Jane Lindschou

Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis.

BackgroundThe evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear.MethodsOur objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, ‘active’ placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library’s CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life.ResultsA total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used ‘active’ placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference −1.94 HDRS points; 95% CI −2.50 to −1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI −2.70 to −1.18); Bayes factor below predefined threshold (2.01*10−23). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects.ConclusionsSSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.Systematic review registrationPROSPERO CRD42013004420.

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

BackgroundEvery 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.Methods/DesignSafeBoosC 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.DiscussionCerebral 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 registrationClinicalTrial.gov, NCT01590316

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised, placebo-controlled, blinded trial.

Objectives. We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. Methods. Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine cessation proportion, and benzodiazepine withdrawal symptoms. Results. In total, 86 patients (21–74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents; difference between means –2.29; 95% CI –5.78 to 1.21; P = 0.20). Benzodiazepine cessation proportion was 38.1% (16/42) in the melatonin group versus 47.7% (21/44) in the placebo group (OR 0.64; 95% CI 0.26 to 1.56; P = 0.32). Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms. Conclusions. Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction. In this context, prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation.

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial.

BACKGROUND The CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10years follow up. METHODS The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression. RESULTS Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10years was violated for cardiovascular death (P=0.01) and cardiovascular death outside hospital (P<0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88). CONCLUSION Clarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition.

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

BackgroundAdvanced 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’.Methods/DesignDanPaCT 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.DiscussionOnly 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 registrationCurrent controlled Trials NCT01348048

Randomised clinical trial of early specialist palliative care plus standard care versus standard care alone in patients with advanced cancer: The Danish Palliative Care Trial.

Background: Beneficial effects of early palliative care have been found in advanced cancer, but the evidence is not unequivocal. Aim: To investigate the effect of early specialist palliative care among advanced cancer patients identified in oncology departments. Setting/participants: The Danish Palliative Care Trial (DanPaCT) (ClinicalTrials.gov NCT01348048) is a multicentre randomised clinical trial comparing early referral to a specialist palliative care team plus standard care versus standard care alone. The planned sample size was 300. At five oncology departments, consecutive patients with advanced cancer were screened for palliative needs. Patients with scores exceeding a predefined threshold for problems with physical, emotional or role function, or nausea/vomiting, pain, dyspnoea or lack of appetite according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were eligible. The primary outcome was the change in each patient’s primary need (the most severe of the seven QLQ-C30 scales) at 3- and 8-week follow-up (0–100 scale). Five sensitivity analyses were conducted. Secondary outcomes were change in the seven QLQ-C30 scales and survival. Results: Totally 145 patients were randomised to early specialist palliative care versus 152 to standard care. Early specialist palliative care showed no effect on the primary outcome of change in primary need (−4.9 points (95% confidence interval −11.3 to +1.5 points); p = 0.14). The sensitivity analyses showed similar results. Analyses of the secondary outcomes, including survival, also showed no differences, maybe with the exception of nausea/vomiting where early specialist palliative care might have had a beneficial effect. Conclusion: We did not observe beneficial or harmful effects of early specialist palliative care, but important beneficial effects cannot be excluded.

Feedback in group psychotherapy for eating disorders: A randomized clinical trial.

Objective: To investigate the effect of client feedback in group psychotherapy on attendance and treatment outcome for patients with eating disorders. Method: We conducted a randomized clinical trial with central randomization stratified for diagnosis and treatment type according to a computer-generated allocation sequence concealed to the investigators. One-hundred and 59 adult participants, diagnosed with bulimia nervosa, binge eating disorder, or eating disorder not otherwise specified according to DSM–IV, were included. Eighty participants were allocated to the experimental group, and 79 participants to the control group. Both groups received 20–25 weekly group psychotherapy sessions. In the experimental group, participants gave and received feedback about therapy progress and alliance, measured before and after each session using the Outcome Rating Scale and the Group Session Rating Scale. The primary outcome was rate of attendance to treatment sessions; the secondary outcome was severity of eating disorder symptoms measured with the Eating Disorder Examination interview. Exploratory outcomes were psychological distress measured with the Symptom Checklist-90-R and the Outcome Rating Scale, social functioning measured with the Sheehan Disability Scale, and episodes of self-harm and suicide measured with a modified version of the Self-Harm Inventory. Results: Feedback compared with control did not affect the rate of attendance (0.59 vs. 0.58; p = .96), the severity of symptoms (2.03 vs. 2.02; p = .46), or any of the exploratory outcomes (p values from 0.06 to 0.67). Conclusions: Feedback neither increased attendance nor improved outcomes for outpatients in group psychotherapy for eating disorders. The results are discussed from different perspectives.

The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data.

Background Immunological disturbances are hypothesised to play a role in recurrent miscarriage (RM) and therefore intravenous immunoglubulins (IVIg) have been tested in RM patients. Objectives The objectives were to investigate the benefits and harms of IVIg versus placebo, no intervention, or treatment as usual in women with RM. Search Strategy We searched the published literature in all relevant databases. Selection Criteria Randomised trials investigating IVIg versus placebo, no intervention, or treatment as usual in women with RM. Data Collection and Analysis We undertook meta-analyses of aggregated data and individual patient data using a two-step approach, and we conducted bias domain assessments and trial sequential analyses to assess the risks of systematic and random errors. Main Results We identified 11 randomised clinical trials. No significant difference in the frequency of no live birth was found when IVIg was compared with placebo or treatment as usual (RR 0.92, 95% CI 0.75–1.12, p = 0.42). Trial sequential analysis showed that the required information size of 1,008 participants was not obtained. IVIg compared with placebo seems to increase the risk of adverse events. Subgroup analysis suggests that women with RM after a birth (secondary RM) seemed most likely to obtain a potential beneficial effect of IVIg (RR for no live birth 0.77, 95%CI 0.58–1.02, p = 0.06), however, trial sequential analysis showed that insufficient information is presently accrued. Conclusion We cannot recommend or refute IVIg in women with RM. IVIg should therefore be assessed in further randomised clinical trials with positive outcomes before any clinical use is considered.

Detailed statistical analysis plan for the Danish Palliative Care Trial (DanPaCT)

BackgroundAdvanced 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.ResultsThis 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.ConclusionsOnly 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 registrationClinicaltrials.gov identifier: NCT01348048 (May 2011).

Cardiac rehabilitation increases physical capacity but not mental health after heart valve surgery: a randomised clinical trial

Objective The evidence for cardiac rehabilitation after valve surgery remains sparse. Current recommendations are therefore based on patients with ischaemic heart disease. The aim of this randomised clinical trial was to assess the effects of cardiac rehabilitation versus usual care after heart valve surgery. Methods The trial was an investigator-initiated, randomised superiority trial (The CopenHeartVR trial, VR; valve replacement or repair). We randomised 147 patients after heart valve surgery 1:1 to 12 weeks of cardiac rehabilitation consisting of physical exercise and monthly psycho-educational consultations (intervention) versus usual care without structured physical exercise or psycho-educational consultations (control). Primary outcome was physical capacity measured by VO2 peak and secondary outcome was self-reported mental health measured by Short Form-36. Results 76% were men, mean age 62 years, with aortic (62%), mitral (36%) or tricuspid/pulmonary valve surgery (2%). Cardiac rehabilitation compared with control had a beneficial effect on VO2 peak at 4 months (24.8 mL/kg/min vs 22.5 mL/kg/min, p=0.045) but did not affect Short Form-36 Mental Component Scale at 6 months (53.7 vs 55.2 points, p=0.40) or the exploratory physical and mental outcomes. Cardiac rehabilitation increased the occurrence of self-reported non-serious adverse events (11/72 vs 3/75, p=0.02). Conclusions Cardiac rehabilitation after heart valve surgery significantly improves VO2 peak at 4 months but has no effect on mental health and other measures of exercise capacity and self-reported outcomes. Further research is needed to justify cardiac rehabilitation in this patient group. Trial registration number NCT01558765, Results.