Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine

Objective To investigate the efficacy of hypericum extract WS 5570 (St John''s wort) compared with paroxetine in patients with moderate to severe major depression.Design Randomised double blind, double dummy, reference controlled, multicentre non-inferiority trial.Setting 21 psychiatric primary care practices in Germany.Participants 251 adult outpatients with acute major depression with total score ≥ 22 on the 17 item Hamilton depression scale.Interventions 900 mg/day hypericum extract WS 5570 three times a day or 20 mg paroxetine once a day for six weeks. In initial non-responders doses were increased to 1800 mg/day hypericum or 40 mg/day paroxetine after two weeks.Main outcome measures Change in score on Hamilton depression scale from baseline to day 42 (primary outcome). Secondary measures were change in scores on Montgomery-Åsberg depression rating scale, clinical global impressions, and Beck depression inventory.Results The Hamilton depression total score decreased by mean 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value, in the hypericum group and by 11.4 (SD 8.6) points (44.8% (SD 33.5%) of baseline value) in the paroxetine group (intention to treat analysis; similar results were observed in the per protocol analysis). The intention to treat analysis (lower one sided 97.5% confidence limit 1.5 points for the difference hypericum minus paroxetine) and the per protocol analysis (lower confidence limit 0.7 points) showed non-inferiority of hypericum and statistical superiority over paroxetine. The lower limits in both cases exceeded the pre-specified non-inferiority margin of -2.5 points and the superiority margin of 0. The incidence of adverse events was 0.035 and 0.060 events per day of exposure for hypericum and paroxetine, respectively.Conclusions In the treatment of moderate to severe major depression, hypericum extract WS 5570 is at least as effective as paroxetine and is better tolerated.     

Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial): study protocol for a randomised controlled trial

Background

Human immunodeficiency virus (HIV)-related chronic lung disease (CLD) among children is associated with substantial morbidity, despite antiretroviral therapy. This may be a consequence of repeated respiratory tract infections and/or dysregulated immune activation that accompanies HIV infection. Macrolides have anti-inflammatory and antimicrobial properties, and we hypothesised that azithromycin would reduce decline in lung function and morbidity through preventing respiratory tract infections and controlling systemic inflammation.

Methods/design

We are conducting a multicentre (Malawi and Zimbabwe), double-blind, randomised controlled trial of a 12-month course of weekly azithromycin versus placebo. The primary outcome is the mean change in forced expiratory volume in 1 second (FEV₁) z-score at 12 months. Participants are followed up to 18 months to explore the durability of effect. Secondary outcomes are FEV₁ z-score at 18 months, time to death, time to first acute respiratory exacerbation, number of exacerbations, number of hospitalisations, weight for age z-score at 12 and 18 months, number of adverse events, number of malaria episodes, number of bloodstream Salmonella typhi infections and number of gastroenteritis episodes. Participants will be followed up 3-monthly, and lung function will be assessed every 6 months. Laboratory substudies will be done to investigate the impact of azithromycin on systemic inflammation and on development of antimicrobial resistance as well as impact on the nasopharyngeal, lung and gut microbiome.

Discussion

The results of this trial will be of clinical relevance because there are no established guidelines on the treatment and management of HIV-associated CLD in children in sub-Saharan Africa, where 80% of the world’s HIV-infected children live and where HIV-associated CLD is highly prevalent.

Trial registration

ClinicalTrials.gov, NCT02426112. Registered on 21 April 2015.

     

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group

ObjectiveTo evaluate the efficacy and safety of galantamine in the treatment of Alzheimer''s disease.DesignRandomised, double blind, parallel group, placebo controlled trial.Setting86 outpatient clinics in Europe and Canada.Participants653 patients with mild to moderate Alzheimer''s disease.InterventionPatients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg.ResultsAt six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer''s disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician''s interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study.ConclusionGalantamine is effective and well tolerated in Alzheimer''s disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.     

Antidepressant effects of combination of sleep deprivation and early evening treatment with melatonin or placebo for winter depression

Patients with winter depression (seasonal affective disorder) respond beneficially to sleep deprivation and bright light, but the mechanisms of these responses remain unknown. The study was designed to test whether afternoon/evening melatonin can prevent further relapse after sleep deprivation (presumably due to a pharmacologically induced advance shift of circadian phase). Compared to phase advancing by alteration of sleep - wake schedule or by bright light exposure, the melatonin intake is a more tolerated treatment procedure, and it provides a possibility of blind comparison between chronotherapeutic and placebo treatments. The depression was scored in 16 female patients with winter depression and 17 age-matched female controls before and after total night sleep deprivation and after subsequent six-day administration of melatonin (0.5 mg) or placebo under double blind conditions. The melatonin intake was scheduled at 17:00 in order to produce a phase advance of circadian rhythms. Sleep deprivation resulted in 38% reduction of depression score in patients, but it did not reduce depression score in controls. After subsequent treatment with placebo or melatonin, slight but significant improvement of mood was found in controls. These treatments also stabilized the antidepressant response to sleep deprivation in patients. However, neither differential effect of melatonin and placebo on depression score nor alteration of habitual sleep timing was found in patients and controls. Thus, the study results do not provide evidence for the antidepressant potential of melatonin in patients with winter depression under realistic clinical conditions. The finding of stabilization of mood in patients with placebo points to the contribution of psychological factors to the therapeutic action of this and other types of innovative treatments for winter depression. To include psychosocial aspects in the theoretical framework of seasonal depression, we conceptualized depression as an evolved feature of emotional response to psychosocial rather than physical environment. The seasonality of depression might be explained by cumulative effects of aperiodical psychosocial factors and periodical physical factors on one of the mechanisms of brain neurotransmission.     

Effect of chronic escitalopram versus placebo on personality traits in healthy first-degree relatives of patients with depression: a randomized trial

Introduction

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).

Methods

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.

Results

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).

Conclusion

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

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00386841","term_id":"NCT00386841"}}NCT00386841     

Improvement in bronchial hyper-responsiveness in patients with moderate asthma after treatment with a hypnotic technique: a randomised controlled trial.

A prospective, randomised, single blind, and controlled trial of a hypnotic technique was undertaken in 39 adults with mild to moderate asthma graded for low and high susceptibility to hypnosis. After a six week course of hypnotherapy 12 patients with a high susceptibility score showed a 74.9% improvement (p less than 0.01) in the degree of bronchial hyper-responsiveness to a standardised methacholine challenge test. Daily home recordings of symptoms improved by 41% (p less than 0.01), peak expiratory flow rates improved by 5.5% (p less than 0.01), and use of bronchodilators decreased by 26.2% (p less than 0.05). The improvement in bronchial hyper-reactivity occurred without a change in subjective appreciation of the degree of bronchoconstriction. A control group 17 patients and 10 patients undergoing treatment with low susceptibility to hypnosis had no change in either bronchial hyper-responsiveness or any of the symptoms recorded at home. This study shows the efficacy of a hypnotic technique in adult asthmatics who are moderately to highly susceptible to hypnosis.     

Zopiclone versus placebo for short-term treatment of insomnia in patients with advanced cancer: study protocol for a double-blind,randomized, placebo-controlled,clinical multicenter trial

Background

Despite the high prevalence of insomnia in patients with advanced cancer, there are no randomized controlled trials on pharmacological interventions for insomnia in this group of patients. A variety of pharmacological agents is recommended to manage sleep disturbance for insomnia in the general population, but their efficacy and safety in adults with advanced cancer are not established. Thus, there is a need to evaluate the effectiveness of medications for insomnia in order to improve the evidence in patients with advanced cancer. One of the most used sleep medications at present in patients with cancer is zopiclone.

Methods

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 100 patients with metastatic cancer who report insomnia will be randomly allocated to zopiclone or placebo. The treatment duration with zopiclone/placebo is 6 consecutive nights. The primary endpoint is patient-reported sleep quality during the final study night (night 6) assessed on a numerical rating scale of 0–10, where 0?=?Best sleep and 10?=?Worst possible sleep. Secondary endpoints include the mean patient-reported total sleep time and sleep onset latency during the final study night (night 6).

Discussion

Results from this study on treatment of insomnia in advanced cancer will contribute to clinical decision-making and improve the treatment of sleep disturbance in this patient cohort.

Trial registration

ClinicalTrials.gov, NCT02807922. Registered on 21 June 2016.

     

Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials

Objective: To determine whether preventive treatment for tuberculosis in adults infected with HIV reduces the frequency of tuberculosis and overall mortality. Design: Systematic review and data synthesis of randomised placebo controlled trials. Main outcome measures: Active tuberculosis, mortality, and adverse drug reaction requiring cessation of the study regimen. Outcomes stratified by status of purified protein derivative skin test. Results: Four trials comprising 4055 adults from Haiti, Kenya, the United States, and Uganda were included. All compared isoniazid (6-12 months) with placebo, and one trial also compared multidrug treatment for 3 months with placebo. Mean follow up was 15-33 months. Overall, frequency of tuberculosis (relative risk 0.57, 95% confidence interval 0.41 to 0.79) was reduced in those receiving preventive treatment compared with placebo: mortality was not significantly reduced (0.93, 0.83 to 1.05). In subjects positive for purified protein derivative receiving preventive treatment, the risk of tuberculosis was reduced substantially (0.32, 0.19 to 0.51) and the risk of death was reduced moderately (0.73, 0.57 to 0.95) compared with those taking placebo. In adults negative for purified protein derivative receiving preventive treatment, the risk of tuberculosis (0.82, 0.50 to 1.36) and the risk of death (1.02, 0.89 to 1.17) were not reduced significantly. Adverse drug reactions were more frequent, but not significantly so, in patients receiving drug compared with placebo (1.45, 0.98 to 2.14). Conclusions: Preventive treatment given for 3-12 months protects against tuberculosis in adults infected with HIV, at least in the short to medium term. Protection is greatest in subjects positive for purified protein derivative, in whom death is also less frequent. Long term benefits remain to be shown.

Key messages

• One third of the world’s population is infected with Mycobacterium tuberculosis
• People infected with HIV are at much increased risk of developing active tuberculosis
• Short term preventive drug treatment given to people infected with HIV reduces the occurrence of active tuberculosis
• The benefit is greatest in people with latent infection, as shown by a positive skin test for tuberculosis, and this group also exhibits a survival benefit

     

Patch: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre,randomised, controlled trial

Background  

Patients suffering from intracerebral haemorrhage have a poor prognosis, especially if they are using antiplatelet therapy. Currently, no effective acute treatment option for intracerebral haemorrhage exists. Limiting the early growth of intracerebral haemorrhage volume which continues the first hours after admission seems a promising strategy. Because intracerebral haemorrhage patients who are on antiplatelet therapy have been shown to be particularly at risk of early haematoma growth, platelet transfusion may have a beneficial effect.     

Proliferative diabetic retinopathy: treatment with xenon-arc photocoagulation. Interim report of multicentre randomised controlled trial.

One hundred patients with symmetrical proliferative diabetic retinopathy had one eye randomly chosen for treatment with xenonarc photocoagulation while the other was left untreated as a control. Patients were subdivided into those with new vessels on both optic discs and those with only peripheral new vessels. In patients with new vessels on the optic discs the vision of the untreated eyes deteriorated more than that of the treated eyes and the difference in deterioration was significant after one, two, and three years. There was no such difference in patients who had only peripheral new vessels. Eighteen patients had become blind in one or both eyes by the last assessment, but only one patient became blind in the treated eye without concomitant blindness in the untreated eye. Thirteen were blind only in the untreated eye. Both photographic and ophthalmoscopic examinations showed that new vessels on the disc regressed more in the treated eyes than in the untreated ones. As some forms of diabetic retinopathy are now treatable, early diagnosis and evaluation is increasingly important.     

A randomised double blind placebo controlled clinical trial of a standardised extract of fresh Crataegus berries (Crataegisan) in the treatment of patients with congestive heart failure NYHA II.

A placebo controlled, randomised, parallel group, multicentre trial conducted in accordance with the guidelines of Good Clinical Practice (GCP) shows the efficacy and safety of a standardised extract of fresh berries of Crataegus oxyacantha L. and monogyna Jacq. (Crataegisan) in patients with cardiac failure NYHA class II. A total of 143 patients (72 men, 71 women, mean age of 64.8 (8.0 years) were recruited and treated with 3 times 30 drops of the extract (n = 69) or placebo (n = 74) for 8 weeks. The primary variable for the evaluation of efficacy was the change in exercise tolerance determined with bicycle exercise testing, secondary variables included the blood pressure-heart rate product (BHP). Subjective cardiac symptoms at rest and at higher levels of exertion were assessed by the patient on a categorical rating scale. An overall assessment of efficacy at the final visit was provided by the patient and the investigator. In the ITT population there was a significant increase in exercise tolerance in both groups between visit 1 and visit 3. The difference between the treatment groups was 8.3 watts in favour of the standardised extract of fresh Crataegus berries (p = 0.045). The result is confirmed in the PP population (p = 0.047). Changes in BHP at 50 watts and at comparable maximum load were in favour of Crataegus extract but the results are not statistically significant. The subjective assessment of cardiac symptoms at rest and at higher levels of exertion did not change significantly and the patient and investigator overall assessment of efficacy were similar for the two groups. The medication was well tolerated and had a high level of patient acceptability. The significant improvement, due to the fact that dyspnoea and fatigue do not occur until a significantly higher wattage has been reached in the bicycle exercise testing allows the conclusion that the recruited NYHA II patients may expect an improvement in their heart failure condition under long term therapy with the standardised extract of fresh Crataegus berries.