Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial

Background: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder.Hypothesis: We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events.Study design: Phase II randomized placebo controlled clinical trial.Methods: 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models.Results: Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (−8.2, 95% confidence interval [CI], −12.7 to −3.6) versus R. rosea (−5.1, 95% CI: −8.8 to −1.3) and placebo (−4.6, 95% CI: −8.6 to −0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44–8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38–5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012).Conclusions: Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression.     

A randomized,double-blind,placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients

IntroductionFibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia.MethodsThis randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure.ResultsOverall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups.ConclusionsAlthough the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QoL in Japanese patients with fibromyalgia.

Trial registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01552057","term_id":"NCT01552057"}}NCT01552057. Registered 9 March 2012.     

A randomized, placebo-controlled, double-blind clinical trial of curcuminoids in oral lichen planus.

We studied the efficacy of curcuminoids in the treatment of oral lichen planus (OLP), a chronic, mucocutaneous, immunological disease. Curcuminoids are components of turmeric (Curcuma longa) that have anti-inflammatory activity. Turmeric has been used in Ayurveda (Indian traditional medicine) for centuries. A randomized, double-blind, placebo-controlled trial was conducted. In all, 100 consecutive, eligible patients with OLP presenting to the oral medicine clinic at the University of California, San Francisco, were to be selected. Two interim analyses were to be conducted during the trial. The trial was conducted between February 2003 and September 2004. The first interim analysis was conducted in October 2004 using data from the first 33 subjects. Study subjects were randomized to receive either placebo or curcuminoids at 2000 mg/day for 7 weeks. In addition, all subjects received prednisone at 60 mg/day for the first 1 week. The primary outcome was a change in symptoms from baseline. Secondary outcomes were changes in clinical signs and occurrence of side effects. The first interim analysis did not show a significant difference between the placebo and curcuminoids groups. Conditional power calculations suggested a less than 2% chance that the curcuminoids group would have a significantly better outcome as compared with the placebo group if the trial were continued to completion. Therefore, the study was ended early for futility. Reaching a conclusion regarding the efficacy of curcuminoids based on the results of this study is not possible as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, a higher dose and/or longer duration of curcuminoids administration should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids, and without an initial course of prednisone, should be considered.     

The effect of fish oil on physical aggression in schoolchildren--a randomized, double-blind, placebo-controlled trial

OBJECTIVES: The aim of the study was to investigate whether fish oil supplementation affected Japanese schoolchildren's behavior, with changes in aggression over time as the primary endpoint. DESIGN AND SUBJECTS: A placebo-controlled double-blind study with 166 schoolchildren 9-12 years of age was performed. The subjects of the fish oil group (n=83) took fish oil-fortified foods (bread, sausage and spaghetti). These foods were provided in amounts such that each subject in the fish oil group had an intake of 3600 mg of docosahexaenoic acid+840 mg of eicosapentaenoic acid (EPA)/week for 3 months. The rest (the controls, n=83) took control supplements. At the start and end of the study, psychological tests were performed to assess their aggression. RESULTS: Physical aggression assessed by Hostility-Aggression Questionnaire for Children in girls increased significantly (median: 13 to 15, n=42) in the control group and did not change (13 to 13, n=43) in the fish oil group with a significant intergroup difference (P=.008) with baseline as covariate. The changes in physical aggression scores over time and those of the ratio of EPA/arachidonic acid in RBC (DeltaEPA/AA) were significantly correlated in girls who agreed to blood collection (r=-.53, P=.01, n=23). On the contrary, there were no significant changes in physical aggression in boys. Aggression against others (extraggression) assessed by Picture Frustration Study did not change in the control group (median: 5 to 5) but increased significantly in the fish oil group (4 to 5) with a significant intergroup difference (P=.02) with baseline as covariate. These changes in extraggression might be explained partly by significantly lower baseline values of extraggression in the fish oil group (P=.02) than in the control group. There were no significant correlations between Deltaextraggression and DeltaEPA/AA in blood-sampled children (n=49). Impulsivity of girls assessed by parents/guardians using the diagnostic criteria for attention deficit/hyperactivity disorder of DSM-IV was reduced in the fish oil group (1 to 0) with a significant (P=.008) intergroup difference from the control group (1 to 1). There were no significant correlations between Deltaimpulsivity and DeltaEPA/AA in blood-sampled girls. In males, impulsivity reduced in both groups without any intergroup differences. CONCLUSION: There is a possibility that changes in fatty acid nutrition might affect physical aggression especially in girls.     

A randomized placebo-controlled trial of acetaminophen for prevention of post-vaccination fever in infants

Background

Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States.

Methods

Children six weeks through nine months of age were randomized 1∶1 to receive up to five doses of acetaminophen (10–15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents'' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo.

Results

A temperature ≥38°C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40–1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25–0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11–0.83) than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03).

Conclusion

The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00325819","term_id":"NCT00325819"}}NCT00325819     

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Background

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C₁₂U), in patients with debilitating CFS/ME.

Methods and Findings

A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

Conclusions/Significance

Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00215800","term_id":"NCT00215800"}}NCT00215800     

Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.     

Oral intake of Lactobacillus pentosus strain b240 accelerates salivary immunoglobulin A secretion in the elderly: A randomized, placebo-controlled, double-blind trial

Background

Immunoglobulin A (IgA) secretion in saliva decreases with age and may be the cause of increased vulnerability of the elderly to respiratory infections. The effect of oral intake of lactic acid bacteria on salivary secretory IgA (SIgA) in the elderly has not been reported. The objective of this study was to demonstrate the acceleration of salivary SIgA secretion by oral intake of Lactobacillus pentosus strain b240 (b240) in the elderly.

Results

A total of 80 healthy elderly individuals were randomly allocated to either an intervention (i.e., b240) or a control (i.e., placebo) group. The elderly individuals in the b240 group were given a sterile water beverage (125 mL) containing heat-killed b240 (4 × 10⁹ cells), while those in the placebo group were given only a sterile water beverage (125 mL); both groups received their respective beverages once daily for 12 weeks. Saliva was collected before initiation of the study and every 2 weeks thereafter. Saliva flow rate and SIgA concentration were determined, and the SIgA secretion rate was calculated. The mean salivary SIgA secretion rate in the b240 group steadily increased until week 4 (exhibiting a 20% elevation relative to that at week 0), and then remained stable until week 12. Changes in SIgA secretion rate over the intervention period were significantly greater in the b240 group than in the placebo group. The treatment groups exhibited no significant differences in adverse events.

Conclusions

Oral intake of L. pentosus strain b240 for 12 weeks significantly accelerated salivary SIgA secretion, thereby indicating its potential utility in the improvement of mucosal immunity and resistance against infection in the elderly.     

Antipyretic effect of ibuprofen in Gabonese children with uncomplicated falciparum malaria: a randomized, double-blind, placebo-controlled trial

Background

The protection afforded by human erythrocyte polymorphisms against the malaria parasite, Plasmodium falciparum, has been proposed to be due to reduced ability of the parasite to invade or develop in erythrocytes. If this were the case, variable levels of parasitaemia and rates of seroconversion to infected-erythrocyte variant surface antigens (VSA) should be seen in different host genotypes.

Methods

To test this hypothesis, P. falciparum parasitaemia and anti-VSA antibody levels were measured in a cohort of 555 asymptomatic children from an area of intense malaria transmission in Papua New Guinea. Linear mixed models were used to investigate the effect of α⁺-thalassaemia, complement receptor-1 and south-east Asian ovalocytosis, as well as glucose-6-phosphate dehydrogenase deficiency and ABO blood group on parasitaemia and age-specific seroconversion to VSA.

Results

No host polymorphism showed a significant association with both parasite prevalence/density and age-specific seroconversion to VSA.

Conclusion

Host erythrocyte polymorphisms commonly found in Papua New Guinea do not effect exposure to blood stage P. falciparum infection. This contrasts with data for sickle cell trait and highlights that the above-mentioned polymorphisms may confer protection against malaria via distinct mechanisms.     

A randomized,double-blind,multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia

Introduction

Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.

Methods

This randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.

Results

A total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.

Conclusions

This trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.

Trial Registration

ClinicalTrials.gov: NCT00830167     

CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial

ABSTRACT: BACKGROUND: Worldwide, over 10 million people are killed or hospitalized because of traumatic brain injury each year. About 90% of deaths occur in low- and middle-income countries. The condition mostly affects young adults, and many experience long lasting or permanent disability. The social and economic burden is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. It has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients. Methods/design The CRASH-3 trial is an international, multicenter, pragmatic, randomized, double-blind, placebo-controlled trial to quantify the effects of the early administration of TXA on death and disability in patients with traumatic brain injury. Ten thousand adult patients who fulfil the eligibility criteria will be randomized to receive TXA or placebo. Adults with traumatic brain injury, who are within 8 h of injury and have any intracranial bleeding on computerized tomography (CT scan) or Glasgow Coma Score (GCS) of 12 or less can be included if the responsible doctor is substantially uncertain as to whether or not to use TXA in this patient. Patients with significant extracranial bleeding will be excluded since there is evidence that TXA improves outcome in these patients. Treatment will entail a 1 g loading dose followed by a 1 g maintenance dose over 8 h. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses for the primary outcome will be based on time from injury to randomization, the severity of the injury, location of the bleeding, and baseline risk. Interaction tests will be used to test whether the effect of treatment differs across these subgroups. A study with 10,000 patients will have approximately 90% power to detect a 15% relative reduction from 20% to 17% in all-cause mortality. Trial registration Current Controlled Trials ISRCTN15088122; Clinicaltrials.gov NCT01402882.     

CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial

Background

Single-limb knee extension exercises have been found to be effective at improving lower extremity exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Since the positive local physiological effects of exercise training only occur in the engaged muscle(s), should upper extremity muscles also be included to determine the effect of single limb exercises in COPD patients.

Methods/design

Trial design: a prospective, assessor-blind, block randomized controlled, parallel-group multicenter trial. Participants: stage II-IV COPD patients, > 40?years of age, ex-smokers, with stable medical treatment will be included starting May 2011. Recruitment at three locations in Sweden. Interventions: 1) high-repetitive single limb exercise (HRSLE) training with elastic bands, 60 minutes, three times/week for 8?weeks combined with four sessions of 60 minutes patient education, or 2) the same patient education alone. Outcomes: Primary: determine the effects of HRSLE on local muscle endurance capacity (measured as meters walked during 6-minute walk test and rings moved on 6-minute ring and pegboard test) and quality of life (measured as change on the Swedish version of the Chronic Respiratory Disease Questionnaire). Secondary: effects on maximal strength, muscular endurance, dyspnea, self-efficacy, anxiety and depression. The relationship between changes in health-related variables and changes in exercise capacity, sex-related differences in training effects, feasibility of the program, strategies to determine adequate starting resistance and provide accurate resistance for each involved movement and the relationship between muscle fatigue and dyspnea in the different exercise tests will also be analyzed. Randomization: performed by a person independent of the recruitment process and using a computer random number generator. Stratification by center and gender with a 1:1 allocation to the intervention or control using random block sizes. Blinding: all outcome assessors will be blinded to group assignment.

Discussion

The results of this project will contribute to increase the body of knowledge regarding COPD and HRSLE.

Trial registration

ClinicalTrials.gov Identifier: NCT01354067. Registration date: 2011-05-11. First participant randomized: 2011-09-02     

A prospective, randomized, double-blind trial of the use of fibrin sealant for face lifts.

Fibrin sealant imitates the final phase of the blood coagulation process. Fibrinogen is converted into fibrin on a tissue surface by the action of thrombin, which is then cross-linked by factor XIIIa, creating a mechanically stable fibrin network. This fibrin network is thought to reduce the amount of postoperative bleeding by sealing capillary vessels and allowing raw operative surfaces to adhere.The authors conducted a prospective, double-blind, randomized, controlled trial on the use of fibrin sealant in 20 consecutive patients undergoing bilateral face lifts by the same surgeon. Each patient was randomized for the use of fibrin sealant on either the right or the left side with the contralateral side acting as the control. Total drainage was recorded on each side for 24 hours before drains were removed. The age range of the patients in the trial (all of whom were women) was 44 to 70 years (mean, 55). The side treated with fibrin glue had a median drainage of 10 ml and the control side 30 ml. The Wilcoxon signed rank test shows a significant difference in drainage between sides (p = 0.002). The reduction in postoperative drainage could also reduce pain and bruising, increasing patient satisfaction with this procedure. The need for drains may also be obviated.     

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

ABSTRACT: BACKGROUND: Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess. Methods/design Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease. The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1--84) as the primary endpoint and (2) 24-hour systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24 hours urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints. DISCUSSION: In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular and bone health in patients with primary hyperparathyroidism. Trial registration ISRCTN33941607.