<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04470297</url>
  </required_header>
  <id_info>
    <org_study_id>MELCOV2020</org_study_id>
    <nct_id>NCT04470297</nct_id>
  </id_info>
  <brief_title>Melatonin Agonist on Hospitalized Patients With Confirmed or Suspected COVID-19</brief_title>
  <official_title>Adjuvant Therapeutic Effects of Melatonin Agonist on Hospitalized Patients With Confirmed or Suspected COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Associação Fundo de Incentivo à Pesquisa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Associação Fundo de Incentivo à Pesquisa</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      COVID-19 is impacting on health systems in Brazil and worldwide. Reducing the risk of&#xD;
      clinical deterioration and prolonged disease duration in hospitalized patients with COVID-19&#xD;
      may alleviate the burden caused by the pandemic. Melatonin (N-acetyl-5-methoxytryptamine) has&#xD;
      demonstrated antiapoptotic, antioxidative, and anti-inflammatory roles and has been suggested&#xD;
      as a potential protector against organ injuries and even mediate lower mortality rates after&#xD;
      polymicrobial sepsis in animal models. Melatonin agonists may modulate protective effects&#xD;
      against acute lung injury and play a clinical role in individuals with SARS-CoV-2 infection.&#xD;
      The investigators proposed a clinical trial testing the effects of ramelteon 8mg in&#xD;
      hospitalized patients with COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) pandemic, also denominated&#xD;
      Coronavirus Disease 2019 (COVID-19), is currently challenging health systems in Brazil and&#xD;
      worldwide. The mortality rate of confirmed cases of COVID-19 in Brazil seems to be close to&#xD;
      twice that of countries like Germany and Canada. (1-3) The resulted viral interstitial&#xD;
      pneumonia can lead to severe hypoxemic respiratory failure, overcrowded intensive care units&#xD;
      (ICUs), shortages of equipment and personnel, and increased mortality. (4-6)&#xD;
&#xD;
      Some reasons for higher mortality risk in Brazil can be related to an increased propensity of&#xD;
      clinical worsening in hospitalized patients. Consequently, reducing the risk of clinical&#xD;
      deterioration and prolonged disease duration in hospitalized patients with mild-to-moderate&#xD;
      COVID-19 has become a priority to reduce the burden of such pandemic and the admission to&#xD;
      ICUs. However, to our knowledge, few and complex specific interventions have been tested&#xD;
      targeting outcomes related to a reduction of the immediate risk of severe disease and&#xD;
      prolonged hospitalization in inpatients with mild-to-moderate clinical signs and symptoms.&#xD;
&#xD;
      Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized mainly by the pineal gland&#xD;
      and also by other nonendocrine organs, including the immune system. Among its multiple&#xD;
      properties, melatonin has demonstrated antiapoptotic, antioxidative, and anti-inflammatory&#xD;
      roles exerted via both receptor-dependent and receptor-independent signalling cascades. (7,8)&#xD;
      It has been suggested that melatonin receptors activation protects against organ injuries.&#xD;
      (9-10). Additionally, melatonin receptors can mediate lower mortality rates after&#xD;
      polymicrobial sepsis in animal models. (11)&#xD;
&#xD;
      Melatonin potentially modulates immune response by enhancing the secretion of&#xD;
      anti-inflammatory cytokines including IL-10, which is involved in the Th2-like immune&#xD;
      response. (12) IL-10 has effects on a myriad of cell types and, in lung cells under damaging&#xD;
      circumstances, its production turns undermined. (13) Recent findings indicated that melatonin&#xD;
      receptors are modulators of protective effects against acute lung injury induced by the&#xD;
      ventilator in rats through the up-regulation of IL-10 production. (14) This evidence upsurged&#xD;
      testing the effects of ramelteon, a potent and highly selective agonist of high-affinity&#xD;
      melatonin receptors 1 (MT1) and MT2, which further displays antioxidative and&#xD;
      anti-inflammatory properties. (15-17) Melatonin agonism may play a clinical role in&#xD;
      individuals with acute lung injuries, including those induced by SARS-CoV-2 infection, which&#xD;
      has not yet been investigated. The investigators designed a clinical trial testing standard&#xD;
      care versus ramelteon 8mg under diverse clinical and laboratory outcomes related to the&#xD;
      COVID-19 in hospitalized patients with this condition.&#xD;
&#xD;
      References&#xD;
&#xD;
        1. Robert Koch Institut. Coronavirus Disease 2019 (COVID-19) Daily Situation Report of the&#xD;
           Robert Koch Institute. Available from:&#xD;
           https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situationsberichte/Gesamt.h&#xD;
           tml Updated 14.05.20&#xD;
&#xD;
        2. DATASUS. Ministério da Saúde do Brasil. Available from: https://covid.saude.gov.br/.&#xD;
           Atualizada em: 14/05/2020&#xD;
&#xD;
        3. Government of Canada. Coronavirus Disease 2019 (COVID-19): Daily Epidemiology Update.&#xD;
           Available from:&#xD;
           https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infectio&#xD;
           n.html?topic=tilelink#a1. Updated 14.05.20.&#xD;
&#xD;
        4. P.H.S. Pelicioni, S.R. Lord. COVID-19 will severely impact older people's lives, and in&#xD;
           many more ways than you think!. Braz J Phys Ther, (2020),&#xD;
           http://dx.doi.org/10.1016/j.bjpt.2020.04.005&#xD;
&#xD;
        5. [3] R.D. Branson, D.R. Hess, L. Rubinson. SARS CoV-2: Guidance Document. American&#xD;
           Association for Respiratory Care, (2020),&#xD;
&#xD;
        6. World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report 46.&#xD;
           (2020)&#xD;
&#xD;
        7. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos&#xD;
           DP. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol. 2016;173:2702-2725.&#xD;
           doi: 10.1111/bph.13536.&#xD;
&#xD;
        8. Radogna F, Paternoster L, Albertini MC, Cerella C, Accorsi A, Bucchini A, Spadoni G,&#xD;
           Diamantini G, Tarzia G, De Nicola M, et al. Melatonin antagonizes apoptosis via receptor&#xD;
           interaction in U937 monocytic cells. J Pineal Res. 2007;43:154-162. doi:&#xD;
           10.1111/j.1600-079X.2007.00455.x.&#xD;
&#xD;
        9. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of&#xD;
           melatonin on myocardial post-ischemic recovery. J Pineal Res. 2006;40:56-63. doi:&#xD;
           10.1111/j.1600-079X.2005.00280.x.&#xD;
&#xD;
       10. Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial&#xD;
           effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are&#xD;
           receptor-mediated. J Pineal Res. 2006;41:288-295. doi: 10.1111/j.1600-079X.2006.00368.x.&#xD;
&#xD;
       11. Fink T, Glas M, Wolf A, Kleber A, Reus E, Wolff M, Kiefer D, Wolf B, Rensing H, Volk T,&#xD;
           Mathes AM. Melatonin receptors mediate improvements of survival in a model of&#xD;
           polymicrobial sepsis. Crit Care Med. 2014;42:e22-e31. doi: 10.1097/CCM.0b013e3182a63e2b.&#xD;
&#xD;
       12. Ren Wenkai, Liu Gang, Chen Shuai, Yin Jie, Wang Jing, Tan Bie, Wu Guoyao, Bazer Fuller&#xD;
           W., Peng Yuanyi, Li Tiejun, Reiter Russel J., Yin Yulong. Melatonin signalling in T&#xD;
           cells: Functions and applications. Journal of Pineal Research. 2017;62(3):e12394. doi:&#xD;
           10.1111/jpi.12394.&#xD;
&#xD;
       13. Hokenson MA, Wang Y, Hawwa RL, Huang Z, Sharma S, Sanchez-Esteban J. Reduced IL-10&#xD;
           production in fetal type II epithelial cells exposed to mechanical stretch is mediated&#xD;
           via activation of IL-6-SOCS3 signalling pathway. PLoS One. 2013;8:e59598. doi:&#xD;
           10.1371/journal.pone.0059598.&#xD;
&#xD;
       14. Wu GC, Peng CK, Liao WI, Pao HP, Huang KL, Chu SJ. Melatonin receptor agonist protects&#xD;
           against acute lung injury induced by ventilator through up-regulation of IL-10&#xD;
           production. Respir Res. 2020 Mar 6;21(1):65. doi: 10.1186/s12931-020-1325-2.&#xD;
&#xD;
       15. Mathes AM, Kubulus D, Waibel L, Weiler J, Heymann P, Wolf B, Rensing H. Selective&#xD;
           activation of melatonin receptors with ramelteon improves liver function and hepatic&#xD;
           perfusion after hemorrhagic shock in the rat. Crit Care Med. 2008;36:2863-2870. doi:&#xD;
           10.1097/CCM.0b013e318187b863.&#xD;
&#xD;
       16. Shimizu N, Nozawa M, Sugimoto K, Yamamoto Y, Minami T, Hayashi T, Yoshimura K, Ishii T,&#xD;
           Uemura H. Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients&#xD;
           with insomnia associated with lower urinary tract symptoms. Res Rep Urol.&#xD;
           2013;5:113-119.&#xD;
&#xD;
       17. Zhou W, Zhang X, Zhu CL, He ZY, Liang JP, Song ZC. Melatonin receptor agonists as the&#xD;
           &quot;Perioceutics&quot; agents for the periodontal disease through modulation of Porphyromonas&#xD;
           gingivalis virulence and inflammatory response. PLoS One. 2016;11:e0166442. doi:&#xD;
           10.1371/journal.pone.0166442&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 2020</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">November 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to resolution of symptoms [National Early Warning Score 2 (NEWS2) of 0]</measure>
    <time_frame>enrollment is day 0</time_frame>
    <description>Defined as a National Early Warning Score 2 (NEWS2) of 0 maintained for 24 hours [Time Frame: Assessed daily (enrollment is day 0)] The NEWS consists of a simple aggregate scoring system based on physiological measurements, regularly registered in inpatient settings, including six parameters: respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, and temperature.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical worsening to critical COVID-19 illness</measure>
    <time_frame>until Day 30</time_frame>
    <description>Critical COVID-19 illness as a composite of admission to the intensive care unit (ICU), invasive ventilation, or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of supplemental oxygen therapy</measure>
    <time_frame>until day 14</time_frame>
    <description>Measured by duration of use of supplemental oxygen (if applicable)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of mechanical ventilation (if applicable)</measure>
    <time_frame>until day 30</time_frame>
    <description>Measured by duration of use of mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalisation</measure>
    <time_frame>until day 30</time_frame>
    <description>Measured by duration of hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants with virologic clearance in nasopharyngeal swab RT-PCR</measure>
    <time_frame>Day 14</time_frame>
    <description>Presence or absence of SARS-CoV-2 Viral RNA in nasopharyngeal swab or lower respiratory secretions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive protein (CRP) level's reduction</measure>
    <time_frame>Days 3, 5 and 8</time_frame>
    <description>Reduction of C-reactive protein levels &gt; 50% in comparison with PCR levels at the admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of New Onset Lymphopenia</measure>
    <time_frame>Through study completion, average of 15 days</time_frame>
    <description>Incidence of new onset lymphopenia during hospitalization measured by blood draw</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Direct bilirubin level's reduction</measure>
    <time_frame>Measured in study Days 3, 5, and 8</time_frame>
    <description>Reduction of mean direct bilirubin levels in comparison with levels at the admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side Effects</measure>
    <time_frame>until day 14</time_frame>
    <description>Differences in number of patients in study arms who experienced side effects</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Covid19</condition>
  <condition>Lung Injury</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>A placebo with the same physical characteristics of the experimental drug pill will be administered at the same time and daily schedule as the experimental intervention for 10 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ramelteon</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A pill containing ramelteon 8mg will be administered daily at bedtime for 10 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ramelteon 8mg</intervention_name>
    <description>Standard care combined with oral placebo or ramelteon 8mg at bedtime for 10 days</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Ramelteon</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Individuals (or legally authorized representative) providing written informed consent&#xD;
             prior to initiation of any study procedures.&#xD;
&#xD;
          2. Male or non-pregnant female adult ≥18 years of age at time of enrollment&#xD;
&#xD;
          3. Subject consents to randomization within 48 hours of hospital admission&#xD;
&#xD;
          4. Symptom duration of 14 days or less upon recruitment&#xD;
&#xD;
          5. At least one of the following:&#xD;
&#xD;
               1. Radiographic infiltrates by imaging (chest x-ray or CT scan), OR&#xD;
&#xD;
               2. Clinical assessment (evidence of rales/crackles on the exam) AND SpO2 ≤ 94% on&#xD;
                  room air&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Mild COVID-19 disease (minor clinical symptoms, imaging does not show signs of lung&#xD;
             inflammation)&#xD;
&#xD;
          2. Recent history of or any in-hospital exposure to investigational medications targeting&#xD;
             COVID-19&#xD;
&#xD;
          3. ALT/AST &gt; 5 times the upper limit of normal.&#xD;
&#xD;
          4. Known hypersensitivity to ramelteon&#xD;
&#xD;
          5. Pregnancy&#xD;
&#xD;
          6. Severe hepatic insufficiency&#xD;
&#xD;
          7. Fluvoxamine use&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dalva Poyares, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Associação Fundo de Incentivo a Pesquisa</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ronaldo D Piovezan, PhD</last_name>
    <phone>+5511984153364</phone>
    <email>rdpiovezan@gmail.com</email>
  </overall_contact>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 12, 2020</study_first_submitted>
  <study_first_submitted_qc>July 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>July 22, 2020</last_update_submitted>
  <last_update_submitted_qc>July 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Associação Fundo de Incentivo à Pesquisa</investigator_affiliation>
    <investigator_full_name>Ronaldo Delmonte Piovezan</investigator_full_name>
    <investigator_title>PhD</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Acute Distress Respiratory Syndrome</keyword>
  <keyword>Melatonin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Lung Injury</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04470297
org study id: MELCOV2020
nct id: NCT04470297
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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/Situationsberichte/Gesamt.h
           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-coronavirus-infectio
           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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Time to resolution of symptoms [National Early Warning Score 2 (NEWS2) of 0]
time frame: enrollment is day 0
description: Defined as a National Early Warning Score 2 (NEWS2) of 0 maintained for 24 hours [Time Frame: Assessed daily (enrollment is day 0)] The NEWS consists of a simple aggregate scoring system based on physiological measurements, regularly registered in inpatient settings, including six parameters: respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, and temperature.
measure: Clinical worsening to critical COVID-19 illness
time frame: until Day 30
description: Critical COVID-19 illness as a composite of admission to the intensive care unit (ICU), invasive ventilation, or death
measure: Duration of supplemental oxygen therapy
time frame: until day 14
description: Measured by duration of use of supplemental oxygen (if applicable)
measure: Duration of mechanical ventilation (if applicable)
time frame: until day 30
description: Measured by duration of use of mechanical ventilation
measure: Duration of hospitalisation
time frame: until day 30
description: Measured by duration of hospitalization
measure: Proportion of participants with virologic clearance in nasopharyngeal swab RT-PCR
time frame: Day 14
description: Presence or absence of SARS-CoV-2 Viral RNA in nasopharyngeal swab or lower respiratory secretions
measure: C-reactive protein (CRP) level's reduction
time frame: Days 3, 5 and 8
description: Reduction of C-reactive protein levels > 50% in comparison with PCR levels at the admission
measure: Incidence of New Onset Lymphopenia
time frame: Through study completion, average of 15 days
description: Incidence of new onset lymphopenia during hospitalization measured by blood draw
measure: Direct bilirubin level's reduction
time frame: Measured in study Days 3, 5, and 8
description: Reduction of mean direct bilirubin levels in comparison with levels at the admission
measure: Side Effects
time frame: until day 14
description: Differences in number of patients in study arms who experienced side effects
arm group label: Placebo
arm group type: Placebo Comparator
description: A placebo with the same physical characteristics of the experimental drug pill will be administered at the same time and daily schedule as the experimental intervention for 10 days.
arm group label: Ramelteon
arm group type: Experimental
description: A pill containing ramelteon 8mg will be administered daily at bedtime for 10 days.
intervention type: Drug
intervention name: Ramelteon 8mg
description: Standard care combined with oral placebo or ramelteon 8mg at bedtime for 10 days
arm group label: Placebo
arm group label: Ramelteon
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Dalva Poyares, PhD
role: Study Director
affiliation: Associação Fundo de Incentivo a Pesquisa
last name: Ronaldo D Piovezan, PhD
phone: +5511984153364
email: rdpiovezan@gmail.com
responsible party type: Principal Investigator
investigator affiliation: Associação Fundo de Incentivo à Pesquisa
investigator full name: Ronaldo Delmonte Piovezan
investigator title: PhD
mesh term: COVID-19
mesh term: Lung Injury
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)