Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696]

Background

Stent length serves as a predictor of restenosis in use of bare metal stents (BMS). This has been demonstrated in a feasibility study that used a single short BMS implant (<9 mm) in a high proportion of lesions; the study observed a low rate of restenosis.

Methods

We performed a pilot prospective study to investigate in a series of consecutive patients the immediate and long-term effects of implantation of either 1) a single short BMS for all lesions with low probability of restenosis or 2) a drug-eluting stent (DES) for all other lesions.

Results

The 200 patients studied had 236 coronary artery lesions that were treated with short BMS in 168/236 patients (71.2%) and with DES in 68/236 patients (28.8%). Angiographic success was achieved in 230/236 lesions (97.5%) and procedural success in 194/200 patients (97.0%). Restenosis occurred in 15/153 lesions (9.8%) after short BMS, in 3/62 lesions (4.8%) after DES, and in 18/215 of all lesions (8.4%) angiographically controlled after six to eight months. Target vessel revascularization was performed in 16/218 lesion (7.4%).

Conclusion

Most of the coronary artery lesions in this small group of consecutive patients were treated sufficiently with a single BMS implant. This differential approach of treating suitable lesions in medium- to large-sized vessels with a single short BMS device and treating all other lesions with a DES implant resulted in a low incidence of restenosis.     

Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

Background

The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.

Design

GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.

Conclusion

372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.

Trial Registration

Current Controlled Trials ISRCTN45122933     

Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690]

Background

Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.

Methods

Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.

Results

No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.

Conclusions

Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.     

Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE)

ABSTRACT: BACKGROUND: Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia. METHODS: The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30--80 who have suffered an ischemic stroke (<=7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22 %, at least 656 patients are required in this study to obtain statistical power of 90 %. The first patient was recruited in November 2010. DISCUSSION: Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer's disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke.     

Effect of Omacor on HRV parameters in patients with recent uncomplicated myocardial infarction - A randomized, parallel group, double-blind, placebo-controlled trial: study design [ISRCTN75358739

BACKGROUND: A large body of data derived from animal, epidemiological and clinical studies indicate that n-3 polyunsaturated fatty acids have a favourable effect on the prognosis of patients with cardiovascular disease in general, and on reducing sudden death in particular.Depressed heart rate variability (HRV), an indicator of impairment of the autonomic nervous system, has been shown to be a powerful predictor of subsequent mortality in patients surviving an acute myocardial infarction. A multitude of studies have demonstrated this strong association, suggesting that the imbalance in the sympathic/parasympathetic system may facilitate emergence of ventricular arrhythmias.Heart rate variability parameters will be assessed in the present study, with the primary objective of evaluating the possible superiority of Omacor (a highly refined, concentrated omega-3 fatty acid) versus placebo in improving HRV from baseline to endpoint in patients with recent uncomplicated myocardial infarction. Both groups will receive optimal conventional treatment.The study will also explore and quantify improvement in time domain HRV indices and will assess the safety of administering Omacor to optimally treated post-infarction patients (conventional treatment). METHODS: This multi-centre study will evaluate the effect of Omacor 1 g, o.d. on time-domain HRV parameters in comparison to placebo o.d. in patients with recent uncomplicated transmural myocardial infarction.Patients will be screened during the first few days after the acute event as appropriate for the patient's condition, and after obtaining informed consent. Based on inclusion/exclusion criteria, a first 24-hour Holter recording will be performed. Two to five days later, screened patients still eligible for the study will undergo a second 24-hour Holter recording. After the second Holter recording, all patients will be randomly allocated to treatment with Omacor 1 g, o.d. or placebo o.d.One hundred patients will be followed in double-blind fashion for a six-month period after randomization. Visits, including 24-hour Holter recording and assessment of adverse events, will take place at one-month intervals +/- five days after randomization, i.e., six times in all.     

Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial

The efficacy and tolerability of clomipramine in the treatment of separation anxiety in dogs was tested in a prospective, randomized, double-blind, placebo-controlled, parallel-group, international multicenter clinical trial. For a diagnosis of separation anxiety, dogs had to exhibit at least one of the following signs in the absence of their owner: destruction, defecation, urination and/or vocalization, as well as the behaviour suggestive of "hyper-attachment" to their owner. A total of 95 dogs were randomized to receive one of the three treatments for 2-3 months: "standard-dose" clomipramine (1 to <2 mg/kg, PO, q. 12 h); "low-dose" clomipramine (0.5 to <1 mg/kg, PO, q. 12 h); and placebo (PO, q. 12 h). All dogs received behavioural therapy. Dogs were examined at four time points (days 0, 28, 56 and 84) after the initiation of therapy. Improvement in each dog's behaviour at days 28, 56 and 84 was evaluated in comparison to its behaviour at day 0.The results showed that, compared to placebo, dogs receiving standard-dose clomipramine were rated improved at least three times faster for the signs destruction, defecation and urination. At most time points, more dogs in the standard-dose clomipramine group were rated improved for the signs destruction, defecation and urination, and in an owner's global assessment of the dog's overall behaviour (p<0.05 at certain time points). However, there were no statistically significant differences at any time point between the standard dose and the placebo groups in the sign vocalization. The low-dose clomipramine group produced no statistically significant effect when compared with placebo. Mild and transient vomiting was noted as a side effect of clomipramine in a small number of dogs.It is concluded that addition of standard-dose (1 to <2 mg/kg, PO, q. 12 h) clomipramine to conventional behavioural therapy for 2-3 months ameliorated the signs of separation anxiety in dogs.     

Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial

BACKGROUND: Helicobacter pylori infection is a major cause of peptic ulcer disease and gastric cancer. This study postulated that cranberry juice would be effective in the suppression of H. pylori in an endemically infected population at high risk for gastric cancer. MATERIALS AND METHODS: A prospective, randomized, double-blind, placebo-controlled trial was conducted in Linqu County of Shandong Province, China, where 189 adults aged 48.9 +/- 11.2 years (mean +/- SD) with H. pylori infection were randomly divided into two groups: cranberry juice (n = 97) and placebo (n = 92). Participants were assigned to orally receive two 250-ml juice boxes of cranberry juice or matching placebo beverage daily for 90 days. The degree of H. pylori infection was determined using the 13C-urea breath test before randomization at 35 and 90 days of intervention to assess the efficacy of cranberry juice in alleviating infection. RESULTS: A total of 189 subjects with positive 13C-urea breath test results prior to randomization completed the study. At day 35 of intervention, 14 of the 97 (14.43%) from the the cranberry juice treatment group and 5 of the 92 (5.44%) of the placebo recipients had negative 13C-urea breath test results. After 90 days, the study concluded that 14 of the 97 subjects in the cranberry juice treatment group versus 5 of the 92 in the placebo group yielded negative test results. Eleven individuals from the cranberry juice treatment group and only two from the placebo group were negative at 35 and 90 days of experiment. These results are significant (p < .05). CONCLUSIONS: Regular consumption of cranberry juice can suppress H. pylori infection in endemically afflicted populations.     

The Lescol(R) Intervention Prevention Study (LIPS): a double-blind,placebo-controlled,randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit atherosclerosis and reduce both morbidity and mortality in patients with coronary heart disease. No randomised prospective study, however, has investigated the long-term effect of statins on clinical outcomes in patients who have undergone first successful transcatheter therapy. METHODS: The Lescol((R)) Intervention Prevention Study (LIPS) is a double-blind randomized trial designed to compare the effect of fluvastatin (Lescol) with that of placebo on the time which patients with serum cholesterol >/= 3.5 mmol/l and < 7.0 mmol/l (135-270 mg/dl) remain free of major adverse cardiac events (MACE) after successful first transcatheter therapy (TCT). Patients, aged 18-80 years inclusive, will be randomized in a 1 : 1 ratio to receive fluvastatin, 40 mg, or placebo, twice daily for three to five years. The primary endpoint is the survival time during which patients remain MACE free after first TCT. Secondary endpoints are the incidence of MACE, noncardiac death, hospitalization for other atherosclerotic diseases, changes in serum lipid concentrations and anginal status. SUMMARY: LIPS is unique because it is the first study that will investigate whether MACE can be prevented or reduced by fluvastatin in patients who have undergone successful first transcatheter therapy for coronary heart disease.     

Assessment of single-dose benzodiazepines on insulin secretion,insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind,placebo-controlled,randomized cross-over trial [ISRCTN08745124]

Background  

The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg^-1) glucose tolerance test with minimal-model analysis.     

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed) controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 hours' duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45cmH2O and peak pressure of 60cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4-6 mL/kg of predicted body weight) and targeting plateau pressure [less than or equal to]30cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from day 1 to day 28; ICU, in-hospital and 6-month survival. ART is an event guided-trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum-recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.     

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.     

A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state

Objective

To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD).

Methods

73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery- Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo.

Results

The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms.

Conclusions

There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00490542","term_id":"NCT00490542"}}NCT00490542     

Rationale and design of EXPLORE: a randomized, prospective, multicenter trial investigating the impact of recanalization of a chronic total occlusion on left ventricular function in patients after primary percutaneous coronary intervention for acute ST-elevation myocardial infarction

Background

Hypothyroidism is a prevalent endocrine condition. Individuals with this disease are commonly managed through supplementation with synthetic thyroid hormone, with the aim of alleviating symptoms and restoring normal thyroid stimulating hormone levels. Generally this management strategy is effective and well tolerated. However, there is research to suggest that a significant proportion of hypothyroid sufferers are being inadequately managed. Furthermore, hypothyroid patients are more likely to have a decreased sense of well-being and more commonly experience constitutional and neuropsychiatric complaints, even with pharmacological intervention. The current management of hypothyroidism follows a biomedical model. Little consideration has been given to a biopsychosocial approach to this condition. Within the chiropractic profession there is growing support for the use of a biopsychosocial-based intervention called Neuro-Emotional Technique (NET) for this population.

Methods/Design

A placebo-controlled, single-blinded, randomised clinical pilot-trial has been designed to assess the influence of Neuro-Emotional Technique on a population with primary overt hypothyroidism. A sample of 102 adults (≥18 years) who meet the inclusion criteria will be randomised to either a treatment group or a placebo group. Each group will receive ten treatments (NET or placebo) over a six week period, and will be monitored for six months. The primary outcome will involve the measurement of depression using the Depression, Anxiety and Stress Scale (DASS). The secondary outcome measures to be used are; serum thyroid stimulating hormone, serum free-thyroxine, serum free-triiodothyronine, serum thyroid peroxidase auto-antibodies, serum thyroglobulin auto-antibodies as well as the measurement of functional health and well-being using the Short-Form-36 Version 2. The emotional states of anxiety and stress will be measured using the DASS. Self-measurement of basal heart rate and basal temperature will also be included among the secondary outcome measures. The primary and secondary measures will be obtained at commencement, six weeks and six months. Measures of basal heart rate and basal temperature will be obtained daily for the six month trial period, with recording to commence one week prior to the intervention.

Discussion

The study will provide information on the influence of NET when added to existing management regimens in individuals with primary overt hypothyroidism.

Trial Registration

ANZCTR Number: 12607000040460     

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.     

Orlistat 60 mg reduces visceral adipose tissue: a 24-week randomized, placebo-controlled, multicenter trial

It is well established that abdominal obesity or upper body fat distribution is associated with increased risk of metabolic and cardiovascular disease. The purpose of the present study was to determine if a 24 week weight loss program with orlistat 60 mg in overweight subjects would produce a greater change in visceral adipose tissue (VAT) as measured by computed tomography (CT) scan, compared to placebo. The effects of orlistat 60 mg on changes in total fat mass (EchoMRI‐AH and BIA), ectopic fat (CT) and glycemic variables were assessed. One‐hundred thirty‐one subjects were randomized into a multicenter, double‐blind placebo controlled study in which 123 subjects received at least one post baseline efficacy measurement (intent‐to‐treat population). Both orlistat‐and placebo‐treated subjects significantly decreased their VAT at 24 weeks with a significantly greater loss of VAT by orlistat treated subjects (?15.7% vs. ?9.4%, P < 0.05). In addition, orlistat‐treated subjects had significantly greater weight loss (?5.93 kg vs. ?3.94 kg, P < 0.05), total fat mass loss (?4.65 kg vs. ?3.01 kg, P < 0.05) and trended to a greater loss of intermuscular adipose tissue and content of liver fat compared with placebo‐treated subjects. This is the first study to demonstrate that orlistat 60 mg significantly reduces VAT in addition to total body fat compared to placebo treated subjects after a 24 week weight loss program. These results suggest that orlistat 60 mg may be an effective weight loss tool to reduce metabolic risk factors associated with abdominal obesity.     

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.

     

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     

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 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