Selective Estrogen Modulation and Melatonin in Early COVID-19 (SENTINEL)

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.

Study Overview

• Status: Withdrawn
• Conditions: Covid19
• Intervention / Treatment: Drug: Toremifene; Drug: Melatonin; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Toremifene + Melatonin; 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; Participants will be instructed to take 60mg of oral toremifene capsule daily, 30 minutes before bedtime.; Drug: Melatonin; 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.
Active Comparator: Melatonin + Placebo; 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; 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.; Other: Placebo; Oral placebo will be used with the same number and appearance to the pills as the interventions.
Placebo Comparator: Placebo; Oral placebo will be used with the same number and appearance to the pills as the interventions	Other: Placebo; Oral placebo will be used with the same number and appearance to the pills as the interventions.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Reena Mehra, MD
• Investigators: Principal Investigator: Reena Mehra, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2021
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: August 27, 2020
• First Submitted That Met QC Criteria: August 27, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2021
• Last Update Submitted That Met QC Criteria: May 5, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: covid19; coronavirus
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Hormone Antagonists; Bone Density Conservation Agents; Antioxidants; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Melatonin; Toremifene
• Other Study ID Numbers: 20-842

Drug and device information, study documents

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