Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial

Design

Double-blind, randomized placebo-controlled trial

N=152

Objective

To determine if fluvoxamine, given as early treatment in individuals with mild COVID-19 illness, may prevent clinical deterioration

Study Groups

Fluvoxamine (n=80)

Placebo (n=72)

Inclusion Criteria

Age > 18 years; confirmed Covid-19 PCR test; symptomatic within 7 days of first study dose

Exclusion Criteria

Required hospitalization due to COVID-19 at baseline; severe underlying lung disease; decompensated cirrhosis; congestive heart failure; immunocompromised; enrolled in another COVID-19 trial; currently taking chloroquine, hydroxychloroquine, azithromycin, or colchicine

Methods

Patients were randomized 1:1 to fluvoxamine 50 mg or matching placebo capsules in the evening immediately after the baseline assessment and confirmation of eligibility, then for two days at a dose of 100 mg twice daily as tolerated, and then increasing to a dose of 100 mg 3 times daily as tolerated through day 15 then stopped.

This dose range was determined based on the binding affinity of fluvoxamine for the Sigma-1 Receptor. After the completion of 15 days of fluvoxamine or placebo, participants were given the option to receive a 6-day open-label course of fluvoxamine. This optional open-label phase was a change from the original study protocol. Randomization schedules were generated that stratified by age (18-44, 45-54, 55-64, and ≥65 years) and sex. 

Duration

April 10 to August 5, 2020

Treatment: 15 days

Outcome Measures

Primary: Clinical deterioration

Secondary: Clinical status on a 7-point 

• 0: no clinical deterioration
• 1: O₂ sat <92%, but no supplemental O₂ needed
• 2: supplemental O₂ needed
• 3: hospitalization needed
• 4: ventilator needed (<3 days)
• 5: ventilator needed (>3 days)
• 6: death

Baseline Characteristics

Fluvoxamine (n=80)

Placebo (n=72)

Age, years (IQR)

Female

White

Pre-existing condition

Asthma

Hypertension

Diabetes

17 (21%)

15 (19%)

9 (11%)

9 (13%)

15 (21%)

8 (11%)

Duration of Covid-19 symptoms, days (IQR)

Oxygen saturation, % (IQR)

Most severe Covid-19 symptom at baseline

Loss of sense of smell

Fatigue

Body aches

Cough

Subjective fever

26 (33%)

17 (21%)

9 (11%)

9 (11%)

8 (10%)

18 (25%)

18 (25%)

13 (18%)

1 (1)

4 (6%)

Results

Fluvoxamine (n=80)

Placebo (n=72)

P-value

Clinical deterioration

Clinical status scale

0

Any nonzero value

1

3

5

80 (100%)

0

0

0

0

66 (91.7%)

6 (8.3%)

2 (2.8%)

3 (4.2%)

1 (1.4%)

0.009

0.009

0.15

0.07

0.36

Clinical status on 7 point scale

Adverse Events

Common Adverse Events: Pneumonia 3.8% vs 8.3%, shortness of breath 2.5% vs 5.6%, headache 2.5% vs 1.4%, nausea or vomiting 1.3% vs 6.9%, low oxygen saturation or hypoxia 0 vs 8.3%, chest pain or tightness 0 vs 2.8%, fever 0 vs 2.8%

Serious Adverse Events: Fluvoxamine 1 (1.3%) vs placebo 5 (6.9%)

Study Author Conclusions

Fluvoxamine (an S1R agonist) was associated with a reduction in clinical deterioration in adult outpatients with COVID-19. However, the study is limited by a small sample size and short follow-up duration. 

InpharmD Researcher Critique

With such a short duration and small size, these results can only be considered preliminary. This relied on patient completed follow-up surveys; 20% of patients stopped responding during the study. This study was also only conducted in one geographic area (St. Louis), so extrapolations to other areas may not be applicable depending on variant spread. 

There was a small number of overall events, which makes the findings extremely fragile and susceptible to error. It is possible that the differences in clinical deterioration may have been a reflection of the comparative baseline distributions of oxygen saturation rather than an effect of treatment.

The method of measuring the most severe baseline symptom over time did not appear to provide valid data, so potential effects of fluvoxamine on symptomatic improvement are unknown. 

Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19 

Design

Prospective, open-label cohort study

N= 113 

Objective

To determine the effectiveness of fluvoxamine an early treatment coronavirus disease 19

Study Groups

Fluvoxamine (n= 65)

No therapy (n= 48)

Inclusion Criteria

Persons positive for COVID-19 via rapid testing coupled with polymerase chain reaction (PCR) confirmation

Exclusion Criteria

Contraindications, any drug-drug interactions between fluvoxamine and medications that the patients are taking currently 

Methods

Patients in the fluvoxamine group were prescribed a 50 to 100-mg loading dose, then 50 mg twice daily for 14 days, and the control group (no therapy) did not receive fluvoxamine. These two groups were observed for two weeks.

The choice of whether to receive fluvoxamine was at the patient’s discretion.

Duration

Outcome Measures

Hospitalization, and symptoms such as persistent anxiety and difficulty concentrating 

Baseline Characteristics

Fluvoxamine (n= 65)

No therapy (n= 48)

Age, years 

Male

Latino 

Chronic comorbidities

Diabetes

Hypertension

Lung disease

16 (25%)

11 (17%)

11 (17%)

2 (3%)

18 (38%)

4 (8%)

17 (35%)

1 (2%)

Disease Status at Time of Testing 

Asymptomatic

Mild

Moderate

25 (38%)

24 (37%)

16 (25%)

28 (58%)

9 (19%)

11 (23%)

Results

Fluvoxamine (n= 65)

No therapy (n= 48)

P-value

Hospitalized within 14 days 

ICU care and/or death 

0

0

6 (12.5%)

2 (4.2%)

0.005

No symptoms at day 14

65 (100%)

19 (40%)

<0.001

Symptoms assessed at day 14 included the following: persistent anxiety (n = 19); difficulty concentrating, or memory challenges, or brain fog (n = 18); fatigue (n = 16); insomnia (n = 12); persistent body aches, muscle or joint pain (n = 10); headache (n = 9); dizziness (n = 9); inability to exercise (n = 6); chills or sweats (n = 5); persistent, intermittent nonproductive cough (n = 5); episodic chest tightness; pressure, or pain (n = 3); intermittent heart palpitations or tachycardia (n = 3); shortness of breath or difficulty breathing (n = 3); diarrhea (n = 0); elevated temperature (n = 0).

Adverse Events

Study Author Conclusions

Fluvoxamine seems to be promising as early treatment for COVID-19 to prevent clinical deterioration requiring hospitalization and to prevent possible long haul symptoms persisting beyond 2 weeks.

InpharmD Researcher Critique

This was an observational, open-label study that was not randomized. The majority of the patients are middle age, and half of the patient population were asymptomatic at time of testing, which is not the typical patient population that is at risk of hospitalization due to COVID-19.