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1.  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
2.  Detailed statistical analysis plan for the target temperature management after out-of-hospital cardiac arrest trial 
Trials  2013;14:300.
Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial.
The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33°C or 36°C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy.
The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
Trial registration identifier: NCT01020916
PMCID: PMC3848451  PMID: 24044764
Cardiac arrest; Induced hypothermia; Mortality; Neurological function; Targeted temperature management; Randomized clinical trial; Statistical analysis plan
3.  A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial 
Trials  2013;14:120.
Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.
SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.
Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.
Trial registration, NCT01590316
PMCID: PMC3680969  PMID: 23782447
Randomized clinical trial; Preterm; Near infrared spectroscopy; Protocol
4.  Selenium supplementation for patients with Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial 
Trials  2013;14:119.
Graves’ hyperthyroidism is an autoimmune disease causing hyperfunction of the thyroid gland. The concentration of selenium is high in the thyroid gland and two important groups of enzymes within the thyroid are selenoproteins, that is, they depend on selenium. Selenium may have beneficial effects on autoimmune hypothyroidism and on Graves' orbitopathy, but the effects of selenium on Graves' hyperthyroidism is unknown.
We hypothesize that adjuvant selenium may be beneficial in the treatment of Graves' hyperthyroidism. The objective is to investigate if selenium supplementation plus standard treatment with anti-thyroid drugs versus standard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid drug treatment failure (that is, failure to remain euthyroid, without further treatment, one year after cessation of anti-thyroid drug treatment), faster and longer lasting remission (that is, anti-thyroid drug treatment success), and improved quality of life in patients with Graves’ hyperthyroidism.
Methods and design
The trial is an investigator-initiated, randomised, blinded, multicentre clinical trial. Inclusion criteria are: age 18 years or older; diagnosis of active Graves' hyperthyroidism within the last two months; and informed consent. Exclusion criteria are major co-morbidity; previous radioactive iodine treatment; ongoing anti-thyroid drug treatment for more than two months; treatment with immunomodulatory drugs; known allergy towards the components in the selenium and placebo pills; pregnancy or breast-feeding; and intake of selenium supplementation above 70 μg per day. We plan to include 492 participants, randomised (1:1) to two tablets of 100 μg selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily.
The primary outcome is the proportion of participants with anti-thyroid drug treatment failure (see above) at the end of the intervention period (24 to 30 months). Secondary outcomes are: thyroid-specific quality of life during the first year after randomisation; level of thyroid stimulating hormone-receptor antibodies at 18 months after randomisation and at the end of the intervention period (24 to 30 months); hyperthyroid symptoms during the first year after randomisation; eye symptoms during the first year after randomisation, and at the end of the intervention period (24 to 30 months); adverse reactions during the intervention period; and serious adverse events during the intervention period.
It was of great importance to the initiators of this trial, that the results would be directly applicable to daily clinical practice. Therefore, it was designed as a pragmatic trial: the patients follow their usual treatment at their usual hospitals. In order to still collect high quality data on the clinical course and quality of life, an elaborate trial management system was designed to keep track of patient input, need for trial personnel input and action, and to collect data from medical chart systems. Meticulous follow-up on missing responses to the QoL measurements has been incorporated into the system, to minimise missing quality of life data. Monitoring of adverse reactions and events is achieved by thorough instruction of the participants, surveillance of patient-reported outcomes, and integration with national databases regarding hospitalizations. A very long intervention period was necessary, since patients are not considered in remission until one year after stopping anti-thyroid drugs. Usually, patients are treated for 12 to 18 months with anti-thyroid drugs, yielding a total intervention period of 24 to 30 months.
Trial registration NCT01611896.
PMCID: PMC3748826  PMID: 23782950
Graves' disease; Selenium supplementation; Pragmatic trial; Quality of life; ThyPRO
5.  Effect of comprehensive cardiac rehabilitation after heart valve surgery (CopenHeartVR): study protocol for a randomised clinical trial 
Trials  2013;14:104.
Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising due to 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 hypothesise that a comprehensive cardiac rehabilitation programme can improve physical capacity and self-assessed mental health and reduce hospitalisation and healthcare costs after heart valve surgery.
A randomised 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 intervention to control group, using central randomisation, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise, and a psycho-educational intervention comprising five consultations. Primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. Secondary outcome is self-assessed mental health measured by the standardised questionnaire Short Form 36. Also, long-term healthcare utilisation and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design is used to evaluate qualitative and quantitative findings encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study.
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 (http://NCT01558765).
PMCID: PMC3748823  PMID: 23782510
Heart valve surgery; Rehabilitation; Physical exercise; Psycho-education
6.  The effect of integrated cardiac rehabilitation versus treatment as usual for atrial fibrillation patients treated with ablation: the randomised CopenHeartRFA trial protocol 
BMJ Open  2013;3(2):e002377.
Atrial fibrillation affects almost 2% of the population in the Western world. To preserve sinus rhythm, ablation is undertaken in symptomatic patients. Observational studies show that patients with atrial fibrillation often report a low quality of life and are less prone to be physically active due to fear of triggering fibrillation. Small trials indicate that exercise training has a positive effect on exercise capacity and mental health, and both patients with recurrent atrial fibrillation and in sinus rhythm may benefit from rehabilitation in managing life after ablation. No randomised trials have been published on cardiac rehabilitation for atrial fibrillation patients treated with ablation that includes exercise and psychoeducational components.
To test the effects of an integrated cardiac rehabilitation programme versus treatment as usual for patients with atrial fibrillation treated with ablation.
Methods and analysis design
The trial is a multicentre parallel arm design with 1:1 randomisation to the intervention and control group with blinded outcome assessment. 210 patients treated for atrial fibrillation with radiofrequency ablation will be included. The intervention consists of a rehabilitation programme including four psychoeducative consultations with a specially trained nurse and 12 weeks of individualised exercise training, plus the standard medical follow-up. Patients in the control group will receive the standard medical follow-up. The primary outcome measure is exercise capacity measured by the VO2 peak. The secondary outcome measure is self-rated mental health measured by the Short Form 36 questionnaire. Postintervention, qualitative interviews will be conducted in 10% of the intervention group.
Ethics and dissemination
The protocol is approved by the regional research ethics committee (number H-1-2011-135), the Danish Data Protection Agency (reg. nr. 2007-58-0015) and follows the latest version of the Declaration of Helsinki. The results will be published in peer-reviewed journals and may possibly impact on rehabilitation guidelines.
Trial registration identifier: NCT01523145.
PMCID: PMC3586151  PMID: 23430599
Atrial Fibrillation ; QUALITATIVE RESEARCH
7.  The Nordic Aortic Valve Intervention (NOTION) trial comparing transcatheter versus surgical valve implantation: study protocol for a randomised controlled trial 
Trials  2013;14:11.
Degenerative aortic valve (AV) stenosis is the most prevalent heart valve disease in the western world. Surgical aortic valve replacement (SAVR) has until recently been the standard of treatment for patients with severe AV stenosis. Whether transcatheter aortic valve implantation (TAVI) can be offered with improved safety and similar effectiveness in a population including low-risk patients has yet to be examined in a randomised setting.
This randomised clinical trial will evaluate the benefits and risks of TAVI using the transarterial CoreValve System (Medtronic Inc., Minneapolis, MN, USA) (intervention group) compared with SAVR (control group) in patients with severe degenerative AV stenosis. Randomisation ratio is 1:1, enrolling a total of 280 patients aged 70 years or older without significant coronary artery disease and with a low, moderate, or high surgical risk profile. Trial outcomes include a primary composite outcome of myocardial infarction, stroke, or all-cause mortality within the first year after intervention (expected rates 5% for TAVI, 15% for SAVR). Exploratory safety outcomes include procedure complications, valve re-intervention, and cardiovascular death, as well as cardiac, cerebral, pulmonary, renal, and vascular complications. Exploratory efficacy outcomes include New York Heart Association functional status, quality of life, and valve prosthesis and cardiac performance. Enrolment began in December 2009, and 269 patients have been enrolled up to December 2012.
The trial is designed to evaluate the performance of TAVI in comparison with SAVR. The trial results may influence the choice of treatment modality for patients with severe degenerative AV stenosis.
Trial registration NCT01057173
PMCID: PMC3551839  PMID: 23302232
Aortic valve stenosis; Aortic valve prosthesis; Transcatheter aortic valve implantation; Surgical aortic valve replacement; Randomised clinical trial design
8.  ‘Third wave’ cognitive therapy versus mentalization-based therapy for major depressive disorder. A protocol for a randomised clinical trial 
BMC Psychiatry  2012;12:232.
Most interventions for depression have shown small or no effects. ‘Third wave‘ cognitive therapy and mentalization-based therapy have both gained some ground as treatments of psychological problems. No randomised trial has compared the effects of these two interventions for patients with major depression.
Methods/ design
We plan a randomised, parallel group, assessor-blinded superiority clinical trial. During two years we will include 84 consecutive adult participants diagnosed with major depressive disorder. The participants will be randomised to either ‘third wave‘ cognitive therapy versus mentalization-based therapy. The primary outcome will be the Hamilton Rating Scale for Depression at cessation of treatment at 18 weeks. Secondary outcomes will be the proportion of patients with remission, Symptom Checklist 90 Revised, Beck’s Depression Inventory, and The World Health Organisation-Five Well-being Index 1999.
Interventions for depression have until now shown relatively small effects. Our trial results will provide knowledge about the effects of two modern psychotherapeutic interventions.
Trial registration
ClinicalTrials: NCT01070134
PMCID: PMC3534354  PMID: 23253305
9.  A randomised clinical trial of comprehensive cardiac rehabilitation versus usual care for patients treated for infective endocarditis—the CopenHeartIE trial protocol 
BMJ Open  2012;2(6):e001929.
Infective endocarditis (IE) is among the most serious infectious diseases in the western world. Treatment requires lengthy hospitalisation, high-dosage antibiotic therapy and possible valve replacement surgery. Despite advances in treatment, the 1-year mortality remains at 20–40%. Studies indicate that patients experience persisting physical symptoms, diminished quality of life and difficulties returning to work up to a year postdischarge. No studies investigating the effects of rehabilitation have been published. We present the rationale and design of the CopenHeartIE trial, which investigates the effect of comprehensive cardiac rehabilitation versus usual care for patients treated for IE.
Methods and analysis
We will conduct a randomised clinical trial to investigate the effects of comprehensive cardiac rehabilitation versus usual care on the physical and psychosocial functioning of patients treated for IE. The trial is a multicentre, parallel design trial with 1 : 1 individual randomisation to either the intervention or control group. The intervention consists of five psychoeducational consultations provided by specialised nurses and a 12-week exercise training programme. The primary outcome is mental health (MH) measured by the standardised Short Form 36 (SF-36). The secondary outcome is peak oxygen uptake measured by the bicycle ergospirometry test. Furthermore, a number of exploratory analyses will be performed. Based on sample size calculation, 150 patients treated for left-sided (native or prosthetic valve) or cardiac device endocarditis will be included in the trial. A qualitative and a survey-based complementary study will be undertaken, to investigate postdischarge experiences of the patients. A qualitative postintervention study will explore rehabilitation participation experiences.
Ethics and dissemination
The study complies with the Declaration of Helsinki and was approved by the regional research ethics committee (no H-1-2011-129) and the Danish Data Protection Agency (no 2007-58-0015). Study findings will be disseminated widely through peer-reviewed publications and conference presentations.
Registration identifier: NCT01512615.
PMCID: PMC3533051  PMID: 23175738
Infective Endocarditis; RCT; Mixed Method
10.  Social-Skills and Parental Training plus Standard Treatment versus Standard Treatment for Children with ADHD – The Randomised SOSTRA Trial 
PLoS ONE  2012;7(6):e37280.
To investigate the effects of social-skills training and parental training programme for children with attention deficit hyperactivity disorder (ADHD).
We conducted a randomized two-armed, parallel group, assessor-blinded superiority trial consisting of social-skills training plus parental training and standard treatment versus standard treatment alone. A sample size calculation showed at least 52 children should be included for the trial with follow up three and six months after randomization. The primary outcome measure was ADHD symptoms and secondary outcomes were social skills and emotional competences.
Results 56
children (39 boys, 17 girls, mean age 10.4 years, SD 1.31) with ADHD were randomized, 28 to the experimental group and 27 to the control group. Mixed-model analyses with repeated measures showed that the time course (y  =  a + bt + ct2) of ADHD symptoms (p = 0.40), social skills (p = 0.80), and emotional competences (p = 0.14) were not significantly influenced by the intervention.
Social skills training plus parental training did not show any significant benefit for children with attention deficit hyperactivity disorder when compared with standard treatment. More and larger randomized trials are needed.
Trial Registration NCT00937469
PMCID: PMC3380035  PMID: 22745657
11.  Effect of Chronic Escitalopram versus Placebo on Personality Traits in Healthy First-Degree Relatives of Patients with Depression: A Randomized Trial 
PLoS ONE  2012;7(2):e31980.
The serotonergic neurotransmitter system is closely linked to depression and personality traits. It is not known if selective serotonin reuptake inhibitors (SSRI) have an effect on neuroticism that is independent of their effect on depression. Healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects personality. The present trial is the first to test the hypothesis that escitalopram may reduce neuroticism in healthy first-degree relatives of patients with major depressive disorder (MD).
The trial used a randomized, blinded, placebo-controlled parallel-group design. We examined the effect of four weeks escitalopram 10 mg daily versus matching placebo on personality in 80 people who had a biological parent or sibling with a history of MD. The outcome measure on personality traits was change in self-reported neuroticism scores on the Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the Eysenck Personality Inventory (EPQ) from entry until end of four weeks of intervention.
When compared with placebo, escitalopram did not significantly affect self-reported NEO-PI-R and EPQ neuroticism and extroversion, EPQ psychoticism, NEO-PI-R openness, or NEO-PI-R conscientiousness (p all above 0.05). However, escitalopram increased NEO-PI-R agreeableness scores significantly compared with placebo (mean; SD) (2.38; 8.09) versus (−1.32; 7.94), p = 0.046), but not following correction for multiplicity. A trend was shown for increased conscientiousness (p = 0.07). There was no significant effect on subclinical depressive symptoms (p = 0.6).
In healthy first-degree relatives of patients with MD, there is no effect of escitalopram on neuroticism, but it is possible that escitalopram may increase the personality traits of agreeableness and conscientiousness.
Trial Registration NCT00386841
PMCID: PMC3290539  PMID: 22393376
12.  Instructor feedback versus no instructor feedback on performance in a laparoscopic virtual reality simulator: a randomized educational trial 
Several studies have found a positive effect on the learning curve as well as the improvement of basic psychomotor skills in the operating room after virtual reality training. Despite this, the majority of surgical and gynecological departments encounter hurdles when implementing this form of training. This is mainly due to lack of knowledge concerning the time and human resources needed to train novice surgeons to an adequate level. The purpose of this trial is to investigate the impact of instructor feedback regarding time, repetitions and self-perception when training complex operational tasks on a virtual reality simulator.
The study population consists of medical students on their 4th to 6th year without prior laparoscopic experience. The study is conducted in a skills laboratory at a centralized university hospital. Based on a sample size estimation 98 participants will be randomized to an intervention group or a control group. Both groups have to achieve a predefined proficiency level when conducting a laparoscopic salpingectomy using a surgical virtual reality simulator. The intervention group receives standardized instructor feedback of 10 to 12 min a maximum of three times. The control group receives no instructor feedback. Both groups receive the automated feedback generated by the virtual reality simulator. The study follows the CONSORT Statement for randomized trials. Main outcome measures are time and repetitions to reach the predefined proficiency level on the simulator. We include focus on potential sex differences, computer gaming experience and self-perception.
The findings will contribute to a better understanding of optimal training methods in surgical education.
Trial Registration
PMCID: PMC3311079  PMID: 22373062
Virtual reality simulation; Laparoscopy; Training; Salpingectomy; Feedback
13.  Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol 
BMC Psychiatry  2011;11:160.
Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life.
Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s) and at least one benzodiazepine derivative for the last three months before inclusion. Exclusion criteria: currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up.
The results from this trial will examine whether melatonin has a role in withdrawing long-term benzodiazepine administration in schizophrenia patients. This group of patients is difficult to treat and therefore often subject to polypharmacy which may play a role in the reduced life expectancy of patients compared to the background population. The results will also provide new information on the association of chronic benzodiazepine treatment with sleep, psychophysiology, cognition, social function, and quality of life. Knowledge of these important clinical aspects is lacking in this group of patients.
Trial Registration
ClinicalTrials NCT01431092
PMCID: PMC3213077  PMID: 21975110
14.  A randomized trial of the effect of escitalopram versus placebo on cognitive function in healthy first-degree relatives of patients with depression 
The effect of selective serotonin receptor inhibitors (SSRIs) on healthy individuals remains unclear. The aim of the trial was to evaluate the effect of the SSRI escitalopram on cognitive function in healthy first-degree relatives of patients with major depressive disorder (FDRs). A total of 80 FDRs were randomized to escitalopram (10 mg/day) (n = 41) versus placebo (n = 39) for 4 weeks. Neuropsychological tests and ratings of mood were applied at entry (T0) and at 4 weeks (T4). The main outcome measure was calculated as the change (T4–T0) in a general cognition score, which was the standardized mean of 13 test measures. Mean change in the general cognition score was not significantly increased with escitalopram compared with placebo (p = 0.37) or for any of the specific tests. In univariate analyses no statistically significant correlations were found between change in the general cognitive score and the variables age, sex, Hamilton depression score 17 items, Danish Adult Reading Test-45, and plasma escitalopram levels, respectively. These results suggest that treatment with escitalopram does not improve or impair cognitive function in FDRs. Improvement in cognitive function following treatment of depressed patients with SSRIs seems to be related to the effects on depressive symptoms rather than to a direct effect of the SSRI.
PMCID: PMC3736905  PMID: 23983938
cognitive function; escitalopram; healthy; high risk; major depressive disorder; placebo-controlled; trial
15.  Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial 
PLoS ONE  2011;6(6):e21224.
The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).
Eighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention.
Change in CorAUCtotal showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUCtotal, rho = −0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal.
The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age.
Trial Registration [NCT00386841
PMCID: PMC3124484  PMID: 21738622
16.  Randomised social-skills training and parental training plus standard treatment versus standard treatment of children with attention deficit hyperactivity disorder - The SOSTRA trial protocol 
Trials  2011;12:18.
Children with attention deficit hyperactivity disorder (ADHD) are hyperactive and impulsive, cannot maintain attention, and have difficulties with social interactions. Medical treatment may alleviate symptoms of ADHD, but seldom solves difficulties with social interactions. Social-skills training may benefit ADHD children in their social interactions. We want to examine the effects of social-skills training on difficulties related to the children's ADHD symptoms and social interactions.
The design is randomised two-armed, parallel group, assessor-blinded trial. Children aged 8-12 years with a diagnosis of ADHD are randomised to social-skills training and parental training plus standard treatment versus standard treatment alone. A sample size calculation estimated that at least 52 children must be included to show a 4-point difference in the primary outcome on the Conners 3rd Edition subscale for 'hyperactivity-impulsivity' between the intervention group and the control group. The outcomes will be assessed 3 and 6 months after randomisation. The primary outcome measure is ADHD symptoms. The secondary outcome is social skills. Tertiary outcomes include the relationship between social skills and symptoms of ADHD, the ability to form attachment, and parents' ADHD symptoms.
We hope that the results from this trial will show that the social-skills training together with medication may have a greater general effect on ADHD symptoms and social and emotional competencies than medication alone.
Trial registration
ClinicalTrials (NCT): NCT00937469
PMCID: PMC3038941  PMID: 21255399
17.  ExStroke Pilot Trial of the effect of repeated instructions to improve physical activity after ischaemic stroke: a multinational randomised controlled clinical trial  
Objectives To investigate if repeated verbal instructions about physical activity to patients with ischaemic stroke could increase long term physical activity.
Design Multicentre, multinational, randomised clinical trial with masked outcome assessment.
Setting Stroke units in Denmark, China, Poland, and Estonia.
Participants 314 patients with ischaemic stroke aged ≥40 years who were able to walk—157 (mean age 69.7 years) randomised to the intervention, 157 (mean age 69.4 years) in the control group.
Interventions Patients randomised to the intervention were instructed in a detailed training programme before discharge and at five follow-up visits during 24 months. Control patients had follow-up visits with the same frequency but without instructions in physical activity.
Main outcome measures Physical activity assessed with the Physical Activity Scale for the Elderly (PASE) at each visit. Secondary outcomes were clinical events.
Results The estimated mean PASE scores were 69.1 in the intervention group and 64.0 in the control group (difference 5.0 (95% confidence interval −5.8 to 15.9), P=0.36. The intervention had no significant effect on mortality, recurrent stroke, myocardial infarction, or falls and fractures.
Conclusion Repeated encouragement and verbal instruction in being physically active did not lead to a significant increase in physical activity measured by the PASE score. More intensive strategies seem to be needed to promote physical activity after ischaemic stroke.
Trial registration Clinical Trials NCT00132483
PMCID: PMC2714611  PMID: 19900934
18.  Effect of perioperative β blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial 
BMJ : British Medical Journal  2006;332(7556):1482.
Objectives To evaluate the long term effects of perioperative β blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery.
Design Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat.
Setting University anaesthesia and surgical centres and one coordinating centre.
Participants 921 patients aged > 39 scheduled for major non-cardiac surgery.
Interventions 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days.
Main outcome measures The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity.
Results Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%).
Conclusions Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment.
Trial registration Current Controlled Trials ISRCTN58485613.
PMCID: PMC1482337  PMID: 16793810
19.  Skin care education and individual counselling versus treatment as usual in healthcare workers with hand eczema: randomised clinical trial 
Objective To evaluate the effect of a secondary prevention programme with education on skin care and individual counselling versus treatment as usual in healthcare workers with hand eczema.
Design Randomised, observer blinded parallel group superiority clinical trial.
Setting Three hospitals in Denmark.
Participants 255 healthcare workers with self reported hand eczema within the past year randomised centrally and stratified by profession, severity of eczema, and hospital. 123 were allocated to the intervention group and 132 to the control group.
Interventions Education in skin care and individual counselling based on patch and prick testing and assessment of work and domestic related exposures. The control was treatment as usual.
Main outcome measures The primary outcome was clinical severity of disease at five month follow-up measured by scores on the hand eczema severity index. The secondary outcomes were scores on the dermatology life quality index, self evaluated severity of hand eczema, skin protective behaviours, and knowledge of hand eczema from onset to follow-up.
Results Follow-up data were available for 247 of 255 participants (97%). At follow-up, the mean score on the hand eczema severity index was significantly lower (improved) in the intervention group than control group: difference of means, unadjusted −3.56 (95% confidence interval −4.92 to −2.14); adjusted −3.47 (−4.80 to −2.14), both P<0.001 for difference. The mean score on the dermatology life quality index was also significantly lower (improved) in the intervention group at follow-up: difference of means: unadjusted −0.78, non-parametric test P=0.003; adjusted −0.92, −1.48 to −0.37). Self evaluated severity and skin protective behaviour by hand washings and wearing of protective gloves were also statistically significantly better in the intervention group, whereas this was not the case for knowledge of hand eczema.
Conclusion A secondary prevention programme for hand eczema improved severity and quality of life and had a positive effect on self evaluated severity and skin protective behaviour by hand washings and wearing of protective gloves.
Trial registration NCT01012453.
PMCID: PMC3520547  PMID: 23236031

Results 1-19 (19)