covid: fluvoxamine decreases hospitalization

 A Brazilian study found that early treatment with fluvoxamine decreased hospitalizations among high-risk patients with documented Covid-19 (see covid fluvoxamine dec hosp lancet2021 in dropbox, or doi.org/10.1016/ S2214-109X(21)00448-4 

 

Details: 

--741 patients were allocated to fluvoxamine and 756 to placebo in a large study (the TOGETHER trial), which also had arms testing many other potentially repurposed meds (hydoxychlorozuine, lopinavir-ritonavir, metformin, ivermectin, doxazocin, interferon lambda, with the fluvoxamine component beginning Jan 20, 2021 and ending Sept 9, 2021 

    -- fluvoxamine arm: 100 mg twice daily for 10 days vs placebo 

-- All patients had presented to a patient care setting with an acute clinical condition consistent with Covid-19 within seven days of symptom onset, were positive for SARS-CoV-2 and had at least one high risk factor for progression to severe disease, including:

diabetes, hypertension on meds, known cardiovascular disease (heart failure, valvular heart disease, coronary artery disease, cardiomyopathy), symptomatic lung disease (e.g. COPD), symptomatic asthma on meds, BMI at least 30, stage IV kidney disease or dialysis, immunosuppression or use of steroids equivalent to 10 mg of prednisone per day, other immunocompromising conditions

-- age 50 yo (18–102), 58% female. 95% self-identified as mixed race, 51% BMI > 30, time since onset of symptoms 0 to 3 days (44%)/4-7 days (32%)

-- comorbidities: uncontrolled hypertension 14%, type II diabetes 14%, rest < 3%

-- exclusions included pregnancy, prior vaccination

-- outcome data were collected on days 1, 2, 3, 4, 5, 7, 10, 14, and 28

-- primary outcome: composite of medical admission to a hospital setting due to Covid-19 related illness, or remaining under observation more than six hours in an emergency setting (this was a proxy for hospitalization, since some hospitals were at hospitalization capacity, though 89% were hospitalized) within 28 days of randomization, on the basis of intention to treat.

--also assessed were modified intention-to-treat: patients receiving at least 24 h of treatment before a primary outcome event, and per-protocol analysis explored patients with a high level adherence (>80%).

-- secondary outcomes: viral clearance, time to event outcomes

 

Results:  

-- access to care in a Covid emergency setting:

    --fluvoxamine 27% less than placebo, relative risk RR 0.73 (0.62-0.88)

 -- Primary outcome (patients transferred to hospital or prolonged ED stay due to Covid):

    -- fluvoxamine 32% lower than placebo, 79 [11%] of 741 patients on med vs 119 [16%] of 756 on placebo, RR 0·68 (0.52-0.88) by intention-to-treat analysis (essentially no difference in modified intention-to-treat analysis); absolute risk reduction 5.0%, number needed to treat = 20

    -- by per-protocol analysis (those actually taking the med): 66% fewer primary outcomes, RR 0.34 (0.21-0.54)

-- the data safety monitoring committee stopped the trial early because of clear superiority of fluvoxamine over placebo

 

Secondary outcomes:

-- statistically significant ones:

    -- death, per-protocol, 1/548 (<1%) Fluvoxamine versus 12/618 (2%) placebo, 91% fewer, RR 0.09 (0.01-0.47), p=0.022)

    -- medication adherence: 548/741 (74%) for fluvoxamine versus 618/738 (82%) placebo, 38% difference, odds ratio 0.62 (0.48-0.47) [confidence interval must have been typo in original article...]

 

Adverse events: 84 people stopped fluvoxamine and 64 stopped the placebo because of intolerability, but the only close to statistically different effect was for grade 1 (mild), with 20/741 (3%) with fluvoxamine and 11/756 (1%) with placebo, odds ratio 1.88 (0.91-4.09),p=0.096

    -- though not statistically significant, more severe adverse events (Grades 2-5) were more common in the placebo group

 

Commentary:

--Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalization or retention in a COVID-19 emergency setting

-- Fluvoxamine is an anti-depressant and anti-anxiety med, both a selective serotonin reuptake inhibitor (SSRI) and a σ-1 receptor agonist, which has anti-inflammatory effects from the σ-1 receptor, antiplatelet effects through the SSRI effect which can inhibit platelet activation, and possible antiviral effects

-- a small RCT found that fluvoxamine might reduce the risk of clinical deterioration in outpatients with Covid-19. 152 adult outpatients with confirmed Covid and symptom onset within seven days found zero patients had clinical deterioration with fluvoxamine 100 mg TID versus six (8.3%) on placebo over the 15-day course of therapy (see https://jamanetwork.com/journals/jama/fullarticle/2773108 ). This study included community-dwelling outpatient adults with symptomatic Covid and oxygen saturation at least 92%. there have also been a few observational studies suggesting benefit from fluvoxamine. this larger Brazilian RCT was done to elucidate the potential role of fluvoxamine, though notably with only twice a day fluvoxamine and longer outcome analysis.

-- The per-protocol analysis (actually looking at patients who had at least 80% adherence with the medication) had a significantly higher benefit from fluvoxamine than the standard intention-to-treat analysis

    -- though the medication adherence to the fluvoxamine was only 74%, leading to the discrepancy between the intention-to-treat analysis and the per-protocol analysis, it might well be that real-world experience with fluvoxamine might be higher than in a study. The study patients are told they are getting medications versus placebo to see if the medicine worked. In the real world, if people were told they were at significant risk of severe Covid-19 with its potential egregious consequences, side-effects from the med have almost all been mild (and there were actually fewer serious side-effects than with placebo!!), and that a short course of medication really worked to prevent getting sicker, adherence might be significantly higher. And it might be useful, as with hepatitis C treatments which have a very high adherence rate (at least our local experience), assigning an outreach person to contact the patients a few times during the course of therapy might help make sure they are not having a problem with the fluvoxamine and that they are taking meds as prescribed. 

-- fluvoxamine, as a potentially repurposed drug, has the advantages of known safety, tolerability, ease-of-use, low-cost, and widespread availability

-- the treatment effect sizes in this study in the per-protocol analysis (66% decrease) were reasonably comparable to those of monoclonal antibodies

   -- REGEN-COV-2, a combination of monoclonal antibodies casirivimab and imdevimab, dramatically reduced the viral load and number of medical visits in a phase 3 trial in those with risk factors for severe disease, and found a hospitalization or death rate of 18/1355 (1.3%) patients on the medication versus 62/1341 (4.6%) in those on placebo, a relative risk reduction of 71.3% (see https://www.binasss.sa.cr/covidoct/13.pdf ) 

 

Limitations: 

-- the study was done only in Brazil and it is not clear that there was the same threshold for hospital admission as in other countries, or that this threshold for admission was consistent among the different sites, which might limit generalizability

-- not much sociodemographic data, which could also limit generalizability 

-- this was an early study, prior to the availability of vaccinations, which could potentially limit generalizability to those who are vaccinated

 

So, finally a larger trial documenting benefit of fluvoxamine, which had shown promise in prior smaller studies. Fluvoxamine has the benefit of being the repurposing of an existing inexpensive and accessible medication. It would be important to repeat this trial in other settings, and perhaps widen it to include those not at high risk (though the Brazilian definition of high risk would include about 100% of my patients…). There are ongoing trials around the world, per clinicaltrials.gov, including in the US. It might also be useful to have a comparative trial of fluvoxamine vs monoclonal antibodies, since if fluvoxamine were essentially as good, it would be a great drug world-wide, given its low cost and availability 

geoff

 

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