Short- and long-term effects of imatinib in patients hospitalised for COVID-19 infection: A randomised controlled trial (preprint)

We report the short- and long-term results of the SOLIDARITY Finland on mortality and other patient-important outcomes in patients hospitalised for COVID-19. Between 08/2021 and 03/2023, we randomised 156 patients in 15 hospitals. In the imatinib group, 7.2% of patients had died at 30 days and 13.3% at 1 year and in the standard of care group 4.1% and 8.3% (adjusted HR at 30 days 1.09, 95% CI 0.23-5.07). In a meta-analysis of randomised trials of imatinib versus standard of care (n=732), allocation to imatinib was associated with a mortality risk ratio of 0.73 (95% CI 0.32-1.63). At 1-year, self-reported recovery occurred in 79.0% in imatinib and in 88.3% in standard of care (RR 0.91, 95% CI 0.78-1.06). Of the 21 potential long COVID symptoms, patients often reported moderate or major bother from fatigue (24%), sleeping problems (19%) and memory difficulties (17%). We found no convincing difference between imatinib and standard of care groups in quality of life or symptom outcomes. The evidence raises serious doubts regarding the benefit of imatinib in reducing mortality, improving recovery and preventing potential long COVID symptoms when given to patients hospitalised for COVID-19.

Comparison of different isolation periods for preventing the spread of COVID-19: a rapid systematic review and a modelling study (preprint)

Background: The optimal isolation duration for COVID-19 patients remains unclear. To support an update of WHO Living Clinical management guidelines for COVID-19 (https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2022.2), this rapid systematic review and modelling study addresses the effects of different isolation periods for preventing onward transmission leading to hospitalization and death among secondary cases. Methods: We searched World Health Organization (WHO) COVID-19 database for clinical studies evaluating the impact of isolation periods for COVID-19 patients up to July 28, 2022. We performed random-effects meta-analyses to summarize testing rates of persistent test positivity rates after COVID-19 infection. We developed a model to compare the effects of the five-day isolation and removal of isolation based on a negative antigen test with ten-day isolation on onward transmission leading to hospitalization and death. We assumed that patients with a positive test are infectious and those with a negative test are not. If the test becomes negative, patients will stay negative. The model included estimates of test positivity rates, effective reproduction number, and hospitalization rate or case fatality rate. Findings: Twelve studies addressing persistent test positivity rates including 2799 patients proved eligible. Asymptomatic patients (27.1%, 95% CI: 15.8% to 40.0%) had a significantly lower rapid antigen test (RAT) positive rate than symptomatic patients (68.1%, 95% CI: 40.6% to 90.3%) on day 5. The RAT positive rate was 21.5% (95% CI: 0 to 64.1%; moderate certainty) on day 10. Our modelling study suggested that the risk difference (RD) for asymptomatic patients between five-day isolation and ten-day isolation in hospitalization (2 more hospitalizations of secondary cases per 1000 patients isolated, 95% uncertainty interval (UI) 2 more to 3 more) and mortality (1 more per 1000 patients, 95% UI 0 to 1 more) of secondary cases proved very small (very low certainty). For symptomatic patients, the potential impact of five- versus ten-day isolation was much greater in hospitalizations (RD 19 more per 1000 patients, 95% UI 14 more to 24 more; very low certainty) and mortality (RD 5 more per 1000 patients, 95% UI 4 more to 6 more; very low certainty). There may be no difference between removing isolation based on a negative antigen test and ten-day isolation in the onward transmission leading to hospitalization or death, but the average isolation period (mean difference -3 days) will be shorter for the removal of isolation based on a negative antigen test (moderate certainty). Interpretation: Five versus 10 days of isolation in asymptomatic patients may result in a small amount of onward transmission and negligible hospitalization and mortality, but in symptomatic patients concerning transmission and resulting hospitalization and mortality. The evidence is, however, very uncertain.

Effectiveness of early-treatment interventions on self-reported long COVID: A multi-arm, multi-stage adaptive platform control trial (preprint)

Approximately 20% of people infected with COVID-19 develop at least one persistent condition potentially attributable to their SARS-CoV-2 infection. We sought to determine the effectiveness of early COVID-19 treatment interventions on long COVID symptoms. We conducted a multi-arm multi-stage adaptive platform trial at 12 public health clinics in Brazil between June 2020 and July 2022. Participants were followed for 60. Patients received one of six interventions (doxazosin, fluvoxamine, fluvoxamine in combination with inhaled budesonide, interferon-lambda, ivermectin, or metformin) or matching placebo. The primary outcome was persistence of COVID-19 symptoms at 60 days after randomization. We analyzed data from 5,700 participants across study cohorts. Overall, approximately 22% of patients reported at least one ongoing symptom 60 days after randomization, regardless of the early treatment they received. At day 60, we did not find any statistical benefit of any intervention on recovery, cure fractions, or PROMIS scores (mental and physical).

The trustworthiness and impact of trial preprints for COVID-19 decision-making: A methodological study (preprint)

Purpose: To assess the trustworthiness and impact of preprint trial reports during the COVID-19 pandemic. Data sources: WHO COVID-19 database and the L-OVE COVID-19 platform by the Epistemonikos Foundation (up to August 3rd, 2021) Design: We compare the characteristics of COVID-19 trials with and without preprints, estimate time to publication of COVID-19 preprint reports, describe discrepancies in key methods and results between preprint and published trial reports, report the number of retracted preprints and publications, and assess whether including versus excluding preprint reports affects meta-analytic estimates and the certainty of evidence. For the effects of eight therapies on mortality and mechanical ventilation, we performed meta-analyses including preprints and excluding preprints at 1 month, 3 months, and 6 months after the first trial addressing the therapy became available either as a preprint or publication (120 meta-analyses in total). Results: We included 356 trials, 101 of which are only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. Half of all preprints remain unpublished at six months and a third at one year. There were few important differences in key methods and results between trial preprints and their subsequent published reports. We identified four retracted trials, three of which were published in peer-reviewed journals. With two exceptions (2/60; 3.3%), point estimates were consistent between meta-analyses including versus excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. There were nine comparisons (9/60; 15%) for which the rating of the certainty of evidence differed when preprints were included versus excluded, for four of these comparisons the certainty of evidence including preprints was higher and for five of these comparisons the certainty of evidence including preprints was lower. Limitations: The generalizability of our results is limited to COVID-19. Preprints that are subsequently published in journals may be the most rigorous and may not represent all trial preprints. Conclusion: We found no compelling evidence that preprints provide less trustworthy results than published papers. We show that preprints remain the only source of findings of many trials for several months, for a length of time that is unacceptable in a health emergency. We show that including preprints may affect the results of meta-analyses and the certainty of evidence. We encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed.

EFFECT OF EARLY TREATMENT WITH FLUVOXAMINE ON RISK OF EMERGENCY CARE AND HOSPITALIZATION AMONG PATIENTS WITH COVID-19: THE TOGETHER RANDOMIZED PLATFORM CLINICAL TRIAL (preprint)

BackgroundRecent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER randomized platform clinical trial for acutely symptomatic patients with COVID-19, we assessed the efficacy of fluvoxamine vs. placebo in preventing either extended emergency room observation or hospitalization due to COVID-19. Herein, we report the preliminary findings. MethodsThis placebo-controlled, randomized, adaptive, platform trial conducted among symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients with a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) or placebo. The primary endpoint was a composite outcome of emergency room observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization using intention to treat. Modified intention to treat (mITT) explored patients receiving at least 24 hours of treatment before a primary outcome event. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian analytic framework to determine effects along with probability of success of intervention compared to placebo. The trial is registered at clinicaltrials.gov (NCT04727424) and is ongoing. FindingsThe study team screened 9020 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization from January 15, 2021 to August 6th 2021, when the trial arms were stopped for superiority. A total of 3238 patients were allocated to fluvoxamine (n=739), placebo (n=733) and other treatments (n=1766). Herein, we report the effectiveness of fluvoxamine vs. a concurrent placebo control. The average age of participants was 50 years (range 18-102 years); 57% were female. The proportion of patients observed in an emergency room for >6 hours or admitted to hospital due to COVID-19 was lower for the fluvoxamine group compared to placebo (77/739 vs 108/733; Relative Risk [RR]: 0.71; 95% Bayesian Credible Interval [95% BCI]: 0.54 - 0.93), with a probability of superiority of 99.4% surpassing the prespecified superiority threshold of 97.6% (risk difference 4.3%). Of the composite primary outcome events, 88% were hospitalizations. Findings were similar for the mITT analysis (RR0.68, 95% BCI : 0.50- 0.91). We found no significant relative effects between the fluvoxamine and placebo groups on viral clearance at day 7 (Odds ratio [OR]: 0.75; 95% Confidence Intervals [95% CI]: 0.53 - 1.07), mortality (OR: 0.70; 95% CI: 0.36 - 1.30), time to death (Hazard ratio [HR]: 0.79; 95% CI: 0.58 - 1.08), days hospitalized (Mean Difference (MD) 1.22 days; 95% CI: 0.98 - 1.53), number of days ventilated (MD 1.10; 95% CI: 0.70 - 1.73) or other secondary outcomes. Data capturing all 28 days of follow-up will be reported after August 26th, 2021. InterpretationTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalization. FundingThe trial was supported by FastGrants and The Rainwater Foundation.

Patient-important Outcomes Reported in Clinical Studies of Pharmacologic Treatments for COVID-19: A Protocol of a Meta-epidemiological Study (preprint)

Background: The coronavirus disease 19 (covid-19) pandemic has underscored the need to expedite clinical research, which may lead investigators to shift away from measuring patient-important outcomes (PIOs), limiting research applicability. We aim to describe the extent to which randomized controlled trials (RCTs) of covid-19 therapies will determine PIOs. Methods: We will perform a meta-epidemiological study of RCTs that included people at risk for, or with suspected, probable, or confirmed covid-19, examining any pharmacological treatment or blood product aimed at prophylaxis or treatment. We will obtain data from all RCTs identified in a recent published network metanalysis (NMA). To categorize the outcomes according to their importance to patients, we will adapt a previously defined hierarchy: a) mortality, b) quality of life/ functional status/symptoms, c) morbidity, and d) surrogate outcomes. Outcomes within the category a) and b) will be considered critically important to patients, and outcomes within the category c) will be regarded as important. We will use descriptive statistics to assess the proportion of studies that report each category of outcomes. We will perform univariable and multivariable analysis to explore associations between trial characteristics and the likelihood of reporting PIOs. Discussion: The findings from this meta-epidemiological study will help health care professionals and researchers understand if the current covid-19 trials are effectively assessing and reporting the outcomes that are important to patients. If a deficiency in capturing PIOs is identified, this information may help inform the development of future RCTs in covid-19.Systematic Review registrations: Open Science Framework registration: osf.io/6xgjz