Results
From the TOGETHER Trial
Hydroxychloroquine or Lopinavir/Ritonavir
Summary:
Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group.
Research Paper:
Metformin
Summary:
The trial was initiated June 2, 2020. We randomized patients to metformin starting January 15, 2021 to April 3, 2021, after which the independent Data and Safety Monitoring Committee recommended stopping enrollment of metformin arm due to futility. We recruited 423 participants, 217 were randomized to the metformin arm and 206 to the placebo arm. More than half of participants (55.6%) were over the age of 50 years and 57.0% were female. Median age was 52 (range 18-90), with IQR 17. The proportion of patients hospitalized or visited an emergency room for 6 hours was not different between the metformin and placebo group (relative risk [RR] 1.15 [95 % Credible Intervals 0.73; 1.83]), probability of superiority 0.27. We found no significant differences between the metformin and placebo group on viral clearance through day 7 (Odds ratio [OR], 1.04, 95% Confidence Intervals 0.91-1.18) or other secondary outcomes.
Research Paper:
A Research Paper detailing the Metformin arm of the together trial has been submitted to The Journal of the American Medical Association (JAMA) and is currently under review. The prepublication version of the paper can be found here A visual abstract can be found below.
Fluvoxamine
Summary:
The 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 41 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. 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.
Research Paper:
A Research Paper detailing the Fluvoxamine findings of the together trial has been submitted and is currently under review. The prepublication version of the paper can be found here. Supplementary materials can be found here.
Additionally the SAP and Master Protocol are available.
