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What is the current data regarding fluvoxamine to treat COVID-19 at different ages? What is the proposed dose? Should it be administered if there's only exposure or if patients are symptomatic with COVID-19? Were patients on fluvoxamine excluded from the Pfizer, Moderna, and Janssen COVID-19 vaccine trials?

Comment by InpharmD Researcher

A randomized controlled trial found fluvoxamine to be promising as early treatment for COVID-19 to prevent clinical deterioration requiring hospitalization; however, more data is still needed to determine the ideal population and timing of fluvoxamine use for COVID-19. Patients included in the study were adult outpatients who were symptomatic, and patients were excluded if they were enrolled in another COVID-19 study (including vaccine trials).

Pubmed: fluvoxamine covid-19 = 8 results



Background

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) and sigma-1-receptor agonist that is hypothesized to be beneficial to patients with COVID-19. Sigma-1 receptor ligands are shown to block SARs-CoV-2 replication. Fluvoxamine possesses anti-inflammatory and immunomodulatory properties, and it may also affect endolysosomal trafficking and prevent the hypercoagulative state in COVID-19. Furthermore, fluvoxamine has a favorable safety profile and low cost. [1-2]

There is currently a randomized placebo-controlled trial recruiting patients aged >30 years to determine if fluvoxamine can be used early in the course of the COVID-19 infection to prevent more serious complications like shortness of breath. Participants will take up to 100mg of fluvoxamine or placebo by mouth twice a day for a daily total of 200mg for 15 days. The estimated enrollment will be 1,100 patients and the study is expected to be completed in September 2021. [3]

References:

[1] Hashimoto K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor [published online ahead of print, 2021 Jan 5]. Eur Arch Psychiatry Clin Neurosci. 2021;1-10. doi:10.1007/s00406-020-01231-x
[2] Marčec R, Likić R. Could fluvoxamine keep COVID-19 patients out of hospitals and intensive care units?. Croat Med J. 2021;62(1):95-100.
[3] ClinicalTrials.gov. Fluvoxamine for Early Treatment of Covid-19 (Stop Covid 2). https://clinicaltrials.gov/ct2/show/NCT04668950. Updated March 3, 2021. Accessed March 17, 2021.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the current data regarding fluvoxamine to treat COVID-19 at different ages? What is the proposed dose? Should it be administered if there's only exposure or if patients are symptomatic with COVID-19? Were patients on fluvoxamine excluded from the Pfizer, Moderna, and Janssen COVID-19 vaccine trials?

Please see Tables 1-2 for your response.


 

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)

46 (35-58) 45 (36-54)  

Female

56 (70%) 53 (69%)  

White

56 (70%) 50 (69%)  

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)

4 (3-5) 4 (3-5)  

Oxygen saturation, % (IQR)

97 (96-98) 97 (96-98)  

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%)

 
IQR=interquartile range

Results

 

Fluvoxamine (n=80)

Placebo (n=72)

P-value

Clinical deterioration

0 6 (8.3%) 0.009 

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

0 0.22 ± 0.84 0.02

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. 

 

References:

Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292–2300.

 

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

14 days 

Outcome Measures

Hospitalization, and symptoms such as persistent anxiety and difficulty concentrating 

Baseline Characteristics

 

Fluvoxamine (n= 65)

No therapy (n= 48)

 

Age, years 

44 ± 15 43 ± 15  

Male

50 (59%) 35 (41%)  

Latino 

61 (94%)  4 (71%)  

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

N/A

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.

 

References:

Seftel D, Boulware DR. Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19. Open Forum Infect Dis. 2021;8(2):ofab050. Published 2021 Feb 1. doi:10.1093/ofid/ofab050


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