COVID-19 is impacting on health systems in Brazil and worldwide. Reducing the risk of clinical deterioration and prolonged disease duration in hospitalized patients with COVID-19 may alleviate the burden caused by the pandemic. Melatonin (N-acetyl-5-methoxytryptamine) has demonstrated antiapoptotic, antioxidative, and anti-inflammatory roles and has been suggested as a potential protector against organ injuries and even mediate lower mortality rates after polymicrobial sepsis in animal models. Melatonin agonists may modulate protective effects against acute lung injury and play a clinical role in individuals with SARS-CoV-2 infection. The investigators proposed a clinical trial testing the effects of ramelteon 8mg in hospitalized patients with COVID-19.
The severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) pandemic, also denominated
Coronavirus Disease 2019 (COVID-19), is currently challenging health systems in Brazil and
worldwide. The mortality rate of confirmed cases of COVID-19 in Brazil seems to be close to
twice that of countries like Germany and Canada. (1-3) The resulted viral interstitial
pneumonia can lead to severe hypoxemic respiratory failure, overcrowded intensive care units
(ICUs), shortages of equipment and personnel, and increased mortality. (4-6)
Some reasons for higher mortality risk in Brazil can be related to an increased propensity of
clinical worsening in hospitalized patients. Consequently, reducing the risk of clinical
deterioration and prolonged disease duration in hospitalized patients with mild-to-moderate
COVID-19 has become a priority to reduce the burden of such pandemic and the admission to
ICUs. However, to our knowledge, few and complex specific interventions have been tested
targeting outcomes related to a reduction of the immediate risk of severe disease and
prolonged hospitalization in inpatients with mild-to-moderate clinical signs and symptoms.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized mainly by the pineal gland
and also by other nonendocrine organs, including the immune system. Among its multiple
properties, melatonin has demonstrated antiapoptotic, antioxidative, and anti-inflammatory
roles exerted via both receptor-dependent and receptor-independent signalling cascades. (7,8)
It has been suggested that melatonin receptors activation protects against organ injuries.
(9-10). Additionally, melatonin receptors can mediate lower mortality rates after
polymicrobial sepsis in animal models. (11)
Melatonin potentially modulates immune response by enhancing the secretion of
anti-inflammatory cytokines including IL-10, which is involved in the Th2-like immune
response. (12) IL-10 has effects on a myriad of cell types and, in lung cells under damaging
circumstances, its production turns undermined. (13) Recent findings indicated that melatonin
receptors are modulators of protective effects against acute lung injury induced by the
ventilator in rats through the up-regulation of IL-10 production. (14) This evidence upsurged
testing the effects of ramelteon, a potent and highly selective agonist of high-affinity
melatonin receptors 1 (MT1) and MT2, which further displays antioxidative and
anti-inflammatory properties. (15-17) Melatonin agonism may play a clinical role in
individuals with acute lung injuries, including those induced by SARS-CoV-2 infection, which
has not yet been investigated. The investigators designed a clinical trial testing standard
care versus ramelteon 8mg under diverse clinical and laboratory outcomes related to the
COVID-19 in hospitalized patients with this condition.
References
1. Robert Koch Institut. Coronavirus Disease 2019 (COVID-19) Daily Situation Report of the
Robert Koch Institute. Available from:
https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situations…
tml Updated 14.05.20
2. DATASUS. Ministério da Saúde do Brasil. Available from: https://covid.saude.gov.br/.
Atualizada em: 14/05/2020
3. Government of Canada. Coronavirus Disease 2019 (COVID-19): Daily Epidemiology Update.
Available from:
https://www.canada.ca/en/public-health/services/diseases/2019-novel-cor…
n.html?topic=tilelink#a1. Updated 14.05.20.
4. P.H.S. Pelicioni, S.R. Lord. COVID-19 will severely impact older people's lives, and in
many more ways than you think!. Braz J Phys Ther, (2020),
http://dx.doi.org/10.1016/j.bjpt.2020.04.005
5. [3] R.D. Branson, D.R. Hess, L. Rubinson. SARS CoV-2: Guidance Document. American
Association for Respiratory Care, (2020),
6. World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report 46.
(2020)
7. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos
DP. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol. 2016;173:2702-2725.
doi: 10.1111/bph.13536.
8. Radogna F, Paternoster L, Albertini MC, Cerella C, Accorsi A, Bucchini A, Spadoni G,
Diamantini G, Tarzia G, De Nicola M, et al. Melatonin antagonizes apoptosis via receptor
interaction in U937 monocytic cells. J Pineal Res. 2007;43:154-162. doi:
10.1111/j.1600-079X.2007.00455.x.
9. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of
melatonin on myocardial post-ischemic recovery. J Pineal Res. 2006;40:56-63. doi:
10.1111/j.1600-079X.2005.00280.x.
10. Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial
effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are
receptor-mediated. J Pineal Res. 2006;41:288-295. doi: 10.1111/j.1600-079X.2006.00368.x.
11. Fink T, Glas M, Wolf A, Kleber A, Reus E, Wolff M, Kiefer D, Wolf B, Rensing H, Volk T,
Mathes AM. Melatonin receptors mediate improvements of survival in a model of
polymicrobial sepsis. Crit Care Med. 2014;42:e22-e31. doi: 10.1097/CCM.0b013e3182a63e2b.
12. Ren Wenkai, Liu Gang, Chen Shuai, Yin Jie, Wang Jing, Tan Bie, Wu Guoyao, Bazer Fuller
W., Peng Yuanyi, Li Tiejun, Reiter Russel J., Yin Yulong. Melatonin signalling in T
cells: Functions and applications. Journal of Pineal Research. 2017;62(3):e12394. doi:
10.1111/jpi.12394.
13. Hokenson MA, Wang Y, Hawwa RL, Huang Z, Sharma S, Sanchez-Esteban J. Reduced IL-10
production in fetal type II epithelial cells exposed to mechanical stretch is mediated
via activation of IL-6-SOCS3 signalling pathway. PLoS One. 2013;8:e59598. doi:
10.1371/journal.pone.0059598.
14. 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.
15. Mathes AM, Kubulus D, Waibel L, Weiler J, Heymann P, Wolf B, Rensing H. Selective
activation of melatonin receptors with ramelteon improves liver function and hepatic
perfusion after hemorrhagic shock in the rat. Crit Care Med. 2008;36:2863-2870. doi:
10.1097/CCM.0b013e318187b863.
16. Shimizu N, Nozawa M, Sugimoto K, Yamamoto Y, Minami T, Hayashi T, Yoshimura K, Ishii T,
Uemura H. Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients
with insomnia associated with lower urinary tract symptoms. Res Rep Urol.
2013;5:113-119.
17. Zhou W, Zhang X, Zhu CL, He ZY, Liang JP, Song ZC. Melatonin receptor agonists as the
"Perioceutics" agents for the periodontal disease through modulation of Porphyromonas
gingivalis virulence and inflammatory response. PLoS One. 2016;11:e0166442. doi:
10.1371/journal.pone.0166442
Drug: Ramelteon 8mg
Standard care combined with oral placebo or ramelteon 8mg at bedtime for 10 days
Inclusion Criteria:
1. Individuals (or legally authorized representative) providing written informed consent
prior to initiation of any study procedures.
2. Male or non-pregnant female adult ≥18 years of age at time of enrollment
3. Subject consents to randomization within 48 hours of hospital admission
4. Symptom duration of 14 days or less upon recruitment
5. At least one of the following:
1. Radiographic infiltrates by imaging (chest x-ray or CT scan), OR
2. Clinical assessment (evidence of rales/crackles on the exam) AND SpO2 ≤ 94% on
room air
Exclusion Criteria:
1. Mild COVID-19 disease (minor clinical symptoms, imaging does not show signs of lung
inflammation)
2. Recent history of or any in-hospital exposure to investigational medications targeting
COVID-19
3. ALT/AST > 5 times the upper limit of normal.
4. Known hypersensitivity to ramelteon
5. Pregnancy
6. Severe hepatic insufficiency
7. Fluvoxamine use
Ronaldo D Piovezan, PhD
+5511984153364
rdpiovezan@gmail.com
Dalva Poyares, PhD, Study Director
Associação Fundo de Incentivo a Pesquisa