Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments.

Importance: Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. Objective: To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. Design, Setting, and Participants: In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Exposures: Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Main Outcomes and Measures: Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. Results: A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. Conclusions and Relevance: In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

Adaptive designs in public health: Vaccine and cluster randomized trials go Bayesian.

Clinical trials in public health-particularly those conducted in low- and middle-income countries-often involve communicable and non-communicable diseases with high disease burden and unmet needs. Trials conducted in these regions often are faced with resource limitations, so improving the efficiencies of these trials is critical. Adaptive trial designs have the potential to save trial time and resources and reduce the number of patients receiving ineffective interventions. In this paper, we provide a detailed account of the implementation of vaccine and cluster randomized trials within the framework of Bayesian adaptive trials, with emphasis on computational efficiency and flexibility with regard to stopping rules and allocation ratios. We offer an educated approach to selecting prior distributions and a data-driven empirical Bayes method for plug-in estimates for nuisance parameters.

The Human Mpox Global Outbreak: Available Control Tools and the Opportunity to Break a Cycle of Neglect in Endemic Countries.

The 2022 global outbreak of human Mpox (formerly monkeypox) virus (MPXV) infection outside of the usual endemic zones in Africa challenged our understanding of the virus's natural history, transmission dynamics, and risk factors. This outbreak has highlighted the need for diagnostics, vaccines, therapeutics, and implementation research, all of which require more substantial investments in equitable collaborative partnerships. Global multidisciplinary networks need to tackle MPXV and other neglected emerging and reemerging zoonotic pathogens to address them locally and prevent or quickly control their worldwide spread. Political endorsement from individual countries and financial commitments to maintain control efforts will be essential for long-term sustainability.

Global HIV control: is the glass half empty or half full?

The massive scale-up of HIV treatment and prevention over the past two decades has resulted in important reductions in new infections and mortality globally. Reduction in HIV incidence, however, has been unequal, with worsening epidemics in regions where the reach and scale of HIV control programmes have been insufficient, especially in eastern Europe, central Asia, the Middle East, north Africa, and Latin America where HIV epidemics are concentrated among key populations, including people who inject drugs, men who have sex with men, transgender people, and some minority racial and ethnic groups. The global state of the HIV pandemic highlights disparities in HIV control efforts and provides a roadmap for what should be done, including investment to better implement the effective HIV prevention and treatment tools that are available, but whose adoption and scale-up are not yet sufficient to get us close to an AIDS-free generation. To achieve the full potential of global HIV control, we call for urgent, evidence-informed implementation at scale of our existing and novel HIV prevention and treatment strategies in ways that are better, faster, more efficient, and cost-effective, especially in key populations and regions where the HIV pandemic continues to expand.

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

The effect of group support psychotherapy on adherence to anti-retroviral therapy and viral suppression among HIV positive young people: Study protocol for a pilot randomized controlled trial.

Background: Several studies have demonstrated an association between psychological risk factors and HIV disease progression. However, there is limited information on the use of psychological interventions to improve HIV treatment outcomes in young people living with HIV. Objective: This pilot trial aims to evaluate the feasibility, acceptability and preliminary effectiveness of group support psychotherapy in improving adherence to anti-retroviral therapy and viral suppression in young people living with HIV in Uganda. Methods: We recruited 120 young people with HIV, aged 10-18 years, who had non-viral suppression 6 months after initiating first-line anti-retroviral therapy (ART) from community based HIV clinics in Kitgum district, northern Uganda. Participants were randomly assigned to receive GSP plus IAC (N = 60) or IAC alone (N = 60). Primary outcomes will be indicators of feasibility and acceptability as well as preliminary effectiveness of GSP in improving ART adherence and viral suppression analysed by intention to treat using cluster-adjusted t tests and permutation tests. Secondary outcomes will be measures of depression, anxiety and cost-effectiveness. Results: The trial has been approved by the Makerere College of Health Sciences School of Health Sciences Research Ethics Committee, and the Uganda National Council of Science and Technology. Recruitment began in June 2021 and 120 young people living with HIV with their adult caregivers have been recruited to the trial. An analysis of baseline and 6-month data is in progress. The results of this trial will not only be presented at national and international conferences but also submitted for publication in peer-reviewed journals and as a report to the funding agencies. Conclusions: This pilot trial will provide critical evidence to support the ongoing mental health integration into routine HIV care in Uganda. Trial Registration: Pan African Clinical Trials Registry (PACTR): 202006601935462.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Advancing detection and response capacities for emerging and re-emerging pathogens in Africa.

Recurrent disease outbreaks caused by a range of emerging and resurging pathogens over the past decade reveal major gaps in public health preparedness, detection, and response systems in Africa. Underlying causes of recurrent disease outbreaks include inadequacies in the detection of new infectious disease outbreaks in the community, in rapid pathogen identification, and in proactive surveillance systems. In sub-Saharan Africa, where 70% of zoonotic outbreaks occur, there remains the perennial risk of outbreaks of new or re-emerging pathogens for which no vaccines or treatments are available. As the Ebola virus disease, COVID-19, and mpox (formerly known as monkeypox) outbreaks highlight, a major paradigm shift is required to establish an effective infrastructure and common frameworks for preparedness and to prompt national and regional public health responses to mitigate the effects of future pandemics in Africa.

Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model.

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost-consequence analysis to assess the health system benefits of preventing progression to severe COVID-19 in outpatient populations in the United States. A decision-analytic model in the form of a decision tree was constructed to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19 in the primary analysis: treatment with a 10-day course of fluvoxamine (100 mg twice daily) and current standard-of-care. A secondary analysis comparing a 5-day course of nirmatrelvir-ritonavir was also conducted. We used a time horizon of 28 days. Reported outcomes included cost-savings and hospitalization days avoided. The results of our analysis indicated that administration of fluvoxamine to symptomatic outpatients at high risk of progressing to severe COVID-19 was substantially cost-saving, in the amount of $232 per eligible patient and prevented an average of 0.15 hospital days per patient treated, compared with standard of care. Nirmatrelvir-ritonavir was also shown to be cost-saving despite its higher acquisition cost and provided savings to the healthcare system of $625 per patient treated. These findings suggest that fluvoxamine is likely to be a cost-effective addition to frontline COVID-19 mitigation strategies in many settings, particularly where access to nirmaltrevir-ritonavir or monoclonal antibodies is limited.

Use of trained scent dogs for detection of COVID-19 and evidence of cost-saving.

Background: One of the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic is the importance of early, flexible, and rapidly deployable disease detection methods. Currently, diagnosis of COVID-19 requires the collection of oro/nasopharyngal swabs, nasal turbinate, anterior nares and saliva but as the pandemic continues, disease detection methods that can identify infected individuals earlier and more quickly will be crucial for slowing the spread of the virus. Previous studies have indicated that dogs can be trained to identify volatile organic compounds (VOCs) produced during respiratory infections. We sought to determine whether this approach could be applied for detection of COVID-19 in Rwanda and measured its cost-saving. Methods: Over a period of 5 months, four dogs were trained to detect VOCs in sweat samples collected from human subjects confirmed positive or negative for COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) testing. Dogs were trained using a detection dog training system (DDTS) and in vivo diagnosis. Samples were collected from 5,253 participants using a cotton pad swiped in the underarm to collect sweat samples. Statistical analysis was conducted using R statistical software. Findings: From August to September 2021 during the Delta wave, the sensitivity of the dogs' COVID-19 detection ranged from 75.0 to 89.9% for the lowest- and highest-performing dogs, respectively. Specificity ranged from 96.1 to 98.4%, respectively. In the second phase coinciding with the Omicron wave (January-March 2022), the sensitivity decreased substantially from 36.6 to 41.5%, while specificity remained above 95% for all four dogs. The sensitivity and specificity by any positive sample detected by at least one dog was 83.9, 95% CI: 75.8-90.2 and 94.9%; 95% CI: 93.9-95.8, respectively. The use of scent detection dogs was also found to be cost-saving compared to antigen rapid diagnostic tests, based on a marginal cost of approximately $14,000 USD for testing of the 5,253 samples which makes 2.67 USD per sample. Testing turnaround time was also faster with the scent detection dogs, at 3 h compared to 11 h with routine diagnostic testing. Conclusion: The findings from this study indicate that trained dogs can accurately identify respiratory secretion samples from asymptomatic and symptomatic COVID-19 patients timely and cost-effectively. Our findings recommend further uptake of this approach for COVID-19 detection.

Toward a New Paradigm of North-South and South-South Partnerships for Pandemic Preparedness: Lessons Learned from COVID-19 and Other Outbreaks.

COVID-19 underscores the need to reimagine North-South partnerships and redefine best practices for building public health and research capacity to address emergent health threats and pandemic preparedness in low- and-middle income countries (LMICs). Historically, outbreak and emergency responses have failed to ensure that the Global South has the autonomy and capacity to respond to public health threats in a timely and equitable manner. The COVID-19 response, however, has demonstrated that innovations and solutions in the Global South can not only fill resource and capacity gaps in LMICs but can also provide solutions to challenges globally. These innovations offer valuable lessons about strengthening local manufacturing capacity to produce essential diagnostic, treatment, and prevention tools; implementing high-quality research studies; expanding laboratory and research capacity; and promoting effective cooperation and governance. We discuss specific examples of capacity-building from Rwanda, South Africa, and Senegal. To fulfill promises made to the Global South during the COVID-19 pandemic, restore and resume health service delivery, and effectively prevent and respond to the next health threat, we need to prioritize equitable access to local manufacturing of basic health tools while building health systems capacities in the Global South.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19.

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP−HP (Assistance Publique−Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35−0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41−0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Pregnancy in Sub-Saharan Africa: A 6-Country Retrospective Cohort Analysis.

BACKGROUND: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. METHODS: We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models. RESULTS: Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42-4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44-2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08-3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20-3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17-2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79-14.13). CONCLUSIONS: Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women.

Long-Term Effect of Group Support Psychotherapy on Depression and HIV Treatment Outcomes: Secondary Analysis of a Cluster Randomized Trial in Uganda.

OBJECTIVE: We aimed to determine the effect of group support psychotherapy (GSP) compared with group HIV education (GHE) on depression and HIV treatment outcomes 24 months after treatment. We further aimed to investigate the mediating role of depression and antiretroviral therapy (ART) adherence in the relationship between GSP and viral load suppression. METHODS: Thirty HIV clinics across three districts were randomly assigned to deliver either GSP or GHE for depression. Depression and optimal (≥95%) ART adherence was assessed at baseline and 6, 12, 18, and 24 months after treatment. Viral load was drawn from the medical charts at baseline and 12 and 24 months after treatment. Multilevel mixed-effects regression models and generalized structural equation modeling were used to estimate 24-month outcomes and mediation effects. RESULTS: Participants ( N = 1140) were enrolled from HIV clinics offering either GSP ( n = 578 [51%]) or GHE ( n = 562 [49%]). Fewer GSP than GHE participants met the criteria for depression at 24 months after treatment (1% versus 25%; adjusted odds ratio [aOR] = 0.002, 95% confidence interval [CI] = 0.0002-0.018). More GSP than GHE participants reported optimal (≥95%) ART adherence (96% versus 88%; aOR = 20.88, 95% CI = 5.78-75.33) and improved viral suppression (96% versus 88%; aOR = 3.38, 95% CI = 1.02-11.02). The indirect effects of GSP through sequential reduction in depression and improvement in ART adherence at 12 months may partially explain the higher viral suppression rates at 24 months in GSP than GHE groups. CONCLUSION: In settings where the HIV epidemic persists, depression treatment with GSP may be critical for optimal HIV treatment outcomes.Trial Registration: The Pan African Clinical Trials Registry, number PACTR201608001738234.

Economic Evaluation of Cost and Time Required for a Platform Trial vs Conventional Trials.

Importance: Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials. Objective: To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example. Design, Setting, and Participants: For this economic evaluation, an online survey was administered to a group of international experts (146 participants) with publication records of platform trials to elicit their opinions on cost and time to set up and conduct platform, multigroup, and 2-group trials. Using the reported entry dates of 10 interventions into Systemic Therapy in Advancing Metastatic Prostate Cancer: Evaluation of Drug Efficacy, the longest ongoing platform trial, 3 scenarios were designed involving a single platform trial (scenario 1), 1 multigroup followed by 5 2-group trials (scenario 2), and a series of 10 2-group trials (scenario 3). All scenarios started with 5 interventions, then 5 more interventions were either added to the platform or evaluated independently. Simulations with the survey results as inputs were used to compare the platform vs conventional trial designs. Data were analyzed from July to September 2021. Exposure: Platform trial design. Main Outcomes and Measures: Total trial setup and conduct cost and cumulative duration. Results: Although setup time and cost requirements of a single trial were highest for the platform trial, cumulative requirements of setting up a series of multiple trials in scenarios 2 and 3 were larger. Compared with the platform trial, there was a median (IQR) increase of 216.7% (202.2%-242.5%) in cumulative setup costs for scenario 2 and 391.1% (365.3%-437.9%) for scenario 3. In terms of total cost, there was a median (IQR) increase of 17.4% (12.1%-22.5%) for scenario 2 and 57.5% (43.1%-69.9%) for scenario 3. There was a median (IQR) increase in cumulative trial duration of 171.1% (158.3%-184.3%) for scenario 2 and 311.9% (282.0%-349.1%) for scenario 3. Cost and time reductions in the platform trial were observed in both the initial and subsequently evaluated interventions. Conclusions and Relevance: Although setting up platform trials can take longer and be costly, the findings of this study suggest that having a single infrastructure can improve efficiencies with respect to costs and efforts.

A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection.

BACKGROUND: Although micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH). METHODS: This study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/µL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/µL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months. RESULTS: Of 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/µL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/µL and -79.763 cells/µL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/µL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed. CONCLUSIONS: In ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00798772.