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• Recruitment Status: Withdrawn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

Tracking Information

• First Submitted Date: August 27, 2020
• First Posted Date: August 28, 2020
• Last Update Posted Date: May 10, 2021
• Estimated Study Start Date: December 2021
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2020)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 27, 2020)

• Nadir Oxygen Saturation [ Time Frame: Day 1 through day 14 ]
  Daily mean values
• Peak Heart Rate [ Time Frame: Day 1 through day 14 ]
  Daily mean values
• 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.
• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Selective Estrogen Modulation and Melatonin in Early COVID-19
• Official Title: Selective Estrogen Modulation and Melatonin in Early COVID-19
• 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.

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
• Study Phase: Phase 2

Study Design

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

• Condition: Covid19

Intervention

• 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.
• Other: Placebo
  Oral placebo will be used with the same number and appearance to the pills as the interventions.

Study Arms

• 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.

  Interventions:

  • Drug: Toremifene
  • Drug: Melatonin
• 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).
  Interventions:

  • Drug: Melatonin
  • Other: Placebo
• Placebo Comparator: Placebo
  Oral placebo will be used with the same number and appearance to the pills as the interventions
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: May 5, 2021): 0
• Original Estimated Enrollment (submitted: August 27, 2020): 390
• Estimated Study Completion Date: September 2022
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04531748
• Other Study ID Numbers: 20-842
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Reena Mehra, MD, The Cleveland Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: Reena Mehra, MD
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: The Cleveland Clinic
• Verification Date: May 2021