Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL)

Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged ≥ 50 and women aged ≥ 55), with an oversampling of African Americans (n = 5,107). In a 2 × 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D₃ (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1 g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit–risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD.     

VITAL-Bone Health: Rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL)

RationaleAlthough vitamin D is widely used to promote skeletal health, definitive data on benefits and risks of supplemental vitamin D alone on bone are lacking. Results from large, randomized controlled trials in the general population are sparse. Data on the effects of supplemental omega-3 fatty acids (FAs) on bone are also limited.DesignThe VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled trial assessing the role of vitamin D₃ (2000 IU/d) and omega-3 FA (1 g/d) supplements in reducing risks of cancer and cardiovascular disease among U.S. men aged ≥50 and women aged ≥55. To comprehensively test effects of supplemental vitamin D and/or omega-3 FAs on skeletal health, the VITAL: Effects on Fractures ancillary study is determining the effects of these supplements on incident fractures among 25,875 participants enrolled in the parent trial. Study investigators adjudicate fractures through a detailed review of medical records and radiological images (hip and femur). In a complementary ancillary, VITAL: Effects on Structure and Architecture is determining the effects of supplemental vitamin D and/or omega-3 FAs on bone with detailed phenotyping during in-person visits. Comprehensive assessments of bone density, turnover, structure/architecture, body composition, and physical performance are being performed at baseline and 2 years post-randomization.ConclusionResults from these studies will clarify the relationship between supplemental vitamin D and/or omega-3 FAs on bone health outcomes, and inform clinical care and public health guidelines on the use of supplemental vitamin D for the primary prevention of fractures in women and men.     

Serum 25-hydroxyvitamin D in the VITamin D and OmegA-3 TriaL (VITAL): Clinical and demographic characteristics associated with baseline and change with randomized vitamin D treatment

BackgroundThe VITamin D and OmegA-3 TriaL (VITAL) is a completed randomized, placebo-controlled trial of vitamin D₃ (2000 IU/day) and marine omega-3 (1 g/day) supplements in the primary prevention of cancer and cardiovascular disease. Here we examine baseline and change in 25-hydroxyvitamin D (25(OH)D) and related biomarkers with randomized treatment and by clinical factors.MethodsBaseline 25(OH)D was measured in 15,804 participants (mean age 68 years.; 50.8% women; 15.7% African Americans) and in 1660 1-year follow-up samples using liquid chromatography-tandem mass spectrometry and chemiluminescence. Calcium and parathyroid hormone (iPTH) were measured by chemiluminescence and spectrophotometry respectively.ResultsMean baseline total 25(OH)D (ng/mL ± SD) was 30.8 ± 10.0 ng/mL, and correlated inversely with iPTH (r = −0.28), p < .001. After adjusting for clinical factors, 25(OH)D (ng/mL ± SE) was lower in men vs women (29.7 ± 0.30 vs 31.4 ± 0.30, p < .0001) and in African Americans vs whites (27.9 ± 0.29 vs 32.5 ± 0.22, p < .0001). It was also lower with increasing BMI, smoking, and latitude, and varied by season. Mean 1-year 25(OH)D increased by 11.9 ng/mL in the active group and decreased by 0.7 ng/mL in placebo. The largest increases were noted among individuals with low baseline and African Americans. Results were similar for chemiluminescent immunoassay. Mean calcium was unchanged, and iPTH decreased with treatment.ConclusionIn VITAL, baseline 25(OH)D varied by clinical subgroups, was lower in men and African Americans. Concentrations increased with vitamin D supplementation, with the greatest increases in those with lower baseline 25(OH)D. The seasonal trends in 25(OH)D, iPTH, and calcium may be relevant when interpreting 25(OH)D levels for clinical treatment decisions.Clinical Trial Registration: VITAL ClinicalTrials.gov number NCT01169259.     

Lung VITAL: Rationale,design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease,asthma control,pneumonia and lung function in adults

Laboratory and observational research studies suggest that vitamin D and marine omega-3 fatty acids may reduce risk for pneumonia, acute exacerbations of respiratory diseases including chronic obstructive lung disease (COPD) or asthma, and decline of lung function, but prevention trials with adequate dosing, adequate power, and adequate time to follow-up are lacking. The ongoing Lung VITAL study is taking advantage of a large clinical trial—the VITamin D and OmegA-3 TriaL (VITAL)—to conduct the first major evaluation of the influences of vitamin D and marine omega-3 fatty acid supplementation on pneumonia risk, respiratory exacerbation episodes, asthma control and lung function in adults. VITAL is a 5-year U.S.-wide randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of supplementation with vitamin D3 ([cholecalciferol], 2000 IU/day) and marine omega-3 FA (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) for primary prevention of CVD and cancer among men and women, at baseline aged ≥ 50 and ≥ 55, respectively, with 5107 African Americans. In a subset of 1973 participants from 11 urban U.S. centers, lung function is measured before and two years after randomization. Yearly follow-up questionnaires assess incident pneumonia in the entire randomized population, and exacerbations of respiratory disease, asthma control and dyspnea in a subpopulation of 4314 randomized participants enriched, as shown in presentation of baseline characteristics, for respiratory disease, respiratory symptoms, and history of cigarette smoking. Self-reported pneumonia hospitalization will be confirmed by medical record review, and exacerbations will be confirmed by Center for Medicare and Medicaid Services data review.     

The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease

It has long been recognized from epidemiological studies that Greenland Eskimos have substantially reduced rates of acute myocardial infarction (MI) compared with Western controls. From these epidemiological observations, the benefits of fatty fish consumption have been explored in cell culture and animal studies, as well as randomized controlled trials investigating the cardioprotective effects of omega-3 fatty acids. Dietary omega-3 fatty acids seem to stabilize the myocardium electrically, resulting in reduced susceptibility to ventricular arrhythmias, thereby reducing the risk of sudden death. These fatty acids also have potent anti-inflammatory effects, and may also be antithrombotic and anti-atherogenic. Furthermore, the recent GISSI-Prevention study of 11 324 patients showed a marked decrease in risk of sudden cardiac death as well as a reduction in all-cause mortality in the group taking a highly purified form of omega-3 fatty acids, despite the use of other secondary prevention drugs, including beta-blockers and lipid-lowering therapy. The use of omega-3 fatty acids should be considered as part of a comprehensive secondary prevention strategy post-myocardial infarction.     

Design and rationale of a randomized controlled trial to reduce cardiovascular disease risk for patients with bipolar disorder

BackgroundPersons with bipolar disorder (BD) experience a disproportionate burden of medical comorbidity, notably cardiovascular disease (CVD), contributing to decreased function and premature mortality. We describe the design, rationale, and baseline findings for the Self-Management Addressing Heart Risk Trial (SMAHRT), a randomized controlled effectiveness trial of an intervention (Life Goals Collaborative Care; LGCC) designed to reduce CVD risk factors and improve physical and mental health outcomes in patients with BD.MethodsPatients with BD and at least one CVD risk factor were recruited from a VA healthcare system and randomized to either LGCC or usual care (UC). LGCC participants attended four weekly, group-based self-management sessions followed by monthly individual contacts supportive of health behavior change and ongoing medical care management. In contrast, UC participants received monthly wellness newsletters. Physiological and questionnaire assessments measured changes in CVD outcomes and quality of life (QOL) over 24 months.ResultsOut of the 180 eligible patients, 134 patients were enrolled (74%) and 118 started the study protocols. At baseline (mean age = 54, 17% female, 5% African American) participants had a high burden of clinical risk with nearly 70% reporting at least three CVD risk factors including, smoking (41%) and physical inactivity (57%). Mean mental and physical HRQOL scores were 1.5 SD below SF-12 population averages.ConclusionSMAHRT participants experienced substantial CVD morbidity and risk factors, poor symptom control, and decreased QOL. LGCC is the first integrated intervention for BD designed to mitigate suboptimal health outcomes by combining behavioral medicine and care management strategies.     

The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer

BackgroundVitamin D, specifically serum 25(OH)D has been associated with mortality, cancer and multiple other health endpoints in observational studies, but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population-wide supplementation. We have therefore launched the D-Health Trial, a randomized trial of vitamin D supplementation for prevention of mortality and cancer. Here we report the methods and describe the trial cohort.MethodsThe D-Health Trial is a randomized placebo-controlled trial, with planned intervention for 5 years and a further 5 years of passive follow-up through linkage with health and death registers. Participants aged 65–84 years were recruited from the general population of Australia. The intervention is monthly oral doses of 60,000 IU of cholecalciferol or matching placebo. The primary outcome is all-cause mortality. Secondary outcomes are total cancer incidence and colorectal cancer incidence.ResultsWe recruited 21,315 participants to the trial between February 2014 and May 2015. The participants in the two arms of the trial were well-balanced at baseline. Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health, to be current smokers or to have diabetes than the Australian population. However, the proportion overweight or with health conditions such as arthritis and angina was similar.ConclusionsObservational data cannot be considered sufficient to support interventions delivered at a population level. Large-scale randomized trials such as the D-Health Trial are needed to inform public health policy and practice.     

Design and rationale of the WELCOME trial: A randomised,placebo controlled study to test the efficacy of purified long chain omega-3 fatty treatment in non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) represents a range of liver conditions from simple fatty liver to progressive end stage liver disease requiring liver transplantation. NAFLD is common in the population and in certain sub groups (e.g. type 2 diabetes) up to 70% of patients may be affected. NAFLD is not only a cause of end stage liver disease and hepatocellular carcinoma, but is also an independent risk factor for type 2 diabetes and cardiovascular disease. Consequently, effective treatments for NAFLD are urgently needed.ObjectivesThe WELCOME study is testing the hypothesis that treatment with high dose purified long chain omega-3 fatty acids will have a beneficial effect on a) liver fat percentage and b) two histologically validated algorithmically-derived biomarker scores for liver fibrosis.DesignIn a randomised double blind placebo controlled trial, 103 participants with NAFLD were randomised to 15–18 months treatment with either 4 g/day purified long chain omega-3 fatty acids (Omacor) or 4 g/day olive oil as placebo. Erythrocyte percentage DHA and EPA enrichment (a validated proxy for hepatic enrichment) was determined by gas chromatography. Liver fat percentage was measured in three discrete liver zones by magnetic resonance spectroscopy (MRS). We also measured body fat distribution, physical activity and a range of cardiometabolic risk factors.MethodsRecruitment started in January 2010 and ended in June 2011. We identified 178 potential participants, and randomised 103 participants who met the inclusion criteria. The WELCOME study was approved by the local ethics committee (REC: 08/H0502/165; www.clinicalTrials.gov registration number NCT00760513).     

Effect of trans fatty acid isomers from ruminant sources on risk factors of cardiovascular disease: study design and rationale

Substantial evidence clearly demonstrates the deleterious effects of industrially-produced trans fatty acids (TFA); however, data are lacking from large, well controlled human feeding studies that directly compare the effects of industrially-produced and naturally-occurring TFA. The purpose of the current study is to determine whether consumption of TFA derived from different sources differentially affect risk factors of cardiovascular disease (CVD). The study was a randomized, crossover design, controlled-feeding intervention designed to compare the effects of the following diet treatments on risk factors of CVD: low TFA diet (base diet, 34% energy from fat; 0.1% energy from TFA), base diet with vaccenic acid (3.0% energy), base diet with mixed isomers of TFA from partially hydrogenated vegetable oil (3.0% energy), and base diet with cis-9, trans-11 CLA (1.0% energy). The added energy from TFA replaced energy from stearic acid. Participants were required to be between the ages of 25 and 65 years, have a body mass index between 20 and 38 kg/m(2), total cholesterol <280 mg/dl, fasting triacylglycerol <300 mg/dl, fasting glucose <126 mg/dl, and blood pressure <160/100 mm Hg (controlled with certain medications). Of the 116 participants who were randomized, a total of 95 completed the intervention. Results from this study will be important in determining whether ruminant TFA and industrially produced TFA differentially affect markers of cardiovascular risk, in the context of a highly controlled feeding study.     

Enteral omega-3 fatty acid supplementation in adult patients with acute respiratory distress syndrome: a systematic review of randomized controlled trials with meta-analysis and trial sequential analysis

Purpose

Controversy remains as to whether enteral supplementation of ω-3 fatty acids (FA) could improve outcomes in patients with acute respiratory distress syndrome (ARDS). Thus, we did a meta-analysis and aimed to investigate the benefit and harm of enteral ω-3 FA supplementation in adult patients with ARDS.

Methods

Databases including PubMed, Embase, the Cochrane Register of Controlled Trials, and Google Scholar were searched to find relevant articles. Randomized controlled trials (RCTs) comparing enteral ω-3 FA supplementation with a control or placebo intervention in adult patients with ARDS were included. The primary outcome was all-cause 28-day mortality. We used the Cochrane Collaboration methodology.

Results

Seven RCTs with 955 adult patients qualified for inclusion, and all the selected trials were considered as at high risk of bias. The use of enteral ω-3 FA did not significantly reduce all-cause 28-day mortality [relative risk (RR), 0.90; 95 % confidence intervals (CI), 0.68–1.18; p = 0.44; I ² = 31 %; random effects]. Trial sequential analysis indicated lack of firm evidence for a 20 % RR reduction in all-cause 28-day mortality. PaO₂/FiO₂ ratio was significantly increased in the ω-3 FA group on day 4 [weighted mean difference (WMD), 45.14; 95 % CI, 16.77–73.51; p = 0.002; I ² = 86 %; random effects] and day 7 (WMD, 33.10; 95 % CI, 1.67–64.52; p = 0.04; I ² = 88 %; random effects). Meta-analysis using a random effects model showed no significant differences in ventilator-free days (VFD) (WMD, 2.47 days; 95 % CI, ?2.85 to 7.79; p = 0.36; I ² = 91 %) or intensive care unit-free days (ICU) (WMD, 2.31 days; 95 % CI, ?2.34 to 6.97; p = 0.33; I ² = 89 %) between the two groups.

Conclusions

Among patients with ARDS, enteral supplementation of ω-3 FA seemed ineffective regarding all-cause 28-day mortality, VFD, and ICU-free days. Routine use of enteral ω-3 FA cannot be recommended based on the available evidence.     

Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated fatty acids (PUFAs) on apo C-III levels.

Methods: Randomized placebo-controlled trials investigating the impact of omega-3 on apo C-III levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters.

Results: This meta-analysis comprising 2062 subjects showed a significant reduction of apo C-III concentrations following treatment with omega-3 (WMD: ?22.18?mg/L, 95% confidence interval: ?31.61, ?12.75, p?<?.001; I²: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by eicosapentaenoic acid (EPA) ethyl esters but not omega-3 carboxylic acids or omega-3 ethyl esters. There was a greater apo C-III reduction with only EPA as compared with supplements containing EPA and docosahexaenoic acid (DHA) or only DHA. A positive association between the apo C-III-lowering effect of omega-3 with baseline apo C-III concentrations and treatment duration was found.

Conclusions: This meta-analysis has shown that omega-3 PUFAs might significantly decrease apo C-III.

• Key messages

• Omega-3 PUFA supplements significantly reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose (more than 2?g/day)

• Triglyceride (TG)-lowering effect is achieved via peroxisome proliferator-activated receptors α

• Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs in order to provide a final answer whether apo C-III could be an important target for prevention of cardiovascular disease

• New apo C-III antisense oligonucleotide drug (Volanesorsen) showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA

     

Acupuncture for dysphagia after chemoradiation in head and neck cancer: rationale and design of a randomized, sham-controlled trial

IntroductionDysphagia is a common side effect following chemoradiation therapy (CRT) in head and neck cancer (HNC) patients. Current dysphagia management includes swallowing therapy and dilation procedures, but these treatments have limitations. While acupuncture has been reported to positively impact swallowing function and quality of life (QOL) in patients with dysphagia, current evidence is inconclusive.Material and methodsIn an ongoing trial, 42 squamous cell carcinoma HNC patients, who are receiving platinum-based CRT with curative intent, are being recruited from a comprehensive cancer center. They are randomized to 12 sessions of either active acupuncture or to sham acupuncture during and following CRT over a 24-week period. Blinded research staff assesses outcomes at baseline, 20 weeks post-CRT (end of acupuncture), and 12 months after baseline (6-month follow-up). The primary outcome is change in M.D. Anderson Dysphagia Inventory score from baseline to 12 months. Secondary outcomes include QOL measures pertaining to HNC patients. In addition, a subset of study patients are tested for salivary flow rates and cytokines, including plasma transforming growth factor-β1 and interleukin 6 (n = 10 per arm), to preliminarily explore the biological mechanisms of acupuncture for dysphagia.DiscussionThis paper addresses unique challenges related to study design in nonpharmacological, sham-controlled acupuncture trials including development of evidence-based credible verum and sham treatment protocols, blinding, and assuring fidelity of treatment. Results of this study will inform the feasibility of conducting a large scale trial and will provide preliminary evidence regarding the value of acupuncture for dysphagia in HNC patients.     

Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: A meta-analysis of randomized controlled trials

Aim. To systematically review trials concerning the effects of omega-3 fatty acids on sudden cardiac death (SCD), cardiac death, and all-cause mortality in coronary heart disease (CHD) patients.

Methods. PubMed, Embase, and the Cochrane database (1966–2007) were searched. We identified randomized controlled trials that compared dietary or supplementary intake of omega-3 fatty acids with control diet or placebo in CHD patients. Eligible studies had at least 6 months of follow-up data, and cited SCD as an end-point. Two reviewers independently assessed methodological quality. Meta-analysis of relative risk was carried out using the random effect model.

Results. Eight trials were identified, comprising 20,997 patients. In patients with prior myocardial infarction (MI), omega-3 fatty acids reduced relative risk (RR) of SCD (RR = 0.43; 95% CI: 0.20–0.91). In patients with angina, omega-3 fatty acids increased RR of SCD (RR = 1.39; 95% CI: 1.01–1.92). Overall, RR for cardiac death and all-cause mortality were 0.71 (95% CI: 0.50–1.00) and 0.77 (95% CI: 0.58–1.01), respectively.

Conclusions. Dietary supplementation with omega-3 fatty acids reduces the incidence of sudden cardiac death in patients with MI, but may have adverse effects in angina patients.     

Asthma randomized trial of indoor wood smoke (ARTIS): rationale and methods

BackgroundParticulate matter (PM) exposures have been linked with poor respiratory health outcomes, especially among susceptible populations such as asthmatic children. Smoke from biomass combustion for residential home heating is an important source of PM in many rural or peri-urban areas in the United States.AimTo assess the efficacy of residential interventions that reduce indoor PM exposure from wood stoves and to quantify the corresponding improvements in quality of life and health outcomes for asthmatic children.DesignThe asthma randomized trial of indoor wood smoke (ARTIS) study is an in-home intervention study of susceptible children exposed to biomass combustion smoke. Children, ages 7 to 17, with persistent asthma and living in homes that heat with wood stoves were recruited for this three arm randomized placebo-controlled trial. Two household-level intervention strategies, wood stove replacement and air filters, were compared to a sham air filter placebo. Improvement in quality of life of asthmatic children was the primary outcome. Secondary asthma-related health outcomes included peak expiratory flow (PEF) and forced expiratory volume in first second (FEV₁), biomarkers in exhaled breath condensate, and frequency of asthma symptoms, medication usage, and healthcare utilization. Exposure outcomes included indoor and outdoor PM_2.5 mass, particle counts of several size fractions, and carbon monoxide.DiscussionTo our knowledge, this was the first randomized trial in the US to utilize interventions targeting residential wood stoves to assess the impact on indoor PM and health outcomes in a susceptible population.     

ENHANCE: Design and rationale of a randomized controlled trial for promoting enduring happiness & well-being

Individuals who are higher in subjective well-being not only feel happier, they are more likely have fulfilling relationships, increased work performance and income, better physical health, and longer lives. Over the past several decades, the science of subjective well-being has produced insights into these benefits of happiness, and—recognizing their importance—has begun to examine the factors that lead to greater well-being, from cultivating strong relationships to pursuing meaningful goals. However, studies to date have typically focused on improving subjective well-being by intervening with singular constructs, using primarily college student populations, and were short-term in nature. Moreover, little is understood about the impact of a well-being treatment delivered online vs. in-person. In the present article, we describe a comprehensive intervention program including 3-month initial treatment followed by a 3-month follow-up, ENHANCE: Enduring Happiness and Continued Self-Enhancement. One-hundred and sixty participants will be recruited from two different sites to participate in one of two versions of ENHANCE: in-person (n = 30) vs. wait-list control (n = 30); or online (n = 50) vs. wait-list control (n = 50). Assessments will be completed at baseline, three months and six months. Our primary outcome is change in subjective well-being across treatment (3 months) and follow-up (6 months). Secondary outcomes include self-report and objective measures of health, as well as a psychological mediators (e.g., psychological needs) and moderators (e.g., personality) of treatment outcomes. We hope to provide researchers, practitioners, and individuals with an evidence-based treatment to improve happiness and subjective well-being.     

The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.