Selective Estrogen Modulation and Melatonin in Early COVID-19

Study Overview
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Brief Summary
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This study is a randomized, double-blind, controlled clinical trial to evaluate the effects of toremifene and/or melatonin in adults with mild COVID-19.

Detailed Description
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This study is a randomized, double-blind, controlled clinical trial to evaluate the effects of a 14 day intervention of toremifene plus melatonin or melatonin in adults with mild COVID-19. The study will evaluate the progression of clinical signs and symptoms (fever, dyspnea, cough, fatigue daily score) and any adverse outcomes in comparison to placebo for 30 days. The successful completion of this project offers high potential to identify effective treatment (e.g., toremifene plus melatonin and/or melatonin) rapidly for patients with early COVID-19 and to provide, important, fundamental mechanistic insights.

Official Title
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Selective Estrogen Modulation and Melatonin in Early COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Drug: Toremifene
* Drug: Melatonin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical testing positive for SARS-Cov-2 by standard RT-PCR or equivalent test Willing and able to give informed consent for participation in the study and agrees with the study and its conduct Age>18 years Fluency in English or Spanish language, functional literacy Able to swallow pills COVID-19 Daily Sign and Symptom score of 2-8 Exclusion Criteria: History of deep venous thrombosis or pulmonary embolism Hypercoagulable disorders (e.g. lupus anticoagulant, deficiency of protein C or S) Embolic stroke Liver disease History of endometrial cancer Menopausal hormone therapy or oral, injectable or transdermal contraceptives Depression which is not optimally treated (assessed via medical record and patient will be asked if she/he feels that depression is optimally treated) Medications which prolong the QT interval (e.g. hydroxychloroquine or azithromycin) or those with long QT syndrome (heritable or acquired). Examples of other medications which prolong the QT interval include: Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron) (Please refer to Appendix for detailed list of medications) Inability to participate in follow up assessment Dementia/cognitive dysfunction Pregnancy (pregnancy testing will be performed to determine eligibility) Breastfeeding Participating in other COVID-19 trials Immunodeficiency (including HIV, Hepatitis C, bone marrow transplant history, on immunosuppressant medications) Current hospitalization Seizure disorder History of rheumatoid arthritis Heart failure (NYHA Class III or IV) Current diagnosis of renal insufficiency/failure QTc >470ms per 12-lead ECG Calcium >10.2mg/dL AST or ALT > 2x upper limit of normal (ULN) D-dimer >= 1000 u/L Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 On other treatment(s) for COVID-19 (e.g. hydroxychloroquine, remdesivir) Anticoagulant medications (e.g. coumadin, glycoprotein IIa/IIIb inhibitors) Clinical signs of severe or critical severity of COVID-19 (e.g. shortness of breath at rest, Respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air) Use of supplemental oxygen Moderate to severe pulmonary disease up to PI discretion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Toremifene + Melatonin<br>100mg oral Melatonin on Days 1 & 2 (40mg in the morning and 60mg in the evening), 60 mg on Days 3-14, (20mg in the morning and 40mg in the evening). 60mg oral toremifene daily days 1-14. | Drug: Toremifene<br>* Participants will be instructed to take 60mg of oral toremifene capsule daily, 30 minutes before bedtime.<br>Drug: Melatonin<br>* Participants will be instructed to take the pills orally around the same time in the morning and 30 minutes prior to bedtime in the evening.<br>|
| Active Comparator: Melatonin + Placebo<br>100mg oral Melatonin on Days 1 & 2 (40mg in the morning and 60mg in the evening) and 60 mg on Days 3-14, (20mg in the morning and 40mg in the evening). | Drug: Melatonin<br>* Participants will be instructed to take the pills orally around the same time in the morning and 30 minutes prior to bedtime in the evening.<br>Other: Placebo<br>* Oral placebo will be used with the same number and appearance to the pills as the interventions.<br>|
| Placebo Comparator: Placebo<br>Oral placebo will be used with the same number and appearance to the pills as the interventions | Other: Placebo<br>* Oral placebo will be used with the same number and appearance to the pills as the interventions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak increase in COVID-19 Sign and Symptom score | Score total of 0-12 assessed daily. Each category based on severity of symptoms of Cough, Shortness of breath, Fatigue/tiredness and daily temperature on a rating scale of 0-3. | Screening to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nadir Oxygen Saturation | Daily mean values | Day 1 through day 14 | 
| Peak Heart Rate | Daily mean values | Day 1 through day 14 | 
| Time to COVID-19 Sign and Symptom score resolution | Score total of 0-12 assessed daily. Each category based on severity of symptoms of Cough, Shortness of breath, Fatigue/tiredness and daily temperature on a rating scale of 0-3. | Screening to 28 days | 
| Time to WHO 7-point ordinal scale score of 3 or higher | not hospitalized, no limitation of activities (or resumption of normal activity) not hospitalized but limitation on activities hospitalized, not requiring supplemental oxygen hospitalized, requiring supplemental oxygen (low-flow, e.g., nasal prong) hospitalized, requiring non-invasive ventilation and/or high-flow oxygen hospitalized, on invasive ventilation or ECMO death | Day 1 to Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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covid19, coronavirus