Fluvoxamine for COVID-19: real-time analysis of all 12 studies

Fluvoxamine for COVID-19: real-time meta analysis of 6 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality and recovery. 4 studies from 4 independent teams in 3 different countries show statistically significant improvements in isolation (1 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 34% [7‑53%] improvement. Results are similar for Randomized Controlled Trials and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 33% of fluvoxamine studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments may be more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	6	64% [-93‑93%]	40% [23‑53%]	-58% [-493‑58%]	2,599	56
Peer-reviewed	5	89% [15‑99%]	40% [23‑53%]	-58% [-493‑58%]	2,052	55
RCTs	3	62% [-310‑96%]	30% [-26‑63%]		2,196	39
Percentage improvement with fluvoxamine treatment

Covid Analysis et al., 1/13/2022, preprint, 1 author.

Mechanisms of action of fluvoxamine for COVID-19: a historical review

Hashimoto et al., Molecular Psychiatry, doi:10.1038/s41380-021-01432-3 (Review) (Peer Reviewed)

Review of the potential mechanisms of action of fluvoxamine for COVID-19.

Hashimoto et al., 1/7/2022, peer-reviewed, 3 authors.

Fluvoxamine for Outpatient COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-Analysis

Lee et al., medRxiv, doi:10.1101/2021.12.17.21268008 (Preprint) (meta analysis)

Systematic review and meta analysis of outpatient RCTs, showing hospitalization RR 0.75 [0.57-0.97]. For discussion see [1].

[1] twitter.com/Covid19Crusher/status/1473623109525815296

Lee et al., 12/21/2021, preprint, 7 authors.

Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants

Oskotsky et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.33090 (Peer Reviewed)

Retrospective database analysis of 83,584 patients in the USA, showing lower mortality with existing fluoxetine use in PSM analysis. There were 11 fluvoxamine patients, showing non-statistically significant higher mortality.

risk of death, 57.9% higher, RR 1.58, p = 0.62, treatment 2 of 11 (18.2%), control 19 of 165 (11.5%), fluvoxamine.

risk of death, 26.0% lower, RR 0.74, p = 0.04, treatment 48 of 481 (10.0%), control 956 of 7,215 (13.3%), NNT 31, fluoxetine.

Oskotsky et al., 11/15/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 8 authors.

Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls

Calusic et al., British Journal of Clinical Pharmacology, doi:10.1111/bcp.15126 (Peer Reviewed)

Prospective PSM study of 51 COVID-19 ICU patients in Croatia and 51 matched controls, showing significantly lower mortality with treatment.

risk of death, 42.0% lower, RR 0.58, p = 0.03, treatment 30 of 51 (58.8%), control 39 of 51 (76.5%), NNT 5.7, adjusted, propensity score matching.

Calusic et al., 11/1/2021, prospective, propensity score matching, Croatia, Europe, peer-reviewed, 7 authors, study period 1 April, 2021 - 31 May, 2021.

Ongoing use of SSRIs and the hospital course of COVID-19 patients: a retrospective outcome analysis

Rauchman et al., medRxiv, doi:10.1101/2021.10.25.21265218 (Preprint)

Retrospective 9,043 COVID-19+ patients in the USA, 832 with existing SSRI use, showing no significant difference in mortality. None of the patients were on fluvoxamine. Authors note that specific SSRIs such as fluvoxamine may be effective, and that fluvoxamine is a sigma-1 receptor (S1R) agonist and has the strongest binding affinity to S1R of all SSRIs.

risk of death, 2.0% lower, RR 0.98, p = 0.83, RR approximated with OR.

Rauchman et al., 10/26/2021, retrospective, USA, North America, preprint, 6 authors.

Old drug fluvoxamine, new hope for COVID-19

Hashimoto et al., European Archives of Psychiatry and Clinical Neuroscience, doi:10.1007/s00406-021-01326-z (Review) (Peer Reviewed)

Review of research supporting the use of fluvoxamine for COVID-19. Authors note the favorable safety profiles, widespread availability, very low cost, and oral administration.

Hashimoto et al., 9/2/2021, peer-reviewed, 3 authors.

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

Reis et al., The Lancet Global Health, doi:10.1016/S2214-109X(21)00448-4 (preprint 8/23/2021) (Peer Reviewed)

Together Trial showing significantly lower hospitalization/extended ER visits with fluvoxamine treatment. Adherence was only 73.2%. Symptom onset was unspecified or >= 4 days for 57% of patients. The schedule of study activities specifies treatment administration only one day after randomization, adding an additional day delay. Overall mortality is high for the patient population. Results may be impacted by late treatment, poor SOC, and may be specific to local variants [1, 2]. Per-protocol analysis shows significantly improved results in this trial, however this may be subject to bias - the probability of adherence may be related to the probability of the outcome.

Regarding the combined hospitalization/extended ER observation outcome, authors have noted that at the study sites, extended medical observation was essentially equivalent to being hospitalized. “These were not standard emergency rooms but instead were COVID-19 emergency centers that were set up due to hospitals being overloaded,” Reiersen noted in an email to The Scientist. “A stay in these centers >6 hours was an indication that the patient was receiving care equivalent to hospitalization.”

Authors state "this study is only the second study to show an important treatment benefit for a repurposed drug in the early treatment population", however the actual number is at least 66 based on our database at the time of publication, using a conservative definition of at least 10% benefit (with statistical significance).

The total dose used is less than half of that in Lenze et al. There is an unusual amount of missing data - age is unknown for 6.5% of patients according to the sub-group analysis. Both age <=50 and >50 show better results on the primary outcome than the overall result. The number of placebo patients changed significantly between the preprint and journal version. The number of treatment patients with viral clearance results reduced significantly between the preprint and journal version. Also see [3]. NCT04727424.

For other issues with this trial see: [4, 5].

[1] science.sciencemag.org/content/372/6544/815

[2] thelancet.com/article/S0140-6736(21)00183-5/fulltext

[3] twitter.com/Covid19Crusher/status/1430170252575395843

[4] twitter.com/Covid19Crusher/status/1453726471499894787

[5] twitter.com/Covid19Crusher/status/1453803654608269318

risk of death, 30.3% lower, RR 0.70, p = 0.24, treatment 17 of 741 (2.3%), control 25 of 756 (3.3%), NNT 99, OR converted to RR, ITT.

risk of death, 90.8% lower, RR 0.09, p = 0.02, treatment 1 of 548 (0.2%), control 12 of 618 (1.9%), NNT 57, OR converted to RR, per protocol.

risk of mechanical ventilation, 22.2% lower, RR 0.78, p = 0.33, treatment 26 of 741 (3.5%), control 34 of 756 (4.5%), NNT 101, OR converted to RR, ITT.

risk of hospitalization, 21.6% lower, RR 0.78, p = 0.10, treatment 75 of 741 (10.1%), control 97 of 756 (12.8%), NNT 37, OR converted to RR, ITT.

extended ER observation or hospitalization, 32.0% lower, RR 0.68, p = 0.004, treatment 79 of 741 (10.7%), control 119 of 756 (15.7%), NNT 20, ITT.

extended ER observation or hospitalization, 31.0% lower, RR 0.69, p = 0.006, treatment 78 of 740 (10.5%), control 115 of 752 (15.3%), NNT 21, mITT.

extended ER observation or hospitalization, 66.0% lower, RR 0.34, p < 0.001, treatment 541, control 609, per protocol.

risk of no virological cure, 49.3% higher, RR 1.49, p = 0.09, treatment 167 of 207 (80.7%), control 163 of 221 (73.8%), adjusted.

Reis et al., 8/23/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 27 authors.

Fluvoxamine for Early Treatment of COVID-19: The STOP COVID Clinical Trials

Lenze, E. (News)

Presentation noting that STOP COVID 2 was terminated early for futility with only 30/551 cases of detioration and no significant treatment effect. The main results are not available yet, however partial results presented suggest that early treatment was more effective. NCT04668950. Hospitalization results are from [1].

[1] medrxiv.org/content/10.1101/2021.12.17.21268008v1

risk of hospitalization, 7.3% lower, RR 0.93, p = 1.00, treatment 11 of 272 (4.0%), control 12 of 275 (4.4%), NNT 313.

Lenze et al., 8/20/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 1 author, average treatment delay 5.0 days.

Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: A retrospective case-control study

Németh et al., Ideggyógyászati szeml, doi:10.18071/ISZ.74.0389 (preprint 8/12/2021) (Peer Reviewed)

Retrospective 269 hospitalized patients in Hungary, 110 treated with fluoxetine, showing lower mortality with treatment.

risk of death, 58.4% lower, RR 0.42, p = 0.002, treatment 15 of 110 (13.6%), control 49 of 159 (30.8%), NNT 5.8, adjusted, OR converted to RR, multivariable logistic regression.

Németh et al., 8/12/2021, retrospective, Hungary, Europe, peer-reviewed, 6 authors.

Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms

Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01254-3 (Review) (Peer Reviewed)

Review of the mechanisms of action and clinical studies for the treatment of COVID-19 with FIASMA antidepressants such as fluoxetine, fluvoxamine, paroxetine, escitalopram, or amitriptyline.

Hoertel et al., 8/12/2021, peer-reviewed, 12 authors.

Fluvoxamine in the Treatment of Patients with COVID-19

Assanovich et al., Psychiatry, Psychotherapy and Clinical Psychology, doi:10.34883/PI.2021.12.2.007 (Peer Reviewed)

Report on the use of fluvoxamine for COVID-19 noting that "patients with COVID-19 taking fluvoxamine did not report clinical complications of coronavirus infection". Only the abstract is currently available.

Assanovich et al., 6/29/2021, peer-reviewed, 1 author.

Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study

Hoertel et al., Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2317 (Peer Reviewed)

Retrospective 2,846 severe COVID-19 patients in France, 277 taking a FIASMA medication, showing lower risk of intubation of death with FIASMA use.

risk of death/intubation, 42.0% lower, RR 0.58, p < 0.001, treatment 104 of 277 (37.5%), control 1,064 of 2,569 (41.4%), NNT 26, adjusted, IPW multivariable Cox regression.

Hoertel et al., 5/29/2021, retrospective, France, Europe, peer-reviewed, 78 authors.

Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19

Sukhatme et al., Front. Pharmacol., doi:10.3389/fphar.2021.652688 (Review) (Peer Reviewed)

Review of mechanisms of action of fluvoxamine and other SSRIs that could be beneficial for COVID-19 treatment, including lower platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation, and increased melatonin levels.

Sukhatme et al., 4/20/2021, peer-reviewed, 4 authors.

COVID FAQ

Kirsch, S. (Review) (Preprint)

COVID FAQ from the founder of the COVID-19 Early Treatment Fund [1], including an extensive analysis of the fluvoxamine trials and other supporting evidence.

[1] treatearly.org/

Kirsch et al., 3/6/2021, preprint, 1 author.

Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study

Darquennes et al., Pharmaceuticals, doi:10.3390/ph14030226 (Peer Reviewed)

Retrospective 350 COVID-19 hospitalized patients in Belgium, showing lower mortality with existing long-term FIASMA treatment, not quite reaching statistical significance for all FIASMA medications, but reaching statistical significance for amlodipine.

risk of death, 41.3% lower, RR 0.59, p = 0.06, treatment 93, control 257, OR converted to RR, multivariable logistic regression, control prevalance approximated with overall prevalence.

Darquennes et al., 3/7/2021, retrospective, Belgium, Europe, peer-reviewed, 4 authors.

Prospective cohort of fluvoxamine for early treatment of COVID-19

Seftel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab050 (Peer Reviewed)

Prospective quasi-randomized (patient choice) study with 125 outpatients, 77 treated with fluvoxamine, showing lower death/ICU admission (0 of 77 vs. 2 of 48), lower hospitalization (0 of 77 vs. 6 of 48), and faster recovery with treatment. Note that 12 treatment patients were added but are not reflected in the table in the paper (because the numbers had been previously published and the IRB did not allow updating the table).

risk of death/ICU, 83.9% lower, RR 0.16, p = 0.15, treatment 0 of 77 (0.0%), control 2 of 48 (4.2%), NNT 24, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 94.0% lower, RR 0.06, p = 0.003, treatment 0 of 77 (0.0%), control 6 of 48 (12.5%), NNT 8.0, relative risk is not 0 because of continuity correction due to zero events.

risk of no recovery, 98.7% lower, RR 0.01, p < 0.001, treatment 0 of 77 (0.0%), control 29 of 48 (60.4%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events.

Seftel et al., 2/1/2021, prospective quasi-randomized (patient choice), USA, North America, peer-reviewed, 2 authors.

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

Lenze et al., JAMA, doi:10.1001/jama.2020.22760 (Peer Reviewed)

RCT 152 outpatients, 80 treated with fluvoxamine showing lower progression with treatment (0 of 80 versus 6 of 72 control). STOP COVID trial. NCT04342663.

risk of progression, 92.7% lower, RR 0.07, p = 0.009, treatment 0 of 80 (0.0%), control 6 of 72 (8.3%), NNT 12, relative risk is not 0 because of continuity correction due to zero events, clinical deterioration over 15 days.

risk of hospitalization, 82.0% lower, RR 0.18, p = 0.009, treatment 1 of 80 (1.2%), control 5 of 72 (6.9%), NNT 18, COVID-19 hospitalization within 15 days, see supplemental appendix for details.

Lenze et al., 11/12/2020, Double Blind Randomized Controlled Trial, USA, North America, peer-reviewed, 11 authors, average treatment delay 4.0 days.

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study

Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01021-4 (Peer Reviewed)

Retrospective 7,230 hospitalized COVID-19 patients in France, 345 receiving an antidepressant medication within 48 hours of admission. There was a significant association between antidepressant use and reduced risk of intubation or death. There was only one patient for fluvoxamine.

risk of death/intubation, 44.0% lower, RR 0.56, p < 0.001, treatment 84 of 345 (24.3%), control 1,188 of 6,885 (17.3%), adjusted, IPW multivariable Cox regression.

Hoertel et al., 8/17/2020, retrospective, France, Europe, peer-reviewed, 17 authors.

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies

Hooper, P., Cell Stress and Chaperones, doi:10.1007/s12192-020-01126-9 (Peer Reviewed) (Theory)

Proposal that COVID-19 risk is related to low intracellular heme oxygenase (HO-1), and that therapies that raise HO-1 may be beneficial, which includes fluvoxamine, certain anesthetics (sevoflurane or isoflurane), hemin, estrogen, statins, curcumin, resveratrol, and melatonin. Authors note that cigarette smoke is associated with increased HO-1 in lung fibroblasts and vascular endothelial cells, which may help explain the lower risk for smokers seen in several studies.

Hooper et al., 6/4/2020, peer-reviewed, 1 author.

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Aspirin	(meta)	Molnupiravir	(meta)
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Casirivimab/i..	(meta)	Paxlovid	(meta)
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Fluvoxamine	(meta)	Sotrovimab	(meta)
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