[1]
Institute for Evidence in Medicine, Medical Center – University of Freiburg, Faculty
of Medicine, University of Freiburg, Freiburg, Germany
[2]
Public Health Department, Faculty of Applied Sciences, University of Livingstonia,
Mzuzu, Malawi
[3]
Institute of General Practice/Family Medicine, Faculty of Medicine, Medical Center
– University of Freiburg, Freiburg, Germany
[4]
NHS South West England, National Health Service, England, UK
[5]
Fellow, Royal College of General Practitioners, FRCGP, London, UK
[6]
Centre for Biological Threats and Special Pathogens (ZBS), Strategy and Incident Response
(ZBS7), Clinical Management and Infection Control (ZBS7.1), Robert Koch Institute,
Berlin, Germany
[7]
Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin
Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin,
Berlin, Germany
[8]
Department of Anesthesiology, University Heart Center Freiburg, Bad Krozingen, Freiburg,
Germany
[9]
Faculty of Medicine and University Hospital Cologne, University of Cologne, Department
I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf,
Cochrane Haematology, Cologne, Germany
Nyirenda JLZ, Sofroniou M, Toews I, Mikolajewska A, Lehane C, Monsef I, Abu-taha A,
Maun A, Stegemann M, Schmucker C. Fluvoxamine for the treatment of COVID-19. Cochrane
Database of Systematic Reviews 2022, Issue 9.
Art. No.: CD015391. DOI: 10.1002/14651858.CD015391.
Dates
Revision published:
Issue 9, 2022
(2022-9-14)
Version published (citation changed):
Issue 9,
2022
(2022-09-14)
Review first published:
Issue 9,
2022
Protocol first published:
N/A
Abstract
Background
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been approved
for the treatment of depression, obsessive–compulsive disorder, and a variety of anxiety
disorders; it is available as an oral preparation. Fluvoxamine has not been approved
for the treatment of infections, but has been used in the early treatment of people
with mild to moderate COVID-19. As there are only a few effective therapies for people
with COVID-19 in the community, a thorough understanding of the current evidence regarding
the efficacy and safety of fluvoxamine as an anti-inflammatory and possible anti-viral
treatment for COVID-19, based on randomised controlled trials (RCTs), is needed.
Objectives
To assess the efficacy and safety of fluvoxamine in addition to standard care, compared
to standard care (alone or with placebo), or any other active pharmacological comparator
with proven efficacy for the treatment of COVID-19 outpatients and inpatients.
Search methods
We searched the Cochrane COVID‐19 Study Register (including Cochrane Central Register
of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv), Web
of Science and WHO COVID‐19 Global literature on COVID-19 to identify completed and
ongoing studies up to 1 February 2022.
Selection criteria
We included RCTs that compared fluvoxamine in addition to standard care (also including
no intervention), with standard care (alone or with placebo), or any other active
pharmacological comparator with proven efficacy in clinical trials for the treatment
of people with confirmed COVID‐19, irrespective of disease severity, in both inpatients
and outpatients. Co‐interventions needed to be the same in both study arms. We excluded
studies comparing fluvoxamine to other pharmacological interventions with unproven
efficacy.
Data collection and analysis
We assessed risk of bias of primary outcomes using the Cochrane Risk of Bias 2 tool
for RCTs. We used GRADE to rate the certainty of evidence to treat people with asymptomatic
to severe COVID‐19 for the primary outcomes including mortality, clinical deterioration,
clinical improvement, quality of life, serious adverse events, adverse events of any
grade, and suicide or suicide attempt.
Main results
We identified two completed studies with a total of 1649 symptomatic participants.
One study was conducted in the USA (study with 152 participants, 80 and 72 participants
per study arm) and the other study in Brazil (study with 1497 high-risk participants
for progression to severe disease, 741 and 756 participants per study arm) among outpatients
with mild COVID‐19. Both studies were double-blind, placebo-controlled trials in which
participants were prescribed 100 mg fluvoxamine two or three times daily for a maximum
of 15 days.
We identified five ongoing studies and two studies awaiting classification (due to
translation issues, and due to missing published data). We found no published studies
comparing fluvoxamine to other pharmacological interventions of proven efficacy.
We assessed both included studies to have an overall high risk of bias.
Fluvoxamine for the treatment of COVID-19 in inpatients
We did not identify any completed studies of inpatients.
Fluvoxamine for the treatment of COVID-19 in outpatients
Fluvoxamine in addition to standard care may slightly reduce all‐cause mortality at
day 28 (RR 0.69, 95% CI 0.38 to 1.27; risk difference (RD) 9 per 1000; 2 studies,
1649 participants; low-certainty evidence), and may reduce clinical deterioration
defined as all-cause hospital admission or death before hospital admission (RR 0.55,
95% CI 0.16 to 1.89; RD 57 per 1000; 2 studies, 1649 participants; low-certainty evidence).
We are very uncertain regarding the effect of fluvoxamine on serious adverse events
(RR 0.56, 95% CI 0.15 to 2.03; RD 54 per 1000; 2 studies, 1649 participants; very
low-certainty evidence) or adverse events of any grade (RR 1.06, 95% CI 0.82 to 1.37;
RD 7 per 1000; 2 studies, 1649 participants; very low-certainty evidence).
Neither of the studies reported on symptom resolution (clinical improvement), quality
of life or suicide/suicide attempt.
Authors' conclusions
Based on a low-certainty evidence, fluvoxamine may slightly reduce all-cause mortality
at day 28, and may reduce the risk of admission to hospital or death in outpatients
with mild COVID-19. However, we are very uncertain regarding the effect of fluvoxamine
on serious adverse events, or any adverse events.
In accordance with the living approach of this review, we will continually update
our search and include eligible trials as they arise, to complete any gaps in the
evidence.
Plain language summary
Fluvoxamine for treating COVID-19
Review question
Is fluvoxamine an effective treatment for people with COVID‐19 and does it cause any
unwanted effects?
Key messages
It is unclear whether fluvoxamine is an effective treatment for COVID-19 in people
with mild to moderate COVID-19. This is because there is currently not enough research
available to make a definite decision.
We found five ongoing studies that are currently investigating fluvoxamine as a possible
treatment for COVID‐19, and two studies for which we need more information. We will
update this review if their results change our conclusions.
What is fluvoxamine?
Fluvoxamine is a type of medication known as a selective serotonin reuptake inhibitor
(SSRI), available in tablet form. Recent research has found that fluvoxamine may have
an effect on COVID-19. When the immune system fights the virus, the lungs and airways
can become inflamed, causing breathing difficulties. Fluvoxamine could help reduce
this inflammation, potentially reducing the risk of developing severe COVID-19 and
its associated lung symptoms through its possible anti-inflammatory and anti-viral
effects. We know that most people do not experience any serious side effects with
fluvoxamine when it is taken as an antidepressant. Some people can, however, experience
the following common side effects, especially when starting the medication: nausea,
anxiety or restlessness, insomnia, or diarrhoea, and in rare cases, suicidal ideation.
What did we want to find out?
We wanted to know if fluvoxamine reduces death, severity of disease, and length of
infection in people with COVID‐19, if it has an effect on quality of life, or causes
any unwanted effects. We included studies that compared fluvoxamine to placebo (dummy
treatment), no treatment, usual care, or any other treatment for COVID‐19 that is
known to work to some extent, such as remdesivir or dexamethasone. We excluded treatments
that we know do not work for COVID‐19, such as hydroxychloroquine, or have an unknown
effect on the disease.
We evaluated the effects of fluvoxamine in adults with COVID‐19 on:
• people dying;
• whether people needed to be treated in a hospital;
• whether people's COVID‐19 symptoms got better or worse;
• unwanted effects;
• quality of life;
• and whether there is a risk of suicide or suicide attempt when taking this medication.
What did we do?
We searched for studies that investigated fluvoxamine as a treatment for adults with
COVID‐19 in hospital or as outpatients. We compared and summarised the results of
the studies and rated our confidence in the evidence, based on common criteria such
as study methods and study sizes.
What did we find?
We found two studies that investigated fluvoxamine as an early treatment for mild
COVID-19 in 1649 self-isolated people at home (outpatients). All studies compared
fluvoxamine to placebo together with standard care. The studies used different durations
of treatment (10 or 15 days).
We found five ongoing studies and two studies that are awaiting classification. We
did not find any studies that investigated the effect of fluvoxamine on people in
hospital with COVID-19.
Main results
• Compared to placebo, fluvoxamine may slightly reduce the number of people who die
in the 28 days after starting treatment (2 studies, 1649 people).
• Compared to placebo, fluvoxamine may reduce number of people who are admitted to
a hospital or who die before hospital admission (2 studies, 1649 people).
•The number of unwanted (serious) events did not clearly differ between fluvoxamine
and placebo treatment (2 studies, 1649 people).
•Neither of the studies reported on quality of life, the time needed until all initial
symptoms resolved, or suicide attempts.
What are the limitations of the evidence?
We cannot be confident in the current evidence for fluvoxamine in treating people
with COVID-19, mainly due to the lack of studies that are currently available and
some flaws in study design. We will continue to search for new studies to complete
the current evidence gap.
It would also be important to find out the effects of a medication such as fluvoxamine
on long-Covid. We are currently waiting for research on this to become available in
the near future.
Unfortunately, the studies available did not focus on children and young adults, women
who are planning or trying to conceive, women who are pregnant or breastfeeding, older
adults, or those people who have a weakened immune system (immunocompromised people).
Likewise, no information was available on whether women or men were more likely to
benefit from fluvoxamine.
Search date
The evidence is current to February 2022.
Summary of findings 1
Fluvoxamine plus standard care compared to placebo plus standard care for outpatients
with mild COVID-19
Patient or population: symptomatic people with COVID-19
Setting: outpatients
Intervention: fluvoxamine plus standard care
Comparison: placebo plus standard care
Outcomes
Anticipated absolute effects (95% CI)*
Relative effect
(95% CI)
N of participants (studies)
Certainty in the evidence (GRADE)
Comment
Risk with placebo plus standard care
Risk with fluvoxamine plus standard care
All-cause mortality
(at day 28)
30 per 1000
(95% CI 11 to 38)
21 per 1000
(95% CI 2 to 29)
RR 0.69
(0.38 to 1.27)
1649
(2 RCTs)
Lowa
Fluvoxamine may slightly reduce all-cause mortality at day 28.
All-cause admission to hospital or death (before hospital admission)
126 per 1000
(95% CI 105 to 150)
94 per 1000
(95% CI 76 to 116)
RR 0.55
(0.16 to 1.89)
1649
(2 RCT)
Lowb
Fluvoxamine may reduce admission to hospital or death (before hospital admission).
Symptom resolution
All initial symptoms resolved
Not reported
Time to symptom resolution
Numerical data not derivable, outcome was illustrated in a figure (graph) indicating
an overlap of confidence intervals (TOGETHER 2021).
Quality of life
(at longest follow-up)
Not reported
Serious adverse events
(during study period)
122 per 1000 (95% CI 18 to 248)
95 per 1000
(95% CI 41 to 221)
RR 0.56
(0.15 to 2.03)
1649
(2 RCTs)
Very lowc
The evidence is very uncertain about the effects of fluvoxamine on serious adverse
events.
Any adverse events
(during study period)
118 per 1000
(95% CI 97 to 162)
125 per 1000
(95% CI 104 to 169)
RR 1.06
(0.82 to 1.37)
1649
(2 RCTs)
Very lowd
The evidence is very uncertain about the effects of fluvoxamine on any adverse events.
Suicide or suicide attempt
(at longest follow-up)
Not reported
*The risk in the intervention group and its 95% CI is based on the assumed risk in
the comparison group and the relative effect of the intervention and its 95% CI.
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
aRisk difference 9 per 1000 (19 fewer to 8 more), small important effect (since mortality
is the most critical outcomes for patients and clinicians). Downgraded by 2 levels
for very serious imprecision since CI suggests both potential benefit and no effect/potential
harm, and number of events is small.
bRisk difference 57 per 1000 (106 fewer to 112 more), moderate effect. Downgraded by
2 levels for very serious imprecision since CI suggests both potential benefit and
no effect/potential harm, and number of events is small.
cRisk difference 54 per 1000 (50 fewer to 4 more), moderate effect. Downgraded by 1
level for serious risk of bias and by 2 levels for very serious imprecision since
CI suggests both potential benefit and potential harm.
dRisk difference 7 per 1000 (21 fewer to 44 more), small unimportant effect. Downgraded
by 1 level for serious risk of bias and by 2 levels for very serious imprecision since
CI suggests both potential benefit and potential harm.
Background
This work constitutes part of a series of Cochrane Reviews investigating the use of
potential pharmacotherapies for coronavirus disease 2019 (COVID-19) in both inpatients
and outpatients. This particular review evaluates the efficacy and safety of fluvoxamine,
specifically evaluating its possible use in ambulatory-managed patients, from here
on referred to as outpatients, but also considers inpatients. Reviews in this series
carry a degree of overlap with the background and methodology sections of other published
reviews from the German research project 'CEOsys' (COVID-19 Evidence Ecosystem) on
antibiotics [1], monoclonal antibodies [2], convalescent plasma [3], ivermectin [1], vitamin D supplementation [4], systemic corticosteroids [5], colchicine [6] and remdesivir [7].
Description of the condition
COVID-19 is a rapidly spreading infectious disease caused by Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) [8]. COVID-19 is unprecedented in comparison to previous coronavirus outbreaks such
as SARS and Middle East Respiratory Syndrome (MERS), which caused 813 and 858 deaths,
respectively [9, 10]. Despite international efforts to contain its spread, as of February 2022, COVID-19
had resulted in more than 420 million confirmed cases and over 5.9 million deaths
worldwide [11]. The emergence of novel SARS-CoV-2 variants is also of great concern, with the potential
for augmented transmission of the disease, a shortened incubation period and a negative
impact on established and proven disease control methods [12, 13].
Vaccination has been shown to be highly effective in reducing severe illness and death
from COVID-19. More than 10.4 billion doses of vaccines had been administered globally
as of February 2022, with additional vaccines in continuous development [11]. The majority of vaccines have been administered in high-income countries, leaving
populations including health care workers and older people in other countries vulnerable.
The mean incubation period is estimated at five to six days, with 97.5% of cases developing
symptoms within 11.5 days of exposure [14]. Sore throat, cough, fever, headache, fatigue, myalgia (muscle pain) and arthralgia
(joint pain) are the most commonly reported symptoms [15]. Other symptoms may include dyspnoea, rigors, nausea and vomiting, diarrhoea, and
nasal congestion [8]. The majority of infected individuals develop mild symptoms not requiring hospitalisation,
or remain completely asymptomatic (80% to 90%) depending on the timing of the investigation,
the cohort investigated, and the virus variant [16, 17, 18, 19, 20]. The reported frequency of asymptomatic cases also varies greatly and ranges from
6% to 96% [21, 18, 22].
In the first two years of the pandemic (2020 to 2021), there were estimates that approximately
11% to 20% of infected individuals went on to develop severe disease, with 1% to 5%
developing critical illness with respiratory failure, septic shock or multi-organ
dysfunction syndrome requiring intensive care unit (ICU) treatment [18, 23, 20]. Furthermore, COVID-19 case fatality rates varied widely between countries and reporting
periods, from 0% to over 25% [24, 25]. These numbers may have been misleading, as they depended on testing frequency,
delays in reporting dates and incomplete capture of case data at the time [24, 25]. Case definitions have been adjusted and modified during the course of the pandemic
[26], whilst contemporary considerations such as the levels of immunity in the population
and type of viral strains present at the time of data collection should also be taken
into account [27].
Description of the intervention
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) and a σ-1 receptor
(S1R) agonist that has been approved for the treatment of depression, obsessive–compulsive
disorder, and a variety of anxiety disorders. Available as an oral preparation, it
is widely prescribed in the primary care setting worldwide for major depressive and
obsessive-compulsive disorders; in treating anxiety disorders such as panic disorder,
social anxiety disorder, and post-traumatic stress [28]; as well as for menopausal symptoms and functional gut disorders (off-label use).
When fluvoxamine is used to treat psychiatric conditions, the most common adverse
effect is nausea (particularly at the beginning of the treatment), but adverse effects
can include other gastrointestinal effects (e.g. diarrhoea, indigestion), neurological
effects (e.g. asthaenia, insomnia, somnolence, anxiety, headache), and suicidal ideation.
There has been much discussion over the years about increased suicide rates in people
taking serotonin reuptake inhibitors. Increased suicide rates are particularly evident
in younger people [29].
Fluvoxamine can enhance the serotonergic effects of other SSRIs or monoamine oxidase
inhibitors (MAOIs), resulting in serotonin syndrome; therefore, it should not be used
within two weeks of administration of other SSRIs or MAOIs. Fluvoxamine may enhance
the effects of antiplatelets and anticoagulants. Hence, people receiving these drugs
should be closely monitored [30].
How the intervention might work
There are many important mechanisms of action of fluvoxamine and other SSRIs that
could play a role in COVID-19 treatment. These effects include: reduction in platelet
aggregation, decreased mast cell degranulation, interference with endolysosomal viral
trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and increased
melatonin levels, collectively having a direct antiviral effect, as well as regulating
coagulopathy or mitigating the cytokine storm, which are known hallmarks of severe
COVID-19 [31].
Anti-inflammatory effects of certain pharmacological interventions are thought to
be effective during phases of COVID-19 with high inflammatory activity. S1R is an
endoplasmic reticulum (ER) chaperone membrane protein involved in many cellular functions,
including regulation of ER stress response–unfolded protein response and regulation
of cytokine production in response to inflammatory triggers. In a preclinical model
of septic shock, fluvoxamine was found to bind to S1R on immune cells, resulting in
a reduced inflammatory response with inhibited cytokine production [33]. In the presence of fluvoxamine, S1R might prevent the ER stress sensor inositol-requiring
enzyme 1α from splicing and activating the mRNA of X-box protein 1, a key regulator
of cytokine production including interleukins IL-6, IL-8, IL-1β, and IL-12.
The anti-inflammatory effects of fluvoxamine through activation of S1R observed in
preclinical studies suggest fluvoxamine could be evaluated as a treatment option for
COVID-19 in clinical settings [34]. The anti-inflammatory effects of fluvoxamine were also shown by a significantly
decreased expression of some inflammatory genes, such as intracellular adhesion molecule
(ICAM1), vascular cell adhesion molecule (VCAM1), cyclooxygenase 2 (COX2), and inducible nitric oxide synthase (iNOS) in human endothelial cells and macrophages
[35].
In a murine sepsis model, fluvoxamine was found to bind to the S1R on immune cells,
resulting in reduced production of inflammatory cytokines [33]. Furthermore, in-vitro studies of human endothelial cells and macrophages showed
that fluvoxamine reduced the expression of inflammatory genes [31]. Ongoing studies are currently looking to establish whether the anti-inflammatory
effects of fluvoxamine observed in non-clinical studies are relevant to the clinical
setting of COVID-19 [36].
Why it is important to do this review
The COVID-19 pandemic places healthcare systems under tremendous pressure to provide
adequate care. The emergence of variants of concern [37, 27], with the potential for increased transmissibility and altered disease characteristics,
combined with the ongoing scarcity of effective and established drug treatments, in
addition to low global vaccination coverage [38], highlights the obvious and urgent need for effective and safe pharmacotherapies.
The repurposing of existing medications that are also widely available, inexpensive,
and with well-understood safety profiles, such as fluvoxamine, is of great importance.
Evidence-based reviews are therefore needed to guide clinical decision-making for
people with COVID-19.
Current treatment consists of supportive care with oxygen therapy in cases with moderate
disease, and with respiratory support, such as mechanical ventilation, and extracorporeal
membrane oxygenation in cases of severe disease (CDC 2020; 26]. Overall, data from randomised controlled trials (RCTs) do not demonstrate a clear,
major clinical benefit with most of the drugs evaluated thus far. Data from RCTs at
this stage support the role of corticosteroids for severe COVID‐19 and clinical guidelines
recommend their use [39; National COVID‐19 Clinical Evidence Taskforce 2021). Further, tocilizumab and janus kinase inhibitor baricitinib are recommended for
certain patient groups, while other drugs, such as hydroxychloroquine, azithromycin
and ivermectin, are not recommended for the treatment of COVID‐19 [39; National COVID‐19 Clinical Evidence Taskforce 2021).
Effective therapy regimens are particularly necessary for the early viral phase of
the disease in order to prevent a severe course of COVID-19. Evidence is emerging
about the efficacy of anti‐COVID-19 specific neutralising monoclonal antibodies as
early treatments for COVID‐19 [2]. If used in the early phase of the disease (up to day five to seven after the onset
of symptoms), the neutralising monoclonal antibodies significantly reduce the risk
of a severe course of the disease [40, 41]. However, a parenteral form of administration and currently limited availability
represent an important challenge that makes widespread use in the non-hospitalised
setting difficult. Furthermore, the effectiveness of many of the neutralising monoclonal
antibodies against the new virus variants may be reduced [42, 43]. Other antiviral drugs are promising, such as the ribonucleoside analogue molnupiravir
or the protease inhibitor nirmatrelvir in combination with ritonavir, but are still
under investigation and not yet widely available [44].
Systematic reviews for interventions to treat COVID‐19 have already been undertaken,
including treatment with fluvoxamine [45, 46, 47, 48]. However, they did not fulfil all the methodological standards for evidence synthesis.
For example, they did not apply the GRADE approach for rating the certainty of the
evidence or assess the risk of bias [45, 48]. Furthermore, [47] considered only preliminary data of a single study on fluvoxamine and [46] focused on unpublished data. Therefore, we aim to provide a complete evidence profile
for oral fluvoxamine as a treatment for COVID‐19, in both inpatients and outpatients.
Objectives
To assess the efficacy and safety of fluvoxamine in addition to standard care, compared
to standard care (alone or with placebo), or any other active pharmacological comparator
with proven efficacy for the treatment of COVID-19 outpatients and inpatients.
Methods
Criteria for considering studies for this review
Types of studies
The main outline of the methods section is based on the standard template of the Cochrane
Haematology review group and is in line with a series of Cochrane Reviews investigating
treatments and therapies for COVID‐19 [e.g. 2, 1, 4]. The original review protocol for this review was registered with PROSPERO (CRD42022299758) on 4 January 2022. As this review and the other reviews of the Cochrane Review series
are living systematic reviews during the COVID‐19 pandemic, specific adaptations relating
to the research question, including participants, interventions, comparators, outcomes,
and methods may be necessary in further updates.
To assess the efficacy and safety of fluvoxamine for the treatment of people with
COVID‐19 in outpatient and inpatient settings, we included randomised controlled trials
(RCTs), as this study design, if performed appropriately, provides the best evidence
for experimental therapies in highly controlled therapeutic settings. We used the
methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions [49]. In addition to observational studies, non‐standard RCT designs, such as cluster‐randomised
and cross‐over trials, were not eligible for the review. The latter are not appropriate
in this context, since the underlying cause of COVID‐19 is an infection with the SARS‐CoV‐2
virus and the medical condition evolves over time. Furthermore, we excluded controlled
non‐randomised studies of interventions, animal studies, pharmacokinetic studies,
and in vitro studies.
We included the following formats, if sufficient information was available on study
design, characteristics of participants, interventions, and outcomes.
Full‐text journal publications
Abstract publications
Preprint articles
Results published in trial registries
Additional personal communication with investigators, if results were available in
any of the above-listed formats
We included preprints and conference abstracts to have a complete overview of the
ongoing research activity, especially for tracking newly emerging studies on treatments
for COVID‐19. We did not apply any limitations with respect to the length of follow‐up
or language of the publication.
Types of participants
We included studies investigating adults with a confirmed diagnosis of COVID‐19 (with
reverse transcription-polymerase chain reaction (RT‐PCR) or antigen testing) irrespective
of age, sex, ethnicity and disease severity. If studies included participants with
a confirmed or suspected COVID‐19 diagnosis, we only used data for patient populations
with a confirmed COVID‐19 diagnosis. In cases where data were not reported separately
for participants with confirmed or suspected COVID‐19 diagnosis, we included the mixed
population. The status of participants in the included studies, as well as the type
of COVID‐19 diagnosis, is reported in the section Included studies. If mixed population
studies contributed data to the meta‐analyses, we excluded these studies in Sensitivity analysis to test the robustness of the results.
We excluded studies that evaluated fluvoxamine for other coronavirus diseases such
as SARS or MERS, or other viral diseases, such as influenza. If studies enrolled populations
with, or exposed to, mixed viral diseases, we only planned to include studies if the
trial authors provided subgroup data for COVID‐19.
Types of interventions
The intervention was defined as treatment with fluvoxamine. All doses and therapeutic
regimes were eligible.
We compared fluvoxamine in addition to standard care (including no intervention),
to standard care (alone or with placebo), or any other active pharmacological comparator
with proven efficacy (within clinical trials with a high weight of evidence) for the
treatment of COVID-19.
For example, dexamethasone has been shown to reduce mortality from COVID-19 amongst
participants who were randomised to receive dexamethasone compared to those who received
standard care [39, 50], in people who were oxygenated or received respiratory support. Remdesivir showed
some benefit for people hospitalised with COVID-19, though to a lesser extent [51]. For people who qualify for dexamethasone therapy, for instance, or for any other
intervention that is proven to be beneficial in the future, it would be unethical
to further conduct trials that compare an intervention to placebo only. On the contrary,
studies using comparators without proven efficacy, such as hydroxychloroquine, may
confound the assessment of the efficacy or safety of fluvoxamine, so we excluded these.
Although these types of intervention were possibly used at certain time points during
the pandemic with the best intentions, their use was never supported through the evidence,
and they may also be associated with adverse effects [52]. From those comparisons, no reliable evidence could be obtained; therefore, active
comparators without proven efficacy were not eligible for this review. For the current
review, we did not find any studies using an active comparator with proven efficacy.
We excluded studies evaluating fluvoxamine in combination with other active treatments,
if the same treatment was not used in the control group. We also excluded studies
investigating its efficacy and safety in preventing COVID-19. We created the following
comparisons.
Fluvoxamine in addition to standard care (including no intervention) versus standard
care (alone or with placebo)
Fluvoxamine in addition to standard care (including no intervention) versus active
pharmacological intervention for the treatment of COVID-19 with proven efficacy (no
studies were available for the current review version)
Types of outcome measures
We evaluated core outcomes in accordance with the Core Outcome Measures in Effectiveness
Trials (COMET) Initiative for people with COVID‐19 [53, 54], and additional outcomes that have been prioritised by consumer representatives
and the German guideline panel for inpatient therapy of people with COVID‐19, as well
as the German Primary Care Association Guidelines (DEGAM) for the treatment of acute
COVID-19 in the outpatient setting [55]. The current outcome set is in alignment with the previous review in this series
of Cochrane Reviews investigating the use of potential pharmacotherapies for COVID-19
in both inpatients and outpatients [1].
We defined outcome sets with primary and secondary outcomes for two populations.
Inpatients (hospitalised individuals, secondary care) with moderate to severe (World
Health Organization (WHO) severity score > 4) [56] ) COVID‐19
Outpatients (ambulatory-managed individuals, primary care) with asymptomatic or mild
COVID‐19 (WHO severity score ≤ 4) [56]
We collected information on outcomes from all time points reported in the publications.
If only a few studies contributed data to an outcome, we pooled different time points,
provided the studies had produced valid data and pooling was clinically reasonable.
In the case of time‐to‐event analysis, for instance as with 'time to death', we included
the outcome measure based on the longest follow-up time and measured from randomisation.
We included serious adverse events and adverse events occurring during the study period,
including both adverse events during active treatment and long-term adverse events.
If sufficient data were available, we grouped the measurement time points of eligible
outcomes (e.g. adverse events and serious adverse events) into those measured directly
after treatment (up to seven days after treatment), medium-term outcomes (up to 14
days after treatment) and longer‐term outcomes (more than 28 days after treatment).
Primary outcomes
Inpatients with moderate to severe COVID‐19
All‐cause mortality at day 28, day 60, time‐to‐event, and at hospital discharge
Clinical status at day 28, day 60, and up to the longest follow‐up, including
worsening of clinical status
participants with clinical deterioration (new need for invasive mechanical ventilation)
or death
improvement of clinical status
participants discharged alive (participants should be discharged without clinical
deterioration or death)
Quality of life, including fatigue and neurological status, assessed with standardised
scales (e.g. with the WHO Quality of Life-100 (WHOQoL-100) scale) at up to seven days;
up to 28 days, and longest follow‐up available
Serious adverse events during the study period
Adverse events (any grade) during the study period, defined as the number of participants
with any event
Outpatients with asymptomatic or mild COVID‐19 (WHO < 4)
All-cause mortality at day 28, day 60, time-to-event, and up to the longest follow-up
All-cause admission to hospital or death (before hospital admission)
Symptom resolution
all initial symptoms resolved (asymptomatic) at day 14, day 28, and up to the longest
follow-up
duration to symptom resolution
Quality of life, including fatigue and neurological status, assessed with standardised
scales (e.g. WHOQOL-100) at day seven, up to day 28, and the longest follow-up available
Serious adverse events during the study period
Adverse events (any grade) during the study period, defined as number of participants
with any event
Suicide or suicide attempt
Secondary outcomes
Inpatients with moderate to severe COVID‐19
Additional outcomes
Clinical status at day 15, day 28 and up to the longest follow‐up
worsening of clinical status
need for invasive mechanical ventilation
need for non‐invasive mechanical ventilation or high flow
need for oxygen by mask or nasal prongs
need for hospitalisation without oxygen therapy
improvement of clinical status
weaning or liberation from invasive mechanical ventilation in surviving patients
ventilator‐free days
duration to liberation from invasive mechanical ventilation
liberation from supplemental oxygen in surviving patients
duration to liberation from supplemental oxygen
Need for dialysis at up to day 28
Admission to the intensive care unit (ICU) at day 28
Duration of hospitalisation
Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to day three,
day seven, and day 14
Hospital‐acquired infections up to day 28
Outpatients with asymptomatic or mild COVID‐19 (WHO < 4)
Additional outcomes
Clinical status at day 15, day 28 and up to the longest follow‐up
worsening of clinical status (moderate to severe COVID‐19 symptoms)
need for invasive mechanical ventilation
need for non‐invasive mechanical ventilation or high flow
need for hospitalisation (with need for oxygen by mask or nasal prongs)
need for hospitalisation (without oxygen therapy)
Viral clearance, assessed with RT‐PCR for SARS‐CoV‐2 at baseline, up to day three,
day seven, and day 14
Search methods for identification of studies
Electronic searches
Our Information Specialist (IM) designed systematic search strategies and a second
Information Specialist peer reviewed them. We searched in the following sources from
the inception of each database up to 1 February 2022 and did not place restrictions
on the language of the publication.
We searched for other potentially eligible studies or ancillary publications by searching
the reference lists of included studies, systematic reviews and meta‐analyses. In
addition, we contacted the investigators of included studies to obtain additional
information on the retrieved studies when needed.
Data collection and analysis
Selection of studies
In accordance with the Cochrane Handbook for Systematic Reviews of Interventions [57], two review authors (JN, IT, AAT or CS) independently screened the results of the
search strategies for eligibility of this review by reading the titles and abstracts
using Covidence. We then retrieved full‐text articles and assessed eligibility of the remaining records
against predefined eligibility criteria in duplicate. We resolved discrepancies by
discussion within the group of review authors. We included studies in the review irrespective
of whether the measured outcome data were reported in a ‘usable’ way. We collated
multiple reports of the same study, so that the study, rather than the report, was
the unit of interest in the review.
We documented the study selection process in a flow diagram, as recommended in the
PRISMA statement [58], and show the total number of retrieved references and the numbers of included,
ongoing, excluded studies, as well as those awaiting classification in Figure 1. We listed all studies that we excluded after full‐text assessment and the reasons
for their exclusion in the Supplementary material 3, and used the same procedure for the Supplementary material 4.
Data extraction and management
We conducted data extraction according to the guidelines proposed by Cochrane (Li 2020). Two review authors (JN, IT or CS) extracted data independently and in duplicate,
using a customised data extraction form developed in Microsoft Excel (Microsoft 2018). We solved disagreements by discussion. If no agreement was reached, we involved
a third review author to resolve the disagreement.
We extracted the following information, if reported.
General information: author, title, source, country, language, type of publication,
publication date
Study characteristics: setting and dates, inclusion/exclusion criteria, number of
study arms, comparability of groups, treatment cross‐overs, treatment tailoring, intervention
modification, length of follow‐up, funding
Participant characteristics: number of participants randomised/received intervention/analysed,
COVID‐19 diagnostics, severity of disease, age, gender, comorbidities (e.g. diabetes,
immunosuppression), concurrent interventions, time since symptom onset
Intervention: dose, frequency, duration, and route of administration
Control intervention: type of control, frequency, duration, and route of administration
We used the Risk of Bias 2 (RoB 2) tool to analyse the risk of bias of study results
contributing information to our primary outcomes (risk of bias 2.0; 59]. Of interest for this review was the effect of the assignment to the intervention
(the intention‐to‐treat (ITT) effect), so we performed all assessments with RoB 2
on this effect. The outcomes that we assessed are the primary outcomes specified for
inclusion in the summary of findings tables.
Two review authors (JN, IT) independently assessed the risk of bias for each outcome.
In case of discrepancies among their judgements and inability to reach consensus,
we consulted the third review author to reach a final decision. We assessed the following
types of bias as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions [60].
Bias arising from the randomisation process
Bias due to deviations from the intended interventions
Bias due to missing outcome data
Bias in measurement of the outcome
Bias in selection of the reported result
To address these types of bias we used the signalling questions recommended in RoB
2 and make a judgement using the following options.
'Yes': if there is firm evidence that the question is fulfilled in the study (i.e.
the study is at low or high risk of bias for the given the direction of the question)
'Probably yes': a judgement has been made that the question is fulfilled in the study
(i.e. the study is at low or high risk of bias given the direction of the question)
'No': if there is firm evidence that the question is unfilled in the study (i.e. the
study is at low or high risk of bias for the given the direction of the question)
'Probably no': a judgement has been made that the question is unfilled in the study
(i.e. the study is at low or high risk of bias given the direction of the question)
'No information': if the study report does not provide sufficient information to allow
any judgement
We used the algorithms proposed by RoB 2 to assign each domain one of the following
levels of bias.
Low risk of bias
Some concerns
High risk of bias
Subsequently, we derived an overall risk of bias rating for each prespecified outcome
in each study in accordance with the following suggestions.
'Low risk of bias': we judged the trial to be at low risk of bias for all domains
for this result
'Some concerns': we judged the trial to raise some concerns in at least one domain
for this result, but not to be at high risk of bias for any domain
'High risk of bias': we judged the trial to be at high risk of bias in at least one
domain for the result, or we judged the trial to have some concerns for multiple domains
in a way that substantially lowers confidence in the results
For dichotomous outcomes, we recorded the number of events and total number of participants
in both treatment and control groups and reported the pooled risk ratio (RR) with
95% confidence intervals (CIs) and the risk difference (RD) [61].
For continuous outcomes, we recorded the mean, standard deviation and total number
of participants in both treatment and control groups. Where continuous outcomes used
the same scale, we performed analyses using the mean difference (MD) with 95% CIs
[61]. For continuous outcomes measured with different scales, we planned to perform analyses
using the standardised mean difference (SMD) [61]. For interpreting SMDs, we planned to re‐express SMDs in the original units of a
particular scale with the most clinical relevance and impact. For the current review,
all outcomes were measured on comparable scales.
If available, we extracted and reported hazard ratios (HRs) for time‐to‐event outcomes
(e.g. time to hospital discharge). If HRs were not available, we would have made every
effort to estimate the HR as accurately as possible from available data using the
methods proposed by Parmar and Tierney (Parmar 1998; Tierney 2007). If sufficient studies provided HRs, we would have used HRs rather than RRs or MDs
in a meta‐analysis, as HRs provide more information.
Unit of analysis issues
The unit of analysis for this review is the individually‐randomised participant. In
studies with multiple intervention groups, we followed the recommendations in Chapter
6 of the Cochrane Handbook for Systematic Reviews of Interventions [62]. For studies with multiple treatment groups of the same intervention (i.e. dose,
route of administration), we combined the study arms if they were sufficiently homogeneous.
If arms could not be pooled, which was not the case for the current review, we had
planned to compare each arm with the common comparator separately. For pairwise meta‐analysis,
we had planned to split the ‘shared’ group into two or more groups with smaller sample
size, and include two or more (independent) comparisons. For this purpose, in the
case of dichotomous outcomes, we would have divided both the number of events and
the total number of participants. For continuous outcomes, we would have divided the
total number of participants and retained unchanged means and standard deviations
(SDs).
Dealing with missing data
There are many potential sources of missing data in a systematic review or meta‐analysis,
which can affect the level of studies, outcomes, summary data, individuals, or study‐level
characteristics [61]. Incomplete data can introduce bias into the meta‐analysis if they are not missing
at random, which is addressed in the section Assessment of risk of bias in included studies.
First, when data were missing at outcome and study level, we checked for any evidence
for the data being missing at random. When we could not retrieve information about
data being missing at random, we contacted principal investigators and requested these
data (Table 1). If, after this, data were still missing, we would have assumed that data were not
missing at random. On the other hand, if there were indications that data were not
missing at random, we would have conducted complete case analysis for the primary
analysis and would have discussed its potential impact in the discussion section.
If we were concerned regarding missing data across studies, we would not have performed
meta-analyses, but would have provided subtotals per study.
Assessment of heterogeneity
We used the descriptive statistics reported in the Supplementary material 2 to assess whether the studies within each pairwise comparison were homogenous enough,
with respect to study and intervention details and population baseline characteristics,
that the assumption of homogeneity might be plausible. In case of excessive clinical
heterogeneity, we did not pool the findings of included studies.
We measured statistical heterogeneity using the Chi2 test and the I2 statistic [61], and the 95% prediction interval (PI) for random‐effects meta‐analysis [63]. The prediction interval helps in the clinical interpretation of heterogeneity by
estimating what true treatment effects can be expected in future settings [63].
We restricted the calculation of a 95% PI to meta‐analyses with four or more studies
(≥ 200 participants), since the interval would be imprecise if a summary estimate
were based on only a few small studies. We planned to use the open-source statistical
software R package Meta to calculate 95% PIs, and declare statistical heterogeneity if the P value was less
than 0.1 for the Chi2 statistic, or the I2 statistic was 40% or more (40% to 60%: moderate heterogeneity; 50% to 90%: substantial
heterogeneity; 75% to 100%: considerable heterogeneity) [61]; or the range of the 95% PI revealed a different clinical interpretation of the
effect estimate compared to the 95% CI.
Assessment of reporting biases
We sought to identify all research that meets our predefined eligibility criteria.
Missing studies can introduce bias to the analysis. We searched for completed non‐published
trials in trials registers, contacted authors to seek assurance that the results will
be made available, and classified them as 'awaiting classification' until the results
are reported. We reported the number of completed non‐published trials.
We planned to investigate the risk of reporting bias (publication bias) in pairwise
meta‐analyses using contour‐enhanced funnel plots, when there were 10 or more relevant
studies pooled in a meta‐analysis. In the current review, there are no meta‐analyses
including 10 or more studies. For future review updates, if funnel plot asymmetry
is suggested by a visual assessment, we plan to perform exploratory analyses (e.g.
Ruecker’s arcsine test for dichotomous data and Egger’s linear regression test for
continuous data) to further investigate funnel plot asymmetry [64]. A P value of less than 0.1 will be considered as the level of statistical significance.
In future review updates, we will analyse reporting bias using the open‐source statistical
software R package Meta.
Data synthesis
We analysed trials including different severities of disease separately, grouping
them into asymptomatic to mild, and moderate to severely ill, as these are different
populations in different settings, resulting in different outcome sets (see Types of outcome measures). We analysed trials with the following participant populations separately.
Inpatients with moderate to severe COVID‐19
Outpatients with asymptomatic or mild COVID‐19
For these two distinct populations, we created the following comparisons.
Fluvoxamine in addition to standard care versus standard care (alone or with placebo)
Fluvoxamine in addition to standard care versus active pharmacological intervention
for the treatment of COVID-19 with proven efficacy in clinical trials with a high
weight of evidence (no studies were available for the current review version) in addition
to standard care
Placebo and standard care alone (including no intervention) were treated as the same
intervention, as well as standard care at different institutions and time points during
the pandemic.
We performed meta‐analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [61]. If clinical and methodological characteristics of individual studies were sufficiently
homogeneous, we pooled the data into meta‐analyses. We used the RevMan Web software
for meta‐analyses [65]. One review author entered the data in the software, and a second review author
checked the data for accuracy. When meta‐analysis was feasible, we used the random‐effects
model as we assumed that the intervention effects were related but were not the same
for the included studies. For dichotomous outcomes, we performed meta‐analyses using
the Mantel‐Haenszel method under a random‐effects model to calculate the summary (combined)
intervention effect estimate as a weighted average of the intervention effects estimated
in the individual studies. For continuous outcomes, we used the inverse‐variance method.
We planned to present descriptive statistics only if we deemed meta‐analysis inappropriate
for a certain outcome because of heterogeneity or because of serious study limitations
leading to a considerably high risk of bias (e.g competing risk of death not taken
into account in outcome measurements). This was not the case for the current review
version.
If meta‐analysis was possible, we assessed the effects of potential biases in sensitivity
analyses (see Sensitivity analysis) and considered investigating heterogeneity in subgroup analyses (see Subgroup analysis and investigation of heterogeneity). Subgroup analyses were not possible due to the low number of studies per outcome.
For future review updates, if we cannot find a cause for the heterogeneity, we will
not undertake a meta‐analysis but will comment instead on the results as a narrative
and present the results from all studies in tables.
We used forest plots to visualise meta‐analyses of primary outcomes only, including
risk of bias assessment. We reported secondary outcomes without risk of bias assessments
in additional tables.
Subgroup analysis and investigation of heterogeneity
We planned subgroup analyses to investigate clinical heterogeneity for the following
characteristics (considering primary outcomes):
Disease severity at baseline as defined by the WHO Clinical Progression Scale (mild,
moderate, severe)
Dose of fluvoxamine (usual dose versus low dose versus high dose)
In the current review version, none of these analyses were possible due to a lack
of data and trials (only two included studies).
If enough studies are identified during future review updates, we will also perform
subgroup analyses, if statistical heterogeneity is present (P < 0.1 for the Chi2 test of heterogeneity, I2 ≥ 50%), or a different clinical conclusion (when comparing 95% CI with 95% PI). We
also plan to undertake tests for interaction to test for differences between subgroup
results.
Sensitivity analysis
We planned sensitivity analyses of the following characteristics (considering primary
outcomes).
Risk of bias assessment (only trials with a low risk of bias or some concerns)
Comparison of preprint articles versus peer‐reviewed publications (only trials published
as journal articles)
Confirmed versus mixed (suspected and confirmed) COVID‐19 diagnosis (only trials/participants
with confirmed COVID‐19 diagnosis)
Similar to the subgroup analyses, such analyses were not possible in the current review
version (due to the low number of trials).
Summary of findings and assessment of the certainty of the evidence
Summary of findings
We evaluated the certainty of the evidence using the GRADE approach for the interventions
evaluated in RCTs.
We planned to create a separate summary of findings tables for the different patient
populations (outpatients, inpatients) and for the different comparisons. For the current
review version, there were no studies addressing inpatients or an active comparator.
We used the [66] to create a summary of findings table. For time‐to‐event outcomes, we planned to
calculate absolute effects at specific time points, as recommended in the GRADE guidance
27 [67]. For the current review, there were no time‐to‐event data available. According to
Chapter 14 of the updated Cochrane Handbook for Systematic Reviews of Interventions, the “most critical and/or important health outcomes, both desirable and undesirable,
limited to seven or fewer outcomes” should be included in the summary of findings
table [68]. We included the following outcomes prioritised according to the Core Outcome Set
for intervention studies [53, [54] and patient relevance.
Inpatients with moderate to severe COVID‐19
All‐cause mortality (most favourable time point: at hospital discharge, if not reported
for this time point we considered day 60, followed by day 28, or time‐to‐event estimate)
Worsening of clinical status at day 28
participants with clinical deterioration (new need for invasive mechanical ventilation)
or death
Improvement of clinical status at day 28
participants discharged alive
Quality of life at longest follow‐up available
Serious adverse events during the study period
Any adverse events during the study period
Suicide or suicide attempt
Outpatients with asymptomatic or mild COVID‐19
All‐cause mortality (most favourable at longest follow‐up (> 60 days), if not reported
at longest follow-up we considered day 60, followed by day 28, or time‐to‐event estimate)
Admission to hospital (all cause) or death (combined outcome, within 28 days)
Symptom resolution
all initial symptoms resolved (asymptomatic) at day 14
duration to symptom resolution
Quality of life at longest follow‐up available
Serious adverse events during the study period
Any adverse events during the study period
Suicide or suicide attempt
Assessment of certainty in the evidence
We used the GRADE approach to assess the certainty in the evidence for the outcomes
listed above. The GRADE approach uses five domains (risk of bias, consistency of effect,
imprecision, indirectness and publication bias) to assess the certainty in the body
of evidence for each prioritised outcome.
We downgraded our certainty of evidence as follows.
Serious (‐1) or very serious (‐ 2) risk of bias
Serious (‐1) or very serious (‐ 2) inconsistency
Serious (‐1) or very serious (‐ 2) uncertainty about directness
Serious (‐1) or very serious (‐ 2) imprecise or sparse data
Serious (‐1) or very serious (‐ 2) probability of reporting bias
The GRADE system used the following criteria for assigning grade of evidence.
High: we are very confident that the true effect lies close to that of the estimate
of the effect.
Moderate: we are moderately confident in the effect estimate; the true effect is likely
to be close to the estimate of effect, but there is a possibility that it is substantially
different.
Low: our confidence in the effect estimate is limited; the true effect may be substantially
different from the estimate of the effect.
Very low: we have very little confidence in the effect estimate; the true effect is
likely to be substantially different from the estimate of effect.
We followed the current GRADE guidance for these assessments in its entirety as recommended
in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 14 [68]. We used the overall risk of bias judgement, derived from the RoB 2 Excel tool,
to inform our decision on downgrading for risk of bias. We phrased the findings and
certainty in the evidence as suggested in the informative statement guidance [69].
Methods for future updates (living systematic review considerations)
Our information specialists (IM, KG) will provide us with new search records each
week, which two review authors will screen, extract, evaluate, and integrate following
the guidance for Cochrane living systematic reviews (Cochrane LSR). We will also manually check platform trials that were previously identified and
listed as Supplementary material 4 for additional relevant treatment arms.
We will wait until the accumulating evidence changes our conclusions of the implications
of research and practice before republishing the review. We will consider one or more
of the following components to inform this decision.
The findings of one or more prioritised outcomes
The credibility (e.g. GRADE rating) of one or more prioritised outcomes
New settings, populations, interventions, comparisons or outcomes studied
In case of emerging policy relevance because of global controversies on the intervention,
we will consider republishing an update the review even though our conclusions will
remain unchanged. We will review the review scope and methods approximately monthly,
or more frequently if appropriate, in light of potential changes in COVID‐19 research
(for example, when additional comparisons, interventions, subgroups or outcomes, or
new review methods become available).
The literature search resulted in 94 records. No records were identified via additional
searches of reference lists. After removing duplicates, 86 records remained. During
title and abstract screening, we judged 63 records to be irrelevant.
We proceeded to full-text screening with 23 records, considering published full texts
or, if these were not available, trial register entries. From these 23 records, we
excluded 12 records: one record (one study) was cancelled before starting patient
recruitment and 11 records (11 studies) were not RCTs. From the 11 records (nine studies)
that we considered to be relevant (included), five records referred to ongoing studies
and two are awaiting classification. Finally, we included two studies (four records)
in our quantitative synthesis, contributing data to the primary and secondary outcomes
of this review. The flow of records is illustrated in Figure 1.
Inpatients
We did not include any clearly-eligible, completed studies that investigated fluvoxamine
in the inpatient setting.
Studies awaiting classification
We considered one study conducted in the inpatient setting to be relevant [70], and listed this study in the section Supplementary material 4. This study was only available in the Persian language, and we will re-evaluate it
once the study authors have clarified some translation issues.
Ongoing studies
The characteristics of ongoing studies are available in the section Supplementary material 5. In the inpatient setting, we identified one ongoing study [72]. This trial is still active and compares fluvoxamine with placebo treatment (both
in addition to standard care) in people hospitalised with COVID-19. The expected completion
date is December 2022. The trial records refer to a planned sample size of 100.
We included two randomised controlled trials in this review with a total of 1649 allocated
participants, of whom 821 were allocated to fluvoxamine in addition to standard care
and 828 to placebo and standard care (Lenze 2020 [74, 75]; TOGETHER 2021 [76, 77]). TOGETHER 2021 was a randomised, adaptive platform trial to investigate the efficacy
of different repurposed treatments for non-hospitalised people with COVID-19, allocating
1497 participants to the comparison of interest. Lenze 2020 allocated 152 participants
in total.
The study by Lenze 2020 was performed as a remote outpatient trial and the TOGETHER
2021 study used both in-person and remote follow-up assessments (i.e. relying on physical
examination or self-assessments via phone contact or video calls). Both studies were
multicentric: Lenze 2020 was performed in two centres in the greater St. Louis metropolitan
area, USA, while the TOGETHER 2021 study was conducted at 11 clinical sites in Brazil.
With regard to equity, applicability, and resources, we must highlight that one of
the included studies was performed in a high-income country while the other was performed
in an upper-middle-income country. Both studies reported information about the responsible
ethics committee and financial support. TOGETHER 2021 was supported by FastGrants
and the Rainwater Foundation, while Lenze 2020 was supported by the Taylor Family
Institute for Innovative Psychiatric Treatment at Washington University and the COVID-19
Early Treatment Fund, the Center for Brain Research in Mood Disorders at Washington
University, the Bantly Foundation, and a grant from the National Institutes of Health.
In both studies, a number of co-authors reported conflicts of interests.
Both trials were peer-reviewed publications in indexed journals and were prospectively
registered.
Participants
Both studies recruited participants from the outpatient setting. Lenze 2020 used an
electronic health record system, physician referrers, doctors' hotlines, COVID-19
Test Centres, Emergency Rooms (microbiology lab) as per the Healthy Mind Lab website
(www.healthymind.wustl.edu), flyers, and email notifications. TOGETHER 2021 recruited participants at community
health facilities (emergency settings, influenza-symptom referral centres, or primary
care community centres), with the help of notices through physical and social media
as per local public health authorities.
In Lenze 2020, all participants had a polymerase chain reaction (PCR)-confirmed SARS-CoV-2
infection, while in TOGETHER 2021 PCR for SARS-CoV-2 was not mandatory and participants
were also included in the study if they had a positive rapid test for SARS-CoV-2 antigen
done after obtaining informed consent.
Lenze 2020 performed randomisation and start of study medication within seven days
of symptom onset, without further specification. In TOGETHER 2021, all patients had
symptoms beginning within seven days of the screening date: 42.6% within the first
three days of symptom onset and 34.5% between days four and seven. For the remaining
participants, information on the duration of symptoms within the first seven days
was missing.
In both studies, all participants were symptomatic adults. In Lenze 2020 the median
age of participants was 46 years in the intervention group and 45 years in the control
group (interquartile range (IQR) 35 to 58 and 36 to 54 years, respectively). In TOGETHER
2021 the median age of participants was 50 years (IQR 39 to 56) in the intervention
group and 49 years (IQR 38 to 56) in the control group. In total, 50.9% of all participants
in this study were less than 50 years old. The majority of participants were female
(Lenze 2020: 71.7%; TOGETHER 2021: 58.7%).
The most common comorbidities in Lenze 2020 were asthma (21%) and hypertension (19%)
in the intervention group and hypertension (21%) in the control group. In TOGETHER
2021 the most common risk factors were uncontrolled hypertension (in 14% of participants
in the intervention group and 12% of participants in the control group) and type 2
diabetes mellitus (in 14% of participants in the intervention group and 12% of participants
in the control group).
The most common symptoms of COVID-19 in Lenze 2020 were loss of sense of smell (in
33% of participants in the intervention group and 25% of participants in the control
group) and fatigue (in 21% of participants in the intervention group and 25% of participants
in the control group). TOGETHER 2021 did not report the details of baseline symptoms.
Interventions and comparators
Both studies compared fluvoxamine in addition to standard care with placebo and standard
care (Lenze 2020; TOGETHER 2021). In Lenze 2020 the dose of fluvoxamine (capsules
manufactured by Apotex) was titrated from 50 mg on the day of randomisation to 100
mg twice daily on days two and three and finally 100 mg three times daily on the remaining
days up to day 15. After the completion of 15 days of fluvoxamine or placebo, participants
were given the option to receive a six-day open-label course of fluvoxamine. This
was a change from the original study protocol, but no data collection was conducted
for this phase. Matching placebo gelatin capsules contained microcrystalline cellulose
and silica gel, micronised. All active drug and placebo preparations were performed
by the same pharmacy. In TOGETHER 2021 participants were randomly assigned to fluvoxamine
(manufactured by Abbott) at a dose of 100 mg twice daily for 10 days or a corresponding
placebo starting directly after randomisation. Neither study specified the placebo.
In the TOGETHER 2021 study, standard care typically focused on the management of symptoms
and provision of antipyretics, while antibiotics were provided when clinicians suspected
bacterial pneumonia. Lenze 2020 did not report standard care, and the participants
received either fluvoxamine or placebo during quarantine. However, taking immunosuppressant
biological drugs or high-dose corticosteroids (> 20 mg/d of prednisone) were exclusion
criteria in the Lenze 2020 study. TOGETHER 2021 did not allow current use of an SSRI.
Outcome measures
The primary outcome in Lenze 2020 was clinical deterioration, defined by meeting both
criteria of (1) shortness of breath or hospitalisation for shortness of breath or
pneumonia and (2) oxygen saturation < 92% on room air or need for supplemental oxygen
to achieve oxygen saturation of 92% or greater (within 15 days). The primary outcome
in TOGETHER 2021 was admission to hospital, defined as COVID-19 emergency setting
visits (participants remaining under observation for over six hours) or admission
to hospitalisation due to progression of COVID-19 (within 28 days).
Secondary outcomes included in Lenze 2020 were 30 days of post-trial observation events
(emergency department visit, hospitalisation, or both) and ventilator support. All
outcomes were measured using participants’ self-reported responses on twice-daily
surveys during the 15 days after randomisation and assessed remotely (via Zoom videoconference,
phone, text, email, as well as REDCap surveys pushed out to participants via their
smartphones or other devices). In order to standardise the procedure, criteria were
formulated for which an emergency department visit was indicated (a decrease in oxygen
saturation < 90% on room air on more than two readings, persistent increase in respiratory
rate to > 30 breaths per minute, persistent increase in heart rate to > 120 beats
per minute, alteration in mentation, or severe worsening in shortness of breath).
At 30 days after the conclusion of the 15-day trial, a follow-up survey was performed
by phone, email, or electronic medical record review. In the follow-up, the participants
were asked if they were hospitalised or had visited a hospital or emergency department
since the last study survey.
In TOGETHER 2021, secondary outcomes included time to clinical improvement, number
of days with respiratory symptoms, time to hospitalisation (for any cause or due to
COVID-19 progression), length of hospitalisation (days), proportion of participants
with mechanical ventilation, time on mechanical ventilator (days), proportion of participants
who were non-adherent with the study drugs, and adverse reactions to the study medications.
Study personnel collected outcome data on days one, two, three, four, five, seven,
ten, 14, and 28 in-person or via telephone or social media using video-teleconferencing.
At the baseline visit, a six-lead electrocardiogram (Kardiamobile, Mountain View,
CA, USA) was performed for all participants and transferred to a central facility
(Cardresearch, Belo Horizonte, Brazil) for reading. Vital signs included oxygen status
assessed by means of a pulse oximeter for non-invasive arterial oxygen saturation
and pulse (Jumper Medical Equipment, Shenzhen, China), and temperature by a standard
digital oral thermometer.
Studies awaiting classification
We considered one study conducted in the outpatient setting to be relevant [79], and listed it in the section Supplementary material 4. Although the study is related to the included and published study of Lenze 2020
(but conducted across the United States and two provinces of Canada), we have not
yet identified any published reports.
Ongoing Studies
The characteristics of ongoing studies in outpatients are available in the section
Supplementary material 5. We classified four trials as ongoing: three are still active and are currently recruiting
[80, 82, 85], while the other trial [86] is pending (not yet recruiting). In all trials, fluvoxamine is being compared to
placebo or standard care or with other pharmacological interventions in the outpatient
setting. Ongoing studies are evaluating participants aged 18 years and older. The
original completion date for the [86] trial was December 2021, and the expected completion date for [85] was March 2022, while those for [82] and [80] are in early 2023. These four trial records refer to planned sample sizes of 296
[86], 1350 [80], 1800 [85], and 15000 [82], respectively.
Excluded studies
We excluded 12 records after full-text assessment, and these are listed in the section
Supplementary material 3. One record (one study) was cancelled before starting participant recruitment and
11 records (11 studies) were not RCTs.
Risk of bias in included studies
We assessed methodological quality and risk of bias for two RCTs contributing results
to our primary outcomes using the RoB 2 tool. The RoB 2 judgements for all study results
per outcome and for all domains are available in an interactive risk of bias table
(Risk of bias table for Analysis 1.1; Risk of bias table for Analysis 1.2; Risk of
bias table for Analysis 1.3; Risk of bias table for Analysis 1.4) and are briefly
summarised below.
Overall risk of bias by study
We assessed both studies to have an overall high risk of bias (Lenze 2020; TOGETHER
2021), mainly due to concerns with the outcome measurement (mostly self-reported outcomes
collected remotely), and due to missing participant data. In Lenze 2020, 20% of study
participants stopped responding to surveys during the 15-day trial. The possibility
that some of these participants (n = 6) received care at an urgent care centre outside
the trial could not be excluded. For 31 participants, it was confirmed that they did
not receive any medical care for worsening of COVID-19.
Overall risk of bias by outcome
The following section summarises the risk of bias per outcome for all primary outcomes
included in the summary of findings table (Summary of findings table 1.)
We have no concerns regarding the risk of bias across studies for the outcome 'all-cause
mortality at day 28'. We identified a high risk of bias due to missing outcome data
for one trial that contributed data to this outcome (18 out of 80 (22.5%) in the intervention
group and 19 out of 72 (26.4%) in the placebo group did not complete the study and
reasons for missing data were not provided) (Lenze 2020). However, this study did
not impact the result of the analysis (zero event study, Analysis 1.1), so we based
the bias summary on TOGETHER 2021, where the dropout rate was less than 12%.
We also have no concerns regarding risk of bias for the outcome 'admission to hospital
and death' reported by one study (TOGETHER 2021). Although hospital admission rates
may be more frequent in trials with a remote patient assessment, particularly when
patients are diagnosed with an infectious disease, and direct (face-to-face) contact
with a clinician is lacking, the randomised allocation of participants should balance
this issue between study arms.
For 'serious adverse events' and 'adverse events', we also identified a high risk
of bias due to the measurement of the outcome. All (serious and non-serious) adverse
events appear to be self-reported, and it is unclear whether they were verified by
medical records or practitioner reports, which may be associated with an under- or
overestimation of such events. Furthermore, the results could be impacted due to missing
participant data, particularly in the study of Lenze 2020.
Effects of interventions
on time to ssssAs we did not include any studies investigating efficacy and safety
of fluvoxamine in the inpatient setting, this section effectively only addresses the
outpatient setting.
Primary outcomes are displayed in the summary of findings table (Summary of findings table 1 'Fluvoxamine plus standard care compared to placebo plus standard care for outpatients
with mild COVID-19').
We included two placebo-controlled studies in both qualitative synthesis and quantitative
synthesis (meta-analysis) of this review (Lenze 2020; TOGETHER 2021). Both studies
investigated outpatients with confirmed mild COVID-19.
We did not conduct sensitivity analysis regarding the risk of bias, since only one
study had a low risk of bias for the outcome 'all-cause mortality' (TOGETHER 2021).
Lenze 2020 did not report any events reported for this outcome. So the study with
a low risk of bias contributed 100% to the weight of the meta-analysis.
There were no indications of data not missing at random, so predefined analyses for
such cases were not applicable.
In the current review, there are not enough studies available to perform the planned
subgroup analyses to investigate heterogeneity for study characteristics (such as
differing doses and severity of the disease).
Primary outcomes
All‐cause mortality at day 28
Both studies reported on all‐cause mortality either at day 15 (Lenze 2020) or day
28 (TOGETHER 2021). Fluvoxamine may slightly reduce all‐cause mortality (RR 0.69,
95% CI 0.38 to 1.27; 1649 participants; RD 9 per 1000; Analysis 1.1). While no deaths
were recorded in either the treatment group or placebo group at day 15 (Lenze 2020),
at day 28 the risk with fluvoxamine and standard care was 21 per 1000 and the risk
in the placebo group was 30 per 1000 (TOGETHER 2021). Certainty of the evidence for
this outcome was low. While we did not downgrade for risk of bias (as the study with
a high risk of bias had a weight of 0% (Lenze 2020), we did downgrade for very serious
imprecision because the 95% CI suggests both potential benefit and no effect or potential
harm, and the number of events was small.
All-cause admission to a hospital or death (before hospital admission)
Both studies reported data on admission to hospital or death within 28 days for participants
with symptomatic COVID-19. Fluvoxamine may reduce admission to hospital or death (RR
0.55, 95% CI 0.16 to 1.89; 1649 participants; RD 57 per 1000; Analysis 1.2). Certainty
of the evidence for this outcome was low. We downgraded this by two levels due to
concerns of very serious imprecision because the 95% CI suggests both potential benefit
and no effect or potential harm, and the number of events was small.
Symptom resolution
Neither of the studies reported numerical data for this outcome. One study illustrated
data in a graph that indicated an overlap of confidence intervals (TOGETHER 2021).
Quality of life
Neither of the studies reported this outcome.
Serious adverse events
Both studies reported data for this outcome (Lenze 2020; TOGETHER 2021). There is
very low-certainty evidence on fluvoxamine regarding the number of participants with
serious adverse events during the study period (RR 0.56, 95% CI 0.15 to 2.03; 1649
participants; RD 54 per 1000; Analysis 1.3). We downgraded the certainty of the evidence
by three levels: by one level for serious concerns due to high risk of bias (measurement
of the outcome), and by two levels for very serious concerns due to imprecision. The
95% CI includes a potential benefit and harm.
Any adverse events (any grade)
The studies of Lenze 2020 and TOGETHER 2021 also reported data for any adverse events.
There is very low-certainty evidence on fluvoxamine regarding adverse events of any
grade during the short-term follow-up (RR 1.06, 95% CI 0.82 to 1.37; 1649 participants;
RD 7 per 1000; Analysis 1.4). We downgraded the certainty of the evidence by three
levels: by one level for serious concerns due to high risk of bias (measurement of
the outcome), and by two levels for very serious concerns due to imprecision. The
95% CI includes a potential benefit and harm.
Suicide or suicide attempt
None of the included studies reported this outcome.
Secondary outcomes
The secondary outcomes reported included 'clinical status' at day 15, 28 or the longest
follow-up and 'viral clearance'. Clinical status was measured in one study each as
'need for invasive mechanical ventilation', 'need for non-invasive mechanical ventilation
or high flow' and 'need for hospitalisation with oxygen therapy'. Quantitative data
for the secondary outcomes are listed in Table 2.
Need for invasive mechanical ventilation
TOGETHER 2021 reported that 26 of 741 fluvoxamine treated patients versus 34 of 756
participants in the placebo group needed mechanical ventilation (RR 0.77, 95% CI 0.45
to 1.30; 1497 participants; RD 10 per 1000; Table 2).
Need for non-invasive mechanical ventilation or high flow
Lenze 2020 reported that none of the 80 fluvoxamine treated participants versus three
of 72 participants in the placebo group required supplemental oxygen plus ventilator
support for three days or more (absolute difference 0.00, 95% CI -8.41 to 0.49; 152
participants; RD 0 per 1000; Table 2). This outcome was assessed with a 7-point scale.
Need for hospitalisation with oxygen therapy by masks or nasal prongs
Lenze 2020 also reported that none of the 80 participants treated with fluvoxamine
versus three of 72 participants in the placebo group needed hospitalisation and required
supplemental oxygen therapy by masks or nasal prongs (absolute difference -4.21, 95%
CI -13.22 to 2.04; 152 participants; RD 42 per 1000; Table 2). Again, this outcome was assessed with a 7-point scale.
Viral clearance (assessed with PCR) at day 7
TOGETHER 2021 reported that 40 of 207 fluvoxamine treated patients versus 58 of 221
participants in the placebo group showed successful viral clearance at day seven (OR
0.67, 95% CI 0.42 to 1.06; 428 participants; RD 70 per 1000; Table 2).
Discussion
Summary of main results
The aim of this review was to investigate the efficacy and safety of fluvoxamine in
people with COVID‐19. We identified two RCTs including more than 1500 non-hospitalised
people (outpatients) with symptomatic COVID-19 (Lenze 2020; TOGETHER 2021). We did
not find any RCTs that investigated asymptomatic people or those hospitalised with
COVID-19 who were being treated with fluvoxamine.
Both included studies evaluated composite endpoints including clinical worsening according
to the definition of the respective study and retention in a COVID-19 emergency setting
or inpatient setting. From the prioritised primary endpoints of this review, the studies
reported all-cause mortality at day 28 (Lenze 2020; TOGETHER 2021), admission to hospital
(all cause) or death (before hospital admission) (TOGETHER 2021), serious adverse
events (Lenze 2020; TOGETHER 2021) and adverse events (any grade) (Lenze 2020; TOGETHER
2021). Furthermore, the studies also reported data for the secondary outcomes: need
for mechanical ventilation (TOGETHER 2021), need for non-invasive mechanical ventilation
or high flow oxygen supplementation (Lenze 2020), need for hospitalisation with need
for oxygen therapy (by masks or nasal prongs) (Lenze 2020), and viral clearance at
day 7 (TOGETHER 2021).
Our analyses show that fluvoxamine compared to placebo (both in addition to standard
care) may slightly reduce all‐cause mortality at day 28 (RR 0.69, 95% CI 0.38 to 1.27;
2 studies, 1649 participants; low-certainty evidence) and may reduce the number of
people admitted to a hospital or who died beforehand (RR 0.55, 95% CI 0.16 to 1.89;
2 studies, 57 participants; low-certainty evidence). The number of serious adverse
events did not clearly differ between fluvoxamine and placebo, and we are very uncertain
about the effect of fluvoxamine on serious adverse events during the study period
(RR 0.56, 95% CI 0.15 to 2.03; 2 studies, 1649 participants; very low-certainty evidence).
Likewise, we are very uncertain about the effect of fluvoxamine on adverse events
of any grade (RR 1.06, 95% CI 0.82 to 1.37; 2 studies, 1649 participants; very low-certainty
evidence). Although TOGETHER 2021 mentioned that there was no difference in time to
symptom resolution between the groups, we could not derive any numerical data from
this study and contacting the authors was unsuccessful. Neither study reported on
quality of life or suicide and suicide attempt.
Overall completeness and applicability of evidence
The evidence summarised in this review applies to the use of fluvoxamine in symptomatic
COVID-19 outpatients. It is mainly restricted to unvaccinated people at high-risk
and the virus variants of concern that were present at the time of the conducted trials
(up to August 2021). We did not identify any randomised trials for inpatients with
moderate, severe and critical COVID-19, or any studies reporting on fluvoxamine versus
other active pharmacological comparators with proven effectiveness.
One small study was conducted in a single geographical area of the USA, with recruitment
between April and August 2020 (the first phase of the pandemic) (Lenze 2020). The
other, much larger, study was conducted in high-risk people in Brazil and recruitment
took place between January and August 2021 (TOGETHER 2021). The recruitment period
in Lenze 2020 was before the start of the vaccination campaign, and in TOGETHER 2021
only 6% of recruited participants reported one dose of a COVID-19 vaccine at the end
of the trial. Taking into account that widespread vaccination programmes have now
become established in some areas, it is very unclear whether the results of the studies
can be transferred to a predominantly immunised population in case of a breakthrough
infection.
Particularly for immunocompromised people, who have a relevant risk of an inadequate
immune response to vaccination, an effective treatment reducing disease progression
would be clinically important. However, immunosuppression was an exclusion criterion
in Lenze 2020, and in TOGETHER 2021 the number of immunosuppressed participants was
unclear. Older people were also underrepresented in both studies: the median age of
participants was 46 years (intervention arm) and 45 years (control arm) in Lenze 2020,
and 50% of participants in the TOGETHER 2021 trial were younger than 50 years old.
Because the focus of the study of TOGETHER 2021 was people at high-risk, the applicability
of our findings for subgroups including the immunocompromised or older people must
be applied with caution.
Since recruitment in TOGETHER 2021 was based on the results of rapid SARS-CoV-2 antigen
testing, diagnostic uncertainty may be another limitation in the interpretation of
the results of this study. However, the concordance of positive COVID-19 rapid antigen
tests with RT-PCR was evaluated in a group of participants who underwent PCR testing.
A concordance rate of greater than 99% for both tests collected at baseline was found.
Furthermore, the changing dynamics in the development of virus variants, with possible
limitations on the effectiveness of antiviral therapies, needs to be considered when
interpreting these results. There are no studies to date that evaluate the efficacy
of fluvoxamine in the presence of virus variants of concern. Furthermore, we currently
we do not know how immunomodulators will be affected by viral variants.
Certainty of the evidence
We assessed the certainty of evidence for primary outcomes presented in the Summary of findings table 1 according to [68, and this ranged from low to very low. We found all-cause mortality and admission
to hospital, or death prior to hospital admission, to have low-certainty evidence.
The certainty of evidence for the outcomes ‘serious adverse events’ and ‘adverse events
of any grade’ was very low. Downgrading was due to very serious imprecision (because
the 95% CI suggests both potential benefit and no effect or potential harm) and a
serious risk of bias (because of concerns in measurement of the outcome 'adverse events'
which were self-reported in both studies). Although our findings are mainly restricted
to unvaccinated persons and virus variants of concern that were present up to August
2021, we did not downgrade due to indirectness. The reason for not downgrading was
due to the ongoing and still dynamic pandemic. Judging the effectiveness of current
anti-COVID-19 therapies against emerging variants poses an enormous challenge, as
has been seen with the assessment of vaccine effectiveness over the last year [88].
In the current phase of the pandemic, it is also impossible to reliably assess the
risk of publication bias. There are registered studies that are ongoing. We will follow
the publication and trial history of each ongoing study, including those awaiting
classification. We do not suspect any current publication bias to be present, for
any of the outcomes. However, this may change in future updates of this review.
Potential biases in the review process
To avoid potential bias in the review process, we committed ourselves to conducting
this systematic review according to published guidance provided by the Cochrane Handbook for Systematic Reviews of Interventions [49].
Furthermore, this review is part of a Cochrane Living Systematic Reviews Series on
different interventions for treatment of COVID‐19 [7, 2, 1, 89, 4, 5]. Initially, a common core outcome set was established for all reviews in accordance
with the Core Outcome Measures in Effectiveness Trials (COMET) Initiative for people
with COVID‐19 [53, 54]. These outcomes are continuously discussed and modified as necessary, taking into
account the dynamics of the pandemic.
Although we did not exclude preprint studies, this review contains data from peer-reviewed
journal publications only. We contacted study authors if the publication included
unclear or missing information. Details of communication with authors are provided
in Table 1.
Two trials are classified as awaiting classification either due to inconclusive information
regarding outcome measures related to the language of the study (trial in Persian
language in an inpatient setting), or because the study was stopped for futility by
a data safety monitoring board and results have not been published (trial in an inpatient
setting). We will closely monitor these trials for further publications in the near
future.
None of the authors has an affiliation with a stakeholder group that favours or disapproves
of any selective serotonin reuptake inhibitors, or any of the comparators used in
relevant studies.
Agreements and disagreements with other studies or reviews
We have identified two published reviews dedicated solely to the efficacy and safety
of fluvoxamine in the treatment of COVID-19 [45, 46]. Only one review, published as a preprint, analysed randomised trials [46], while [45] also considered observational studies.
[46] came to similar conclusions as our review. However, that review included three randomised
trials. Besides the study of TOGETHER 2021 and Lenze 2020, the review considered a
third completed, but not published, trial [79]. The authors stated that they obtained outcome data directly from the principal
investigators (who were co-authors of the cited review).
[45] (a preprint labelled as a living systematic review) also focused on fluvoxamine
and included two randomised trials and one observational study. The authors concluded
that repurposing of fluvoxamine for the treatment of people with COVID-19 had not
shown any efficacy in reducing the mortality rate or the rate of progress to mechanical
ventilation. Although the authors described a reduced risk of hospitalisation amongst
people with COVID-19, they stressed that there was still an urgent need for more clinical
studies to determine the extent of the effectiveness of fluvoxamine, and to know more
about its mechanism of action in people with COVID-19.
There are several reviews analysing fluvoxamine as one of the therapeutics for COVID-19.
A systematic review by [47] focused on differing oral interventions (including fluvoxamine, bamlanivimab as
monotherapy and combined with etesevimab, casirivimab plus imdevimab, ivermectin,
nitazoxanide, and peginterferon lambda) in the outpatient setting to prevent progression
to severe disease in people with COVID-19. Although this review did not include the
large TOGETHER trial on fluvoxamine (TOGETHER 2021), and most findings of the evaluated
medications were based on single study results, the authors concluded that promising
results in relation to clinical deterioration (defined by dyspnoea or hospitalisation),
oxygen saturation (on room air) or need for supplemental oxygen (in the ambulatory
setting) are available.
[48] conducted a meta-analysis to investigate the effectiveness of fluvoxamine and other
oral antivirals (molnupiravir and nirmatrelvir/ritonavir). The authors included both
randomised and non-randomised trials and concluded that each oral medication assessed
was effective in reducing mortality and hospitalisation rates in people with COVID-19.
In addition, they found that the risk of adverse events did not increase whilst taking
medication compared to placebo or standard care. Taking into account that no bias
assessment had been conducted, and the study results were combined without differentiating
between inpatient and outpatient settings, these findings needed to be interpreted
with caution.
Based on their review of trials, including two RCTs which had the greatest impact
on the Panel's recommendation (Lenze 2020; TOGETHER 2021), the U.S. National Institutes
of Health COVID-19 Treatment Guidelines Panel stated that there is insufficient evidence
to recommend either for or against the use of fluvoxamine in the treatment of COVID-19
[90].
Although there are some published reviews on fluvoxamine as early treatment for COVID-19,
none fulfilled all the methodological standards for evidence syntheses, and they did
not apply the GRADE approach for rating the certainty of the evidence. But, overall,
the findings of these reviews are in alignment with our review, indicating that the
current evidence for fluvoxamine is limited, especially considering that only two
randomised controlled trials currently exist.
Authors' conclusions
Implications for practice
Based on the current evidence, the use of fluvoxamine plus standard care in comparison
to standard care plus placebo in outpatients with mild COVID-19 may reduce slightly
all cause mortality (at day 28) and may reduce admission to hospital or death. However,
we are very uncertain regarding the effect on serious adverse events. These findings
are restricted to unvaccinated symptomatic outpatients and virus variants of concern
that were present at the time that the trials were conducted. There were no numerical
data currently available for other prioritised outcomes, including symptom resolution,
quality of life, and suicide. No completed studies were identified that focused on
inpatients, hence no statements could be made on this aspect of fluvoxamine use.
Implications for research
Effective pharmacological therapies to treat COVID-19 in the outpatient setting are
important to reduce the risk of progression to severe disease in people with COVID-19,
and reduce the need for hospital admission. Trials considering both prioritised outcomes,
such as quality of life, and current vaccination status, as well as older populations,
women who are pregnant or breastfeeding, or people who have a weakened immune system
are needed to further investigate the role of fluvoxamine in the treatment of COVID-19.
Furthermore, it would be important to establish the efficacy and safety of fluvoxamine
as compared to other active pharmacotherapies targeting novel COVID-19 variants, and
whether closely related selective serotonin reuptake inhibitors could be used interchangeably.
[web-only] Supplementary materials published alongside this article contain additional data and
information that support or enhance the content of the article. The supplementary
materials are not subject to the same editorial process as the article and therefore
may not have been checked for accuracy, copyedited, typeset or proofread. The content
and accuracy of the supplementary materials is the responsibility of the author(s).
Cochrane gives no representations or warranties as to the accuracy of the supplementary
materials. To the fullest extent permitted by law, Cochrane disclaims all liability
arising from any reliance on or use of the supplementary materials.
This work is part of a series of reviews investigating treatments and therapies for
COVID-19 as part of the project CEOsys. We thank the authors of the first published
reviews of this series for providing and sharing some information in the background
(particularly in the section 'Why it is important to do this review') and thank the
Cochrane Haematology working group for using the template for the description of methods.
The research was part of a project supported by the German Federal Ministry of Education
and Research (NaFoUniMedCovid19, funding number: 01KX2021; part of the project ‘CEOSys’).
The contents of this document reflect only the authors' views, and the German Ministry
is not responsible for any use that may be made of the information it contains.
Cochrane Haematology supported the authors in the development of this review. Ina
Monsef is a member of Cochrane Haematology but was not involved in the editorial process
or decision-making for this review.
The following people conducted the editorial process for this article:
Sign-off Editor (final editorial decision): Robert Boyle, Imperial College London,
UK; Co-ordinating Editor of the Cochrane Skin Group
Managing Editor (selected peer reviewers, provided comments, collated peer-reviewer
comments, provided editorial guidance to authors, edited the article): Lara Kahale;
Cochrane Central Editorial Service
Editorial Assistant (conducted editorial policy checks and supported editorial team):
Leticia Rodrigues, Cochrane Central Editorial Service
Copy Editor (copy-editing and production): Andrea Takeda (Central Production Service)
Peer-reviewers (provided comments and recommended an editorial decision): Kenji Hashimoto,
Chiba University, Japan (clinical); Eileen Doyle, PharmD (clinical); Robert Walton,
Senior Fellow in General Practice, Cochrane UK (clinical); Liz Doney, Cochrane Skin
University of Nottingham (search); Robin Featherstone, Cochrane Central Editorial
Service (search); Stella Maria O'Brien (consumer); and Nuala Livingstone, Associate
editor, Cochrane Evidence Production and Methods Directorate (methods).
One additional peer reviewer provided clinical peer review, but chose not to be publicly
acknowledged.
Contributions of authors
John Nyirenda (JN)*: search and selection of studies for inclusion in the review;
collection of data for the review; assessment of the risk of bias in the included
studies; analysis of data; assessment of the certainty in the body of evidence; writing
and proofreading of the review.
Mario Sofroniou (MSo)*: conception of the review; interpretation of data; writing
and proofreading of the review.
Ingrid Toews (IT): conception of the review; search and selection of studies for inclusion
in the review; collection of data for the review; assessment of the risk of bias in
the included studies; assessment of the certainty in the body of evidence, writing
and proofreading the review.
Agata Mikolajewska (AMi): conception of the review; interpretation of data; writing
and proofreading of the review.
Cornelius Lehane (CL): interpretation of data and proofreading the review.
Ina Monsef (IM): search strategy design; running the searches and writing the review.
Aesha Abu-taha (AA): search and selection of studies for inclusion in the review.
Andy Maun (AMa): conception of the review; interpretation of data; writing and proofreading
of the review.
Miriam Stegemann (MSt): conception of the review; interpretation of data; writing
and proofreading of the review.
Christine Schmucker (CS): conception of the review; design of the review; co-ordination
of the review; collection of data for the review; assessment of the risk of bias in
the included studies; analysis of data; assessment of the certainty in the body of
evidence; interpretation of data; writing of the review.
*Shared first authorship.
Declarations of interest
John Nyirenda (JN): has no known conflicts of interest to declare.
Mario Sofroniou (MSo): has no known conflicts of interest to declare.
Ingrid Toews (IT): has no known conflicts of interest to declare.
Agata Mikolajewska (AMi): is affiliated with not-for-profit organisation: Coordination
of Section COVRIIN and Work in Office of STAKOB (Competence and Treatment Centres
for high consequence infectious diseases) at Robert Koch Institute Centre for Biological
Threats and Special Pathogens (ZBS), Section Clinical Management and Infection Control.
Cornelius Lehane (CL): has no known conflicts of interest to declare.
Ina Monsef (IM): has no known conflicts of interest to declare. She is part of the
Cochrane Haematology editorial team, but was not involved in the editorial process
of this review.
Aesha Abu-taha (AA): has no known conflicts of interest to declare.
Andy Maun (AMa) is a member of the guideline group 'Covid 19, Ambulatory Treatment',
member of the German College of General Practitioners and Family Physicians, and affiliated
with the Practice Kreusel/Höltner, Titisee-Neustadt, Germany (employed as a General
Practitioner).
Miriam Stegemann (MSt): has no known conflicts of interest to declare.
Christine Schmucker (CS): has no known conflicts of interest to declare.
Sources of support
Internal sources
Charité –University Berlin, Germany, Germany
Department of Infectious Diseases and Respiratory Medicine, corporate member of Freie
Universität Berlin and Humboldt-Universität zu Berlin.
Medical Center - University of Freiburg, Germany
Institute for Evidence in Medicine (for Cochrane Germany Foundation)
External sources
Federal Ministry of Education and Research, Germany
Development, synthesis and translation of evidence in the COVID-19 pandemic (01KA2022).
Differences between protocol and review
There were no changes between the initial review protocol and the final review.
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Table 1
Author communication
Study ID
Date of request and question of the authors' of this review
Date when feedback was received and author response provided
Lenze 2020
9 June 2022: Question regarding the outcome 'all-cause hospitalisation', which is
mentioned in the primary study, but definite numerical data were missing.
9 June 2022: Numbers for all-cause hospitalisation: 1 participant in the fluvoxamine
and 5 participants in the placebo group.
TOGETHER 2021
27 January 2022: Question regarding the outcome 'symptom resolution' which is mentioned
in the primary study, but definite numerical data are not reported.
Feedback was not provided.
Communications are listed after considering communication date
Table 2
Fluvoxamine plus standard care compared to placebo plus standard care for outpatients
with mild COVID-19
Outcomes
Effect estimate (95% CI)
N of participants (studies)
Fluvoxamine
n/N
Placebo
n/N
Measures of heterogeneity
Comment
Need for invasive mechanical ventilation
RR: 0.77
(0.45 to 1.30)
1497a(1)
26/741
(3,5%)
34/756
(4,5%)
NA
TOGETHER 2021
no significant difference
Need for non-invasive mechanical ventilation or high flow (ventilator support)
AD: 0.00
(-8.41 to 0.49)
152 (1)
0/80
(0%)
0/72
(0%)
NA
Lenze 2020
no significant difference
Need for hospitalisation (with oxygen therapy by masks or nasal prongs)
AD: -4.21
(-13.22 to 2.04)
152 (1)
0/80
(0%)
3/72
(4.2%)
NA
Lenze 2020
no significant difference
Viral clearance (assessed with RT-PCR) at day 7
OR: 0.67
(0.42 to 1.06)
428b (1)
40/207
(19%)
58/221
(26%)
NA
TOGETHER 2021
no significant difference
AD: absolute difference; n: number of events; N: number of participants; NA: not applicable;
OR: odds ratio; RR: relative risk; RT-PCR: reverse transcription-polymerase chain
reaction
a Number of participants hospitalised.
b Number of participants available for outcome assessment.
