Fatigue, cognitive problems, post-exertional malaise (PEM) and postural orthostatictachycardia syndrome (POTS) are common and debilitating symptoms after COVID-19. Thepathophysiology of post-COVID is not well understood and there is no establishedbiomedical treatment. Treatment options for post-COVID are thus much needed.A promising candidate intervention is fluvoxamine, a selective serotonin reuptakeinhibitor (SSRI), that may reduce post-COVID symptoms because of its regulatory effect onthe (neuro) immune system, the hypothalamic-pituitary-adrenal (HPA) axis and thetryptophan system. The investigators will randomize 160 participants to eitherfluvoxamine or placebo for 12 weeks.The investigators will use advanced functional neuroimaging techniques during cognitivechallenge (optional substudy) and plasma biomarkers (inflammatory markers, cortisol,serotonin, IDO-2 activity), to facilitate identifying potential mechanistic pathways ofpost -COVID treatment.
In this randomized placebo-controlled trial, the investigators will study the
effectiveness of fluvoxamine in reducing fatigue severity (primary outcome), cognitive
problems, PEM and POTS after 12 weeks of treatment in 160 post-COVID patients.
Moreover, the investigators will study treatment-emergent changes in plasma biomarkers,
including blood-based neuro)inflammatory markers, cortisol, serotonin, aryl hydrocarbon
receptor -indoleamine 2,3-dioxygenase-2 (IDO-2) and kynurenine pathway (KP) metabolites
for potential mechanistic pathways of post-COVID treatment.
Numerous studies have indicated involvement of brain dysfunction in post COVID, which
also relate to the degree of symptom severity (e.g. fatigue / cognitive problems). In an
optional neuro-imaging sub-study, the investigators will use functional neuroimaging
techniques with and without cognitive challenge to gain a better understanding of the
brain functioning and structure in long COVID during fluvoxamine treatment versus
placebo.
Objectives:
- To determine if fluvoxamine treatment (50 mg to 200 mg daily dosing) results in
lower levels of fatigue severity than placebo after 12 weeks of treatment (primary).
- To determine if fluvoxamine treatment results in lower levels of PEM and POTS and a
better cognitive functioning and health-related quality of life (HRQL) than placebo.
- To determine if changes in symptoms, i.e. fatigue severity, PEM, POTS, cognitive
symptoms, are related to changes in biomarkers, i.e., (neuro)inflammation markers,
cortisol, serotonin and IDO-2 -KP metabolites.
- To determine if biomarkers, i.e., (neuro)inflammation markers, cortisol, serotonin
and IDO-2- KP metabolites, change from baseline to week 12 in participants who
received fluvoxamine.
Optional Neuro-imaging sub-study:
-To determine which changes occur on functional brain imaging, brain metabolites and
neuroinflammation during cognitive challenge and to determine if this brain response to
cognitive challenge changes after fluvoxamine treatment versus placebo.
Drug: Fluvoxamine
Subject are randomized in a double-blind manner (1:1 ratio) between fluvoxamine and
placebo. During the first week subjects will receive a low dose daily dose of fluvoxamine
of 25 mg or placebo. In the second week, subjects will receive a daily dose of 50 mg or
placebo. From week 3 onwards, the fluvoxamine or placebo dose is increased by daily 50 mg
every 6 days in a blinded manner but will not be further increased if participants are
unwilling to accept a dose increase. For doses higher than 100 mg per day, dosing is done
twice daily. The dose is increased to a maximum of 200 mg per day (i.e. 100 mg bid). The
minimal daily dose is 50 mg.
Drug: Placebo
Subject are randomized in a double-blind manner (1:1 ratio) between fluvoxamine and
placebo. During the first week subjects will receive a low dose daily dose of fluvoxamine
of 25 mg or placebo. In the second week, subjects will receive a daily dose of 50 mg or
placebo. From week 3 onwards, the fluvoxamine or placebo dose is increased by daily 50 mg
every 6 days in a blinded manner but will not be further increased if participants are
unwilling to accept a dose increase. For doses higher than 100 mg per day, dosing is done
twice daily. The dose is increased to a maximum of 200 mg per day (i.e. 100 mg bid). The
minimal daily dose is 50 mg.
Inclusion Criteria:
- Adults aged 18 to 70 years
- Severely fatigued (CIS fatigue score ≥ 35) at screening
- Fatigue started/increased significantly after Covid-19 (self-declared)
- Fatigue symptoms must be present for at least 3 months following the acute
infection.
- Self-reported confirmation of having a SARS-CoV-2 infection by: Positive SARS-CoV-2
nucleic acid amplification test (NAAT), such as PCR; Positive SARS-CoV-2 rapid
diagnostic test, including home-administered tests; COVID-19 diagnosis by a medical
specialist (GP or in-hospital), based on the above or other clinical test or
assessments. The above information will not be verified in medical records.
- Command of Dutch or English language to complete questionnaires
- Able to participate in video calling.
- Willing and able to provide informed consent
- Allowing the trial team to exchange medical information that is relevant for the
participants' safety and trial assessments with their GP and pharmacy.
Exclusion Criteria:
- Use of medication with interaction with fluvoxamine that cannot be discontinued
- Hospitalized in the acute phase of Covid-19
- Psychiatric/somatic disorders that could explain the severity of fatigue
- Neurodegenerative disorders (i.e. M Parkinson, Multiple sclerosis, M Alzheimer)
- Suicidality (current or recent) (according to WHO suicide screener)
- Starting or started with other medication intended to reduce post-covid symptoms
during the last 2 months
- Pregnancy (a positive urine or serum pregnancy test) or unwilling to use standard
contraception
- Brugada- or Long QT interval syndrome
- epilepsy, porphyria, history of severe liver impairment
- known allergies to fluvoxamine or placebo/excipients
- known current alcohol or drug use problems.
- Bleeding disorders and past medical history of bleeding gastric or duodenal ulcers
or other significant bleeding disorders
- claustrophobia (optional MRI substudy)
- having metal implants (optional MRI substudy)
- inability to lay still for 45 minutes (optional MRI substudy)
- Neurotrauma/ large stroke or brain abnormalities interfering with image analyses
(optional MRI substudy)
- Inability to come to the Amsterdam UMC (optional MRI substudy).
Amsterdam UMC
Amsterdam-Zuidoost, Netherlands
Investigator: ESPRIT study team
Div5-ESPRIT-studie@amsterdamumc.nl
Not Provided