Back to resultsDose-Ranging Study to Assess the Safety and Efficacy of Melatonin in Outpatients Infected With COVID-19
Primary Purpose
COVID-19
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Melatonin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 focused on measuring Melatonin, COVID-19, outpatient, SARS-CoV-2
Eligibility Criteria
Inclusion Criteria:
- Male or non-pregnant female adult ≥18 years of age at time of enrollment.
- Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study.
- Positive testing for COVID-19 infection by standard RT-PCR assay or equivalent test.
- Meets criteria for mild or moderate COVID-19 disease
- Subject provides written informed consent prior to initiation of any study procedures.
- Understands and agrees to comply with planned study procedures.
- Agrees to the collection and storage of saliva samples per protocol.
- Subject can provide an emergency contact who the study team can contact in case the subject is not reachable on any of the study visits.
Exclusion Criteria:
- Severe (eGFR<30 ml/min) and moderate (eGFR 30-60 ml/min) chronic kidney disease or requiring dialysis
- Severe hepatic insufficiency defined as one or more of the following: Cirrhosis diagnosis, Serum ALT > 3x ULN or Alkaline phosphatase >3x ULN or bilirubin >2x ULN in the absence of Gilbert's or hemolysis, Uncontrolled acute or chronic liver disease (e.g. acute hepatitis A, unstable autoimmune hepatitis)
- Pregnancy or breast feeding.
- History of a seizure disorder.
- Patient is taking Fluvoxamine, Capmatinib, Ciprofloxacin (Systemic), Deferasirox, Givosiran, Methoxsalen (Systemic), Mexiletine, Rucaparib, Stiripentol, Thiabendazole, Vemurafenib, Methoxsalen, Sodium oxybate or Echinacea.
- Allergy to the study medication
- Currently taking melatonin
- Currently taking high dose (>500 mg/day) Vitamin C.
- Meets criteria for Severe or Critical COVID-19
Sites / Locations
- University at Buffalo
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Experimental
Experimental
Arm Label
Placebo
Melatonin 3 mg
Melatonin 30 mg
Arm Description
Placebo capsules will be prepared using hypromellose capsules, filled using microcrystalline cellulose. This is the same excipient used in the preparation of the interventional drug. Placebo will be administered orally three times a day for 14 days in the same regimen used for the intervention.
Melatonin capsules will be prepared using hypromellose capsules containing 3 mg of the active component and identical excipient (Microcrystalline Cellulose) used in the placebo preparation. Melatonin will be administered orally three times a day for 14 days.
Melatonin capsules will be prepared using hypromellose capsules containing 30 mg of the active component and identical excipient (Microcrystalline Cellulose) used in the placebo preparation. Melatonin will be administered orally three times a day for 14 days.
Outcomes
Primary Outcome Measures
Cumulative Incidence of Treatment-Emergent Adverse Events
Evaluate the incidence of serious adverse effects and discontinuation secondary to toxicity through 42 days of follow-up as compared to the control arm as assessed by: Cumulative incidence of serious adverse events (SAEs), Cumulative incidence of Grade 3 and 4 adverse events (AEs), Discontinuation or temporary suspension of the investigational medication (for any reason).
Secondary Outcome Measures
Incidence of COVID-19 related hospitalization
Incidence of COVID-19 related hospitalization at 42 days
COVID-19 related symptoms
COVID-19 related symptoms as self-reported and on interview.
Rate of resolution of COVID-19 related symptoms
Change from baseline (day 1) as assessed to days 3, 7, 14, 28 and 42
Mortality
42-day mortality
Full Information
NCT ID
NCT04784754
First Posted
February 22, 2021
Last Updated
July 19, 2022
Sponsor
State University of New York at Buffalo
Collaborators
National Center for Advancing Translational Sciences (NCATS)
1. Study Identification
Unique Protocol Identification Number
NCT04784754
Brief Title
Dose-Ranging Study to Assess the Safety and Efficacy of Melatonin in Outpatients Infected With COVID-19
Official Title
A Pilot Placebo-controlled Randomized Double-blind Trial of Melatonin in Outpatients With COVID-19 Infection
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Withdrawn
Why Stopped
lack of subject enrollment
Study Start Date
April 1, 2021 (Actual)
Primary Completion Date
September 30, 2022 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
State University of New York at Buffalo
Collaborators
National Center for Advancing Translational Sciences (NCATS)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
A pilot placebo-controlled randomized double-blind trial of Melatonin in outpatients with COVID-19 infection to evaluate Safety, Efficacy and Dose-ranging.
Detailed Description
Studies have shown in the blood of patients with COVID-19 there was a marked increase in the cytokines and chemokines interleukin 1β (IL-1β), interferon-γ (IFN-γ), interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interleukin-4 (IL-4). Consequently, treatments that reduce cytokine/chemokine production that result in a less severe course of disease could be potentially beneficial. Melatonin, a pineal hormone, has been shown to have anti-inflammation, anti-oxidation and immune enhancing features. In multiple animal models of lung injury, Melatonin supplementation has been shown to decrease the number of inflammatory cells, reduce the levels of the cytokines IL-4, IL-5, IL-13 and TNF-a and reduce nitric oxide and hydroxyl radical concentrations. We propose a dose ranging pilot study to assess the safety and efficacy of melatonin in reducing hospitalization in COVID-19 patients with mild-moderate disease. A total of 50 participants will be randomized to the intervention arm (melatonin: 3 mg, or 30 mg three times a day for 14 days) or control arm (placebo) in a 2:2:1 fashion using a permuted block randomization scheme. Analyses will be performed with a focus on estimation of specific clinically important parameters, including safety and preliminary evidence of activity, for planning of a subsequent definitive comparative trial designed to fully assess efficacy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
Melatonin, COVID-19, outpatient, SARS-CoV-2
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Placebo-controlled randomized double-blind trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo capsules will be prepared using hypromellose capsules, filled using microcrystalline cellulose. This is the same excipient used in the preparation of the interventional drug. Placebo will be administered orally three times a day for 14 days in the same regimen used for the intervention.
Arm Title
Melatonin 3 mg
Arm Type
Experimental
Arm Description
Melatonin capsules will be prepared using hypromellose capsules containing 3 mg of the active component and identical excipient (Microcrystalline Cellulose) used in the placebo preparation. Melatonin will be administered orally three times a day for 14 days.
Arm Title
Melatonin 30 mg
Arm Type
Experimental
Arm Description
Melatonin capsules will be prepared using hypromellose capsules containing 30 mg of the active component and identical excipient (Microcrystalline Cellulose) used in the placebo preparation. Melatonin will be administered orally three times a day for 14 days.
Intervention Type
Drug
Intervention Name(s)
Melatonin
Other Intervention Name(s)
5-methoxy-N-acetyl tryptamine
Intervention Description
Melatonin capsules will be prepared using hypromellose capsules containing 3 mg or 30 mg of the active component and identical excipient (Microcrystalline Cellulose) used in the placebo preparation. Melatonin will be administered orally three times a day for 14 days.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Microcrystalline Cellulose
Intervention Description
Placebo capsules will be prepared using hypromellose capsules, filled using microcrystalline cellulose. This is the same excipient used in the preparation of the interventional drug. Placebo will be administered orally three times a day for 14 days in the same regimen used for the intervention.
Primary Outcome Measure Information:
Title
Cumulative Incidence of Treatment-Emergent Adverse Events
Description
Evaluate the incidence of serious adverse effects and discontinuation secondary to toxicity through 42 days of follow-up as compared to the control arm as assessed by: Cumulative incidence of serious adverse events (SAEs), Cumulative incidence of Grade 3 and 4 adverse events (AEs), Discontinuation or temporary suspension of the investigational medication (for any reason).
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Incidence of COVID-19 related hospitalization
Description
Incidence of COVID-19 related hospitalization at 42 days
Time Frame
42 days
Title
COVID-19 related symptoms
Description
COVID-19 related symptoms as self-reported and on interview.
Time Frame
42 days
Title
Rate of resolution of COVID-19 related symptoms
Description
Change from baseline (day 1) as assessed to days 3, 7, 14, 28 and 42
Time Frame
up to 42 days
Title
Mortality
Description
42-day mortality
Time Frame
42 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or non-pregnant female adult ≥18 years of age at time of enrollment.
Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study.
Positive testing for COVID-19 infection by standard RT-PCR assay or equivalent test.
Meets criteria for mild or moderate COVID-19 disease
Subject provides written informed consent prior to initiation of any study procedures.
Understands and agrees to comply with planned study procedures.
Agrees to the collection and storage of saliva samples per protocol.
Subject can provide an emergency contact who the study team can contact in case the subject is not reachable on any of the study visits.
Exclusion Criteria:
Severe (eGFR<30 ml/min) and moderate (eGFR 30-60 ml/min) chronic kidney disease or requiring dialysis
Severe hepatic insufficiency defined as one or more of the following: Cirrhosis diagnosis, Serum ALT > 3x ULN or Alkaline phosphatase >3x ULN or bilirubin >2x ULN in the absence of Gilbert's or hemolysis, Uncontrolled acute or chronic liver disease (e.g. acute hepatitis A, unstable autoimmune hepatitis)
Pregnancy or breast feeding.
History of a seizure disorder.
Patient is taking Fluvoxamine, Capmatinib, Ciprofloxacin (Systemic), Deferasirox, Givosiran, Methoxsalen (Systemic), Mexiletine, Rucaparib, Stiripentol, Thiabendazole, Vemurafenib, Methoxsalen, Sodium oxybate or Echinacea.
Allergy to the study medication
Currently taking melatonin
Currently taking high dose (>500 mg/day) Vitamin C.
Meets criteria for Severe or Critical COVID-19
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Margarita L Dubocovich, PhD
Organizational Affiliation
University at Buffalo
Official's Role
Principal Investigator
Facility Information:
Facility Name
University at Buffalo
City
Buffalo
State/Province
New York
ZIP/Postal Code
14203
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31210428
Citation
Aliasgharzadeh A, Farhood B, Amini P, Saffar H, Motevaseli E, Rezapoor S, Nouruzi F, Shabeeb DH, Eleojo Musa A, Mohseni M, Moradi H, Najafi M. Melatonin Attenuates Upregulation of Duox1 and Duox2 and Protects against Lung Injury following Chest Irradiation in Rats. Cell J. 2019 Oct;21(3):236-242. doi: 10.22074/cellj.2019.6207. Epub 2019 Jun 15.
Results Reference
background
PubMed Identifier
26692007
Citation
Andersen LP, Gogenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5.
Results Reference
background
PubMed Identifier
30328031
Citation
Bazyar H, Gholinezhad H, Moradi L, Salehi P, Abadi F, Ravanbakhsh M, Zare Javid A. The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial. Inflammopharmacology. 2019 Feb;27(1):67-76. doi: 10.1007/s10787-018-0539-0. Epub 2018 Oct 16.
Results Reference
background
PubMed Identifier
20964706
Citation
Chen CF, Wang D, Reiter RJ, Yeh DY. Oral melatonin attenuates lung inflammation and airway hyperreactivity induced by inhalation of aerosolized pancreatic fluid in rats. J Pineal Res. 2011 Jan;50(1):46-53. doi: 10.1111/j.1600-079X.2010.00808.x. Epub 2010 Oct 22.
Results Reference
background
PubMed Identifier
15919935
Citation
Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, Wu MH, Chan KH, Yuen KY, Gordon S, Guan Y, Peiris JS. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol. 2005 Jun;79(12):7819-26. doi: 10.1128/JVI.79.12.7819-7826.2005.
Results Reference
background
PubMed Identifier
31986264
Citation
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
Results Reference
background
PubMed Identifier
22377793
Citation
Kim JY, Lee YD, Kim BJ, Kim SP, Kim DH, Jo KJ, Lee SK, Lee KH, Baik HW. Melatonin improves inflammatory cytokine profiles in lung inflammation associated with sleep deprivation. Mol Med Rep. 2012 May;5(5):1281-4. doi: 10.3892/mmr.2012.814. Epub 2012 Feb 29.
Results Reference
background
PubMed Identifier
15860669
Citation
Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, Nicholls JM, Peiris JS, Lau YL. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood. 2005 Oct 1;106(7):2366-74. doi: 10.1182/blood-2004-10-4166. Epub 2005 Apr 28.
Results Reference
background
PubMed Identifier
18805959
Citation
Pedreira PR, Garcia-Prieto E, Parra D, Astudillo A, Diaz E, Taboada F, Albaiceta GM. Effects of melatonin in an experimental model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L820-7. doi: 10.1152/ajplung.90211.2008. Epub 2008 Sep 19.
Results Reference
background
PubMed Identifier
29990691
Citation
Peng Z, Zhang W, Qiao J, He B. Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1beta in rats with COPD. Int Immunopharmacol. 2018 Sep;62:23-28. doi: 10.1016/j.intimp.2018.06.033. Epub 2018 Jun 30.
Results Reference
background
PubMed Identifier
30595364
Citation
Sanchez-Lopez AL, Ortiz GG, Pacheco-Moises FP, Mireles-Ramirez MA, Bitzer-Quintero OK, Delgado-Lara DLC, Ramirez-Jirano LJ, Velazquez-Brizuela IE. Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Arch Med Res. 2018 Aug;49(6):391-398. doi: 10.1016/j.arcmed.2018.12.004. Epub 2018 Dec 27.
Results Reference
background
PubMed Identifier
19567158
Citation
Shang Y, Xu SP, Wu Y, Jiang YX, Wu ZY, Yuan SY, Yao SL. Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J (Engl). 2009 Jun 20;122(12):1388-93.
Results Reference
background
PubMed Identifier
25161126
Citation
Shin IS, Park JW, Shin NR, Jeon CM, Kwon OK, Kim JS, Kim JC, Oh SR, Ahn KS. Melatonin reduces airway inflammation in ovalbumin-induced asthma. Immunobiology. 2014 Dec;219(12):901-8. doi: 10.1016/j.imbio.2014.08.004. Epub 2014 Aug 10.
Results Reference
background
PubMed Identifier
30063115
Citation
Wang S, Zhao Z, Feng X, Cheng Z, Xiong Z, Wang T, Lin J, Zhang M, Hu J, Fan Y, Reiter RJ, Wang H, Sun D. Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition. J Cell Mol Med. 2018 Oct;22(10):5132-5144. doi: 10.1111/jcmm.13802. Epub 2018 Jul 31.
Results Reference
background
PubMed Identifier
32143642
Citation
Wu GC, Peng CK, Liao WI, Pao HP, Huang KL, Chu SJ. Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production. Respir Res. 2020 Mar 6;21(1):65. doi: 10.1186/s12931-020-1325-2.
Results Reference
background
PubMed Identifier
22609835
Citation
Wu WS, Chou MT, Chao CM, Chang CK, Lin MT, Chang CP. Melatonin reduces acute lung inflammation, edema, and hemorrhage in heatstroke rats. Acta Pharmacol Sin. 2012 Jun;33(6):775-82. doi: 10.1038/aps.2012.29. Epub 2012 May 21.
Results Reference
background
PubMed Identifier
29642520
Citation
Zhao X, Sun J, Su W, Shan H, Zhang B, Wang Y, Shabanova A, Shan H, Liang H. Melatonin Protects against Lung Fibrosis by Regulating the Hippo/YAP Pathway. Int J Mol Sci. 2018 Apr 9;19(4):1118. doi: 10.3390/ijms19041118.
Results Reference
background
PubMed Identifier
32217117
Citation
Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, Liu C, Reiter RJ. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020 Jun 1;250:117583. doi: 10.1016/j.lfs.2020.117583. Epub 2020 Mar 23.
Results Reference
background
Links:
URL
https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html
Description
CDC COVID-19 Information
Learn more about this trial
Dose-Ranging Study to Assess the Safety and Efficacy of Melatonin in Outpatients Infected With COVID-19
We'll reach out to this number within 24 hrs