Investigator-initiated clinical trial on the effect of fluvoxamine to prevent exacerbation of COVID-19

JRCT ID: jRCT2031220558

Registered date:06/01/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: COVID-19
• Date of first enrollment: 04/01/2023
• Target sample size: 80
• Study type: Interventional

Intervention(s)

[Test treatment group]
"Fluvoxamine maleate (25mg) + lactose capsule"
Administer a single initial daily dose of 50 mg (2 capsules of 25 mg) orally. From the next day, 75 mg once (3 capsules of 25 mg), twice daily orally, 150 mg (6 capsules of 25 mg)/day.

[Control group (placebo)]
"lactose capsule"
Placebo (2 capsules) is orally administered once daily for the first dose. From the next day, once a placebo (3 capsules) will be administered orally twice a day, 6 capsules/day.

Outcome(s)

Primary Outcome

A score of 3 or higher (SpO2 =< 93%, but oxygen is not administered) is defined as "clinical exacerbation" and the exacerbation rate is evaluated.

[Criteria for clinical symptom assessment score]
(0) SpO2>=96% without subjective symptoms.
(1) Subjective symptoms but SpO2>=96%.
(2) 93%<SpO2<96% regardless of subjective symptoms.
(3) SpO2 =< 93%, but oxygen is not administered.
(4) SpO2 =< 93% and oxygen is being administered.
(5) Using non-invasive ventilation or high-flow oxygen equipment.
(6) Management by invasive mechanical ventilation or ECMO.
(7) Death

Secondary Outcome

[Secondary efficacy endpoints]
1) Body temperature at each time point.
2) Presence or absence of subjective symptoms at each time point: cough, shortness of breath, sputum, arthralgia, muscle pain, muscle weakness, fatigue/malaise, nasal discharge, sore throat, headache, chest pain, palpitations, nausea/vomiting, abdominal pain, diarrhea, Anosmia (loss of smell), loss of taste (loss of taste), hair loss, forgetfulness (memory impairment), poor concentration, insomnia.
3) Percentage of all deaths: deaths from all causes within 15 days from enrollment.
4) Days to clinical deterioration meeting both of the following two conditions in 15 days.
(1) Based on the clinical judgment of the investigator or sub-investigator, hospitalization or extended hospitalization at a COVID-19 medical institution is required for the treatment of respiratory failure, dyspnea, or pneumonia.
(2) Oxygen replacement therapy is required to maintain percutaneous arterial oxygen saturation SpO2 <= 93% (indoor) or SpO2 >93%. (*Equivalent to the primary endpoint of the STOP COVID trial in the United States)
5) Pneumonia incidence: number of days from enrollment to onset of pneumonia.
6) Percentage of people with pneumonia: Onset of pneumonia judged to be due to COVID-19 from the time of enrollment to 15 days later.
(Definition of pneumonia: presence of pneumonia in plain chest X-ray)
7) Oxygen administration rate: number of days from the time of registration until the start of "oxygen administration lasting for 24 hours or more".
8) Percentage of oxygen users: start of "oxygen administration for more than 24 hours" from the time of enrollment to 15 days later.
9) WHO clinical progression scale score (11-step clinical symptom evaluation).
10) Antipyretic rate: Number of days from enrollment until body temperature recovers to less than 37.0 deg C.
11) Total disappearance of clinical symptoms: Number of days until all clinical symptoms resolved due to COVID-19.
12) Improvement rate for each symptom: Number of days until improvement of clinical symptoms judged to be due to COVID-19 (evaluated by symptom content).
(*Definition of symptom improvement: Body temperature below 37.0 deg C, SpO2 >= 96%, reduction of all subjective symptoms by 50% or more for 48 hours or longer).
13) Quality of life (QOL): EQ-5D-5L (Euroquol5D).

[Secondary safety endpoints]
1) Depressive symptoms (PHQ-9) psychological rating scale (before treatment, 15 days after, follow-up period: 14 days after the end of study drug administration (Day 29), 28 days after administration (Day 43)).
2) Evaluation of withdrawal symptoms after study drug discontinuation by signs and symptoms after discontinuation (DESS) (at the end of study drug administration (Day 15), follow-up period: 1 week after discontinuation (Day 22), 2 weeks after discontinuation (Day 29). When study drug administration is discontinued: at the time of study drug administration discontinuation, 1 week after discontinuation, 2 weeks after discontinuation).
3) Serotonin syndrome-related symptoms: (Once daily during study drug administration, Day 1 to Day 15)
- Psychiatric/neurological/muscular symptoms: Presence or absence of anxiety, confusion, irritability, excitement, moving around, twitching, trembling, stiffness.
- Autonomic nerve symptoms: Presence or absence of sweating, fever, diarrhea, and rapid pulse.
- Other symptoms related to SSRI use: dry mouth, constipation, drowsiness, presence or absence.

Key inclusion & exclusion criteria

• Age minimum: >= 25age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients who meet all of the following conditions are eligible.
1) Patients with symptoms of mild to moderate I (no respiratory failure) (corresponding to scores 1 and 2 of the primary endpoint) in the Guidelines for medical care for new coronavirus infection (COVID-19) (version 8.1).
2) Patients with confirmed fever (37.5 degree or higher) within 72 hours prior to obtaining consent.
3) Patients with one or more of the following symptoms at the time of screening
Cough, shortness of breath, myalgia, nasal discharge, sore throat, headache, nausea/vomiting, abdominal pain, diarrhea, anosmia (loss of sense of smell), loss of taste (loss of taste)
4) Patients whose SARS-CoV-2 was detected by PCR test (nucleic acid amplification method) or antigen test from samples derived from the upper and lower respiratory tract within 3 days before obtaining informed consent.
5) Patients of Japanese nationality who are at least 25 years of age at the time of consent.
6) Patients who have given their voluntary written informed consent after receiving a sufficient explanation regarding their participation in this clinical trial.

Exclude criteria

Those who meet any of the following conditions are not eligible.
1) Patients who have passed more than 8 days from symptom onset to registration.
2) Patients with a percutaneous arterial oxygen saturation (SpO2) of 93% or less.
3) Suicidal patients who meet any of the following criteria:
- Subjects who currently or within the past 6 months had suicidal ideation with any form of suicidal intention according to the Columbia Suicide Rating Scale (C-SSRS). (Item 4 [Some intention to commit suicide but no specific plan] or Item 5 [Active suicidal ideation - with specific plan and intention] equals YES. Only subjects who meet only Item 1 to Item 3 in the suicidal ideation section can be enrolled at the discretion of the investigator or subinvestigator.)
- Subjects who have experienced any suicidal behavior according to C-SSRS within the past year.
4) Patients with psychiatric disorders such as schizophrenia, mood disorders (bipolar disorder and depression), and personality disorders, and patients with a history of them.
5) Patients with convulsive diseases such as epilepsy or a history of these diseases.
6) Patients with cerebral organic disorders or comorbid disorders with high impulsivity.
7) Patients with severe heart disease (fatal arrhythmia, pacemaker-introduced patients).
8) Patients with a history or complication of malignant tumor. However, patients who have a history but have not recurred for 5 years or more can be registered.
9) Patients with a history of bleeding disorders or a bleeding diathesis.
10) Patients with glaucoma or intraocular hypertension.
11) Dialysis patients with severe renal dysfunction.
12) Patients with severe hepatic dysfunction (AST or ALT exceeding 5 times the institution standard).
13) Patients with uncontrolled diabetes mellitus (diabetic patients with HbA1c 9.0% or more despite being treated for diabetes).
14) Women who are breastfeeding, pregnant, or may become pregnant.
15) Immunocompromised (organ transplantation, bone marrow transplantation, AIDS, biologics and/or high-dose steroids (>20 mg prednisolone per day)).
16)Patients who are receiving drugs that are contraindicated for fluvoxamine (pimozide, tizanidine hydrochloride, ramelteon, melatonin).
17) Patients within 4 weeks after discontinuation of fluvoxamine.
18) Patients with a history of serotonin syndrome.
19) Patients who are receiving monoamine oxidase (MAO) inhibitors (selegiline hydrochloride, rasagiline mesylate, safinamide mesylate), drugs with serotonergic effects that may cause serotonin syndrome, or within 2 weeks after discontinuation .
20)Patients who are on or within 2 weeks after discontinuation of psychotropic drugs that have or may have agonist/antagonist effects on sigma-1 receptors.
21)Patients who are receiving approved drugs for the treatment of COVID-19 mild to moderate I, or within 2 weeks after discontinuing the drug.
22) Patients who are otherwise judged by the investigator or subinvestigator to be unsuitable for the safe conduct of this study.

Related Information

• Primary Sponsor: Niitsu Tomihisa