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.).

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.

Sigh Ventilation in Patients With Trauma: The SiVent Randomized Clinical Trial.

Importance: Among patients receiving mechanical ventilation, tidal volumes with each breath are often constant or similar. This may lead to ventilator-induced lung injury by altering or depleting surfactant. The role of sigh breaths in reducing ventilator-induced lung injury among trauma patients at risk of poor outcomes is unknown. Objective: To determine whether adding sigh breaths improves clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized trial of sigh breaths plus usual care conducted from 2016 to 2022 with 28-day follow-up in 15 academic trauma centers in the US. Inclusion criteria were age older than 18 years, mechanical ventilation because of trauma for less than 24 hours, 1 or more of 5 risk factors for developing acute respiratory distress syndrome, expected duration of ventilation longer than 24 hours, and predicted survival longer than 48 hours. Interventions: Sigh volumes producing plateau pressures of 35 cm H2O (or 40 cm H2O for inpatients with body mass indexes >35) delivered once every 6 minutes. Usual care was defined as the patient's physician(s) treating the patient as they wished. Main Outcomes and Measures: The primary outcome was ventilator-free days. Prespecified secondary outcomes included all-cause 28-day mortality. Results: Of 5753 patients screened, 524 were enrolled (mean [SD] age, 43.9 [19.2] years; 394 [75.2%] were male). The median ventilator-free days was 18.4 (IQR, 7.0-25.2) in patients randomized to sighs and 16.1 (IQR, 1.1-24.4) in those receiving usual care alone (P = .08). The unadjusted mean difference in ventilator-free days between groups was 1.9 days (95% CI, 0.1 to 3.6) and the prespecified adjusted mean difference was 1.4 days (95% CI, -0.2 to 3.0). For the prespecified secondary outcome, patients randomized to sighs had 28-day mortality of 11.6% (30/259) vs 17.6% (46/261) in those receiving usual care (P = .05). No differences were observed in nonfatal adverse events comparing patients with sighs (80/259 [30.9%]) vs those without (80/261 [30.7%]). Conclusions and Relevance: In a pragmatic, randomized trial among trauma patients receiving mechanical ventilation with risk factors for developing acute respiratory distress syndrome, the addition of sigh breaths did not significantly increase ventilator-free days. Prespecified secondary outcome data suggest that sighs are well-tolerated and may improve clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02582957.

Network meta analysis to predict the efficacy of an approved treatment in a new indication.

Drug repurposing refers to the process of discovering new therapeutic uses for existing medicines. Compared to traditional drug discovery, drug repurposing is attractive for its speed, cost, and reduced risk of failure. However, existing approaches for drug repurposing involve complex, computationally-intensive analytical methods that are not widely used in practice. Instead, repurposing decisions are often based on subjective judgments from limited empirical evidence. In this article, we develop a novel Bayesian network meta-analysis (NMA) framework that can predict the efficacy of an approved treatment in a new indication and thereby identify candidate treatments for repurposing. We obtain predictions using two main steps: first, we use standard NMA modeling to estimate average relative effects from a network comprised of treatments studied in both indications in addition to one treatment studied in only one indication. Then, we model the correlation between relative effects using various strategies that differ in how they model treatments across indications and within the same drug class. We evaluate the predictive performance of each model using a simulation study and find that the model minimizing root mean squared error of the posterior median for the candidate treatment depends on the amount of available data, the level of correlation between indications, and whether treatment effects differ, on average, by drug class. We conclude by discussing an illustrative example in psoriasis and psoriatic arthritis and find that the candidate treatment has a high probability of success in a future trial.

Patient Outcomes and Unit Composition With Transition to a High-Intensity ICU Staffing Model: A Before-and-After Study.

Provider staffing models for ICUs are generally based on pragmatic necessities and historical norms at individual institutions. A better understanding of the role that provider staffing models play in determining patient outcomes and optimizing use of ICU resources is needed. OBJECTIVES: To explore the impact of transitioning from a low- to high-intensity intensivist staffing model on patient outcomes and unit composition. DESIGN SETTING AND PARTICIPANTS: This was a prospective observational before-and-after study of adult ICU patients admitted to a single community hospital ICU before (October 2016-May 2017) and after (June 2017-November 2017) the transition to a high-intensity ICU staffing model. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital mortality, ICU length of stay (LOS), and unit composition characteristics including type (e.g., medical, surgical) and purpose (ICU-specific intervention vs close monitoring only) of admission. RESULTS: For the primary outcome, 1,219 subjects were included (779 low-intensity, 440 high-intensity). In multivariable analysis, the transition to a high-intensity staffing model was not associated with a decrease in 30-day (odds ratio [OR], 0.90; 95% CI, 0.61-1.34; p = 0.62) or in-hospital (OR, 0.89; 95% CI, 0.57-1.38; p = 0.60) mortality, nor ICU LOS. However, the proportion of patients admitted to the ICU without an ICU-specific need did decrease under the high-intensity staffing model (27.2% low-intensity to 17.5% high-intensity; p < 0.001). CONCLUSIONS AND RELEVANCE: Multivariable analysis showed no association between transition to a high-intensity ICU staffing model and mortality or LOS outcomes; however, the proportion of patients admitted without an ICU-specific need decreased under the high-intensity model. Further research is needed to determine whether a high-intensity staffing model may lead to more efficient ICU bed usage.

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.

Vaccination Against SARS-CoV-2 Is Associated With a Lower Viral Load and Likelihood of Systemic Symptoms.

Background: Data conflict on whether vaccination decreases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load. The objective of this analysis was to compare baseline viral load and symptoms between vaccinated and unvaccinated adults enrolled in a randomized trial of outpatient coronavirus disease 2019 (COVID-19) treatment. Methods: Baseline data from the first 433 sequential participants enrolling into the COVID-OUT trial were analyzed. Adults aged 30-85 with a body mass index (BMI) ≥25 kg/m2 were eligible within 3 days of a positive SARS-CoV-2 test and <7 days of symptoms. Log10 polymerase chain reaction viral loads were normalized to human RNase P by vaccination status, by time from vaccination, and by symptoms. Results: Two hundred seventy-four participants with known vaccination status contributed optional nasal swabs for viral load measurement: median age, 46 years; median (interquartile range) BMI 31.2 (27.4-36.4) kg/m2. Overall, 159 (58%) were women, and 217 (80%) were White. The mean relative log10 viral load for those vaccinated <6 months from the date of enrollment was 0.11 (95% CI, -0.48 to 0.71), which was significantly lower than the unvaccinated group (P = .01). Those vaccinated ≥6 months before enrollment did not differ from the unvaccinated with respect to viral load (mean, 0.99; 95% CI, -0.41 to 2.40; P = .85). The vaccinated group had fewer moderate/severe symptoms of subjective fever, chills, myalgias, nausea, and diarrhea (all P < .05). Conclusions: These data suggest that vaccination within 6 months of infection is associated with a lower viral load, and vaccination was associated with a lower likelihood of having systemic symptoms.