RESUMO
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.
RESUMO
BackgroundIn an effort to contain the COVID-19 epidemic, many governments across the world have enforced lockdown or social distancing measures. Several outbreak models have been developed to investigate the effects of different public health strategies for COVID-19, but they have not been developed for Pakistan and other South East Asian countries, where a large proportion of global population resides. MethodsWe developed a stochastic individual contact model by extending the widely-used Susceptible-Infectious-Recovered (SIR) compartment model with additional compartments to model both anticipated mitigating effects of public health intervention strategies for Pakistan. We estimated the projected spread, number of hospitalizations, and case fatalities under no intervention and four increasingly stringent public health strategies of social distancing and self-isolation at the national and provincial levels of Pakistan. ResultsOur analysis shows that without any public health interventions the expected number of cumulative case fatalities is 671,596 in Pakistan with the virus is expected to peak in terms of the number of required ICU-hospitalizations at 198,593 persons by the end of the June 2020. The estimated total numbers of cumulative case fatalities are lower for other public health strategies with strict social distancing showing the lowest number of deaths at 1,588 (Self-isolation: n=341,359; Flexible social distancing strategy: n=3,995; and Exit strategy: n=28,214). The lowest number of required ICU-hospitalization is also estimated for strict social distancing strategy (n=266 persons at the end of May 2020). Generally, the simulated effects of the different public health strategies at the provincial-level were similar to the national-level with strict social distancing showing the fewest number of case fatalities and ICU-hospitalizations. ConclusionOur results indicate that case fatalities and ICU-hospitalizations for Pakistan will be high without any public health interventions. While strict social distancing can potentially prevent a large number of deaths and ICU-hospitalizations, the government faces an important dilemma of potentially severe economic downfall. Consideration of a temporary strict social distancing strategy with gradual return of the lower-risk Pakistani population, as simulated in our exit strategy scenario, may an effective compromise between public health and economy of Pakistani population.
