Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.

Investigating resilience and its association with stress, anthropometrics, and metabolic health in adolescents with obesity: a pilot study.

The increasing prevalence of children with obesity has contributed to a higher risk of developing cardiometabolic comorbidities. Adversity and chronic stress are negatively linked to cardiometabolic outcomes, and resilience is positively associated with improved outcomes. However, whether resilience is protective against metabolic disturbances preceding disease presentation is less understood. This study explored correlations between stress, anthropometrics, and metabolic parameters with resilience (total, individual, family, peers, school, community), and determined which resilience domains predict metabolically unhealthy obesity. Adolescents with obesity (n = 39; 12-18y) completed anthropometrics, an oral glucose tolerance test, the Adolescent Resilience Questionnaire, and Perceived Stress Scale. Lower stress (r = -0.70, p < 0.001), BMI (r = -0.42, p = 0.01), fat mass (ρ = -0.41, p = 0.01), and fat-free mass (ρ = -0.41, p = 0.01) were associated with greater resilience. Greater school resilience was associated with lower risk for having metabolically unhealthy obesity (odds ratio = 0.87, 95% Confidence Intervals, 0.78-0.98, p = 0.02). Our findings suggest that resilience is associated with lower adiposity, and that lower school resilience is an independent predictor of having metabolically unhealthy obesity. Further work exploring correlations between school resilience, perceived stress, and metabolic outcomes, would optimize programs for obesity-related chronic conditions.

"Counting Carbs to Be in Charge": A Comparison of an Internet-Based Education Module With In-Class Education in Adolescents With Type 1 Diabetes.

Carbohydrate counting is an essential component of type 1 diabetes education but can be difficult for adolescents to learn. Because adolescents are avid users of technology, an Internet-based education module was compared with an in-class education session in terms of carbohydrate counting accuracy in adolescents with type 1 diabetes. Adolescent participants displayed increased carbohydrate counting accuracy after attending an in-class education session compared with an Internet-based education module. These results suggest that online education is best reserved as an adjunctive therapy to in-class teaching in this population.

Determinants of insulin resistance in children exposed to gestational diabetes in utero.

BACKGROUND: The evolution of increased adiposity and cardiometabolic risk in offspring exposed to maternal gestational diabetes (GDM) is not well understood. OBJECTIVE: (a) To evaluate the impact of in utero exposure to GDM and maternal weight status on homeostasis model assessment of insulin resistance (HOMA-IR) in the offspring longitudinally from 1 to 3 years of age and (b) to compare body mass index (BMI) and HOMA-IR in GDM and non-GDM exposed offspring at 1 and 3 years of age. METHODS: A prospective cohort of children born to mothers with and without GDM underwent metabolic characterization between birth and 3 years of age. RESULTS: In the overall cohort, weight gain between birth and 3 years of age was positively associated with HOMA-IR (ß = 0.1491, P = .02), independent of maternal weight status. HOMA-IR was not different between GDM and non-GDM exposed children from 1 to 3 years of age; however, BMI z score was greater in GDM exposed children at 3 years of age. Among non-GDM exposed children, male sex predicted a 35.1% lower HOMA-IR (P = .03). In GDM exposed offspring, a 1 unit increase in maternal insulin sensitivity predicted a 20.8% decrease in HOMA-IR (P = .002). CONCLUSIONS: Overall, weight gain in the first 3 years of life was positively associated with HOMA-IR, while insulin sensitivity of mothers with GDM negatively predicted HOMA-IR in the offspring. Our findings indicate the need to target weight trajectories in early life, as well as maternal factors during gestation to improve metabolic outcomes in the offspring, particularly those exposed to GDM.

Careful conversations: an educational video to support parents in communicating about weight with their children.

BACKGROUND: Parents may struggle to initiate healthy weight-related conversations with their children. Educational videos may be an effective tool for improving parents' knowledge and self-efficacy on this topic. The aim of this pilot study was to develop an educational video to assist parents in weight-related conversations with their child, and to assess changes in parents' self-efficacy on this topic. METHODS: Video development was based on a scoping review and semi-structured interviews with parents. Respondent demographics and user satisfaction were assessed at pre- and post- video, and 4-6 months later. Self-efficacy scores were compared between parent groups based on weight concerns over time. RESULTS: Fifty-seven parents participated in the video questionnaires, and 40 repeated measures 4-6 months later. Significant improvements in self-efficacy in "raising the issue of weight" and "answering questions or concerns" were found after watching the video (p ≤ 0.002) compared to baseline, and scores 4-6 months post baseline remained slightly elevated, but non-significant. Parents with concerns about their child being overweight had significantly lower perceived self-efficacy scores compared to parents with no concerns about their child's weight (p = 0.031). The video was found to be positively received and of relevance to parents across a number of different domains. CONCLUSION(S): Preliminary findings suggest an educational video about initiating weight-related conversations may be an effective tool for increasing parents' perceived self-efficacy in the short term. Further work is needed to validate findings in a randomized controlled trial, and with diverse parent populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03664492 . Registered 10 September 2018 - Retrospectively registered.

Acute decrease in serum testosterone after a mixed glucose and protein beverage in obese peripubertal boys.

BACKGROUND AND OBJECTIVES: Delayed puberty and lower levels of testosterone (T) have been observed in adult obese males and some adolescent males. In adult men, enteral glucose ingestion results in acute lowering of serum testosterone levels; however, this has not been studied in adolescents. We aimed to examine the acute effect of a glucose/protein beverage on serum T concentration changes in obese peripubertal males. A second objective was to determine whether change in T concentration was related to appetite hormone levels. PATIENTS AND METHODS: Twenty-three overweight and obese males aged 8-17 in pre-early (Tanner stage 1-2) and mid-late (Tanner stage 3-5) puberty were included in this cross-sectional study at the Clinical investigative unit at the Hospital for Sick Children. Participants consumed a beverage containing glucose and protein, and blood samples measuring pubertal hormones, ghrelin and glucagon-like peptide-1 (GLP-1) were taken over 60 min. RESULTS: Across pubertal stages, there was a significant decrease in T levels in adolescent boys (-18·6 ± 3·1%, P < 0·01) with no proportional differences between pre-early and mid-late puberty (P = 0·09). Decrease in T was associated with a decrease in LH (r = 0·52, P = 0·02), and fasting T was inversely correlated with fasting ghrelin (r = -0·51, P = 0·03) with no correlation with GLP-1. CONCLUSIONS: Intake of a mixed glucose/protein beverage acutely decreases T levels in overweight and obese peripubertal boys. A potential mechanism for this decrease may be secondary to an acute decrease in LH, but this requires further evaluation.

Greater perceived ability to form vivid mental images in individuals with high compared to low BMI.

Obese individuals report more frequent food cravings than their lean counterparts. Since mental imagery plays a role in eliciting and maintaining craving we hypothesized that one's ability to image may be associated with body mass index (BMI) and account, at least in part, for the association between BMI and craving. Twenty-five participants (BMI range: 17.7 kg/m(2)-34.2 kg/m(2)) completed three measures of perceived mental imagery ability (The Vividness of Visual Imagery Questionnaire, The Vividness of Olfactory Imagery Questionnaire, The Vividness of Food Imagery Questionnaire), and one measure of craving (Food-Craving Inventory). As predicted, correlation analyses revealed positive associations between BMI and perceived ability to image odors and foods, but not visual objects. Olfactory imagery was singled out as the best predictor of BMI in a hierarchical regression analysis. A second experiment with 57 participants (BMI range: 19.1 kg/m(2)-38.7 kg/m(2)) then confirmed the significant positive association between BMI and perceived ability to image odors. These results raise the possibility that imagery ability may play a role in the heightened food cue reactivity observed in obese individuals.

Obesity, sex and pubertal status affect appetite hormone responses to a mixed glucose and whey protein drink in adolescents.

BACKGROUND AND OBJECTIVES: Little information is available on how food intake regulatory hormones may be altered during pubertal development and across the weight spectrum in adolescents. Therefore, the effect of obesity, sex and pubertal status on subjective appetite and appetite hormones in response to a mixed glucose and whey protein drink was determined in 8-18 year old adolescents. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. After a 12 h fast, normal weight (n = 5 female, 4 male) and obese (n = 5 female, 4 male) adolescents (Experiment 1), and pre-early pubertal (n = 10) and mid-late pubertal (n = 10) obese male adolescents (Experiment 2) consumed a 250 ml glucose (30 g) and whey protein (30 g) beverage. Insulin, PYY, ghrelin and subjective appetite were measured over 120 min. RESULTS: Obese adolescents (Experiment 1) have higher insulin, PYY and lower ghrelin (P < 0·006) than normal weight controls, with a more pronounced effect in males (P < 0·037). Puberty (Experiment 2) did not affect insulin (P = 0·305), but the change in PYY in response to the drink was greater (P = 0·032) and ghrelin was lower (P = 0·026) in mid-late pubertal than pre-early pubertal obese males. Average appetite 60 min post-drink was higher in obese and mid-late pubertal adolescents, but not related to hormone changes. CONCLUSIONS: Obesity, sex and pubertal status affect macronutrient-stimulated appetite hormone secretion and these factors may alter food intake in obese children during pubertal development.

Comparing Efficacy of Guselkumab versus Ustekinumab in Patients with Psoriatic Arthritis: An Adjusted Comparison Using Individual Patient Data from the DISCOVER and PSUMMIT Trials.

INTRODUCTION: Two biologic therapies for psoriatic arthritis (PsA), guselkumab and ustekinumab, have demonstrated superior efficacy versus placebo in clinical trials. However, no head-to-head studies have been conducted comparing these two treatments for PsA. The objective was to indirectly compare guselkumab and ustekinumab on joint and skin efficacy up to week 52, using pooled individual patient-level data (IPD) from PsA trials. METHODS: IPD, including baseline characteristics, American College of Rheumatology (ACR) scores and Psoriasis Area Severity Index (PASI) response from guselkumab (DISCOVER-1 and -2) and ustekinumab (PSUMMIT 1 and 2) trials were pooled. Differences in patient characteristics across trials were adjusted using multivariate logistic regression. Odds ratios (OR) were used to derive absolute response probabilities in the guselkumab trial population and were presented with 95% confidence intervals. RESULTS: Most baseline characteristics for guselkumab-treated patients (100 mg every 8 weeks [Q8W]; 100 mg every 4 weeks [Q4W]) were comparable to ustekinumab-treated patients (45/90 mg). In biologic-naïve patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 1.97; 1.37, 2.84; Q4W: 2.04; 1.40, 2.96) and PASI 90 (Q8W: 2.33; 1.52, 3.56; Q4W: 2.57; 1.67, 3.97) versus ustekinumab from week 16 onwards. In biologic-experienced patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 2.57; 1.11, 5.93; Q4W: 2.63; 1.12, 6.17) versus ustekinumab from week 24 onwards; for PASI 90, both guselkumab doses were superior to ustekinumab at week 16 and 52 (Q8W: 3.96; 1.39, 11.27; Q4W: 13.10; 4.18, 41.04). Guselkumab efficacy was similar and robust across primary, scenario, and sensitivity analyses. CONCLUSIONS: IPD analysis demonstrated that both guselkumab doses were superior to ustekinumab for ACR 20 from weeks 16 (biologic-naïve) and 24 (biologic-experienced) onwards, and for PASI 90 at weeks 16 and 52 for both subgroups.

Medical students' perceived comfort and competence performing physical examinations on patients with obesity: A mixed-methods needs assessment.

Physicians are unsatisfied with their training in the care of patients with obesity. Physical examination is a key component of care, and modifications to techniques are often necessary for patients with obesity. To determine learning needs, we examined medical students' perceived comfort and competency in conducting physical examinations on patients with obesity. This mixed-methods study of Canadian medical students used a questionnaire and semi-structured focus groups to assess medical students' perceived comfort and competence in examining patients with obesity. Participants included 175 Canadian medical students. A minority of medical students felt comfortable (42%) or competent (14%) examining patients with obesity. Physical exam challenges included modifying exam manoeuvres, interpreting findings and communicating sensitively around weight. Lack of early exposure to patients with obesity, minimal instruction by preceptors and a lack of curricular focus on obesity were felt to be barriers to improving these skills. Students perceived their lack of confidence as negatively impacting their ability to manage patients with obesity and more training in this area was desired to prevent disparities in care. Medical students feel that adequate training on how to perform an obesity-specific physical examination is lacking. Developing curricula and including formal teaching around these key competencies within medical education is essential.

A Comparison of Recruitment Methods for a Remote, Nationwide Clinical Trial for COVID-19 Treatment.

This study describes decentralized recruitment and enrollment for a COVID-19 treatment trial, while comparing 5 primary recruitment methods: search engine ads, paid advertising within a national testing company, paid advertising within a regional testing company, electronic health record messages, and word of mouth. These are compared across patient demographics, efficiency, and cost. Clinical Trials Registration: NCT04510194.

Social Media Interventions for Nutrition Education Among Adolescents: Scoping Review.

BACKGROUND: Adolescence is a critical period for reinforcing healthy dietary behaviors and supporting the development of cooking skills. Social media may be an avenue for supporting these behaviors, as it is popular among adolescents and can improve access to nutrition education interventions. This study sought to understand the optimal implementation of effective social media-based nutrition education interventions to inform the implementation of future social media-based nutrition education interventions. OBJECTIVE: A scoping review of the characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions for adolescents was conducted. METHODS: We searched MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO databases using a predefined search strategy. Primary research articles were independently screened and included if they involved adolescent populations (10-18 years old) and delivered nutrition education through social media. The information on intervention characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions was extracted. RESULTS: A total of 28 publications out of 20,557 met the eligibility criteria. Twenty-five nutrition interventions were examined by 28 studies. Fourteen interventions used homegrown social media platforms, 8 used Facebook, and 2 used Instagram. Feasibility outcomes were infrequently reported, and the cost of intervention delivery was not reported. Engagement with interventions was variable; high engagement was not required to elicit significant improvements in dietary behaviors. Tailoring interventions, offering practical content, meaningful peer support, and involving families and communities facilitated successful interventions. Strategies to address engagement and technical issues were varied. CONCLUSIONS: Emerging evidence demonstrates that social media interventions for adolescent nutrition are acceptable and improve nutrition outcomes. Future interventions should strengthen peer support components and tailor delivery to specific populations. Further research should examine engagement, adherence, and the impact of interventions on behavioral and physical outcomes. This review is the first to examine the use of social media as the primary medium for nutrition education for adolescent populations. The analysis used in this review argues the importance of peer support in social media-based nutrition interventions and the need for user-centered design of the interventions.

Systematic literature review and network meta-analysis of therapies for psoriatic arthritis on patient-reported outcomes.

OBJECTIVES: Head-to-head clinical trials are common in psoriasis, but scarce in psoriatic arthritis (PsA), making treatment comparisons between therapeutic classes difficult. This study describes the relative effectiveness of targeted synthetic (ts) and biologic (b) disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes (PROs) through network meta-analysis (NMA). DESIGN: A systematic literature review (SLR) was conducted in January 2020. Bayesian NMAs were conducted to compare treatments on Health Assessment Questionnaire Disability Index (HAQ-DI) and 36-item Short Form (SF-36) Health Survey including Mental Component Summary (MCS) and Physical Component Summary (PCS) scores. DATA SOURCES: Ovid MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily),Embase and Cochrane Central Register of Controlled Trials. ELIGIBILITY CRITERIA: Phase III randomised controlled trials (RCTs) evaluating patients with PsA receiving tsDMARDS, bDMARDs or placebo were included in the SLR; there was no restriction on outcomes. DATA EXTRACTION AND SYNTHESIS: Two independent researchers reviewed all citations. Data for studies meeting all inclusion criteria were extracted into a standardised Excel-based form by one reviewer and validated by a second reviewer. A third reviewer was consulted to resolve any discrepancies, as necessary. Risk of bias was assessed using the The National Institute for Health and Care Excellence clinical effectiveness quality assessment checklist. RESULTS: In total, 26 RCTs were included. For HAQ-DI, SF-36 PCS and SF-36 MCS scores, intravenous tumour necrosis factor (TNF) alpha inhibitors generally ranked higher than most other classes of therapies available to treat patients with PsA. For almost all outcomes, several interleukin (IL)-23, IL-17A, subcutaneous TNF and IL-12/23 agents offered comparable improvement, while cytotoxic T-lymphocyte-associated antigen 4, phosphodiesterase-4 and Janus kinase inhibitors often had the lowest efficacy. CONCLUSIONS: While intravenous TNFs may provide some improvements in PROs relative to several other tsDMARDs and bDMARDs for the treatment of patients with PsA, differences between classes of therapies across outcomes were small.

Challenges and Burdens in the Coronary Artery Disease Care Pathway for Patients Undergoing Percutaneous Coronary Intervention: A Contemporary Narrative Review.

Clinical and economic burdens exist within the coronary artery disease (CAD) care pathway despite advances in diagnosis and treatment and the increasing utilization of percutaneous coronary intervention (PCI). However, research presenting a comprehensive assessment of the challenges across this pathway is scarce. This contemporary review identifies relevant studies related to inefficiencies in the diagnosis, treatment, and management of CAD, including clinician, patient, and economic burdens. Studies demonstrating the benefits of integration and automation within the catheterization laboratory and across the CAD care pathway were also included. Most studies were published in the last 5-10 years and focused on North America and Europe. The review demonstrated multiple potentially avoidable inefficiencies, with a focus on access, appropriate use, conduct, and follow-up related to PCI. Inefficiencies included misdiagnosis, delays in emergency care, suboptimal testing, longer procedure times, risk of recurrent cardiac events, incomplete treatment, and challenges accessing and adhering to post-acute care. Across the CAD pathway, this review revealed that high clinician burnout, complex technologies, radiation, and contrast media exposure, amongst others, negatively impact workflow and patient care. Potential solutions include greater integration and interoperability between technologies and systems, improved standardization, and increased automation to reduce burdens in CAD and improve patient outcomes.

Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada.

Aim: The costs and consequences of initial and delayed ofatumumab treatment were evaluated in relapsing-remitting multiple sclerosis with active disease in Canada. Materials & methods: A Markov cohort model was used (10-year horizon, annual cycle length, 1.5% discounting). Scenario analyses examined ofatumumab as first-line treatment versus 3 and 5 years following switch from commonly used first-line therapies. Results: Ofatumumab resulted in improvements in clinical outcomes (relapses and disease progression) and productivity (employment and full-time work), and reduction of economic burden (administration, monitoring and non-drug costs) that were comparable to other high-efficacy therapies (ocrelizumab, cladribine and natalizumab). Switching to ofatumumab earlier in the disease course may improve these outcomes. Conclusion: Results highlight the value of a high-efficacy therapy such as ofatumumab as initial treatment (i.e., first-line) in newly diagnosed relapsing-remitting multiple sclerosis patients with active disease.

Strategies used for the COVID-OUT decentralized trial of outpatient treatment of SARS-CoV-2.

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial.

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.