Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial
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Design
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Double-blind, randomized placebo-controlled trial
N=152
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Objective
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To determine if fluvoxamine, given as early treatment in individuals with mild COVID-19 illness, may prevent clinical deterioration
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Study Groups
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Fluvoxamine (n=80)
Placebo (n=72)
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Inclusion Criteria
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Age > 18 years; confirmed Covid-19 PCR test; symptomatic within 7 days of first study dose
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Exclusion Criteria
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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
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Methods
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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.
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Duration
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April 10 to August 5, 2020
Treatment: 15 days
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Outcome Measures
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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
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Baseline Characteristics
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Fluvoxamine (n=80)
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Placebo (n=72)
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Age, years (IQR)
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46 (35-58) |
45 (36-54) |
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Female
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56 (70%) |
53 (69%) |
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White
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56 (70%) |
50 (69%) |
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Pre-existing condition
Asthma
Hypertension
Diabetes
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17 (21%)
15 (19%)
9 (11%)
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9 (13%)
15 (21%)
8 (11%)
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Duration of Covid-19 symptoms, days (IQR)
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4 (3-5) |
4 (3-5) |
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Oxygen saturation, % (IQR)
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97 (96-98) |
97 (96-98) |
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Most severe Covid-19 symptom at baseline
Loss of sense of smell
Fatigue
Body aches
Cough
Subjective fever
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26 (33%)
17 (21%)
9 (11%)
9 (11%)
8 (10%)
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18 (25%)
18 (25%)
13 (18%)
1 (1)
4 (6%)
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IQR=interquartile range |
Results
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Fluvoxamine (n=80)
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Placebo (n=72)
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P-value
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Clinical deterioration
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0 |
6 (8.3%) |
0.009 |
Clinical status scale
0
Any nonzero value
1
3
5
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80 (100%)
0
0
0
0
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66 (91.7%)
6 (8.3%)
2 (2.8%)
3 (4.2%)
1 (1.4%)
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0.009
0.009
0.15
0.07
0.36
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Clinical status on 7 point scale
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0 |
0.22 ± 0.84 |
0.02 |
Adverse Events
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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%
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Serious Adverse Events: Fluvoxamine 1 (1.3%) vs placebo 5 (6.9%)
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Study Author Conclusions
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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.
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InpharmD Researcher Critique
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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.
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