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1.  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
2.  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
3.  Constraint-induced movement therapy: trial sequential analysis applied to Cochrane collaboration systematic review results 
Trials  2014;15(1):512.
Trial sequential analysis (TSA) may establish when firm evidence about the efficacy of interventions is reached in a cumulative meta-analysis, combining a required information size with adjusted thresholds for conservative statistical significance. Our aim was to demonstrate TSA results on randomized controlled trials (RCTs) included in a Cochrane systematic review on the effectiveness of constraint-induced movement therapy (CIMT) for stroke patients.
We extracted data on the functional independence measure (FIM) and the action research arm test (ARAT) from RCTs that compared CIMT versus other rehabilitative techniques. Mean differences (MD) were analyzed using a random-effects model. We calculated the information size and the cumulative Z-statistic, applying the O’Brien-Fleming monitoring boundaries.
We included data from 14 RCTs. In the conventional meta-analysis (seven trials, 233 patients), the effect of CIMT on FIM was reported as significant (MD 2.88, 95% CI 0.08 to 5.68; P = 0.04). The diversity-adjusted required information size was 142 patients, and the cumulative Z-score did not cross the trial sequential monitoring boundary for benefit (adjusted 95% CI -0.02 to 5.78). The effect of CIMT on ARAT (nine trials, 199 patients) was reported as significant (MD 7.78, 95% CI 1.19 to 14.37; P = 0.02). However, the diversity-adjusted required information size was 252 patients, and the Z-score did not cross the trial sequential monitoring boundary for benefit (adjusted 95% CI -0.06 to 15.62).
Although conventional meta-analyses of CIMT reached statistical significance, their overall results remain inconclusive and might be spurious. Researchers should not be overconfident on CIMT efficacy based on the results of meta-analyses and derived recommendations.
PMCID: PMC4307139  PMID: 25542215
Stroke; Constraint-induced movement therapy; Meta-analysis; Random error; Trial sequential analysis
4.  Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods 
Thresholds for statistical significance when assessing meta-analysis results are being insufficiently demonstrated by traditional 95% confidence intervals and P-values. Assessment of intervention effects in systematic reviews with meta-analysis deserves greater rigour.
Methodologies for assessing statistical and clinical significance of intervention effects in systematic reviews were considered. Balancing simplicity and comprehensiveness, an operational procedure was developed, based mainly on The Cochrane Collaboration methodology and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.
We propose an eight-step procedure for better validation of meta-analytic results in systematic reviews (1) Obtain the 95% confidence intervals and the P-values from both fixed-effect and random-effects meta-analyses and report the most conservative results as the main results. (2) Explore the reasons behind substantial statistical heterogeneity using subgroup and sensitivity analyses (see step 6). (3) To take account of problems with multiplicity adjust the thresholds for significance according to the number of primary outcomes. (4) Calculate required information sizes (≈ the a priori required number of participants for a meta-analysis to be conclusive) for all outcomes and analyse each outcome with trial sequential analysis. Report whether the trial sequential monitoring boundaries for benefit, harm, or futility are crossed. (5) Calculate Bayes factors for all primary outcomes. (6) Use subgroup analyses and sensitivity analyses to assess the potential impact of bias on the review results. (7) Assess the risk of publication bias. (8) Assess the clinical significance of the statistically significant review results.
If followed, the proposed eight-step procedure will increase the validity of assessments of intervention effects in systematic reviews of randomised clinical trials.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-14-120) contains supplementary material, which is available to authorized users.
PMCID: PMC4251848  PMID: 25416419
5.  Detailed statistical analysis plan for the Danish Palliative Care Trial (DanPaCT) 
Trials  2014;15(1):376.
Advanced cancer patients experience considerable symptoms, problems, and needs. Early referral of these patients to specialized palliative care (SPC) could offer improvements. The Danish Palliative Care Trial (DanPaCT) investigates whether patients with metastatic cancer will benefit from being referred to ‘early SPC’. DanPaCT is a multicenter, parallel-group, superiority clinical trial with 1:1 randomization. The planned sample size was 300 patients. The primary data collection for DanPaCT is finished. To prevent outcome reporting bias, selective reporting, and data-driven results, we present a detailed statistical analysis plan (SAP) for DanPaCT here.
This SAP provides detailed descriptions of the statistical analyses of the primary and secondary outcomes in DanPaCT. The primary outcome is the change in the patient’s ‘primary need’. The ‘primary need’ is a patient-individualised outcome representing the score of the symptom or problem that had the highest intensity out of seven at baseline assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Secondary outcomes are the seven scales that are represented in the primary outcome, but each scale evaluated individually for all patients, and survival. The detailed description includes chosen significance levels, models for multiple imputations, sensitivity analyses and blinding. In addition, we discuss the patient-individualized primary outcome, blinding, missing data, multiplicity and the risk of bias.
Only few trials have investigated the effects of SPC. To our knowledge DanPaCT is the first trial to investigate screening based ‘early SPC’ for patients with metastatic cancer from a broad spectrum of cancer diagnosis.
Trial registration identifier: NCT01348048 (May 2011).
PMCID: PMC4190470  PMID: 25257804
palliative care; advanced cancer; randomized clinical trial; quality of life; needs assessment; patient satisfaction; cost-effectiveness; data interpretation; statistical analysis plan; protocol
6.  Interpreting trial results following use of different intention-to-treat approaches for preventing attrition bias: a meta-epidemiological study protocol 
BMJ Open  2014;4(9):e005297.
When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses.
Methods and analysis
Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses.
Ethics and dissemination
This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication.
Protocol registration
In PROSPERO CRD42013006702, 11. December 2013.
PMCID: PMC4179424  PMID: 25260368
7.  Third-wave cognitive therapy versus mentalisation-based treatment for major depressive disorder: a randomised clinical trial 
BMJ Open  2014;4(8):e004903.
To compare the benefits and harms of third-wave cognitive therapy versus mentalisation-based therapy in a small sample of depressed participants.
The trial was conducted at an outpatient psychiatric clinic for non-psychotic patients in Roskilde, Denmark.
44 consecutive adult participants diagnosed with major depressive disorder.
18 weeks of third-wave cognitive therapy (n=22) versus 18 weeks of mentalisation-based treatment (n=22).
The primary outcome was the Hamilton Rating Scale for Depression (HDRS) at end of treatment (18 weeks). Secondary outcomes were: remission (HDRS <8), Beck's Depression Inventory, Symptom Checklist 90 Revised and The WHO-Five Well-being Index 1999.
The trial inclusion lasted for about 2 years as planned but only 44 out of the planned 84 participants were randomised. Two mentalisation-based participants were lost to follow-up. The unadjusted analysis showed that third-wave participants compared with mentalisation-based participants did not differ significantly regarding the 18 weeks HDRS score (12.9 vs 17.0; mean difference −4.14; 95% CI −8.30 to 0.03; p=0.051). In the analysis adjusted for baseline HDRS score, the difference was favouring third-wave cognitive therapy (p=0.039). At 18 weeks, five of the third-wave participants (22.7%) were in remission versus none of the mentalisation-based participants (p=0.049). We recorded no suicide attempts or suicides during the intervention period in any of the 44 participants. No significant differences were found between the two intervention groups on the remaining secondary outcomes.
Third-wave cognitive therapy may be more effective than mentalisation-based therapy for depressive symptoms measured on the HDRS. However, more randomised clinical trials are needed to assess the effects of third-wave cognitive therapy and mentalisation-based treatment for depression.
Trial registration number
Registered with Clinical Trials government identifier: NCT01070134.
PMCID: PMC4139625  PMID: 25138802
8.  Targeting intensive versus conventional glycaemic control for type 1 diabetes mellitus: a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials 
BMJ Open  2014;4(8):e004806.
To assess the benefits and harms of targeting intensive versus conventional glycaemic control in patients with type 1 diabetes mellitus.
A systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
Data sources
The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded and LILACS to January 2013.
Study selection
Randomised clinical trials that prespecified different targets of glycaemic control in participants at any age with type 1 diabetes mellitus were included.
Data extraction
Two authors independently assessed studies for inclusion and extracted data.
18 randomised clinical trials included 2254 participants with type 1 diabetes mellitus. All trials had high risk of bias. There was no statistically significant effect of targeting intensive glycaemic control on all-cause mortality (risk ratio 1.16, 95% CI 0.65 to 2.08) or cardiovascular mortality (0.49, 0.19 to 1.24). Targeting intensive glycaemic control reduced the relative risks for the composite macrovascular outcome (0.63, 0.41 to 0.96; p=0.03), and nephropathy (0.37, 0.27 to 0.50; p<0.00001. The effect estimates of retinopathy, ketoacidosis and retinal photocoagulation were not consistently statistically significant between random and fixed effects models. The risk of severe hypoglycaemia was significantly increased with intensive glycaemic targets (1.40, 1.01 to 1.94). Trial sequential analyses showed that the amount of data needed to demonstrate a relative risk reduction of 10% were, in general, inadequate.
There was no significant effect towards improved all-cause mortality when targeting intensive glycaemic control compared with conventional glycaemic control. However, there may be beneficial effects of targeting intensive glycaemic control on the composite macrovascular outcome and on nephropathy, and detrimental effects on severe hypoglycaemia. Notably, the data for retinopathy and ketoacidosis were inconsistent. There was a severe lack of reporting on patient relevant outcomes, and all trials had poor bias control.
PMCID: PMC4139659  PMID: 25138801
9.  The effects of immunotherapy with intravenous immunoglobulins versus no intervention, placebo, or usual care in patients with recurrent miscarriages: a protocol for a systematic review with meta-analyses, trial sequential analyses, and individual patient data meta-analyses of randomised clinical trials 
Systematic Reviews  2014;3:89.
Recurrent miscarriage is generally defined as three or more miscarriages before gestational week 20. Recurrent miscarriage affects 1% of all women and the condition can only be explained by parental chromosome abnormalities, uterine malformations, or endocrine or thrombophilic disturbances to a limited extent. Immunological disturbances are hypothesised to play an important role in recurrent miscarriage and, therefore, various types of immunologically-based therapies have been tested in recurrent miscarriage patients including intravenous immunoglobulins. So far, at least eight randomised placebo-controlled trials, with opposing results, investigating intravenous immunoglobulins with a total of 324 recurrent miscarriage patients have been published.
We will include randomised clinical trials irrespective of publication date, publication type, publication language, and publication status investigating infusions with immunoglobulins in relation to pregnancy compared to placebo, no intervention, or treatment as usual for assessments of benefits and harms. The relevant published literature will be searched using the following databases: Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, and Ovid Medline In-Process and Other Non-Indexed Citations databases. Two review authors will independently extract data and assess risk of bias. We will undertake meta-analyses according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions. Further, we will conduct trial sequential analyses and individual patient data meta-analyses.
A miscarriage results in great sorrow, loss of life quality, and personal concern. In particular, recurrent miscarriage is extremely stressful and burdensome. It is, therefore, very important to conduct research in this area. There is currently no evidence-based treatment for women with recurrent miscarriage which significantly improves their ability to give live birth. Therefore, a comprehensive up-to-date systematic review is needed. By using individual patient data, it will be possible to provide new knowledge about the benefits and harms of intravenous immunoglobulins and try to identify the subgroup in which the treatment will have the highest impact.
This systematic review protocol was registered within the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42014007112.
PMCID: PMC4139136  PMID: 25128005
Systematic review; Meta-analysis; Recurrent miscarriage; Immunotherapy; Immunoglobulins
10.  Effect of guided self-determination youth intervention integrated into outpatient visits versus treatment as usual on glycemic control and life skills: a randomized clinical trial in adolescents with type 1 diabetes 
Trials  2014;15(1):321.
Providing care for adolescents with type 1 diabetes is complex, demanding, and often unsuccessful. Guided self-determination (GSD) is a life skills approach that has been proven effective in caring for adults with type 1 diabetes. To improve care, GSD was revised for adolescents, their parents, and interdisciplinary healthcare providers (HCP) to create GSD-Youth (GSD-Y). We evaluated the impact of GSD-Y after it was integrated into pediatric outpatient visits versus treatment-as-usual, focusing on glycemic control and the development of life skills in adolescents with type 1 diabetes.
Seventy-one adolescents (mean age: 15 years, mean duration of diabetes: 5.7 years, mean HbA1c: 77 mmol/mol (9.1%), upon entering the study) from two pediatric departments were randomized into a GSD-Y group (n = 37, GSD-Y was provided during individual outpatient sessions) versus a treatment-as-usual group (n = 34). The primary outcome was the HbA1c measurement. The secondary outcomes were life skills development (assessed by self-reported psychometric scales), self-monitored blood glucose levels, and hypo- and hyperglycemic episodes. The analysis followed an intention-to-treat basis.
Fifty-seven adolescents (80%) completed the trial, and 53 (75%) completed a six-month post-treatment follow-up. No significant effect of GSD-Y on the HbA1c could be detected in a mixed-model analysis after adjusting for the baseline HbA1c levels and the identity of the HCP (P = 0.85). GSD-Y significantly reduced the amotivation for diabetes self-management after adjusting for the baseline value (P = 0.001). Compared with the control group, the trial completion was prolonged in the GSD-Y group (P <0.001), requiring more visits (P = 0.05) with a higher rate of non-attendance (P = 0.01). GSD-Y parents participated in fewer of the adolescents’ visits (P = 0.05) compared with control parents.
Compared with treatment-as-usual, GSD-Y did not improve HbA1c levels, but it did decrease adolescents’ amotivation for diabetes self-management.
Trial registration
ISRCTN 54243636, registered on 10 January 2010. Life skills for adolescents with type 1 diabetes and their parents.
PMCID: PMC4247629  PMID: 25118146
Type 1 diabetes mellitus; Adolescents; Outpatient clinic; Hospital; Clinical trials; Randomization; Empowerment
11.  Quetiapine versus aripiprazole in children and adolescents with psychosis - protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial 
BMC Psychiatry  2014;14:199.
The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections.
The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014.
Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size.
Trial registration NCT01119014
PMCID: PMC4227115  PMID: 25015535
Antipsychotics; Quetiapine; Aripiprazole; Psychosis; Schizophrenia; Children; Adolescents; Randomised trial; Benefits; Harms
12.  Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis 
CMAJ Open  2014;2(3):E162-E175.
Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared with metformin.
We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial sequential analysis.
We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient-important outcomes were sparse. Compared with metformin, sulfonylurea did not significantly affect all-cause mortality (relative risk [RR] 0.98, 95% confidence interval [CI] 0.61 to 1.58) or cardiovascular mortality (RR 1.47, 95% CI 0.54 to 4.01). Sulfonylurea significantly decreased the risk of nonfatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93). However, the definition of this outcome varied among trials, and trial sequential analysis showed that more trials are needed before reliable conclusions can be drawn. No differences between sulfonylurea and metformin were found for change in fasting blood glucose level or glycosylated hemoglobin concentration in the random-effects model. Sulfonylurea resulted in greater weight gain compared with metformin, a finding confirmed in the trial sequential analysis. Significantly more patients in the sulfonylurea arm than in the metformin arm had mild hypoglycemia (RR 2.95, 95% CI 2.13 to 4.07) and severe hypoglycemia (RR 5.64, 95% CI 1.22 to 26.00).
Some evidence suggests that, compared with metformin, second- and third-generation sulfonylureas may not affect all-cause or cardiovascular mortality but may decrease the risk of nonfatal macrovascular outcomes among patients with type 2 diabetes. They may also increase the risk of hypoglycemia. In general, the available data were too few and inconsistent to provide firm evidence concerning patient-important outcomes in relation to the benefits and harms of sulfonylurea versus metformin monotherapy.
PMCID: PMC4185978  PMID: 25295236
13.  The DiaS trial: dialectical behavior therapy versus collaborative assessment and management of suicidality on self-harm in patients with a recent suicide attempt and borderline personality disorder traits - study protocol for a randomized controlled trial 
Trials  2014;15:194.
In Denmark 8,000 to 10,000 people will attempt suicide each year. The Centre of Excellence in Suicide Prevention in the Capital Region of Denmark is treating patients with suicidal behavior, and a recent survey has shown that 30% of the patients are suffering from borderline personality disorder. The majority of patients (70% to 75%) with borderline personality disorder have a history of deliberate self-harm and 10% have a lifetime risk to die by suicide. The DiaS trial is comparing dialectical behavior therapy with collaborative assessment and management of suicidality-informed supportive psychotherapy, for the risk of repetition of deliberate self-harm in patients with a recent suicide attempt and personality traits within the spectrum of borderline personality disorder. Both treatments have previously shown effects in this group of patients on suicide ideation and self-harm compared with treatment as usual.
The trial is designed as a single-center, two-armed, parallel-group observer-blinded randomized clinical superiority trial. We will recruit 160 participants with a recent suicide attempt and at least two traits of the borderline personality disorder from the Centre of Excellence in Suicide Prevention, Capital Region of Denmark. Randomization will be performed though a centralized and computer-generated approach that conceals the randomization sequence. The interventions that are offered are a modified version of a dialectical behavior therapy program lasting 16 weeks versus collaborative assessment and management of suicidality-informed supportive psychotherapy, where the duration treatment will vary in accordance with established methods up to 16 weeks. The primary outcome measure is the ratio of deliberate self-harming acts including suicide attempts measured at week 28. Other exploratory outcomes are included such as severity of symptoms, suicide intention and ideation, depression, hopelessness, self-esteem, impulsivity, anger, and duration of respective treatments.
Trial registration
Clinical NCT01512602.
PMCID: PMC4055911  PMID: 24885904
suicide prevention; deliberate self-harm; borderline personality disorder traits; BPD; dialectical behavior therapy; DBT; collaborative assessment and management of suicidality; CAMS
15.  Endoscopic versus open radial artery harvest and mammario-radial versus aorto-radial grafting in patients undergoing coronary artery bypass surgery: protocol for the 2 × 2 factorial designed randomised NEO trial 
Trials  2014;15:135.
Coronary artery bypass grafting using the radial artery has, since the 1990s, gone through a revival. Observational studies have indicated better long-term patency when using radial arteries. Therefore, radial artery might be preferred especially in younger patients where long time patency is important. During the last 10 years different endoscopic techniques to harvest the radial artery have evolved. Endoscopic radial artery harvest only requires a small incision near the wrist in contrast to open harvest, which requires an incision from the elbow to the wrist. However, it is unknown whether the endoscopic technique results in fewer complications or a graft patency comparable to open harvest. When the radial artery has been harvested, there are two ways to use the radial artery as a graft. One way is sewing it onto the aorta and another is sewing it onto the mammary artery. It is unknown which technique is the superior revascularisation technique.
The NEO Trial is a randomised clinical trial with a 2 × 2 factorial design. We plan to randomise 300 participants into four intervention groups: (1) mammario-radial endoscopic group; (2) aorto-radial endoscopic group; (3) mammario-radial open surgery group; and (4) aorto-radial open surgery group.
The hand function will be assessed by a questionnaire, a clinical examination, the change in cutaneous sensibility, and the measurement of both sensory and motor nerve conduction velocity at 3 months postoperatively. All the postoperative complications will be registered, and we will evaluate muscular function, scar appearance, vascular supply to the hand, and the graft patency including the patency of the central radial artery anastomosis. A patency evaluation by multi-slice computer tomography will be done at one year postoperatively.
We expect the nerve conduction studies and the standardised neurological examinations to be able to discriminate differences in hand function comparing endoscopic to open harvest of the radial artery. The trial also aims to show if there is any patency difference between mammario-radial compared to aorto-radial revascularisation techniques but this objective is exploratory.
Trial registration identifier: NCT01848886.
Danish Ethics committee number: H-3-2012-116.
Danish Data Protection Agency: 2007-58-0015/jr.n:30–0838.
PMCID: PMC4033613  PMID: 24754891
Arterial revascularisation; Coronary artery bypass; Endoscopic radial artery harvest; Nerve conduction study; Neurological deficit; Open radial artery harvest; Patency; Quantitative sensory testing; Radial artery harvest
16.  The chronic autoimmune thyroiditis quality of life selenium trial (CATALYST): study protocol for a randomized controlled trial 
Trials  2014;15:115.
Patients with chronic autoimmune thyroiditis have impaired health-related quality of life. The thyroid gland has a high selenium concentration, and specific selenoprotein enzyme families are crucial to immune function, and catalyze thyroid hormone metabolism and redox processes in thyroid cells. Previous randomized controlled trials have found that selenium supplementation decreases thyroid-disease-specific antibody levels. We hypothesize that selenium might be beneficial in the treatment of chronic autoimmune thyroiditis.
The CATALYST trial is an investigator-initiated randomized, blinded, multicentre clinical trial of selenium supplementation versus placebo in patients with chronic autoimmune thyroiditis. Inclusion criteria: age ≥18 years; serum thyroid peroxidase antibody level ≥100 IU/ml within the previous 12 months; treatment with levothyroxine and written informed consent. Exclusion criteria: previous diagnosis of toxic nodular goitre, Graves’ hyperthyroidism, postpartum thyroiditis, Graves’ orbitopathy; previous antithyroid drug treatment, radioiodine therapy or thyroid surgery; immune-modulatory or other medication affecting thyroid function; pregnancy, planned pregnancy or breastfeeding; allergy towards any intervention or placebo component; intake of selenium supplementation >55 μg/day; inability to read or understand Danish or lack of informed consent. The trial will include 2 × 236 participants. The experimental intervention and control groups will receive 200 μg selenium-enriched yeast or matching placebo tablets daily for 12 months. The experimental supplement will be SelenoPrecise®. The primary outcome is thyroid-related quality of life assessed by the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire. Secondary outcomes include serum thyroid peroxidase antibody concentration; serum triiodothyronine/thyroxine ratio; levothyroxine dosage; adverse reactions and serious adverse reactions and events.
In this pragmatic trial, participating patients follow their usual treatment at their usual hospitals. In order to collect high-quality data on the clinical course and quality of life, and to minimize missing data, an elaborate trial management system has been designed. 12 months intervention duration was selected in consideration of the primary outcome, thyroid-related quality of life.
Trial registration ID: NCT02013479.
PMCID: PMC3986429  PMID: 24716668
chronic autoimmune thyroiditis; hypothyroidism; quality of life; selenium supplementation; ThyPRO
17.  STRIDER: Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction – a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis 
Systematic Reviews  2014;3:23.
In pregnancies complicated by early-onset extreme fetal growth restriction, there is a high risk of preterm birth and an overall dismal fetal prognosis. Sildenafil has been suggested to improve this prognosis. The first aim of this review is to assess whether sildenafil benefits or harms these babies. The second aim is to analyse if these effects are modified in a clinically meaningful way by factors related to the women or the trial protocol.
The STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) Individual Participant Data (IPD) Study Group will conduct a prospective IPD and aggregate data systematic review with meta-analysis and trial sequential analysis. The STRIDER IPD Study Group started trial planning and funding applications in 2012. Three trials will be launched in 2014, recruiting for three years. Further trials are planned to commence in 2015.
The primary outcome for babies is being alive at term gestation without evidence of serious adverse neonatal outcome. The latter is defined as severe central nervous system injury (severe intraventricular haemorrhage (grade 3 and 4) or cystic periventricular leukomalacia, demonstrated by ultrasound and/or magnetic resonance imaging) or other severe morbidity (bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, or necrotising enterocolitis requiring surgery). The secondary outcomes are improved fetal growth velocity assessed by ultrasound abdominal circumference measurements, gestational age and birth weight (centile) at delivery, and age-adequate performance on the two-year Bayley scales of infant and toddler development-III (composite cognitive score and composite motor score). Subgroup and sensitivity analyses in the IPD meta-analysis include assessment of the influence of several patient characteristics: an abnormal or normal serum level of placental growth factor, absent/reversed umbilical arterial end diastolic flow at commencement of treatment, and other patient characteristics available at baseline such as gestational age and estimated fetal weight. The secondary outcomes for mothers include co-incidence and severity of the maternal syndrome of pre-eclampsia, mortality, and other serious adverse events.
Trials are expected to start in 2013–2014 and end in 2016–2017. Data analyses of individual trials are expected to finish in 2019. Given the pre-planned and agreed IPD protocol, these results should be available in 2020.
PMCID: PMC3975177  PMID: 24618418
Adverse neonatal outcome; Fetal growth restriction; Individual participant data meta-analysis; Sildenafil
18.  The thresholds for statistical and clinical significance – a five-step procedure for evaluation of intervention effects in randomised clinical trials 
Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore, assessment of intervention effects in randomised clinical trials deserves more rigour in order to become more valid.
Several methodologies for assessing the statistical and clinical significance of intervention effects in randomised clinical trials were considered. Balancing simplicity and comprehensiveness, a simple five-step procedure was developed.
For a more valid assessment of results from a randomised clinical trial we propose the following five-steps: (1) report the confidence intervals and the exact P-values; (2) report Bayes factor for the primary outcome, being the ratio of the probability that a given trial result is compatible with a ‘null’ effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted; (4) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons; and (5) assess clinical significance of the trial results.
If the proposed five-step procedure is followed, this may increase the validity of assessments of intervention effects in randomised clinical trials.
PMCID: PMC4015863  PMID: 24588900
Randomised clinical trial; Threshold for significance; Bayes factor; Confidence interval; P-value
19.  Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention? 
PLoS ONE  2013;8(12):e83313.
Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.
We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).
The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.
SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker.
PMCID: PMC3861485  PMID: 24349487
20.  A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED) 
5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia.
We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks’ gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit.
The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If ‘at risk’ patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome.
Trial registration
Trial registration number NCT01891240
The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU.
PMCID: PMC4029471  PMID: 24314209
Pre-eclampsia; Screening; Proteomics; Metabolomics; Preterm birth; Small for gestational age
21.  The CopenHeartSF trial—comprehensive sexual rehabilitation programme for male patients with implantable cardioverter defibrillator or ischaemic heart disease and impaired sexual function: protocol of a randomised clinical trial 
BMJ Open  2013;3(11):e003967.
Sexuality is an important part of people’s physical and mental health. Patients with heart disease often suffer from sexual dysfunction. Sexual dysfunction has a negative impact on quality of life and well-being in persons with heart disease, and sexual dysfunction is associated with anxiety and depression. Treatment and care possibilities seem to be lacking. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation possess the potential of reducing sexual dysfunction in patients with heart disease. The CopenHeartSF trial will investigate the effect of a comprehensive sexual rehabilitation programme versus usual care.
Methods and analysis
CopenHeartSF is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, with 1:1 central randomisation to sexual rehabilitation plus usual care versus usual care alone. Based on sample size calculations, 154 male patients with impaired sexual function due to implantable cardioverter defibrillator or ischaemic heart disease will be included from two university hospitals in Denmark. All patients receive usual care and patients allocated to the experimental intervention group follow a 12-week sexual rehabilitation programme consisting of an individualised exercise programme and psychoeducative consultation with a specially trained nurse. The primary outcome is sexual function measured by the International Index of Erectile Function. The secondary outcome measure is psychosocial adjustment to illness by the Psychosocial Adjustment to Illness Scale, sexual domain. A number of explorative analyses will also be conducted.
Ethics and dissemination
CopenHeartSF is approved by the regional ethics committee (no H-4-2012-168) and the Danish Data Protection Agency (no 2007-58-0015) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form.
Registration identifier: NCT01796353.
PMCID: PMC3845056  PMID: 24282249
22.  Protocol for a randomised trial on the effect of group education on skin-protective behaviour versus treatment as usual among individuals with newly notified occupational hand eczema – the Prevention of Hand Eczema (PREVEX) Trial 
BMC Dermatology  2013;13:16.
The incidence of occupational hand eczema is approximately 0.32 per 1,000 person years. The burden of the disease is high, as almost 60% has eczema-related sick leave during the first year after notification, and 15% are excluded from the workforce 12 years after disease onset. New treatments and prevention strategies are needed.
Trial design: The PREVEX trial is a randomised, parallel-group, superiority trial.
Participants: All individuals from the Capital Region of Denmark and Region Zealand with a suspected occupational skin disorder notified to the National Board of Industrial Injuries between June 2012 and December 2013 are invited to participate in the trial. Inclusion criteria are: self-reported hand eczema and informed consent. Exclusion criteria are: age <18 years or >65 years; permanent exclusion from the workforce; inability to understand the Danish language; any serious medical condition; and lack of written informed consent. We plan to randomise 742 participants. Interventions: The experimental intervention is an educational course in skin-protective behaviour and written information about skin care related to the participants' specific occupation. Also, a telephone hotline is available and a subgroup will be offered a work-place visit. The experimental and the control group have access to usual care and treatment. All participants are contacted every eighth week with questions regarding number of days with sick leave or other absence from work. 12 months after randomisation follow-up is completed. Objective: To assesses the effect of an educational course versus treatment as usual in participants with newly notified occupational hand eczema. Randomisation: Participants are centrally randomised according to a computer-generated allocation sequence with a varying block size concealed to investigators. Blinding: It is not possible to blind the participants and investigators, however, data obtained from registers, data entry, statistical analyses, and drawing of conclusions will be blinded. Outcomes: The three co-primary outcomes, assessed at 12 months, are: total number of self-reported days with sick leave; health-related quality of life; and subjective assessment of hand eczema severity. Explorative outcomes are: self-reported eczema-related sick leave, absence from work registered by the DREAM-register and by self-report, risk behaviour, knowledge of skin protection and performance management (self-efficacy; and self-evaluated ability to self-care).
The PREVEX trial will be the first individually randomised trial to investigate the benefits and harms of group-based education in patients with newly notified occupational hand eczema.
Trial registration Identifier: NCT01899287
PMCID: PMC4225615  PMID: 24245553
Occupational hand eczema; OHE; Occupational contact dermatitis (OCD); Prevention; Work related; Intervention
23.  A randomised, multicentre clinical trial of specialised palliative care plus standard treatment versus standard treatment alone for cancer patients with palliative care needs: the Danish palliative care trial (DanPaCT) protocol 
BMC Palliative Care  2013;12:37.
Advanced cancer patients experience considerable symptoms, problems, and needs. Early referral of these patients to specialised palliative care (SPC) could improve their symptoms and problems.
The Danish Palliative Care Trial (DanPaCT) investigates whether patients with metastatic cancer, who report palliative needs in a screening, will benefit from being referred to ‘early SPC’.
DanPaCT is a clinical, multicentre, parallel-group superiority trial with balanced randomisation (1:1). The planned sample size is 300 patients. Patients are randomised to specialised palliative care (SPC) plus standard treatment versus standard treatment. Consecutive patients from oncology departments are screened for palliative needs with a questionnaire if they: a) have metastatic cancer; b) are 18 years or above; and c) have no prior contact with SPC. Patients with palliative needs (i.e. symptoms/problems exceeding a certain threshold) according to the questionnaire are eligible. The primary outcome is the change in the patients’ primary need (the most severe symptom/problem measured with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Secondary outcomes are other symptoms/problems (EORTC QLQ-C30), satisfaction with health care (FAMCARE P-16), anxiety and depression (the Hospital Anxiety and Depression scale), survival, and health care costs.
Only few trials have investigated the effects of SPC. To our knowledge DanPaCT is the first trial to investigate screening based ‘early SPC’ for patients with a broad spectrum of cancer diagnosis.
Trial registration
Current controlled Trials NCT01348048
PMCID: PMC3874751  PMID: 24152880
Palliative care; End-of-life care; Advanced cancer; Randomised clinical trial; Quality of life; Needs assessment; Patient satisfaction; Cost-effectiveness; Study protocol
24.  Meta-Regression Analyses, Meta-Analyses, and Trial Sequential Analyses of the Effects of Supplementation with Beta-Carotene, Vitamin A, and Vitamin E Singly or in Different Combinations on All-Cause Mortality: Do We Have Evidence for Lack of Harm? 
PLoS ONE  2013;8(9):e74558.
Background and Aims
Evidence shows that antioxidant supplements may increase mortality. Our aims were to assess whether different doses of beta-carotene, vitamin A, and vitamin E affect mortality in primary and secondary prevention randomized clinical trials with low risk of bias.
The present study is based on our 2012 Cochrane systematic review analyzing beneficial and harmful effects of antioxidant supplements in adults. Using random-effects meta-analyses, meta-regression analyses, and trial sequential analyses, we examined the association between beta-carotene, vitamin A, and vitamin E, and mortality according to their daily doses and doses below and above the recommended daily allowances (RDA).
We included 53 randomized trials with low risk of bias (241,883 participants, aged 18 to 103 years, 44.6% women) assessing beta-carotene, vitamin A, and vitamin E. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all-cause mortality. Beta-carotene in a dose above 9.6 mg significantly increased mortality (relative risk (RR) 1.06, 95% confidence interval (CI) 1.02 to 1.09, I2 = 13%). Vitamin A in a dose above the RDA (> 800 µg) did not significantly influence mortality (RR 1.08, 95% CI 0.98 to 1.19, I2 = 53%). Vitamin E in a dose above the RDA (> 15 mg) significantly increased mortality (RR 1.03, 95% CI 1.00 to 1.05, I2 = 0%). Doses below the RDAs did not affect mortality, but data were sparse.
Beta-carotene and vitamin E in doses higher than the RDA seem to significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA.
All essential compounds to stay healthy cannot be synthesized in our body. Therefore, these compounds must be taken through our diet or obtained in other ways [1]. Oxidative stress has been suggested to cause a variety of diseases [2]. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing diseases and death. Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [3,4], more than one third of adults regularly take antioxidant supplements [5,6].
PMCID: PMC3765487  PMID: 24040282
25.  'In situ simulation' versus 'off site simulation' in obstetric emergencies and their effect on knowledge, safety attitudes, team performance, stress, and motivation: study protocol for a randomized controlled trial 
Trials  2013;14:220.
Unexpected obstetric emergencies threaten the safety of pregnant women. As emergencies are rare, they are difficult to learn. Therefore, simulation-based medical education (SBME) seems relevant. In non-systematic reviews on SBME, medical simulation has been suggested to be associated with improved learner outcomes. However, many questions on how SBME can be optimized remain unanswered. One unresolved issue is how 'in situ simulation' (ISS) versus 'off site simulation' (OSS) impact learning. ISS means simulation-based training in the actual patient care unit (in other words, the labor room and operating room). OSS means training in facilities away from the actual patient care unit, either at a simulation centre or in hospital rooms that have been set up for this purpose.
Methods and design
The objective of this randomized trial is to study the effect of ISS versus OSS on individual learning outcome, safety attitude, motivation, stress, and team performance amongst multi-professional obstetric-anesthesia teams.
The trial is a single-centre randomized superiority trial including 100 participants. The inclusion criteria were health-care professionals employed at the department of obstetrics or anesthesia at Rigshospitalet, Copenhagen, who were working on shifts and gave written informed consent. Exclusion criteria were managers with staff responsibilities, and staff who were actively taking part in preparation of the trial. The same obstetric multi-professional training was conducted in the two simulation settings. The experimental group was exposed to training in the ISS setting, and the control group in the OSS setting. The primary outcome is the individual score on a knowledge test. Exploratory outcomes are individual scores on a safety attitudes questionnaire, a stress inventory, salivary cortisol levels, an intrinsic motivation inventory, results from a questionnaire evaluating perceptions of the simulation and suggested changes needed in the organization, a team-based score on video-assessed team performance and on selected clinical performance.
The perspective is to provide new knowledge on contextual effects of different simulation settings.
Trial registration NCT01792674.
PMCID: PMC3716971  PMID: 23870501
Simulation; In situ simulation; Randomized trial; Obstetric emergencies; Multi-professional education; Stress

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