Fluvoxamine – generic antidepressant looks very promising in treating early COVID

Researchers in Australia, Brazil, Canada and the U.S. designed and conducted a randomized, placebo-controlled study of fluvoxamine, 100 mg twice daily, in people with early-stage COVID-19. The trial was called Together. Participants had at least one underlying condition that heightened their risk for deteriorating. In Together, researchers randomly assigned 3,238 participants to receive one of the following interventions:

• fluvoxamine – 739 people
• placebo – 733 people
• other experimental drugs – 1,766 people

Although Together is testing different interventions, the latest analysis from this study focused on the comparison between people who received fluvoxamine or placebo. The researchers found that participants who received fluvoxamine were significantly less likely to deteriorate than people who received placebo; that is, they were less likely to require a prolonged stay in the emergency room of a hospital or be admitted to a hospital. The Together study was well designed, and its findings may have implications for the medical management of people with early-stage COVID-19.

Study details

The study began in mid-January 2021. Participants were recruited at 11 clinics in Brazil.

Participants were adults who had recent onset of symptoms consistent with acute COVID-19. They underwent screening and tested positive for SARS-CoV-2. All participants had at least one underlying condition or issue that has been associated with an increased risk for developing complications associated with COVID-19. According to the researchers, these underlying conditions/issues included the following:

• type 2 diabetes
• pulmonary hypertension that required treatment
• heart disease
• lung disease
• obesity
• smoking
• age greater than 50 years

Additionally, some participants had medical interventions that weakened their immune systems, such as the following:

• use of immunosuppressive drugs because of organ transplantation
• severe kidney disease or the need for dialysis
• use of corticosteroids
• undergoing treatment for cancer

All participants were not vaccinated against COVID-19.

About key clinical trial results

Many clinical trials are designed to assess the effects of drugs on an infection or disease process. When designing a clinical trials, statisticians and scientists meet beforehand to choose the key results or “endpoints” that the trials will seek to measure.

For instance, some clinical trials assess the length of time people survive after they were given an intervention – drug A or drug B. In such a case, the endpoint was length of survival. Other trials might assess how many people survived after given different interventions. In this case, the endpoint would be the proportions of people surviving.

In Together

The main endpoint of the Together study was the proportion of participants who required one of the following:

• a prolonged stay (more than six hours) in a hospital emergency room
• hospitalization because of worsening symptoms of COVID-19 and/or its complications within 28 days of entering the study

According to the researchers, “all participants received [the] usual standard of care for COVID-19” at local public health facilities (unless they were hospitalized). Such care included the provision of drugs to reduce fever, and, if doctors suspected that bacterial pneumonia had developed, antibiotics could be prescribed.

The average profile of participants at the time they entered the study is as follows:

• age – 50 years
• 58% women, 42% men
• major ethno-racial groups: mixed – 95%; White – 1%; Black – 1%
• most common underlying conditions – obesity, type 2 diabetes and high blood pressure

Results

In August 2021, the study’s independent data safety monitoring committee recommended that researchers stop recruiting and randomizing people to receive fluvoxamine. Other sub-studies within Together continue to assess other potential treatments. This decision to stop assigning people to receive fluvoxamine arose because, statistically, the effect of this drug had been found superior to placebo. That is, people who received fluvoxamine were at reduced risk for an extended emergency room visit or hospitalization due to COVID-19. The proportions of participants who underwent an extended emergency room visit or who were hospitalized due to COVID-19 were distributed as follows:

• fluvoxamine – 11%
• placebo – 16%

The benefit from fluvoxamine was similar regardless of the following:

• age
• gender
• number of days since the onset of COVID-19 symptoms
• underlying conditions that increase a person’s risk for severe COVID-19
• other health conditions
• whether a person smoked

The proportions of people who died were as follows:

• fluvoxamine – 2%
• placebo – 3%

Fluvoxamine had no impact on any of the following:

• clearance of SARS-CoV-2 after one week
• number of days hospitalized
• risk of death
• number of days on mechanical ventilation
• time to recovery from COVID-19

Vaccination

When the study began, COVID-19 vaccines were not available in Brazil. As the study progressed, the distribution of vaccines occurred. According to the researchers, “only 6% of participants reported at least one dose of COVID-19 vaccine at the end of the trial.” The researchers stated that this likely had “minimal effect” on the study’s findings.

Adverse events and adherence

Statistical analysis found no difference in the severity of adverse events reported by participants who took fluvoxamine vs. placebo. However, more participants on fluvoxamine (11%) than placebo (8%) prematurely stopped taking these interventions because of issues of tolerability.

The researchers also found that participants who had what they termed “optimal” adherence to fluvoxamine were significantly less likely to suffer deterioration due to COVID-19.

Other studies

The results from Together are in line with an earlier randomized but smaller study in the U.S. that used a higher dose of fluvoxamine—100 mg three times daily for 15 consecutive days. Participants in that study were generally at lower risk for deterioration than those in the Brazilian study.

A larger study in France reviewed hospital records of 7,230 adults with COVID-19. Researchers noted that this group there were 345 people who initiated treatment with antidepressants within 48 hours of hospitalization. The researchers found that the risk of serious complications or death due to COVID-19 was significantly reduced among these 345 people. Among these 345 people a majority were taking antidepressants similar to fluvoxamine.

Advantages and disadvantages of fluvoxamine

Fluvoxamine has at least the following advantages:

• a long record of generally safe use in the pre-COVID-19 era
• can be taken in pill form
• relatively inexpensive
• widely available

However, fluvoxamine, like many antidepressants, has the potential to interact with some other medicines. Many people at high risk for COVID-19 have underlying conditions that require treatment. If fluvoxamine were to be prescribed to people who are taking other medicines, consultation with a pharmacist would be necessary to reduce the risk of potential drug interactions.

For the future

The results from the Together study are exciting. In the relatively short history of the COVID-19 pandemic, it has been unusual for an existing medicine that has a different use to be successfully repurposed in a clinical trial against SARS-CoV-2. Perhaps additional clinical trials could be done with a combination of fluvoxamine and emerging oral antiviral drugs for the treatment of early COVID-19, such as molnupiravir or Paxlovid.

An important question for the future is: Was the effect of fluvoxamine in the Together study due to this particular drug or would a similar effect be seen with other antidepressants chemically related to fluvoxamine? Large, randomized clinical trials would be needed to answer this question.

Bear in mind

The Together researchers state that there have been more than 2,800 registered randomized clinical trials for assessing potential interventions against COVID-19. However, according these researchers, results from less than 300 have been reported. Other researchers have catalogued that many COVID-19 clinical trials have not been well designed, which makes a clear interpretation of their results difficult. In a situation where there are limited resources and time is of the essence, implementing poorly designed clinical trials is not good practice.

The Together trial should serve as an inspiration for other scientists, showing that it is possible to conduct a well-designed clinical trial that leads to robust conclusions even in the midst of a global health crisis.

—Sean R. Hosein

REFERENCES:

1. Reis G, Moreira-Silva XDS, Silva CM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalization among patients with COVID-19: the Together randomized platform clinical trial. Lancet Global Health. 2021; in press.
2. Berwanger O. Fluvoxamine for outpatients with COVID-19: where do we stand? Lancet Global Health. 2021; in press.
3. Mehta HB, Ehrhardt S, Moore TJ, et al. Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis. BMJ Open. 2020;10(6):e039978.
4. Bauchner H, Fontanarosa PB. Randomized clinical trials and COVID-19: managing expectations. JAMA. 2020 Jun 9;323(22):2262-2263.
5. Oskotsky T, Maric I, Tang A, et al. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Network Open. 2021 Nov 1;4(11):e2133090.  
6. Hoertel N. Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality Among Patients With COVID-19? JAMA Network Open. 2021 Nov 1;4(11):e2136510.