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

• ClinicalTrials.gov Identifier: NCT04531748
• Recruitment Status: Withdrawn
• First Posted: August 28, 2020
• Last Update Posted: May 10, 2021
• Sponsor: Reena Mehra, MD
• Information provided by (Responsible Party): Reena Mehra, MD, The Cleveland Clinic

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19	Drug: Toremifene; Drug: Melatonin; Other: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The Medical Safety Officer will not be blinded.
• Primary Purpose: Treatment
• Official Title: Selective Estrogen Modulation and Melatonin in Early COVID-19
• Estimated Study Start Date: December 2021
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: September 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Peak increase in COVID-19 Sign and Symptom score [ Time Frame: Screening to 28 days ]
   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.

Secondary Outcome Measures :

1. Nadir Oxygen Saturation [ Time Frame: Day 1 through day 14 ]
   Daily mean values
2. Peak Heart Rate [ Time Frame: Day 1 through day 14 ]
   Daily mean values
3. Time to COVID-19 Sign and Symptom score resolution [ Time Frame: Screening to 28 days ]
   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.
4. Time to WHO 7-point ordinal scale score of 3 or higher [ Time Frame: Day 1 to Day 30 ]
   1. not hospitalized, no limitation of activities (or resumption of normal activity)
   2. not hospitalized but limitation on activities
   3. hospitalized, not requiring supplemental oxygen
   4. hospitalized, requiring supplemental oxygen (low-flow, e.g., nasal prong)
   5. hospitalized, requiring non-invasive ventilation and/or high-flow oxygen
   6. hospitalized, on invasive ventilation or ECMO
   7. death

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Sponsors and Collaborators

Reena Mehra, MD

Investigators

• Principal Investigator: Reena Mehra, MD; The Cleveland Clinic

More Information

• Responsible Party: Reena Mehra, MD, Director, Sleep Disorders Research, Neurological Institute, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT04531748
• Other Study ID Numbers: 20-842
• First Posted: August 28, 2020
• Last Update Posted: May 10, 2021
• Last Verified: May 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Reena Mehra, MD, The Cleveland Clinic:

covid19; coronavirus

Additional relevant MeSH terms:

COVID-19; Melatonin; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Toremifene; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Central Nervous System Depressants; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Bone Density Conservation Agents