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 prevents the diagnosis of Long Covid in phase 3 trial of early treatment

OBJECTIVES/GOALS: Chronic or new symptoms after infection with severe-acute-respiratory-coronavirus-2 (SARS-CoV-2) has been termed post-acute sequelae of Covid-19 (PASC) or Long Covid. Our objective is to present results from COVID-OUT, a phase 3 double-blind, randomized controlled trial of early outpatient treatment of Covid-19 with repurposed medications. METHODS/STUDY POPULATION: COVID-OUT enrolled adults age 30 to 85 with overweight or obesity who had proof of SARS-CoV-2 infection and fewer than 7 days of symptoms. In this 2 by 3 factorial design trial of metformin, ivermectin, fluvoxamine, or exact-matching placebo of each medication, participants were randomized 1:1:1:1:1:1 to the 6 treatment allocations. This focuses on whether early treatment with metformin prevented Long Covid. Immediate release metformin was titrated to 1500mg daily over the first 6 days. We assessed the incidence of clinician-diagnosed Long Covid with follow up through 10 months after enrollment. We also assessed where participants were diagnosed with Long Covid, and where they received Long Covid treatment. RESULTS/ANTICIPATED RESULTS: Of 1124 participants, 98 (8.7%) report having a healthcare provider make a diagnosis of long covid. By arm, 6.9% (39/564) of metformin participants report having a diagnosis for long covid as compared with 10.5% (59/560) of matched placebo controls. The absolute reduction attributable to metformin was 3.6% (95%CI, 0.3% to 7.0%;P=0.031) with a relative risk reduction of 34% (95%CI, 3% to 55%). The metformin cost per long covid case averted was $28 (95%CI, $15 to $306). 10-month follow-up data will be available at the time of presentation as well as an analysis of baseline factors associated with the development of Long-Covid, independent of treatment allocation in the trial. DISCUSSION/SIGNIFICANCE: Metformin reduced the incidence of clinician-diagnosed long covid by 34% in a double-blind randomized placebo-controlled trial, and previous research published in-vitro activity by metformin against SARS-CoV-2 and other RNA viruses. Further investigation of metformin as early treatment for SARS-CoV-2 is warranted.

Increased suicidal ideation and suicide attempts in COVID-19 patients in the United States: statistics from a large national insurance billing database

Emerging research suggests suicidality may have increased during the COVID-19 pandemic. This cross-sectional study aimed to advance understanding of suicide risk during the pandemic through novel use of a large insurance database. Using logistic regression across time-points, we estimated the effect of exposure to SARS-CoV-2 infection on rates of suicidal ideation and suicide attempts in infected individuals versus uninfected controls during the pandemic (March 2020 - September 2021). In uninfected individuals, we estimated the effect of exposure to the pandemic period versus the pre-pandemic control period (January 2017 to February 2020) on suicidality rates. We also investigated within-pandemic temporal patterns of suicidality. All patients with data in the UnitedHealth Group claims during those intervals were included. ICD-10 codes defined suicidality measures. There were 525,312,717 (62.3% over age 45, 57.7% female) included encounters. From the pandemic subsample (32.8%), 1.7% were COVID+. Adjusted odds ratios showed that COVID+ patients were significantly more likely to have suicidal ideation and suicide attempts than COVID- patients. Among COVID- patients, adjusted odds of suicidality were significantly lower during versus prior to the pandemic. Results were unfortunately limited by the absence of data on deaths by suicide. Further research should examine how SARS-CoV-2 infection may influence suicidality.

Increased suicidal ideation and suicide attempts in COVID-19 patients in the United States: Statistics from a large national insurance billing database.

Emerging research suggests suicidality may have increased during the COVID-19 pandemic. This cross-sectional study aimed to advance understanding of suicide risk during the pandemic through novel use of a large insurance database. Using logistic regression across time-points, we estimated the effect of exposure to SARS-CoV-2 infection on rates of suicidal ideation and suicide attempts in infected individuals versus uninfected controls during the pandemic (March 2020 - September 2021). In uninfected individuals, we estimated the effect of exposure to the pandemic period versus the pre-pandemic control period (January 2017 to February 2020) on suicidality rates. We also investigated within-pandemic temporal patterns of suicidality. All patients with data in the UnitedHealth Group claims during those intervals were included. ICD-10 codes defined suicidality measures. There were 525,312,717 (62.3% over age 45, 57.7% female) included encounters. From the pandemic subsample (32.8%), 1.7% were COVID+. Adjusted odds ratios showed that COVID+ patients were significantly more likely to have suicidal ideation and suicide attempts than COVID- patients. Among COVID- patients, adjusted odds of suicidality were significantly lower during versus prior to the pandemic. Results were unfortunately limited by the absence of data on deaths by suicide. Further research should examine how SARS-CoV-2 infection may influence suicidality.

Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection. DESIGN: Retrospective cohort study. SETTING: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results. PARTICIPANTS: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490). MAIN OUTCOME MEASURES: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19. RESULTS: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae. CONCLUSIONS: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.

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.

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65. DESIGN: Retrospective cohort study. SETTING: Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database. PARTICIPANTS: Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness. MAIN OUTCOME MEASURES: More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated. RESULTS: 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group. CONCLUSIONS: The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity.

Observational studies suggest outpatient metformin use is associated with reduced mortality from coronavirus disease-2019 (COVID-19). Metformin is known to decrease interleukin-6 and tumor-necrosis factor-α, which appear to contribute to morbidity in COVID-19. We sought to understand whether outpatient metformin use was associated with reduced odds of severe COVID-19 disease in a large US healthcare data set. Retrospective cohort analysis of electronic health record (EHR) data that was pooled across multiple EHR systems from 12 hospitals and 60 primary care clinics in the Midwest between March 4, 2020 and December 4, 2020. Inclusion criteria: data for body mass index (BMI) > 25 kg/m2 and a positive SARS-CoV-2 polymerase chain reaction test; age ≥ 30 and ≤85 years. Exclusion criteria: patient opt-out of research. Metformin is the exposure of interest, and death, admission, and intensive care unit admission are the outcomes of interest. Metformin was associated with a decrease in mortality from COVID-19, OR 0.32 (0.15, 0.66; p = .002), and in the propensity-matched cohorts, OR 0.38 (0.16, 0.91; p = .030). Metformin was associated with a nonsignificant decrease in hospital admission for COVID-19 in the overall cohort, OR 0.78 (0.58-1.04, p = .087). Among the subgroup with a hemoglobin HbA1c available (n = 1193), the adjusted odds of hospitalization (including adjustment for HbA1c) for metformin users was OR 0.75 (0.53-1.06, p = .105). Outpatient metformin use was associated with lower mortality and a trend towards decreased admission for COVID-19. Given metformin's low cost, established safety, and the mounting evidence of reduced severity of COVID-19 disease, metformin should be prospectively assessed for outpatient treatment of COVID-19.