 patients.
The HIGHLOW trial is a randomized multicenter controlled trial that will provide evidence on the merits of the level of arterial ligation during laparoscopic anterior rectal resection with total mesorectal excision in terms of better preserved post-operative genito-urinary function.
Trial registration Identifier: NCT02153801
Protocol Registration Receipt 29/5/2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0537-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4311448  PMID: 25623323
Genito-urinary function; inferior mesenteric artery ligation;anastomotic leakage; rectal cancer; laparoscopic low anterior resection; oncological outcome
19.  Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial 
Trials  2015;16:24.
Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.
The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.
Trial registration
The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health register, reference number: NCT02176122 (registered 24 June 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0541-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4311465  PMID: 25623485
Extended-spectrum beta-lactamase; ESBL; Plasmid-AmpC; Therapy; Resistance; Beta-lactam/beta-lactamase inhibitor; Carbapenem; Clinical trial
20.  Application time for postoperative wound dressing following breast augmentation with implants: study protocol for a randomized controlled trial 
Trials  2015;16:19.
Breast augmentation with silicone implants is one of the most frequently performed cosmetic surgeries worldwide. Surgical site infection (SSI) remains an important complication of this procedure. One of the most important risk factors for SSI is the presence of microorganisms on the skin surrounding the wound. Guidelines by the Centers for Disease Control (CDC) recommend that surgical wounds be covered with a sterile dressing for 24 to 48 hours. However, a recent study showed that the application of a dressing for six days after breast reduction reduced wound colonization by coagulase-negative staphylococci.
A randomized clinical trial was designed to assess two protocols of postoperative wound care to determine how the application duration of the postoperative dressing influences wound colonization in patients undergoing breast augmentation with silicone implants. Women aged between 18 and 60 years who are candidates for breast augmentation with silicone implants will be randomly allocated to group I (n = 48), in which the dressing will be removed on the first postoperative day, or group II (n = 48), in which the dressing will be removed on the sixth postoperative day. Cutaneous colonization will be assessed by cultures of samples of skin flora taken from the wound region. The incidence of SSI, using standardized CDC criteria, and the perceptions of patients towards the dressing will be secondary outcomes.
An important component of SSI prevention is to minimize all possible risk factors, and the application of postoperative dressing plays a key role in this endeavor. The results of this clinical trial may help to standardize postoperative wound care after breast augmentation with silicone implants.
Trial registration
This trial was registered on 12 March 2012 with (identifier: NCT01553604).
PMCID: PMC4311490  PMID: 25623237
Breast; Prosthesis implantation; Augmentation mammaplasty; Postoperative care; Dressings; Surgical wound infection; Bacterial growth; Patient satisfaction
21.  The effects of stimulation of the autonomic nervous system via perioperative nutrition on postoperative ileus and anastomotic leakage following colorectal surgery (SANICS II trial): a study protocol for a double-blind randomized controlled trial 
Trials  2015;16:20.
Postoperative ileus and anastomotic leakage are important complications following colorectal surgery associated with short-term morbidity and mortality. Previous experimental and preclinical studies have shown that a short intervention with enriched enteral nutrition dampens inflammation via stimulation of the autonomic nervous system and thereby reduces postoperative ileus. Furthermore, early administration of enteral nutrition reduced anastomotic leakage. This study will investigate the effect of nutritional stimulation of the autonomic nervous system just before, during and early after colorectal surgery on inflammation, postoperative ileus and anastomotic leakage.
This multicenter, prospective, double-blind, randomized controlled trial will include 280 patients undergoing colorectal surgery. All patients will receive a selfmigrating nasojejunal tube that will be connected to a specially designed blinded tubing system. Patients will be allocated either to the intervention group, receiving perioperative nutrition, or to the control group, receiving no nutrition. The primary endpoint is postoperative ileus. Secondary endpoints include anastomotic leakage, local and systemic inflammation, (aspiration) pneumonia, surgical complications classified according to Clavien-Dindo, quality of life, gut barrier integrity and time until functional recovery. Furthermore, a cost-effectiveness analysis will be performed.
Activation of the autonomic nervous system via perioperative enteral feeding is expected to dampen the local and systemic inflammatory response. Consequently, postoperative ileus will be reduced as well as anastomotic leakage. The present study is the first to investigate the effects of enriched nutrition given shortly before, during and after surgery in a clinical setting.
Trial registration NCT02175979 - date of registration: 25 June 2014.
Dutch Trial Registry: NTR4670 - date of registration: 1 August 2014.
PMCID: PMC4318130  PMID: 25623276
Perioperative nutrition; Colorectal surgery; Postoperative ileus; Anastomotic leakage; Autonomic nervous system; Inflammation
22.  Progressive high-load strength training compared with general low-load exercises in patients with rotator cuff tendinopathy: study protocol for a randomised controlled trial 
Trials  2015;16:27.
Shoulder pain is the third most common musculoskeletal disorder, often affecting people’s daily living and work capacity. The most common shoulder disorder is the subacromial impingement syndrome (SIS) which, among other pathophysiological changes, is often characterised by rotator cuff tendinopathy. Exercise is often considered the primary treatment option for rotator cuff tendinopathy, but there is no consensus on which exercise strategy is the most effective. As eccentric and high-load strength training have been shown to have a positive effect on patella and Achilles tendinopathy, the aim of this trial is to compare the efficacy of progressive high-load exercises with traditional low-load exercises in patients with rotator cuff tendinopathy.
The current study is a randomised, participant- and assessor-blinded, controlled multicentre trial. A total of 260 patients with rotator cuff tendinopathy will be recruited from three outpatient shoulder departments in Denmark, and randomised to either 12 weeks of progressive high-load strength training or to general low-load exercises. Patients will receive six individually guided exercise sessions with a physiotherapist and perform home-based exercises three times a week. The primary outcome measure will be change from baseline to 12 weeks in the patient-reported outcome Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire.
Previous studies of exercise treatment for SIS have not differentiated between subgroups of SIS and have often had methodological flaws, making it difficult to specifically design target treatment for patients diagnosed with SIS. Therefore, it was considered important to focus on a subgroup such as tendinopathy, with a specific tailored intervention strategy based on evidence from other regions of the body, and to clearly describe the intervention in a methodologically strong study.
Trial registration
The trial was registered with (NCT01984203) on 31 October 2013.
PMCID: PMC4318133  PMID: 25622594
Shoulder; Impingement; Tendinopathy; Exercise; Rotator cuff
23.  The FOCUS trial: cognitive remediation plus standard treatment versus standard treatment for patients at ultra-high risk for psychosis: study protocol for a randomised controlled trial 
Trials  2015;16:25.
Cognitive deficits are a distinct feature among people at ultra-high risk (UHR) for psychosis and pose a barrier to functional recovery. Insufficient evidence exists on how to ameliorate these cognitive deficits in patients at UHR for psychosis and hence improve daily living and quality of life. The aim of the trial is to investigate whether cognitive remediation can improve cognitive and psychosocial function in patients at UHR for psychosis.
The FOCUS trial (Function and Overall Cognition in Ultra-high risk States) is a randomised, parallel group, observer-blinded clinical trial enrolling 126 patients meeting the standardised criteria of being at UHR for psychosis. Patients are recruited from psychiatric in- and outpatient facilities in the Copenhagen catchment area. Patients are randomised to one of the two treatment arms: cognitive remediation plus standard treatment versus standard treatment. The cognitive remediation consists of 24 weekly group-based and manualised sessions targeting neurocognition and social cognition. In addition to the group sessions, the patients will be offered 12 individual sessions aiming at maximising the transfer of the effects of the cognitive training to their everyday lives. Follow-up assessments will be conducted at 6 and 12 months after randomisation. The primary outcome is the composite score on the Brief Assessment of Cognition in Schizophrenia at cessation of treatment after 6 months. Secondary outcomes are social and daily functioning, psychosis-like symptoms, negative symptomatology, and depressive symptomatology as measured with the Personal and Social Performance Scale, Brief Psychiatric Rating Scale-Expanded Version, Scale for the Assessment of Negative Symptoms, and the Montgomery-Åsberg Depression Rating Scale.
This is the first trial to evaluate the effects of neurocognitive and social cognitive remediation in UHR patients. The FOCUS trial results will provide evidence on the effect of targeted and comprehensive cognitive rehabilitation on cognition, daily living, and symptomatology as well as long-term outcome in preventing transition to psychosis in UHR patients.
Trial registration NCT 02098408. Date of registration 18 March 2014.
PMCID: PMC4318160  PMID: 25623736
At-risk mental state; Ultra-high risk for psychosis; Prodromal schizophrenia; Prodromal intervention; Cognitive remediation; Cognitive training; Social cognitive training; Neurocognitive training
24.  Clinical and cost effectiveness of computer treatment for aphasia post stroke (Big CACTUS): study protocol for a randomised controlled trial 
Trials  2015;16:18.
Aphasia affects the ability to speak, comprehend spoken language, read and write. One third of stroke survivors experience aphasia. Evidence suggests that aphasia can continue to improve after the first few months with intensive speech and language therapy, which is frequently beyond what resources allow. The development of computer software for language practice provides an opportunity for self-managed therapy. This pragmatic randomised controlled trial will investigate the clinical and cost effectiveness of a computerised approach to long-term aphasia therapy post stroke.
A total of 285 adults with aphasia at least four months post stroke will be randomly allocated to either usual care, computerised intervention in addition to usual care or attention and activity control in addition to usual care. Those in the intervention group will receive six months of self-managed word finding practice on their home computer with monthly face-to-face support from a volunteer/assistant. Those in the attention control group will receive puzzle activities, supplemented by monthly telephone calls.
Study delivery will be coordinated by 20 speech and language therapy departments across the United Kingdom. Outcome measures will be made at baseline, six, nine and 12 months after randomisation by blinded speech and language therapist assessors. Primary outcomes are the change in number of words (of personal relevance) named correctly at six months and improvement in functional conversation. Primary outcomes will be analysed using a Hochberg testing procedure. Significance will be declared if differences in both word retrieval and functional conversation at six months are significant at the 5% level, or if either comparison is significant at 2.5%. A cost utility analysis will be undertaken from the NHS and personal social service perspective. Differences between costs and quality-adjusted life years in the three groups will be described and the incremental cost effectiveness ratio will be calculated. Treatment fidelity will be monitored.
This is the first fully powered trial of the clinical and cost effectiveness of computerised aphasia therapy. Specific challenges in designing the protocol are considered.
Trial registration
Registered with Current Controlled Trials ISRCTN68798818 on 18 February 2014.
PMCID: PMC4318176  PMID: 25623162
Speech and language therapy; Aphasia; Computerised intervention; Self-management; Long term rehabilitation; RCT design; Stroke
25.  A phase II trial for the efficacy of physiotherapy intervention for early-onset hip osteoarthritis: study protocol for a randomised controlled trial 
Trials  2015;16:26.
Early-onset hip osteoarthritis is commonly seen in people undergoing hip arthroscopy and is associated with increased pain, reduced ability to participate in physical activity, reduced quality of life and reduced range of motion and muscle strength. Despite this, the efficacy of non-surgical interventions such as exercise therapies remains unknown. The primary aim is to establish the feasibility of a phase III randomised controlled trial investigating a targeted physiotherapy intervention for people with early-onset hip osteoarthritis. The secondary aims are to determine the size of treatment effects of a physiotherapy intervention, targeted to improve hip joint range and hip-related symptoms in early-onset hip osteoarthritis following hip arthroscopy, compared to a health-education control.
This protocol describes a randomised, assessor- and participant-blind, controlled clinical trial. We will include 20 participants who are (i) aged between 18 and 50 years; (ii) have undergone hip arthroscopy during the past six to 12 months; (iii) have early-onset hip osteoarthritis (defined as chondrolabral pathology) at the time of hip arthroscopy; and (iv) experience hip-related pain during activities. Primary outcome will be the feasibility of a phase III clinical trial. Secondary outcomes will be (i) perceived global change score; (ii) hip-related symptoms (measured using the Hip disability and Osteoarthritis Outcome Score (HOOS) pain subscale, activity subscale, and sport and recreation subscale); (iii) hip quality of life (measured using the HOOS quality of life subscale and International Hip Outcome tool; (iv) hip muscle strength and (v) hip range of motion. The physiotherapy intervention is semi-standardised, including joint and soft tissue mobilisation and stretching, hip and trunk muscle retraining and functional and activity-specific retraining and education. The control intervention encompasses individualised health education, with the same frequency and duration as the intervention. The trial primary end-point is the conclusion of the 12-week intervention, and follow-up measures will be collected at the 12-week post-baseline assessment.
The findings of this study will provide guidance regarding the feasibility of a full-scale phase III randomised controlled trial, prior to its undertaking.
Trial registration
The trial protocol was registered with the Australian Clinical Trials Registry (number: 12614000426684) on 17 April 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0543-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4318367  PMID: 25622524
Osteoarthritis; Hip joint; Hip arthroscopy; Randomised controlled trial; Physiotherapy

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