Fluvoxamine for COVID-19: real-time analysis of all 18 studies

Fluvoxamine for COVID-19: real-time meta analysis of 8 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvement is seen for recovery. 5 studies from 5 independent teams in 3 different countries show statistically significant improvements in isolation (2 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 37% [-1‑60%] improvement, without reaching statistical significance. Results are slightly worse for Randomized Controlled Trials and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that may help recovery but is not antiviral.

• Treatment recommendations are available from Ontario.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 38% of fluvoxamine studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments may be more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. 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. Other meta analyses for fluvoxamine can be found in [Lee, Nakhaee], showing significant improvements for hospitalization and severity.

Covid Analysis et al., 8/10/2022, preprint, 1 author.

Results From the COVID-OUT Trial, a Phase-3 trial of Outpatient Treatment for Covid-19 Using Metformin, Ivermectin, and Fluvoxamine

Bramante et al. (Preprint)

Results for COVID-OUT were reported in a presentation, however they are not currently available due to a news embargo. There were no statistically significant results for metformin, ivermectin, or fluvoxamine, except for a post-hoc metformin composite. Null results are expected based on the trial design and size (with metformin having higher power and a greater chance of showing a result despite the design).

We note that embargo and delay of clinical trial results during a pandemic is not consistent with a goal of minimizing mortality and morbidity, but is consistent with a goal of maximizing press for a trial designed to produce a null result.

Trial outcomes were changed on January 20, 2022 [clinicaltrials.gov], and again on March 2, 2022 [clinicaltrials.gov (B)]. COVIDOUT.

Medication delivery varied significantly over the trial. In this presentation [vimeo.com], author indicates that delivery was initially local, later via FedEx, was much slower in August, there were delays due to team bandwidth issues, and they only realized they could use FedEx same day delivery in September.

1. clinicaltrials.gov, https://clinicaltrials.gov/ct2/his..94?A=15&B=16&C=merged#StudyPageTop.

2. clinicaltrials.gov (B), https://clinicaltrials.gov/ct2/his..94?A=16&B=17&C=merged#StudyPageTop.

3. vimeo.com, https://vimeo.com/622665410.

Bramante et al., 7/8/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, 3 authors, trial NCT04510194 (history) (COVID-OUT).

Repurposing Drugs for Covid-19 by a Developing Country

Valerio Pascua et al., Epidemiology International Journal, doi:10.23880/eij-16000234

Review of a multiphasic multidrug early treatment protocol for COVID-19 in Honduras, showing one death from 415 patients, which was for a patient not receiving early treatment (presenting on the 5th day in need of hospitalization and supplemental oxygen). Treatment included ivermectin, aspirin, colchicine, fluvoxamine, and famotidine.

Valerio Pascua et al., 5/20/2022, Honduras, peer-reviewed, 31 authors, study period November 2020 - October 2021.

Association Between the Use of Psychotropic Medications and the Risk of COVID-19 Infection Among Long-term Inpatients With Serious Mental Illness in a New York State–wide Psychiatric Hospital System

Nemani et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.10743

Retrospective 1,958 consecutive psychiatric patients in the USA, showing higher cases and lower mortality with fluvoxamine, without statistical significance, and there was only 25 fluvoxamine patients.

risk of death, 97.5% lower, RR 0.03, p = 1.00, treatment 0 of 16 (0.0%), control 38 of 953 (4.0%), NNT 25, relative risk is not 0 because of continuity correction due to zero events.

risk of case, 29.8% higher, RR 1.30, p = 0.16, treatment 16 of 25 (64.0%), control 953 of 1,933 (49.3%).

Nemani et al., 5/6/2022, retrospective, USA, peer-reviewed, 12 authors, study period 8 March, 2020 - 1 July, 2020.

The effect of antidepressants on severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis

Nakhaee et al., medRxiv, doi:10.1101/2022.04.11.22273709 (Preprint)

Meta analysis of 12 studies concluding that evidence supports the use of antidepressants, mainly fluvoxamine, for COVID-19. Fluvoxamine significantly reduced severity, RR 0.75 [0.58-0.96].

Nakhaee et al., 4/16/2022, preprint, 6 authors.

Screening Large Population Health Databases for Potential COVID-19 Therapeutics: A Pharmacopeia-Wide Association Study (PWAS) of Commonly Prescribed Medications

MacFadden et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac156

Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing lower cases with chronic use of fluoxetine.

risk of case, 14.0% lower, OR 0.86, p = 0.02, RR approximated with OR.

MacFadden et al., 3/29/2022, retrospective, Canada, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020.

Fluvoxamine Treatment of Patients with Symptomatic COVID-19 in a Community Treatment Center: A Preliminary Result of Randomized Controlled Trial

Seo et al., Infection & Chemotherapy, doi:10.3947/ic.2021.0142

Early terminated RCT with 52 COVID+ patients in South Korea, showing no significant difference in progression with fluvoxamine treatment. There were only 2 events in each arm, and only one event for fluvoxamine in PP analysis. The trial was terminated early because the treatment center closed. 100mg fluvoxamine bid for 10 days.

risk of progression, no change, RR 1.00, p = 1.00, treatment 2 of 26 (7.7%), control 2 of 26 (7.7%).

risk of progression, 34.2% lower, RR 0.66, p = 1.00, treatment 1 of 19 (5.3%), control 2 of 25 (8.0%), NNT 37, PP.

time to progression, 13.3% lower, relative time 0.87, p = 0.16, treatment mean 6.5 (±0.7) n=26, control mean 7.5 (±3.5) n=26.

Seo et al., 3/3/2022, Single Blind Randomized Controlled Trial, placebo-controlled, South Korea, peer-reviewed, median age 53.5, 14 authors, study period 15 January, 2021 - 19 February, 2021.

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

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

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

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 Management of COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-analysis

Lee et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.6269 (preprint 12/21/2021) (meta analysis)

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

1. twitter.com, https://twitter.com/Covid19Crusher/status/1473623109525815296.

Lee et al., 12/21/2021, peer-reviewed, 8 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

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, 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

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, HR 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, 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, OR 0.98, p = 0.83, RR approximated with OR.

Rauchman et al., 10/26/2021, retrospective, USA, 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)

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)

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 [science.sciencemag.org, thelancet.com]. 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 [twitter.com]. NCT04727424.

Authors do not specify if the placebo looks identical to the film-coated Luvox tablets. Reportedly there is no registration of manufacturing for matching tablets by Abbott in Brazil, and no import license for identical placebo tablets abroad. This would be an additional reason for blinding failure if the placebo tablets are not identical in appearance.

For other issues with this trial see: [twitter.com (B), twitter.com (C), twitter.com (D)].

Many of the issues in the companion ivermectin trial may also apply to this trial [c19ivermectin.com], notably the potential for significant use of an effective treatment in the placebo group [doyourownresearch.substack.com], which would reduce the efficacy seen.

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, primary outcome.

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 viral clearance, 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, peer-reviewed, 27 authors, study period 20 January, 2021 - 5 August, 2021, trial NCT04727424 (history) (TOGETHER).

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. Hospitalization results are from [medrxiv.org].

1. medrxiv.org, https://www.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, preprint, median age 47.0 (treatment) 48.0 (control), 1 author, average treatment delay 5.0 days, trial NCT04668950 (history) (STOP COVID 2).

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)

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, 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)

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

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

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%), adjusted, IPW multivariable Cox regression.

Hoertel et al., 5/29/2021, retrospective, France, 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)

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.

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

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, peer-reviewed, 4 authors.

COVID FAQ

Kirsch, S. (Review) (Preprint)

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

1. treatearly.org, https://www.treatearly.org/.

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

Prospective cohort of fluvoxamine for early treatment of COVID-19

Seftel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab050

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, 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

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, peer-reviewed, 11 authors, average treatment delay 4.0 days, trial NCT04342663 (history).

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

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, 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 (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.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption