Table 7a. Fluvoxamine: Selected Clinical Trial Data

Last Updated: December 20, 2023

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s recommendations.

Table 7a. Fluvoxamine: Selected Clinical Trial Data
Methods	Results	Limitations and Interpretation
ACTIV-6: Decentralized, Randomized, Placebo-Controlled, Platform Trial of Low-Dose Fluvoxamine in Patients With Mild to Moderate COVID-19¹
Key Inclusion Criteria Aged ≥30 years Positive SARS-CoV-2 nasopharyngeal RT-PCR result or antigen test result ≥2 COVID-19 symptoms for ≤7 days Key Exclusion Criterion Receipt of fluvoxamine in past 14 days Interventions Fluvoxamine 50 mg PO twice daily for 10 days (n = 674) Placebo (n = 614; 326 received matching placebo, 288 received placebo from another study arm) Primary Endpoint Time to recovery, defined as time to third day of 3 consecutive days without symptoms Key Secondary Endpoints Hospitalization or death by Day 28 Urgent care visit, ED visit, or hospitalization by Day 28	Participant Characteristics Mean age 47 years; 57% women; 81% White 36% with BMI ≥30; 24% with HTN 67% received ≥2 doses of a SARS-CoV-2 vaccine. Median of 5 days from symptom onset to receipt of study drug Primary Outcome Median time to recovery: 12 days in fluvoxamine arm vs. 13 days in placebo arm (HR 0.96; 95% CrI, 0.86–1.06) Secondary Outcomes Hospitalization or death by Day 28: 0.2% in fluvoxamine arm vs. 0.3% in placebo arm (3 events total) Urgent care visit, ED visit, or hospitalization by Day 28: 3.9% in fluvoxamine arm vs. 3.8% in placebo arm (HR 1.1; 95% CrI, 0.5–1.8)	Key Limitation Low number of some clinical events, such as hospitalization Interpretation In outpatients with mild to moderate COVID-19, fluvoxamine 50 mg twice daily for 10 days did not reduce the time to recovery or the incidence of clinical events such as hospitalization, urgent care visits, or ED visits.
ACTIV-6: Decentralized, Randomized, Placebo-Controlled, Platform Trial of High-Dose Fluvoxamine in Patients With Mild to Moderate COVID-19²
Key Inclusion Criteria Aged ≥30 years Positive SARS-CoV-2 nasopharyngeal RT-PCR result or antigen test result ≥2 COVID-19 symptoms for ≤7 days Key Exclusion Criterion Receipt of fluvoxamine or other selective serotonin or norepinephrine reuptake inhibitors in past 14 days Interventions Fluvoxamine 50 mg PO twice daily for 1 day, then fluvoxamine 100 mg PO twice daily for 12 days (n = 589) Placebo (n = 586) Primary Endpoint Time to recovery, defined as time to third day of 3 consecutive days without symptoms Key Secondary Endpoints Hospitalization or death by Day 28 Urgent care visit, ED visit, or hospitalization by Day 28	Participant Characteristics Median age 50 years; 66% women; 73% White 36% with BMI ≥30; 26% with HTN 77% received ≥2 doses of a SARS-CoV-2 vaccine. Median of 5 days from symptom onset to receipt of study drug Primary Outcome Median time to recovery: 10 days in fluvoxamine arm vs. 10 days in placebo arm (HR 0.99; 95% CrI, 0.89–1.09) Secondary Outcomes Hospitalization or death by Day 28: 0.2% in fluvoxamine arm vs. 0.3% in placebo arm (3 events total) Urgent care visit, ED visit, or hospitalization by Day 28: 2.4% in fluvoxamine arm vs. 3.6% in placebo arm (HR 0.69; 95% CrI, 0.27–1.21)	Key Limitation Low number of some clinical events, such as hospitalization Interpretation In outpatients with mild to moderate COVID-19, fluvoxamine 100 mg twice daily did not reduce the time to symptom recovery or the incidence of clinical events such as hospitalization, urgent care visits, or ED visits.
COVID-OUT: Randomized Trial of Metformin, Ivermectin, and Fluvoxamine in Patients With COVID-19³
Key Inclusion Criteria Aged 30–85 years BMI ≥25 or ≥23 if Asian or Latinx Laboratory-confirmed SARS-CoV-2 infection within 3 days of randomization <7 days of symptoms Key Exclusion Criteria Immunocompromised Hepatic impairment, severe kidney disease Interventions Fluvoxamine 50 mg PO twice daily for 14 days (n = 334) Control (n = 327) Primary Endpoint Composite of hypoxemia (as measured by a home pulse oximeter), ED visit, hospitalization, or death by Day 14 Key Secondary Endpoints Individual components of the composite endpoint Total symptom severity score Drug interruption or discontinuation	Participant Characteristics Median age 43–46 years; 54% women; 82% White 27% with CVD; 47% with BMI ≥30 56% received primary vaccination series. Mean of 5 days from symptom onset to randomization Primary Outcome Composite of hypoxemia, ED visit, hospitalization, or death by Day 14: 24% in fluvoxamine arm vs. 25% in control arm (aOR 0.94; 95% CI, 0.66–1.36) Secondary Outcomes Hospitalization by Day 14: 1.8% in fluvoxamine arm vs. 1.5% in control arm (aOR 1.11; 95% CI, 0.33–3.76). Composite of ED visit, hospitalization, or death: 5.5% in fluvoxamine arm vs. 4.6% in control arm (aOR 1.17; 95% CI, 0.57–2.40) No deaths occurred in either arm. No difference between arms in total symptom severity score over 14 days Drug interruption or discontinuation: 30% in those who only received fluvoxamine vs. 25% in those who only received placebo	Key Limitation In this trial, the study arms that did not include metformin were underpowered to detect differences in the primary endpoint. Interpretation Fluvoxamine did not impact the incidence of COVID-19–related complications such as hospitalization. Fluvoxamine did not impact symptom severity.
TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil⁴
Key Inclusion Criteria 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 cardiac arrhythmia Interventions Fluvoxamine 100 mg PO twice daily for 10 days (n = 741) Placebo (n = 756; route, dosing frequency, and duration of placebo may have differed from fluvoxamine for some patients) Primary Endpoint Composite of ED observation >6 hours or hospitalization for COVID-19 by Day 28 Key Secondary Endpoints COVID-19–related hospitalization by Day 28 Composite of hospitalization or ED observation >24 hours Time to symptom resolution Adherence 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 Mean of 3.8 days from symptom onset to randomization Primary Outcome Composite of ED observation >6 hours or hospitalization by Day 28: 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) Lower risk of hospitalization or ED observation >24 hours in fluvoxamine arm than in placebo arm (relative risk 0.74; 95% CI, 0.56–0.98)⁵ 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)	Key Limitations The >6-hour ED observation endpoint has not been used in other studies of interventions for nonhospitalized patients who are at high risk of hospitalization and death. Hospitalization or ED observation for >24 hours was analyzed in a post hoc analysis. 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 ED for >6 hours. The use of fluvoxamine did not impact the incidence of COVID-19-related hospitalizations but did reduce the need for hospitalization or ED observations >24 hours. It is difficult to define the clinical relevance of the >6-hour ED observation endpoint and apply it to practice settings in different countries. Fluvoxamine did not have a consistent impact on mortality. Fluvoxamine did not impact the time to symptom resolution.
STOP COVID 2: Fully Remote RCT of Fluvoxamine Versus Placebo in Outpatients With Symptomatic COVID-19⁶
Key Inclusion Criteria Aged ≥30 years Positive SARS-CoV-2 PCR result per patient self-report ≤7 days of symptoms ≥1 risk factor for clinical deterioration Key Exclusion Criteria Unstable medical comorbidities Significant interacting medications Interventions Fluvoxamine 50 mg PO for 1 dose, then fluvoxamine 100 mg PO twice daily through Day 15 (n = 272) Placebo (n = 275) 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 Endpoints Occurrence of AEs	Participant Characteristics Median age 47 years; 62% women; 27% non-White 44% with obesity; 21% with HTN Median of 5 days from symptom onset to randomization Primary Outcome Clinical deterioration: 4.8% in fluvoxamine arm vs. 5.5% in placebo arm (absolute difference 0.68%; 95% CI, -3.0 to 4.4) Secondary Outcomes GI AEs were significantly more common in fluvoxamine arm	Key Limitations Small sample size compared to other trials Short follow-up period Interpretation Fluvoxamine did not reduce the proportion of patients who experienced clinical deterioration by Day 15.
STOP COVID: Double-Blind RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in the United States⁷
Key Inclusion Criteria 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 PO twice daily, then fluvoxamine 100 mg PO 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 by Day 15	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.	Key Limitations 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.
TOGETHER: Randomized Platform Trial of Oral Fluvoxamine Plus Inhaled Budesonide for the Treatment of Early Onset COVID-19⁸
Key Inclusion Criteria 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 cardiac arrhythmia Interventions Fluvoxamine 100 mg PO twice daily plus budesonide 800 µg inhaled twice daily for 10 days (n = 738) Placebo (n = 738; route, dosing frequency, and duration for some patients may have differed from treatment group) Primary Endpoint Composite of ED observation >6 hours or hospitalization for COVID-19 by Day 28 Key Secondary Endpoints Hospitalization by Day 28 Health care attendance by Day 28 Any ED visit by Day 28 Occurrence of AEs	Participant Characteristics Median age 51 years; 61% women 42% with BMI >30; 44% with HTN; 68% with multiple comorbidities 94% received ≥2 doses of a COVID-19 vaccine. Primary Outcome Composite of ED observation >6 hours or hospitalization by Day 28: 1.8% in fluvoxamine plus inhaled budesonide arm vs. 3.7% in placebo arm (relative risk 0.50; 95% CrI, 0.25–0.92) Secondary Outcomes Hospitalization by Day 28: 0.9% in fluvoxamine plus inhaled budesonide arm vs. 1.1% in placebo arm Health care attendance by Day 28: 2.6% in fluvoxamine plus inhaled budesonide arm vs. 4.1% in placebo arm (relative risk 0.64; 95% CrI, 0.36–1.11) Any ED visit by Day 28: 12.2% in fluvoxamine plus inhaled budesonide arm vs. 13.0% in placebo arm Treatment-emergent AEs: 17.6% in fluvoxamine plus inhaled budesonide arm vs. 12.9% in placebo arm (relative risk 1.37; 95% CrI, 1.07–1.75) Most AEs were grade 2.	Key Limitation Multiple investigational treatments or placebos were evaluated simultaneously. Not all patients in the placebo arm received a matched placebo. Interpretation In adult outpatients with mild COVID-19, fluvoxamine plus inhaled budesonide reduced the need for ED observations >6 hours or hospitalization when compared with placebo. The use of fluvoxamine plus inhaled budesonide did not reduce hospitalization, health care attendance, or the occurrence of any ED visit. It is difficult to define the clinical relevance of the >6-hour ED observation endpoint and apply it to practice settings in different countries. The use of fluvoxamine plus inhaled budesonide resulted in more AEs than placebo.
Key: AE = adverse event; BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; ED = emergency department; GI = gastrointestinal; HTN = hypertension; ITT = intention-to-treat; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PO = oral; PP = per protocol; RCT = randomized controlled trial; RT-PCR = reverse transcription polymerase chain reaction; SpO₂ = oxygen saturation; SSRI = selective serotonin reuptake inhibitor

References

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