Table 7a. Fluvoxamine: Selected Clinical Data

• Aged ≥50 years or aged ≥18 years with comorbidities
• Laboratory-confirmed SARS-CoV-2 infection
• ≤7 days of symptoms

Key Exclusion Criteria

• Use of an SSRI
• Severe mental illness
• Cirrhosis, recent seizures, severe ventricular cardia arrythmia

Interventions

• Fluvoxamine 100 mg PO twice daily for 10 days (n = 741)
• Placebo (route, dosing frequency, and duration for some patients may have differed from fluvoxamine) (n = 756)

Primary Endpoint

• Composite endpoint of emergency setting observation for >6 hours or hospitalization due to progression of COVID-19 within 28 days after randomization

Key Secondary Endpoints

• Occurrence of COVID-19-related hospitalizations
• Time to symptom resolution
• Proportion of patients who were adherent to study drugs, defined as receiving >80% of possible doses
• Mortality in both the primary ITT population and a PP population that included patients who took >80% of the study medication doses

Participant Characteristics

• Median age 50 years; 58% women; 95% self-identified as mixed race
• 13% with uncontrolled HTN; 13% with type 2 DM; 50% with BMI ≥30 kg/m²
• Mean of 3.8 days from symptom onset to randomization

Primary Outcome

• Proportion of patients who met the primary composite endpoint: 11% in fluvoxamine arm vs. 16% in placebo arm (relative risk 0.68; 95% CrI, 0.52–0.88)

Secondary Outcomes

• 87% of clinical events were hospitalizations.
• No difference between arms in COVID-19-related hospitalizations: 10% in fluvoxamine arm vs. 13% in placebo arm (OR 0.77; 95% CI, 0.55–1.05)
• No difference between arms in time to symptom resolution.
• Adherence: 74% in fluvoxamine arm vs. 82% in placebo arm (OR 0.62; 95% CI, 0.48–0.81). 11% in fluvoxamine arm vs. 8% in placebo arm stopped drug due to issues of tolerability.
• Mortality (ITT): 2% in fluvoxamine arm vs. 3% in placebo arm (OR 0.68; 95% CI, 0.36–1.27)
• Mortality (PP): <1% in fluvoxamine arm vs. 2% in placebo arm (OR 0.09; 95% CI, 0.01–0.47)

• The >6-hour emergency setting observation endpoint has not been used in other studies of interventions for nonhospitalized patients who are at high risk for hospitalization and death
• As this was an adaptive platform trial where multiple investigational treatments or placebos were being evaluated simultaneously, not all patients in the placebo arm received a placebo that was matched to fluvoxamine by route of administration, dosing frequency, or duration of therapy
• PP analyses are not randomized comparisons, and they introduce bias when adherence is associated with factors that influence the outcome
• Adherence was self-reported and not verified

Interpretation

• Fluvoxamine reduced the proportion of patients who met the composite endpoint of COVID-19-related hospitalization or retention in an emergency setting for >6 hours.
• The use of fluvoxamine did not impact the incidence of COVID-19-related hospitalizations.
• It is difficult to define the clinical relevance of the >6-hour emergency setting observation endpoint and apply it to practice settings in different countries.
• Fluvoxamine did not have a consistent impact on mortality.
• Fluvoxamine did not impact time to symptom resolution.

• Aged ≥18 years
• Positive SARS-CoV-2 PCR result
• ≤7 days of symptoms

Key Exclusion Criteria

• Immunocompromised
• Unstable medical comorbidities

Interventions

• Fluvoxamine 50 mg PO for 1 dose, then fluvoxamine 100 mg twice daily, then fluvoxamine 100 mg 3 times daily through Day 15 (n = 80)
• Placebo (n = 72)

Primary Endpoint

• Clinical deterioration within 15 days of randomization. Clinical deterioration was defined as:
  • Having dyspnea or being hospitalized for dyspnea or pneumonia; and
  • Having SpO₂ <92% on room air or requiring supplemental oxygen to attain SpO₂ ≥92%

Key Secondary Endpoint

• Hospitalization

Participant Characteristics

• Mean age 46 years; 72% women; 25% Black
• 56% with obesity; 20% with HTN; 17% with asthma
• Median of 4 days from symptom onset to randomization

Primary Outcome

• Clinical deterioration: 0% in fluvoxamine arm vs. 8.3% in placebo arm (absolute difference 8.7%; 95% CI, 1.8% to 16.4%)

Secondary Outcome

• No patients in fluvoxamine arm and 4 patients in placebo arm were hospitalized.

• Small sample size
• Short follow-up period
• Ascertaining clinical deterioration was challenging because all assessments were done remotely
• 24% of patients stopped responding to follow-up prior to Day 15 but were included in the final analysis

Interpretation

• Fluvoxamine reduced the proportion of patients who experienced clinical deterioration.
• Due to significant limitations, it is difficult to draw definitive conclusions about the efficacy of using fluvoxamine to treat COVID-19.