The TOGETHER Trial: COVID-19 and Fluvoxamine Take Two

Background: Despite having a safe and effective set of vaccines for COVID-19, there have been some low resource countries in which it has been very challenging in getting the vaccine allocated.  Therefore, identifying an inexpensive, widely available, and effective therapy against COVID-19 is still an important topic of research.

We have written before on fluvoxamine on REBEL EM. It is a selective serotonin reuptake inhibitor (SSRI) and a sigma-1 receptor (S1R) agonist.  This makes this medication interesting as it has several potential favorable mechanisms in the treatment of COVID-19, including anti-inflammatory and antiviral effects.

Paper: Reis G et al. Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalization Among Patients with COVID-19: the TOGETHER Randomized Platform Clinical Trial. medRxiv Preprint 2021. [Link is HERE]

 Clinical Question: Does outpatient treatment with fluvoxamine compared to placebo prevent either extended emergency room observation or hospitalization due to COVID-19?

What They Did:

• Placebo-controlled, Double-blind, randomized, adaptive, platform trial performed at 11 outpatient clinical sites in Brazil
• Enrollment began on Jan 15^th, 2021, for fluvoxamine
• Symptomatic adults confirmed positive for SARS-CoV-2 with a known risk factor for progression to severe disease were randomized to:
  • Fluvoxamine 100mg BID x10d
  • Placebo
• Analyses:
  • Intention to Treat = Taking all doses of treatment
  • Modified Intention to Treat = Receiving study drug for at least 24 hours before and event
  • Per Protocol = Taking >80% of possible doses

Outcomes:

• Primary: Composite of ED observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization
• Secondary:
  • Viral clearance at day 7
  • Time to hospitalization
  • Mortality
  • Adverse drug reactions

Inclusion:

• >18 years of age
• Presenting to an outpatient care setting with an acute clinical condition consistent with COVID-19 and symptoms beginning within y days of the screening date
• Positive rapid test for SARS-CoV-2 antigen performed or positive SARS-CoV-2 diagnostic test within y days of symptom onset
• At least one additional criterion for high risk:
  • Diabetes mellites
  • Systemic arterial hypertension requiring at least one oral medication for treatment
  • Known cardiovascular diseases (CHF, Congenital heart disease, valve disease, CAD, cardiomyopathies being treated, clinically manifested heart disease with clinical repercussion)
  • Symptomatic lung disease and/or being treated (emphysema, fibrosing diseases)
  • Symptomatic asthma patients requiring chronic use of agents to control symptoms
  • Smoking
  • Obesity (BMI >30kg/m²)
  • Transplant patients
  • Stage IV CKD or on dialysis
  • Immunosuppressed patients using corticosteroid therapy (equivalent to at least 10mg of prednisone per day) and/0r immunosuppressive therapy
  • History of cancer in the last 0.5 years or undergoing current cancer treatment
  • ≥50 years of age
  • Unvaccinated status

Exclusion:

• Diagnostic examination for SARS-CoV-2 negative associated with acute flu-like symptoms (Negative test taken early and becoming positive a few days later were eligible, if he/she was <7d after the onset of flu-like symptoms)
• Acute respiratory condition compatible with COVI-19 treated in the primary care and previously requiring hospitalization
• Acute respiratory condition due to other causes
• Received vaccination for SARS-CoV-2
• Dyspnea secondary to another acute and chronic respiratory causes or infections (i.e decompensated COPD, acute bronchitis, pneumonia, primary pulmonary arterial hypertension)
• Current use of selective serotonin reuptake inhibitors
• Uncontrolled psychiatric disorders
• Suicidal ideation
• Inability or unwillingness to follow research guidelines and procedures
• Pregnant

Results:

• Screened 9020 eligible participants
  • 1472 patient recruited and randomized
    • Fluvoxamine = 739 pts
    • Placebo = 733 pts
  • Average age = 50 years
  • Mean number of days of symptoms prior to randomization = 4d
• Proportion of Patients Observed in an ED for >6hrs or Admitted to Hospital Due to COVID-19:
  • Fluvoxamine: 77/739 (10.4%)
  • Placebo: 108/733 (14.7%)
  • ITT RR 0.71; 95% Bayesian Credible Interval 0.54 to 0.93
  • mITT RR 0.68; 95% Bayesian Credible Interval 0.50 to 0.91
  • PP RR 0.34; 95% Bayesian Credible Interval 0.20 to 0.54
  • Posterior Probability of superiority greater than the preset number of 97.6% in all groups analyzed
  • Of the composite primary outcome 88% were hospitalizations
  • NNT = 24
• No differences in:
  • Viral Clearance at day 7: OR 0.75; 95% CI0.53 to 1.07
  • Mortality: OR 0.70; 95% CI 0.36 to 1.30
  • Time to Death: HR 0.79; 95% CI 0.58 to 1.08
  • Days Hospitalized (Mean Difference): 1.22d; 95% CI 0.98 to 1.53
  • Number of Days Ventilated (Mean Difference): 1.10; 95% CI 0.70 to 1.73
• All Other Secondary Outcomes:

• Adverse Events:
  • Greater number of Grade 1 (mild) treatment emergent adverse events among patients in fluvoxamine arm
  • No differences between fluvoxamine and placebo observed for treatment emergent adverse events Grades 2, 3, 4, or 5 

Strengths:

• Asks a clinically important question about outpatient treatment of COVID-19
• Large randomized controlled trial
• Enrollment of higher-risk patients for development of severe COVID-19
• Only enrolled participants diagnosed with COVID-19 and less than 7 days of symptom onset
• Able to recruit and have data for analysis at 197 days since start of enrollment
• Trial team, site staff, and patients were blinded to treatment allocation
• Active drugs and placebo pills were packaged in identically shaped bottles
• Data and safety monitoring committee provided independent oversight for the trial
• Funders had no role in study design, data collection, analysis, interpretation or writing, or decision to submit for publication
• Groups were well balanced at baseline for age, BMI, and co-morbidities

Limitations:

• Composite outcome of ED observation and hospitalization. An ED visit that ends up in a patient going home is not equivalent to an ED patient that requires hospitalization for higher level of care
• High rate of hospitalization (i.e. 88%) than seen in prior COVID-19 trials which could cause underestimation of effect on the primary outcome
• Hospitalization or observation in the ED for >6hrs is a subjective outcome. Mortality which is a more objective outcome was a secondary outcome and a far more important patient-oriented outcome
• Study was only performed in unvaccinated patients. These results may not be generalizable to vaccinated patients
• Many patients didn’t complete treatment (per protocol analysis)
• Primary outcome changed from >12hrs to >6hrs. Unclear when this was changed (i.e. before or after data analysis)
• Difference in primary outcome driven by ED visits not hospitalizations

Discussion:

• This is now the 2^nd RCT looking at Fluvoxamine treatment for COVID-19
• The 1^st RCT on Fluvoxamine [2]
  • Used a higher dose of Fluvoxamine 100mg TID x15d
  • Included lower risk patients (SpO2 ≥92%)
  • Much smaller only included 115 patients in final analysis
• The exact mechanisms of Fluvoxamine’s benefit are unclear but here are some thoughts (Wrote about this on previous REBEL EM post):
  • Platelet Mediators (i.e. serotonin): Among many pro-aggregant and angiogenic mediators released by activated platelets, serotonin is an omnipotent mediator with a wide range of actions on multiple organs. Excess plasma serotonin is pathogenic, and therefore plasma levels of serotonin are regulated at very low levels under normal conditions, by actively storing 95% of total serotonin content of the body inside platelet granules. COVID19 has been demonstrated to be associated with quantifiably high levels of extracellular plasma serotonin. This is a natural product of platelet activation and degranulation (of serotonin out of platelet granules), combined with poor reuptake of serotonin due to co-existing pulmonary vasculopathy of acute COVID19. This excess plasma serotonin can have untoward and pathologic manifestations such as hyperactive delirium and inappropriate hyperpnea, which may be important contributors to the severity of COVID19.
  • SSRI have been shown to reduce the pool of serotonin available within platelets, thereby reducing the bioavailability of serotonin that could potentially be released in a pathologic manner in a case of severe COVID19 (potentially reducing risk of thrombosis). In addition to this, SSRIs have anti-inflammatory capabilities via the recently described sigma-1 receptor agonism.
• Numerically, although not statistically significant, fluvoxamine did better than placebo in some areas:
  • ED visits >6hrs
  • Serious adverse events
  • Lower respiratory tract infections
  • Number of patients requiring mechanical ventilation
• Fluvoxamine remains an interesting, repurposed medication for COVID-19, however the only outcome of significance was reduced ED visits >6hrs. This did not result in a reduction in hospitalizations or mortality (although the study was not powered for the latter).

Author Conclusion: “Treatment 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.”

Clinical Take Home Point: The author’s conclusion is a bit misleading as there was no difference in hospitalizations.  In an outpatient setting, of COVID-19 positive patients, who are unvaccinated, with high-risk features of progression to severe disease, fluvoxamine reduced the number of patients with ED visits >6hrs compared to placebo. It is unclear when the outcome of ED visits >6hrs was changed from ED visits >12hrs.  Although promising, there is still not a role for fluvoxamine in the outpatient setting without better, high-quality studies.

References:

1. Reis G et al. Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalization Among Patients with COVID-19: the TOGETHER Randomized Platform Clinical Trial. medRxiv Preprint 2021. [Link is HERE]
2. Lenze EJ et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 202. PMID: 33180097

For More Thoughts on This Topic Checkout:

• REBEL EM: COVID-19 Update – An Interesting Study on Serotonin Anatagonism
• First10EM: Fluvoxamine for COVID?

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)