sElective Serotonin reuPtake inhibitoRs In posT-covid After COVID-19 (ESPRIT)

sElective Serotonin reuPtake inhibitoRs In posT-covid: ESPRIT

Fatigue, cognitive problems, post-exertional malaise (PEM) and postural orthostatic tachycardia syndrome (POTS) are common and debilitating symptoms after COVID-19. The pathophysiology of post-COVID is not well understood and there is no established biomedical treatment. Treatment options for post-COVID are thus much needed.

A promising candidate intervention is fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), that may reduce post-COVID symptoms because of its regulatory effect on the (neuro) immune system, the hypothalamic-pituitary-adrenal (HPA) axis and the tryptophan system. The investigators will randomize 160 participants to either fluvoxamine or placebo for 12 weeks.

The investigators will use advanced functional neuroimaging techniques during cognitive challenge (optional substudy) and plasma biomarkers (inflammatory markers, cortisol, serotonin, IDO-2 activity), to facilitate identifying potential mechanistic pathways of post -COVID treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: POST-Covid 19; Post-COVID; Post-COVID Conditions
• Intervention / Treatment: Drug: Fluvoxamine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam-Zuidoost, Netherlands, 1105 AZ
    • Amsterdam UMC
    • Contact: ESPRIT study team; Email: Div5-ESPRIT-studie@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention arm; Fluvoxamine.	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.
Placebo Comparator: Control arm; Placebo	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue severity	Fatigue scale of the Checklist Individual Strength (CIS-20R). This scale has a minimum score of 8 and a maximum score of 56. High score indicate worse outcome.	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
POTS (National Aeronautics and Space Administration (NASA) lean test	NASA lean test	week 12
Brain Perfusion (optional MRI substudy)	Arterial Spin Labeling	week 12
Brain functioning and connectivity (optional MRI substudy)	During resting-state and cognitive effort (challenging N-back (3-back vs. 0-back) on functional MRI	week 12
Brain metabolites and neuroinflammation (optional MRI substudy)	Magnetic Resonance Spectroscopy	week 12
Fatigue severity	Dutch-Flemish Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue short form 8a. A higher scores indicates worse outcome.	week 4, 8, 12
Cognitive functioning	Dutch-Flemish Patient-Reported Outcome Measurement Information System (PROMIS) cognitive function 8a. Higher scores indicate better functioning.	week 4, 8, 12
Cognitive functioning	Concentration score on the Checklist Individual Strength (CIS-20R). This scale has a minimum score of 5 and a maximum score of 35. A higher score indicates worse outcome.	week 4, 8, 12
PEM	DePaul Symptom Questionnaire (DSQ) Post Exertional Malaise (PEM). Higher scores indicate worse outcome.	week 4, 8, 12
POTS	DePaul Symptom Questionnaire (DSQ) Postural Orthostatic Tachycardia Syndrome (POTS). Higher scores indicate worse outcome.	week 4, 8, 12
Health-related Quality of Life	Dutch-Flemish Patient-Reported Outcome Measurement Information System (PROMIS) Profile-29. Higher scores indicate better outcome.	week 4, 8, 12
Disability	Bell disability score. The minimum score is 0. The maximum score is 100. Higher scores indicate better outcome.	week 4, 8, 12
Side effects	Antidepressant Side Effect Checklist-21 (ASEC-21). Higher scores indicate worse outcome.	week 12
Side effects	Frequency, Intensity, Burden of Side Effects Rating scale (FIBSER scale). Higher scores indicate worse outcome.	week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	(neuro) inflammation markers, corticoid receptor activity and cortisol, serotonin, IDO-2/ KP metabolites	week 12

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: January 14, 2026
• First Submitted That Met QC Criteria: January 14, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: fatigue; biomarkers; fluvoxamine; post-COVID
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Post-Acute COVID-19 Syndrome; Fatigue; Organic Chemicals; Amines; Hydroxylamines; Oximes; Fluvoxamine
• Other Study ID Numbers: 2024-519540-32-00; 11080022420014 (Other Grant/Funding Number: ZonMw)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sharing will be in accordance with Dutch privacy laws and regulations.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No