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0 0.5 1 1.5 2+ Mortality 30% Improvement Relative Risk Mortality, PP 91% Ventilation 22% Hospitalization 22% Extended ER observation.. 32% primary Extended ER observat.. (b) 31% Extended ER observat.. (c) 66% Viral clearance -49% Fluvoxamine  TOGETHER  LATE TREATMENT  DB RCT Is late treatment with fluvoxamine beneficial for COVID-19? Double-blind RCT 1,497 patients in Brazil (January - August 2021) Fewer hosp./ER visits with fluvoxamine (p=0.0041) Reis et al., The Lancet Global Health, Aug 2021 Favors fluvoxamine Favors control

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

Reis et al., The Lancet Global Health, doi:10.1016/S2214-109X(21)00448-4 (date from preprint), TOGETHER, NCT04727424
Aug 2021  
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27th treatment shown to reduce risk in November 2021
*, now known with p = 0.00011 from 20 studies, recognized in 3 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
The TOGETHER trial has extreme COI, impossible data, blinding failure, randomization failure, uncorrected errors, and many protocol violations. Authors do not respond to these issues and they have refused to release the data as promised. Some issues may apply only to specific arms.
Together Trial showing significantly lower hospitalization/extended ER visits with fluvoxamine treatment. Adherence was only 73.2%. Symptom onset was unspecified or >= 4 days for 57% of patients. The schedule of study activities specifies treatment administration only one day after randomization, adding an additional day delay. Overall mortality is high for the patient population. Results may be impacted by late treatment, poor SOC, and may be specific to local variants, Per-protocol analysis shows significantly improved results in this trial, however this may be subject to bias - the probability of adherence may be related to the probability of the outcome.
Regarding the combined hospitalization/extended ER observation outcome, authors have noted that at the study sites, extended medical observation was essentially equivalent to being hospitalized. “These were not standard emergency rooms but instead were COVID-19 emergency centers that were set up due to hospitals being overloaded,” Reiersen noted in an email to The Scientist. “A stay in these centers >6 hours was an indication that the patient was receiving care equivalent to hospitalization.”
Authors state "this study is only the second study to show an important treatment benefit for a repurposed drug in the early treatment population", however the actual number is at least 66 based on our database at the time of publication, using a conservative definition of at least 10% benefit (with statistical significance).
The total dose used is less than half of that in Lenze et al. There is an unusual amount of missing data - age is unknown for 6.5% of patients according to the sub-group analysis. Both age <=50 and >50 show better results on the primary outcome than the overall result. The number of placebo patients changed significantly between the preprint and journal version. The number of treatment patients with viral clearance results reduced significantly between the preprint and journal version. Also see NCT04727424 (history).
Authors do not specify if the placebo looks identical to the film-coated Luvox tablets. Reportedly there is no registration of manufacturing for matching tablets by Abbott in Brazil, and no import license for identical placebo tablets abroad. This would be an additional reason for blinding failure if the placebo tablets are not identical in appearance.
For other issues with this trial see: (B), (C), (D).
The TOGETHER trial has extreme COI, impossible data, blinding failure, randomization failure, uncorrected errors, and many protocol violations. Authors do not respond to these issues and they have refused to release the data as promised. Some issues may apply only to specific arms. For more details see Reis, Reis (B), Reis (C), Reis (D), Reis (E).
Viral load measured by PCR may not accurately reflect infectious virus measured by viral culture. Porter show that viral load early in infection was correlated with infectious virus, but viral load late in infection could be high even with low or undetectable infectious virus. Assessing viral load later in infection may underestimate reductions in infectious virus with treatment.
risk of death, 30.3% lower, RR 0.70, p = 0.24, treatment 17 of 741 (2.3%), control 25 of 756 (3.3%), NNT 99, odds ratio converted to relative risk, ITT.
risk of death, 90.8% lower, RR 0.09, p = 0.02, treatment 1 of 548 (0.2%), control 12 of 618 (1.9%), NNT 57, odds ratio converted to relative risk, per protocol.
risk of mechanical ventilation, 22.2% lower, RR 0.78, p = 0.33, treatment 26 of 741 (3.5%), control 34 of 756 (4.5%), NNT 101, odds ratio converted to relative risk, ITT.
risk of hospitalization, 21.6% lower, RR 0.78, p = 0.10, treatment 75 of 741 (10.1%), control 97 of 756 (12.8%), NNT 37, odds ratio converted to relative risk, ITT.
extended ER observation or hospitalization, 32.0% lower, RR 0.68, p = 0.004, treatment 79 of 741 (10.7%), control 119 of 756 (15.7%), NNT 20, ITT, primary outcome.
extended ER observation or hospitalization, 31.0% lower, RR 0.69, p = 0.006, treatment 78 of 740 (10.5%), control 115 of 752 (15.3%), NNT 21, mITT.
extended ER observation or hospitalization, 66.0% lower, RR 0.34, p < 0.001, treatment 541, control 609, per protocol.
risk of no viral clearance, 49.3% higher, RR 1.49, p = 0.09, treatment 167 of 207 (80.7%), control 163 of 221 (73.8%), adjusted per study, inverted to make RR<1 favor treatment.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Reis et al., 23 Aug 2021, Double Blind Randomized Controlled Trial, Brazil, peer-reviewed, 27 authors, study period 20 January, 2021 - 5 August, 2021, trial NCT04727424 (history) (TOGETHER).
This PaperFluvoxamineAll
Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial
PhD, E A dos Gilmar Reis, Eduardo Augusto Dos Santos Moreira-Silva, Daniela Carla Medeiros Silva, Prof Lehana Thabane, Aline Cruz Milagres, Thiago Santiago Ferreira, Castilho Vitor Quirino Dos Santos, Vitoria Helena De Souza Campos, Ana Maria Ribeiro Nogueira, Ana Paula Figueiredo Guimaraes De Almeida, Eduardo Diniz Callegari, Adhemar Dias De Figueiredo Neto, Leonardo Cançado Monteiro Savassi, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, Ofir Harari, Jamie I Forrest, Hinda Ruton, Sheila Sprague, Paula Mckay, Alla V Glushchenko, Craig R Rayner, Eric J Lenze, Angela M Reiersen, Gordon H Guyatt, Dr Edward J Mills
The Lancet Global Health, doi:10.1016/s2214-109x(21)00448-4
Background Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. Methods This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days postrandom assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at (NCT04727424) and is ongoing. Findings The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0•68; 95% Bayesian credible interval [95% BCI]: 0•52-0•88), with a probability of superiority of 99•8% surpassing the prespecified superiority threshold of 97•6% (risk difference 5•0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0•69, 95% BCI 0•53-0•90) and larger in the per-protocol analysis (RR 0•34, 95% BCI, 0•21-0•54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0•68, 95% CI: 0•36-1•27). There was one death in the fluvoxamine group and 12 in the placebo group for the perprotocol population (OR 0•09; 95% CI 0•01-0•47). We found no significant differences in number of treatment..
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Late treatment
is less effective
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