Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

Bramante et al., NEJM, doi:10.1056/NEJMoa2201662, COVID-OUT, NCT04510194

Aug 2022

Source PDF Data All Studies Meta AnalysisMeta

COVID-OUT remote RCT, showing no significant differences compared to a combined metformin/placebo "control" group. Results for other treatments are listed separately - metformin, fluvoxamine.

Authors include metformin patients in the control group, allowing details of adjustments to affect results. Using standard treatment vs. placebo analysis shows 61% lower hospitalization, or 75% lower for patients with onset ≤5 days (not statistically significant with only 7 and 5 events). These results are not reported in the paper or the supplementary appendix, readers need to request the data. Authors note that "hospitalization is perhaps the most accurate and well-documented end point".

There are many major issues as detailed below. We provide more detailed analysis of this study due to widespread incorrect press. Submit Updates or Corrections

Severity	Issue
CRITICAL	1. Ivermectin vs. placebo analysis - 61% lower hospitalization
CRITICAL	2. Severity mismatch for ivermectin treatment but not for any other medication or control
CRITICAL	3. ER results unreliable, not related to symptoms
CRITICAL	4. Mismatch with reported death and symptoms
CRITICAL	5. Ivermectin vs. placebo symptoms consistent with efficacy
CRITICAL	6. Multiple outcomes missing, including time to recovery
CRITICAL	7. Hypoxemia results unreliable but prioritized
CRITICAL	8. Adverse events not reported, partial data shows no increase
CRITICAL	9. Control group includes metformin, adjustment protocol violation
CRITICAL	10. Viral load results missing
CRITICAL	11. Metformin/fluvoxamine conclusions opposite of Together Trial, but matching earlier studies on each team
CRITICAL	12. Author claims results from 596 researchers should be censored for false information
CRITICAL	13. Administration on an empty stomach
CRITICAL	14. Results delayed 6 months (including life-saving metformin results)
CRITICAL	15. Subject to participant fraud
SERIOUS	16. Fewer comorbidities for serious outcomes
SERIOUS	17. Control arm results very different between treatments
SERIOUS	18. COVID-19 specific symptoms hidden in appendix
SERIOUS	19. Authors claim placebo is not better than the treatments
SERIOUS	20. Incorrect claim that no treatment reduced severity
SERIOUS	21. False conclusion
SERIOUS	22. Trial outcomes modified
SERIOUS	23. Very high percentage of missing data
SERIOUS	24. Medication delivery varied significantly
SERIOUS	25. Treatment 3 days for ivermectin, 14 days for metformin and fluvoxamine
SERIOUS	26. SAP dated after trial
SERIOUS	27. Test requirement and delivery prohibits early treatment
SERIOUS	28. Conclusion modified by journal
SERIOUS	29. Symptom results contradictory
SERIOUS	30. Adherence very low
SERIOUS	31. Inconsistent blinding statements
SERIOUS	32. Author indicates a best guess can be used for onset
MAJOR	33. Ivermectin from source chosen has shown lower efficacy
MAJOR	34. Adherence subgroups analysed but not reported
UNKNOWN	35. Maximum symptom duration not clear
UNKNOWN	36. No discontinuation due to hospitalization for ivermectin
COMMENT	37. Authors indicate up to 5 day delay in real-world usage

Author responses
14. Results sent to the US government twitter.com. Note most people live outside the US, and there was no action.
No response for all other items

Ivermectin vs. placebo analysis - 61% lower hospitalization. Authors include metformin patients in the control group, allowing details of adjustments to affect results. Using standard treatment (ivermectin only) vs. placebo analysis shows more favorable results for ivermectin, with 61% lower hospitalization, or 75% lower for patients with onset ≤5 days (not statistically significant with only 7 and 5 events). Authors note that "hospitalization is perhaps the most accurate and well-documented end point".

Severity mismatch for ivermectin treatment but not for any other medication or control. The table shows the percentage of patients reporting severe dyspnea for each active treatment and respective control. We expect that patients reporting ER visits would be more likely to experience severe dyspnea. This is true for all cases except for ivermectin treatment, suggesting unlucky randomization for ivermectin treatment, or a potential data error. The percentages are with respect to the total number of patients reporting symptom data in each case.

	Ivermectin active	Ivermectin control	Metformin active	Metformin control	Fluvoxamine active	Fluvoxamine control
ER	0.0%	9.1%	13.3%	10.0%	10.0%	14.3%
Non-ER	6.1%	6.9%	8.0%	7.8%	6.4%	8.4%

ER results unreliable, not related to symptoms. Authors detail why the main hypoxemia results are unreliable, however the ER results appear to be similarly uninformative. ER visits do not appear to be related to symptoms. The mean total COVID-19 symptom score for patients reporting an ER visit is 55 compared to 56 for patients reporting no ER visit (or hospitalization/death). Visualization of the ER patient symptoms raises the question of why most of them went to the ER. Of the 26 patients reporting an ER visit and symptom data, only one ever reported severe dyspnea, 5 more reported at most moderate dyspnea, 11 more reported at most mild dyspnea, and 9 reported no dyspnea at any time. ER patients were less likely to report severe or moderate dyspnea. The decision to go to the ER appears to be more of a personal preference rather than based on symptoms. Patients that signed up for the trial may be especially concerned about PASC for example, and seek help based on potential future problems rather than current symptoms.

Maximum dyspnea severity	ER patients	Non-ER/hosp./death patients
Severe	3.8%	6.5%
Moderate	19.2%	22.2%

D14

Mismatch with reported death and symptoms. There was only one death for a patient that was treated very late (7 days). The patient was not hospitalized. The death is reported within 14 days, however the patient reported symptom data for all 14 days, showing substantial recovery several days prior, with only 2 of 14 symptoms remaining and reported as mild. Data suggests that the death was not due to COVID-19.

D14

Ivermectin vs. placebo symptoms consistent with efficacy. Authors include metformin patients in the control group, allowing details of adjustments to affect results. Using standard treatment vs. placebo analysis gives the mean COVID-19 symptom scores below, matching expectation for an effective treatment with the low-risk fast recovering population (note that administration on an empty stomach is expected to delay the time when therapeutic effects may be reached).

Multiple outcomes missing, including time to recovery. Multiple outcomes are missing, for example time to recovery (where ACTIV-6 showed superiority of ivermectin): "Time to meaningful recovery (symptoms or severity improved by one category and sustained for at least 36 hours)" (protocol page 91). Notably, the definition is less biased than the ACTIV-6 definition, including improvement by one category, making allowance for mild fatigue and cough, and requiring 36 hours sustained rather than 3 days. More notably, the result is not reported.

Hypoxemia results unreliable but prioritized. Authors detail why the hypoxemia results are unreliable vimeo.com @28:30, however they are still prioritized in the presentation, and included in the abstract without mentioning that these results are unreliable.

Adverse events not reported, partial data shows no increase. Adverse events are not reported (other than to note none were serious). Partial information is contained in Table S2 and Figure S5. Notably, there is no significant increase for ivermectin for any of the expected side effects, in contrast to other trials, e.g. Lim. These results are unexpected if patients received and took authentic ivermectin at the dosage indicated.

Control group includes metformin, adjustment protocol violation. The "control" group includes patients receiving metformin, which is known to be beneficial for COVID-19 c19early.org. Authors present adjusted results however they do not appear to fully account for metformin efficacy. For example, the adjusted result for ivermectin ER/hosp./death is close to the unadjusted result, while a greater difference would be expected based on the metformin efficacy reported (which is not expected to be doubled in the metformin + ivermectin arm). The trial has 5 treatments arms, but is presented as if there was 3, which adds complexity, makes the results subject to potential interactions between treatments, and introduces the potential for investigator bias in adjustments. Notably, the protocol specifies primary and secondary adjustments (page 74), and the paper reports only one set of adjustments, which matches neither the primary or secondary adjustments in the protocol.

Viral load results missing. One of the primary objectives of the trial was "To understand if the active treatment arms are superior to placebo in improving viral load, serologic markers associated with Covid-19, and gut microbiome in non-hospitalized adults with SARS-CoV-2 infection." In the July 8 presentation authors report having analyzed viral load data vimeo.com @19:20. No viral load results have been reported.

Metformin/fluvoxamine conclusions opposite of Together Trial, but matching earlier studies on each team. The Together trial and COVID-OUT both tested metformin and fluvoxamine. Notably, they came to opposite conclusions. In Together, authors found efficacy for fluvoxamine, but the metformin results were so negative that the trial was terminated early. In COVID-OUT it was the opposite, authors (although not the journal editor) found efficacy for metformin, while the fluvoxamine results were so negative that the trial was terminated early twitter.com (B). Note that the Together authors include researchers that found fluvoxamine effective in earlier studies, while the COVID-OUT authors include researchers that found metformin effective in earlier studies.

Author claims results from 596 researchers should be censored for false information. 60 studies by 596 scientists report statistically significant positive results for ivermectin treatment of COVID-19 c19ivm.org. One author claimed that a report of positive results is "disinformation" and distributed a request to report and censor the author twitter.com (C), twitter.com (D), twitter.com (E). While discussion is warranted for all studies, a call for censorship of results is extreme and raises questions. Author provides no basis for the results of the 596 scientists being wrong and warranting of censorship, and there is no indication that author has even read most of the studies. Author cherry-picked two of 99 studies, (COVID-OUT and ACTIV-6 Bramante, Naggie, both very high COI studies with an extensive list of issues and very delayed treatment) and claimed that "no benefit of ivermectin was observed" twitter.com (F). In addition to ignoring the 60 studies reporting statistically significant positive results, ACTIV-6 c19ivm.org (B) reported a posterior probability that ivermectin is effective of 99%, 98%, and 97% for mean time unwell, clinical progression @14 days, and clinical progression @7 days (even though none of the pre-specified primary outcomes were reported, and noting that these preprint results were changed without explanation), and COVID-OUT showed 61% lower hospitalization with ivermectin vs. placebo (not including metformin), although this was not reported.

Administration on an empty stomach. Authors instructed patients to take ivermectin on an empty stomach, but other treatments with food. Guzzo show that the plasma concentration of ivermectin is much higher when administered with food (geometric mean AUC 2.6 times higher). "Ivermectin or matching placebo should be taken by mouth on an empty stomach with water. 1 hour before or 2 hours after a meal. All other agents should be taken by mouth at the end of a balanced snack or small meal."

Results delayed 6 months (including life-saving metformin results). Results were delayed for 6 months with no explanation, with followup ending Feb 14, 2022. Results were not presented until July 8 rethinkingclinicaltrials.org, and they were still not available to the public due to a news embargo for over a month. Embargo and delay of clinical trial results during a pandemic is not consistent with a goal of minimizing mortality and morbidity. Notably authors report very positive results for metformin (although journal editors changed the conclusion as below).

Subject to participant fraud. The self-reported design and absence of professional medical examination opens this kind of remote trial to participant fraud, which may be significant due to extreme politicization in the study country. Participant fraud has been reported for two other remote trials with a shared author academic.oup.com, Lindsell, involving submission of fake surveys and repeated signups.

Fewer comorbidities for serious outcomes. Patients experiencing serious outcomes are expected to be more likely to have comorbidities, however the opposite is seen.

Outcome	Comorbidity prevalence
Non-ER/hosp./death	53%
ER	45%
Hospitalization	12.5%
Death	0%

Control arm results very different between treatments. Control arm results are very different between treatments, for example considering hospitalization/death, this was 1.0% for ivermectin treatment vs. 2.7% for metformin control, however it was 1.3% for the ivermectin control. The metformin arm started earlier, however the difference in outcomes is very large given that most patients are in the shared period.

COVID-19 specific symptoms hidden in appendix. Authors present results for all symptoms in Figure 2, and for COVID-19 symptoms in the appendix Figure S4. Notably, the COVID-19 specific results are better for ivermectin and especially for fluvoxamine.

Authors claim placebo is not better than the treatments. Authors state: Neither overall symptoms nor Covid-19–specific symptoms were reduced faster with placebo than with any of the trial drugs. This may be true, Figure S4 shows symptoms were reduced faster with all treatments (with ivermectin and fluvoxamine showing greater improvement than metformin), but the reverse claim is very unusual — placebo is not expected to be better. Note that the graphs and data refer to the control groups including other treatments, while the statement refers to placebo only.

Incorrect claim that no treatment reduced severity. Authors claim that "None of the trial drugs resulted in a lower severity of symptoms than identically matched placebo." The intended meaning — compared to the "control" groups used, since that is the data reported — is incorrect, multiple results show lower severity in the treatment groups in terms of the symptom scores and severity resulting in hospitalization. Individual results may not reach statistical significance, however ER/hosp./death does in the larger metformin group.

False conclusion. Authors claim "None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19." Taking the literal wording, this is false, there were no deaths with fluvoxamine. Taking the likely meaning (no treatment reduced incidence of these events), this is false, reduced incidence is seen in several results (mostly without statistical significance).

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

Very high percentage of missing data. There is a very high percentage of missing data. 25% of patients have zero symptom data reported for all 14 days in the data file. This does not match the paper which reports 20% of patients did not contribute symptom data (Figure 2).

Medication delivery varied significantly. Medication delivery varied significantly over the trial. In this presentation vimeo.com (B), 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.

Treatment 3 days for ivermectin, 14 days for metformin and fluvoxamine. Treatment was 14 days for metformin and fluvoxamine, but only 3 days for ivermectin.

SAP dated after trial. The SAP is dated February 14, 2022, which authors note is one day before unblinding. However, the protocol notes that the statisticians are unblinded: "There is one unblinded statistician with two unblinded supporting statisticians on the study team", and "All analyses will be carried out by the un-blinded statisticians". The protocol also notes that the SAP will be developed by unblinded statisticians in one case, and blinded in a second case: "detailed statistical analysis plan will be developed by the unblinded statisticians", and "statistical analysis plan will be developed by the blinded statistician."

Test requirement and delivery prohibits early treatment. The requirement for a positive test and delivery of medication introduces substantial delay and largely excludes the possibility of early treatment. The protocol requires verifiable results using a local laboratory standard which excludes most home antigen tests (supplementary data page 5). Note that the trial results do not generalize to real-world usage, where clinicians recommend treatment immediately on symptoms.

Conclusion modified by journal. Author statements indicate that the conclusion was modified by the journal twitter.com (G), twitter.com (H).

Symptom results contradictory. Authors consider only metformin results to be positive (the journal editor considers none to be positive), however the symptom results in Figure S4 show the opposite: ivermectin and fluvoxamine show faster improvement (without statistical significance), while no difference is seen for metformin.

Adherence very low. Adherence was very low, with 77% overall reporting 70+% adherence, and 85% for ivermectin reporting 70+% adherence. An author has claimed 85% took all doses but that is contradicted by the 20% reported "Total Interruption or Discontinuation" in Table S2. Numbers for 100% adherence are not provided.

Inconsistent blinding statements. Protocol page 12 states that "The research team statisticians will remain blinded", while the supplementary data page 40 states that "There is one unblinded statistician with two unblinded supporting statisticians on the study team".

Author indicates a best guess can be used for onset. One author suggests that investigators can use a "best guess" if a patient gives a range for time of onset, which would allow a biased investigator to present an incorrect lower average time from onset twitter.com (I).

Ivermectin from source chosen has shown lower efficacy. Authors chose to source ivermectin from Edenbridge, which ranked 7 out of 11 brands in In Vitro tests for antiparasitic efficacy Williams, requiring 5 days compared to 2 days for the best performing brand, and 3 days for 4 other brands.

Adherence subgroups analysed but not reported. Authors indicate they performed subgroup analysis by adherence vimeo.com @18:30, however these results have not been reported.

Maximum symptom duration not clear. The procol excludes patients with >7 days of symptoms, i.e. patients 7 days from onset are included. The paper claims "less than 7 days" in one instance and "within 7 days" in another. The presentation reports "<7 days" vimeo.com.

No discontinuation due to hospitalization for ivermectin. Table S2 shows 9 placebo patients discontinued treatment due to hospitalization, compared to zero for ivermectin. While ivermectin patients only received 3 days treatment, they received placebo tablets for the remaining days. If this number is only counting discontinuation during the first three days, the result highlights that treatment was stopped before any patients were hospitalized. The protocol notes "Study drug will be stopped at the time of hospitalization for any reason".

Authors indicate up to 5 day delay in real-world usage. Authors note up to 11 days treatment delay with a remote clinical trial compared to up to 5 day for "real-world use" vimeo.com @43:00, where the 5 days derives from testing and medical system delays. However, logical real-world use, as used in many locations, is to have the treatment on hand to take immediately.

This is the 41st of 46 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000014. This is the 90th of 99 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 2 sextillion).

1. academic.oup.com, academic.oup.com/ofid/article/7/7/ofaa277/5868216.academic.oup.com/ofid/article/7/7/ofaa277/5868216.

2. Bramante et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19, NEJM, doi:10.1056/NEJMoa2201662.nejm.org, doi.org.

3. c19early.org, c19early.org/mfmeta.html.c19early.org/mfmeta.html.

4. c19ivm.org, c19ivm.org/meta.html.c19ivm.org/meta.html.

5. c19ivm.org (B), c19ivm.org/activ6ivm.html.c19ivm.org/activ6ivm.html.

6. clinicaltrials.gov, clinicaltrials.gov/ct2/history/NCT04510194?A=15&B=16&C=merged#StudyPageTop.clinicaltrials.gov/ct2/history/NCT04510194?A=15&B=16&C=merged#StudyPageTop.

7. clinicaltrials.gov (B), clinicaltrials.gov/ct2/history/NCT04510194?A=16&B=17&C=merged#StudyPageTop.clinicaltrials.gov/ct2/history/NCT04510194?A=16&B=17&C=merged#StudyPageTop.

8. Guzzo et al., Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, J. Clinical Pharmacology, doi:10.1177/009127002237994.wiley.com, doi.org.

9. Lim et al., Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial, JAMA, doi:10.1001/jamainternmed.2022.0189.jamanetwork.com, doi.org.

10. Lindsell et al., ACTIV-6: Operationalizing a decentralized, outpatient randomized platform trial to evaluate efficacy of repurposed medicines for COVID-19, Journal of Clinical and Translational Science, doi:10.1017/cts.2023.644.cambridge.org, doi.org.

11. Naggie et al., Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2022.18590.jamanetwork.com, doi.org.

12. rethinkingclinicaltrials.org, rethinkingclinicaltrials.org/event/grand-rounds-july-8-results-from-the-covid-out-trial-a-phase-3-trial-of-outpatient-treatment-for-covid-19-using-metformin-ivermectin-and-fluvoxamine/.rethinkingclinicaltrials.org/event/grand-rounds-july-8-results-from-the-covid-out-trial-a-phase-3-trial-of-outpatient-treatment-for-covid-19-using-metformin-ivermectin-and-fluvoxamine/.

13. twitter.com, twitter.com/boulware_dr/status/1557508117835005954.twitter.com/boulware_dr/status/1557508117835005954.

14. twitter.com (B), twitter.com/alexandrosM/status/1563673651924176898.twitter.com/alexandrosM/status/1563673651924176898.

15. twitter.com (C), twitter.com/brontyman/status/1575312617140154368.twitter.com/brontyman/status/1575312617140154368.

16. twitter.com (D), twitter.com/boulware_dr/status/1575344399051112450.twitter.com/boulware_dr/status/1575344399051112450.

17. twitter.com (E), twitter.com/alexandrosM/status/1575588585968844805.twitter.com/alexandrosM/status/1575588585968844805.

18. twitter.com (F), twitter.com/boulware_dr/status/1575346643075010563.twitter.com/boulware_dr/status/1575346643075010563.

19. twitter.com (G), twitter.com/boulware_dr/status/1560142362675798016.twitter.com/boulware_dr/status/1560142362675798016.

20. twitter.com (H), twitter.com/boulware_dr/status/1560136852966805504.twitter.com/boulware_dr/status/1560136852966805504.

21. twitter.com (I), twitter.com/boulware_dr/status/1510330480444456966.twitter.com/boulware_dr/status/1510330480444456966.

22. vimeo.com, vimeo.com/740296727.vimeo.com/740296727.

23. vimeo.com (B), vimeo.com/622665410.vimeo.com/622665410.

24. Williams, T., Not All Ivermectin Is Created Equal: Comparing The Quality of 11 Different Ivermectin Sources, Do Your Own Research, doyourownresearch.substack.com/p/not-all-ivermectin-is-created-equal.substack.com.

Important missing comments or errors? Let us know.

This study includes ivermectin, fluvoxamine, and metformin.

risk of death, 197.1% higher, RR 2.97, p = 1.00, treatment 1 of 408 (0.2%), control 0 of 396 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 28.

risk of death/hospitalization, 26.7% lower, RR 0.73, p = 0.66, treatment 4 of 406 (1.0%), control 5 of 394 (1.3%), NNT 352, odds ratio converted to relative risk.

risk of progression, 36.8% higher, RR 1.37, p = 0.33, treatment 23 of 406 (5.7%), control 16 of 394 (4.1%), odds ratio converted to relative risk, combined ER, hospitalization, death.

risk of progression, 3.7% higher, RR 1.04, p = 0.78, treatment 105 of 407 (25.8%), control 96 of 391 (24.6%), odds ratio converted to relative risk, combined hypoxemia, ER, hospitalization, death, primary outcome.

risk of hospitalization, 60.8% lower, RR 0.39, p = 0.28, treatment 2 of 206 (1.0%), control 5 of 202 (2.5%), NNT 66, IVM vs. placebo.

risk of hospitalization, 74.6% lower, RR 0.25, p = 0.37, treatment 1 of 137 (0.7%), control 4 of 139 (2.9%), NNT 47, IVM vs. placebo, ≤5 days from onset.

risk of hospitalization, 70.1% lower, RR 0.30, p = 0.12, treatment 3 of 406 (0.7%), control 5 of 202 (2.5%), NNT 58, IVM and IVM+MF vs. placebo.

risk of hospitalization, 41.8% lower, RR 0.58, p = 0.50, treatment 3 of 406 (0.7%), control 5 of 394 (1.3%), NNT 189, IVM and IVM+MF vs. placebo and MF.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Bramante et al., 18 Aug 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 3 authors, average treatment delay 4.6 days, dosage 430μg/kg days 1-3, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04510194 (history) (COVID-OUT).

All Studies Meta Analysis Submit Updates or Corrections

This Paper Ivermectin All

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

Carolyn T Bramante, Jared D Huling, Christopher J Tignanelli, John B Buse, David M Liebovitz, Jacinda M Nicklas, Kenneth Cohen, Michael A Puskarich, Hrishikesh K Belani, Jennifer L Proper, Lianne K Siegel, Nichole R Klatt, David J Odde, Darlette G Luke, Blake Anderson, Amy B Karger, Nicholas E Ingraham, Katrina M Hartman, Via Rao, Aubrey A Hagen, Barkha Patel, Sarah L Fenno, Nandini Avula, Neha V Reddy, Spencer M Erickson, Sarah Lindberg, Regina Fricton, Samuel Lee, Adnin Zaman, Hanna G Saveraid, Walker J Tordsen, Matthew F Pullen, Michelle Biros, Nancy E Sherwood, Jennifer L Thompson, David R Boulware, Thomas A Murray

New England Journal of Medicine, doi:10.1056/nejmoa2201662

BACKGROUND Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs -metformin, ivermectin, and fluvoxamine -in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials .gov number, NCT04510194.

Appendix The authors' full names and academic degrees are as follows: Carolyn T. Bramante

References

Bernal, Da Silva, Musungaie, Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Engl J Med

Blitzer, Ham, Colby, Skondra, Association of metformin use with age-related macular degeneration: a casecontrol study, JAMA Ophthalmol

Bolo, Hodé, Nédélec, Lainé, Wagner et al., Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy, Neuropsychopharmacology

Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19

Bramante, Buse, Tamaritz, Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity, J Med Virol

Bramante, Ingraham, Murray, Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis, Lancet Healthy Longev

Bramante, Proper, Boulware, Vaccination against SARS-CoV-2 is associated with a lower viral load and Metformin, Ivermectin, and Fluvoxamine for Covid-19 likelihood of systemic symptoms, Open Forum Infect Dis

Campo, García-Valdecasas, Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy, PLoS One

Cariou, Hadjadj, Wargny, Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study, Diabetologia

Castle, Dock, Hemmat, Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets, doi:10.1101/2020.05.22.111237v2

Cheng, He, Jung, Lu, Gao, Suppression of Kaposi's sarcoma-associated herpesvirus infection and replication by 5′-AMP-activated protein kinase, J Virol

Connors, Brooks, Sciurba, Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial, JAMA

Crouse, Grimes, Li, Might, Ovalle et al., Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes, Front Endocrinol

Dodds, Doyle, Reiersen, Brown, Rayner, Fluvoxamine for the treatment of COVID-19, Lancet Glob Health

Facente, Reiersen, Lenze, Boulware, Klausner, Fluvoxamine for the early treatment of SARS-CoV-2 infection: a review of current evidence, Drugs

Farfan-Morales, Cordero-Rivera, Anti-flavivirus properties of lipid-lowering drugs, Front Physiol

Ferdinands, Rao, Dixon, Waning 2-dose and 3-dose effectiveness of mRNA vaccines against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of delta and omicron variant predominance -VISION Network, 10 states, August 2021, MMWR Morb Mortal Wkly Rep

Gordon, Jang, Bouhaddou, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature

Hales, Carroll, Fryar, Ogden, Prevalence of obesity and severe obesity among adults: United States, 2017-2018, NCHS Data Brief

Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for highrisk, nonhospitalized adults with Covid-19

Karam, Morris, Bramante, mTOR inhibition in COVID-19: a commentary and review of efficacy in RNA viruses, J Med Virol

Keehner, Horton, Binkin, Resurgence of SARS-CoV-2 infection in a highly vaccinated health system workforce, N Engl J Med

Lee, Vigod, Bortolussi-Courval, Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization: a systematic review and meta-analysis, JAMA Netw Open

Lenze, Mattar, Zorumski, Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial, JAMA

Li, Yang, Yan, Sun, Zeng et al., Metformin in patients with COVID-19: a systematic review and meta-analysis, Front Med

Luo, Qiu, Liu, Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis, Am J Trop Med Hyg

López-Medina, López, Hurtado, Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial, JAMA

Marzolini, Kuritzkes, Marra, Prescribing nirmatrelvir-ritonavir: how to recognize and manage drug-drug interactions, Ann Intern Med

Medical, World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects, JAMA

Meng, Db, Performing likelihood ratio tests with multiply-imputed data sets, Biometrika

Nakashima, Takeuchi, Chihara, Hotta, Sada, Inhibition of hepatitis C virus replication through adenosine monophosphate-activated protein kinase-dependent and -independent pathways, Microbiol Immunol

Newberry, Williams, Stauffer, Boulware, Hendel-Paterson et al., Strongyloides hyperinfection presenting as acute respiratory failure and gram-negative sepsis, Chest

O'brien, Forleo-Neto, Musser, Subcutaneous REGEN-COV antibody combination to prevent Covid-19, N Engl J Med

Oldenburg, Pinsky, Brogdon, Effect of oral azithromycin vs placebo on COVID-19 symptoms in outpatients with SARS-CoV-2 infection: a randomized clinical trial, JAMA

Popp, Stegemann, Metzendorf, Ivermectin for preventing and treating COVID-19, Cochrane Database Syst Rev

Portmann-Baracco, Alberti, Accinelli, Antiviral and anti-inflammatory properties of ivermectin and its potential use in COVID-19, Arch Bronconeumol (Engl Ed)

Postler, Peng, Bhatt, Ghosh, Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism, Sci Rep

Reis, Santos Moreira-Silva, Silva, Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, Lancet Glob Health

Reis, Santos, Silva, Silva, Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized platform clinical trial, Lancet Reg Health Am

Schaller, Sharma, Dupee, Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses, JCI Insight

Seftel, Boulware, Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19, Open Forum Infect Dis

Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial, Ann Intern Med

Stauffer, Alpern, Walker, COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection, JAMA

Thompson, Natarajan, Irving, Effectiveness of a third dose of mRNA vaccines against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of delta and omicron variant predominance -VISION Network, 10 states, August 2021, MMWR Morb Mortal Wkly Rep

Timmins, Donahue, Meeker, Marathe, Steady-state pharmacokinetics of a novel extended-release metformin formulation, Clin Pharmacokinet

Xian, Liu, Nilsson, Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation, Immunity

Xin, Wei, Ji, Metformin uniquely prevents thrombosis by inhibiting platelet activation and mtDNA release, Sci Rep

Yu, Sun, Zhao, Kang, Yan, The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance, Int J Infect Dis

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of over 100,000 datapoints from thousands of papers. Community updates help ensure high accuracy. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

@CovidAnalysis

FAQ

Public domain CC0 1.0