Rifaximin antibiotic treatment for restless legs syndrome: a double-blind,placebo-controlled study

Sleep and Biological Rhythms - The purpose was to evaluate rifaximin antibiotic therapy for restless legs syndrome (RLS) patients who have small intestinal bacterial overgrowth (SIBO). Patients...     

Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial

Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency, adenosine triphosphate and its regulator, adenosine diphosphate. In this work, we tested the hypothesis that oral creatine supplementation (5 g d(-1) for six weeks) would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and intelligence (Raven's Advanced Progressive Matrices), both tasks that require speed of processing. These findings underline a dynamic and significant role of brain energy capacity in influencing brain performance.     

Protective effect of budesonide/formoterol compared with formoterol,salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised,double-blind,cross-over study

Background

The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.

Methods

The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV₁ 95% of predicted) who previously demonstrated a ≥30% fall in forced expiratory volume in 1 second (FEV₁) after inhaling adenosine 5''-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 μg), formoterol (4.5 μg), salbutamol (2 × 100 μg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.

Results

In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV₁ within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV₁.

Conclusions

A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

Trial Registration

ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00272753","term_id":"NCT00272753"}}NCT00272753     

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international,randomised, double-blind,placebo-controlled trial

Background

Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women.

Methods/design

The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1?g of TXA or matching placebo by intravenous injection immediately (within 15?min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. 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 will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia.

Discussion

The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia.

Trial registration

ISRCTN, ISRCTN62396133. Registered on 7 December 2017;ClincalTrials.gov, ID: NCT03475342. Registered on 23 March 2018.

     

A randomized,double-blind,placebo-controlled,cross-over pilot study to investigate the efficacy of Rest-ZZZ formula in healthy participants with occasional sleeplessness

Sleep and Biological Rhythms - The purpose of this study was&nbsp;to investigate the safety and efficacy of Rest-ZZZ, a natural sleep supplement, in healthy adults without a diagnosed sleep...     

Serum leptin concentrations during short-term administration of growth hormone and triiodothyronine in healthy adults: a randomised, double-blind placebo-controlled study.

The regulation of adipose tissue mass and energy expenditure is currently subject to intensive research, which primarily relates to the discovery of leptin. Leptin is a peptide, which is the product of the obese (ob) gene expressed in adipose tissue of several species icluding humans. Leptin is supposed to serve both as an index of fat mass and as a sensor of energy balance. Administration of recombinant murine leptin in ob/ob-mice, which do not produce leptin, decreases food intake and increases thermogenesis both of which result in a reduction in body weight and adipose tissue mass. The calorigenic effect of leptin presumably acts through an increase in sympathetic outflow which in turn activates the beta3 adrenergic receptor in brown adipose tissue. The regulation and action of endogenous leptin in humans are less well understood, and clinical grade recombinant human leptin is so far not available. Serum leptin correlates logarithmically with total body fat in both normal weight and obese subjects, which suggest insensitivity to leptin in obese patients. Furthermore, more rapid excursions in serum leptin have been reported following short-term changes in caloric intake and administration of insulin. Growth hormone (GH) exerts pronounced effects on lipid metabolism and resting energy expenditure. The lipolytic actions of GH appear to involve both increased sensitivity to the beta-adrenergic pathway, and a suppression of adipose tissue lipoprotein lipase activity. The calorigenic effects of GH have been shown not only to be secondary to changes in lean body mass. Growth hormone administration furthermore increases the peripheral conversion of thyroxine to triiodothyronine, which may contribute to the overall actions of GH on fuel and energy metabolism. So far, little is known about the effects of GH and iodothyronines on serum leptin levels in humans. We therefore measured serum leptin levels and energy expenditure before and after the administration of GH and triiodothyronine, alone and in combinaion, in a randomized double-blind placebo-controlled study in healthy young male adults. The dose of triiodothyronine was selected to obtain serum levels comparable to those seen after GH administration.     

Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder.

The study was undertaken to determine the safety and efficacy of NIPRISAN, a phytomedicine, developed for the management of patients with Sickle Cell Disorder (SCD). The study design is a placebo-controlled double blind cross-over trial. Eighty-two (82) patients with SCD were recruited and randomised into two groups. An initial 4 month pre-trial study was undertaken to determine the similarity of the groups. The main study was conducted over a twelve-month period with crossover at six months. Safety of the drug was assessed clinically and biochemically. NIPRISAN significantly (P < 0.01) reduced the frequency of SCD crisis associated with severe pains. Acute toxicity to the liver assessed by the activities of liver enzymes, indicate that NIPRISAN is safe. Renal function assessed by the serum levels of creatinine and blood urea nitrogen remained normal. Both the clinical and laboratory results of the present phase IIB (pivot) clinical study suggest that NIPRISAN is a safe and efficacious phytomedicine for the management of patients with Sickle Cell Disorder.     

Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study

BACKGROUND: Allergic rhinitis (AR) is a disease characterized by IgE-mediated, allergic inflammation of the nasal mucosa. T helper (Th) 2 cells play an important role in the development of IgE-mediated diseases such as AR, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL-13) at the site of allergic inflammation. Th1 cytokines (IL-12 and IFN-gamma) are known to suppress this Th2 immune response, aiding the treatment of these diseases. Beta-1,3-1,6-glucan (Glucan) is an immunomodulator stimulating particularly the antitumor response. An efficient antitumor stimulation can be achieved through a Th1-mediated immune response. OBJECTIVE: The aim of this study was to investigate the effects of Glucan on the immunopathogenic processes in the microenvironment to determine if it reverses the Th2-mediated immune response in AR to Th1-mediated response. METHODS: 24 Olea europea mono-sensitized patients with AR were randomized into Glucan and placebo groups. The Glucan group consisted of 12 patients who received Glucan treatment for 12 weeks, while the placebo group of 12 patients received placebo during the same period. A nasal provocation test (NPT) with Olea europea was performed at the beginning and end of treatment, and nasal lavage followed the positive NPT. IL-4, IL-5, IFN-gamma and IL-12 levels and the eosinophil count (%) were measured in nasal lavage fluid (NLF) samples. Simultaneously, peripheral blood eosinophil % values were measured. RESULTS: After treatment, IL-4 and IL-5 levels in NLF from the Glucan group were found to have decreased significantly (p = 0.027, p = 0.04; respectively), while IL-12 levels were found to have significantly increased (p = 0.008). However, IFN-gamma levels had not changed. On the other hand, none of the cytokine levels had changed significantly in the placebo group following treatment. Moreover, the percentage of eosinophils in the NLF was found to have decreased significantly after treatment in the Glucan group (p = 0.01), while that of the placebo group did not change. Peripheral blood percentage eosinophil levels had not changed significantly in any group. CONCLUSION: Th2-originated IL-4 and IL-5 levels responsible for the allergic inflammatory response in the microenvironment of patients with AR, are decreased with Glucan while levels of Th1-originated IL-12 are increased. Moreover, eosinophils, which are important effector cells of the inflammatory response, are decreased in the microenvironment. As a result, Glucan may have a role as an adjunct to standard treatment in patients with AR.     

A double-blind,placebo-controlled,randomised clinical study of the effect of pork collagen peptide supplementation on atherosclerosis in healthy older individuals

We examined whether baPWV could be affected by pork collagen peptide (CP) ingestion. Seventy subjects were randomized into two groups (2.5 g/day CP and 2.5 g/day placebo). A significant reduction in baPWV was observed in the CP group compared to the placebo group. This study demonstrated that pork CP may contribute to the prevention of atherosclerosis in elderly.     

Acetazolamide in prevention of acute mountain sickness: a double-blind controlled cross-over study.

Twenty-four amateur climbers took part in a double-blind controlled cross-over trial of acetazolamide versus placebo for the prevention of acute mountain sickness. They climbed Kilimanjaro (5895 m) and Mt Kenya (5186 m) in three weeks with five rest days between ascents. The severity of acute mountain sickness was gauged by a score derived from symptoms recorded daily by each subject. On kilimanjaro those taking acetazolamide reached a higher altitude (11 v 4 reached the summit) and had a lower symptom score than those taking placebo (mean 4.8 v 14.3). Those who had taken acetazolamide on Kilimanjaro maintained their low symptom scores while taking placebo on Mt Kenya (mean score 1.9), whereas those who had taken placebo on Kilimanjaro experienced a pronounced improvement when they took acetazolamide on Mt Kenya (mean score 2.5). Acute mountain sickness prevented one subject for completing either ascent. Acetazolamide was acceptable to 23 of the 24 subjects. Acetazolamide is recommended as an acceptable and effective prophylactic for acute mountain sickness.     

Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

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.

     

Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial

Background

Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.

Methods and Findings

In total, 1,007 patients were randomized, using a 2×2×2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25–67) at 1 h and by 38% (95% CI 26–49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.

Conclusions

Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00270777","term_id":"NCT00270777"}}NCT00270777 Please see later in the article for the Editors'' Summary     

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     

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.     

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized,placebo-controlled trial

Background

Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.

Methods

Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV₁) 50-80% of predicted normal value and FEV₁ reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV₁ at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV₁.

Results

A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV₁ compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV₁ at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV₁ than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.

Conclusions

FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.

Trial registration

NCT00398645     

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial

Background

Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established.

Methods and Findings

To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3–59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76–2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29–0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%–85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%–99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%–92%) (p<0.001) during the intervention period and by 46% (95% CI 31%–68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%–67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event.

Conclusions

IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00738946","term_id":"NCT00738946"}}NCT00738946 Please see later in the article for the Editors'' Summary