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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 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. |
|
| Ramelteon | Experimental | A pill containing ramelteon 8mg will be administered daily at bedtime for 10 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ramelteon 8mg | Drug | Standard care combined with oral placebo or ramelteon 8mg at bedtime for 10 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to resolution of symptoms [National Early Warning Score 2 (NEWS2) of 0] | 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. | enrollment is day 0 |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical worsening to critical COVID-19 illness | Critical COVID-19 illness as a composite of admission to the intensive care unit (ICU), invasive ventilation, or death | until Day 30 |
| Duration of supplemental oxygen therapy |
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Inclusion Criteria:
Individuals (or legally authorized representative) providing written informed consent prior to initiation of any study procedures.
Male or non-pregnant female adult ≥18 years of age at time of enrollment
Subject consents to randomization within 48 hours of hospital admission
Symptom duration of 14 days or less upon recruitment
At least one of the following:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ronaldo D Piovezan, PhD | Contact | +5511984153364 | rdpiovezan@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Dalva Poyares, PhD | Associação Fundo de Incentivo a Pesquisa | Study Director |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D055370 | Lung Injury |
| D012128 | Respiratory Distress Syndrome |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C495910 | ramelteon |
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Measured by duration of use of supplemental oxygen (if applicable)
| until day 14 |
| Duration of mechanical ventilation (if applicable) | Measured by duration of use of mechanical ventilation | until day 30 |
| Duration of hospitalisation | Measured by duration of hospitalization | until day 30 |
| Proportion of participants with virologic clearance in nasopharyngeal swab RT-PCR | Presence or absence of SARS-CoV-2 Viral RNA in nasopharyngeal swab or lower respiratory secretions | Day 14 |
| C-reactive protein (CRP) level's reduction | Reduction of C-reactive protein levels > 50% in comparison with PCR levels at the admission | Days 3, 5 and 8 |
| Incidence of New Onset Lymphopenia | Incidence of new onset lymphopenia during hospitalization measured by blood draw | Through study completion, average of 15 days |
| Direct bilirubin level's reduction | Reduction of mean direct bilirubin levels in comparison with levels at the admission | Measured in study Days 3, 5, and 8 |
| Side Effects | Differences in number of patients in study arms who experienced side effects | until day 14 |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D013898 | Thoracic Injuries |
| D014947 | Wounds and Injuries |
| D012120 | Respiration Disorders |