Use of a Combined Regimen of Fluoxetine, Prednisolone and Ivermectin in the Treatment of Mild COVID-19 to Prevent Disease Progression Progression in Papua New Guinea

The Fluo-Pred-Iver clinical trial will test the efficacy of a combined regimen of Fluoxetine, Prednisolone and Ivermectin (Fluo-Pred-Iver), as treatment for ambulatory patients with mild COVID-19. The overarching idea of the work proposed herein is to investigate the use of Fluo-Pred-Iver to treat COVID-19, conducting a randomized controlled clinical trial to evaluate a new indication for these widely available drugs. It is estimated to include 954 participants.

In this study, individuals who have a confirmed SARS-CoV-2 infection, as determined by a PCR or antigen rapid diagnostic test within the last 5 days, will be informed about the study.

Interested participants will be screened for eligibility criteria by research study staff. After review of inclusion and exclusion criteria, informed consent will be obtained. Participants who consent will be randomized to receive a combined regimen of Fluoxetine, Prednisolone and Ivermectin (Fluo-Pred-Iver), or a combined regimen of Albendazole and Vitamin C as control.

Patients will be followed remotely and/or in persona with visits on day 3, 7, 10 and 14 after inclusion. The primary objective will be to measure the proportion of a composite endpoint of moderate, severe or critical COVID-19 (as defined by NIH) and Emergency Department attendance of hospitalization, or death up to day 14. The reduction of SARS-CoV-2 viral load at day 7 measured by RT-qPCR will also be evaluated.

As secondary endpoints, the therapeutic potential of early administration of the combined regimen Fluo-Pred-Iver in reducing WHO Clinical progression scale score and the safety and tolerability of Fluo-Pred-Iver will be evaluated.

Eligibility Criteria:
Inclusion Criteria:

1. Adult male or female individuals of ≥18 years old.
2. In women of childbearing potential, negative pregnancy test at inclusion/baseline visit.
3. Has confirmed SARS-CoV-2 infection as determined by PCR, a validated NAAT (i.e., GeneXpert), or validated antigen rapid diagnostic test from nasopharyngeal swabs ≤5 days prior to inclusion/baseline visit.
4. Symptomatic with mild COVID-19 with symptoms onset date ≤ 7 days prior to inclusion/baseline visit. Mild COVID-19, as defined per NIH: Individuals who have any of the common signs and/or symptoms of COVID-19 (i.e., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnoea, or abnormal chest imaging.
5. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
6. Has understood the information provided and capable of giving informed consent.

Exclusion Criteria:

1. If female, pregnant or breastfeeding, or planning a pregnancy during the study.
2. Moderate COVID-19, as defined per NIH:

   a. Moderate COVID-19: Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.
3. Severe or critical COVID-19, as defined per NIH:

   1. Severe COVID-19: respiratory frequency \>30 breaths per minute, SpO2 \<94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) \<300 mmHg, or lung infiltrates \>50%.
   2. Critical COVID-19: respiratory failure, septic shock, and/or multiple organ dysfunction.
4. History of previous confirmed SARS-CoV-2 infection.
5. History of significantly abnormal liver function (Child Pugh C).
6. History of chronic kidney disease (CKD) ≥ stage 4 or need of dialysis treatment.
7. Any pre-existing condition that increases risk of thrombosis.
8. History of allergic reactions to ivermectin, fluoxetine, prednisolone, or vitamins C, albendazole, any of its excipients.
9. Concomitant use of medications that are highly dependent of CYP 2D6 for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events.

   1. Phenytoin
   2. Tricyclic antidepressants
   3. Antipsychotics: phenothiazines (i.e., chlorpromazine) haloperidol and most atypical (i.e., amitriptyline, aripiprazole, brexpiprazole, risperidone).
   4. Donepezil
   5. Tamoxifen
   6. Antiarrhytmics: propafenone, flecainide
   7. Amphetamine
10. Concomitant use of SSRIs, SNRIs, or tricyclic antidepressants, linezolid, or methylene blue (rationale: increased risk of serotonin syndrome or TCA overdose).
11. Concomitant use of drugs that could prolong the QT interval:

    1. Specific antipsychotics: ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol
    2. Specific antibiotics: erythromycin, gatifloxacin, moxifloxacin, sparfloxacin
    3. Class 1A antiarrhytmics: amiodarone, sotalol
12. Concomitant use of donepezil (S1R agonist) or sertraline (S1R antagonist)
13. Uncontrolled psychiatric disorders, or suicidal ideation.
14. Inability to consent and/or comply with study protocol, in the opinion of the investigator.