A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled trial

{ 'indexed': {'date-parts': [[2023, 9, 2]], 'date-time': '2023-09-02T17:14:33Z', 'timestamp': 1693674873869}, 'reference-count': 0, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2020, 8, 5]], 'date-time': '2020-08-05T00:00:00Z', 'timestamp': 1596585600000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2020, 8, 5]], 'date-time': '2020-08-05T00:00:00Z', 'timestamp': 1596585600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [{'name': 'Pharmamel LTD'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'published-print': {'date-parts': [[2020, 12]]}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n' '<jats:title>Objectives</jats:title>\n' '<jats:p>• Primary objective: to evaluate the effect of intravenous melatonin (IVM) on ' 'mortality in adult patients admitted to the intensive care unit (ICU) with ' 'COVID-19.</jats:p>\n' '<jats:p>• Secondary objectives:</jats:p>\n' '<jats:p>◦ To evaluate the effect of IVM on ICU length of stay.</jats:p>\n' '<jats:p>◦ To evaluate the effect of IVM on the length of mechanical ventilation ' '(MV).</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with an increase in the number of ' 'ventilator-free days.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with a reduced number of failing organs ' 'as determined by the sequential organ failure assessment (SOFA) scale.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with a reduction of the frequency and ' 'severity of COVID-19-associated thromboembolic phenomena.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with a decreased systemic inflammatory ' 'response assessed by plasma levels of ferritin, D-dimer, C-reactive protein, procalcitonin ' 'and interleukin-6.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with an improvement in hematologic ' 'parameters.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with an improvement in biochemical ' 'parameters.</jats:p>\n' '<jats:p>◦ To evaluate if the use of IVM is associated with an improvement in blood gas ' 'analysis parameters.</jats:p>\n' '<jats:p>◦ To evaluate adverse events during the 28 day study period.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Trial design</jats:title>\n' '<jats:p>Phase II, single center, double-blind, placebo-controlled randomized trial with a ' 'two-arm parallel group design and 2:1 allocation ratio.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Participants</jats:title>\n' '<jats:p>Only critically ill adult patients that fulfill all of the inclusion criteria and ' 'none of the exclusion criteria will be included. The study will be conducted in a mixed ICU ' 'of a publicly funded tertiary referral center in Madrid, Spain with a 30-bed capacity and ' '1100 admissions per year.</jats:p>\n' '<jats:p>• Inclusion criteria:</jats:p>\n' '<jats:p>◦ Patient, family member or legal guardian has provided written Informed ' 'Consent.</jats:p>\n' '<jats:p>◦ Age ε 18 years.</jats:p>\n' '<jats:p>◦ Confirmed SARS-CoV-2 infection with compatible symptoms AND a positive ' 'RT-PCR.</jats:p>\n' '<jats:p>◦ Admission to the ICU with acute hypoxemic respiratory failure attributed to ' 'SARS-CoV-2 infection.</jats:p>\n' '<jats:p>◦ ICU length of stay of less than 7 days prior to randomization with or without MV ' 'and without signs of improvement in respiratory failure (MURRAY score at randomization ' 'greater or equal to the MURRAY score at ICU admission).</jats:p>\n' '<jats:p>• Exclusion criteria:</jats:p>\n' '<jats:p>◦ Participant in a different COVID-19 study in which the study drug is under clinical ' 'development and hasn’t been previously authorized for commercialization.</jats:p>\n' '<jats:p>◦ Liver enzymes &gt; 5 times the upper normal range.</jats:p>\n' '<jats:p>◦ Chronic kidney disease with GFR &lt; 30 mL/min/1.73 m<jats:sup>2</jats:sup> (stage ' '4 or greater) or need for hemodialysis.</jats:p>\n' '<jats:p>◦ Pregnancy. A pregnancy test will be performed on every woman younger than 55 years ' 'of age prior to inclusion.</jats:p>\n' '<jats:p>◦ Terminal surgical or medical illness.</jats:p>\n' '<jats:p>◦ Autoimmune disease.</jats:p>\n' '<jats:p>◦ Any patient condition that can prevent the study procedures to be carried out at ' 'the treating physician’s judgement.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Intervention and comparator</jats:title>\n' '<jats:p>All patients will receive standard-of-care treatment according to the current ' 'institutional protocols. In addition, patients will be randomized in a 2:1 ratio to ' 'receive:</jats:p>\n' '<jats:p>• Experimental group (12 patients): 7 days of 5 mg per Kg of actual body weight per ' 'day of intravenous melatonin every 6 hours. Maximum daily dose 500 mg per day.</jats:p>\n' '<jats:p>• Control group (6 patients): 7 days of 5 mg per Kg of actual body weight per day of ' 'intravenous identically-looking placebo every 6 hours.</jats:p>\n' '<jats:p>After 3 days of treatment, 3 intensive care physicians will evaluate the participant ' 'and decide whether or not to complete the treatment based on their clinical ' 'assessment:</jats:p>\n' '<jats:p>• If objective or subjective signs of improvement or no worsening of the general ' 'clinical condition, respiratory failure, inflammatory state or multi-organ failure are ' 'observed, the participant will continue the treatment until completion.</jats:p>\n' '<jats:p>• If an adverse effect or clinical impairment is observed that is objectively or ' 'subjectively attributable to the study drug the treatment will be stopped.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Main outcome</jats:title>\n' '<jats:p>Mortality in each study group represented in frequency and time-to-event at day 28 ' 'after randomization</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Randomization</jats:title>\n' '<jats:p>The randomization sequence was created using SAS version 9.4 statistical software ' '(programmed and validated macros) with a 2:1 allocation. No randomization seed was ' 'pre-specified. The randomization seed was generated using the time on the computer where the ' 'program was executed.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Blinding (masking)</jats:title>\n' '<jats:p>Participants, caregivers and study groups will be blinded to arm ' 'allocation.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Numbers to be randomized (sample size)</jats:title>\n' '<jats:p>A total of 18 patients will be randomized in this trial: 12 to the experimental arm ' 'and 6 to the control arm.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Trial Status</jats:title>\n' '<jats:p>Protocol version 2.0, June 5<jats:sup>th</jats:sup> 2020.</jats:p>\n' '<jats:p>Trial status: recruitment not started. The first patient is expected to be recruited ' 'in October 2020. The last patient is anticipated to be recruited in August 2021.</jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Trial registration</jats:title>\n' '<jats:p>EU Clinical Trials Register. Date of trial registration: 10 July 2020. URL: ' '<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES">https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES</jats:ext-link></jats:p>\n' '</jats:sec><jats:sec>\n' '<jats:title>Full protocol</jats:title>\n' '<jats:p>The full protocol is attached as an additional file, accessible from the Trials ' 'website (Additional file 1). In the interest of expediting dissemination of this material, ' 'the familiar formatting has been eliminated; this Letter serves as a summary of the key ' 'elements of the full protocol.</jats:p>\n' '</jats:sec>', 'DOI': '10.1186/s13063-020-04632-4', 'type': 'journal-article', 'created': {'date-parts': [[2020, 8, 5]], 'date-time': '2020-08-05T09:03:02Z', 'timestamp': 1596618182000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 20, 'title': 'A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the ' 'efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive ' 'care unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled ' 'trial', 'prefix': '10.1186', 'volume': '21', 'author': [ {'given': 'Miguel', 'family': 'Rodríguez-Rubio', 'sequence': 'first', 'affiliation': []}, {'given': 'Juan Carlos', 'family': 'Figueira', 'sequence': 'additional', 'affiliation': []}, {'given': 'Darío', 'family': 'Acuña-Castroviejo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alberto M.', 'family': 'Borobia', 'sequence': 'additional', 'affiliation': []}, {'given': 'Germaine', 'family': 'Escames', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-2444-0556', 'authenticated-orcid': False, 'given': 'Pedro', 'family': 'de la Oliva', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2020, 8, 5]]}, 'container-title': 'Trials', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s13063-020-04632-4.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s13063-020-04632-4/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s13063-020-04632-4.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2021, 8, 5]], 'date-time': '2021-08-05T00:08:07Z', 'timestamp': 1628122087000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04632-4'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2020, 8, 5]]}, 'references-count': 0, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2020, 12]]}}, 'alternative-id': ['4632'], 'URL': 'http://dx.doi.org/10.1186/s13063-020-04632-4', 'relation': {}, 'ISSN': ['1745-6215'], 'subject': ['Pharmacology (medical)', 'Medicine (miscellaneous)'], 'container-title-short': 'Trials', 'published': {'date-parts': [[2020, 8, 5]]}, 'assertion': [ { 'value': '16 July 2020', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '26 July 2020', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '5 August 2020', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'Before the trial was initiated, this trial received ethical approval from the ' 'Ethics Committee described below for the trial protocol, written informed ' 'consent form and consent form updates.CEIC Hospital Universitario La Paz. Área ' 'Sanitaria 5 de la CCAA de MadridPaseo de la Castellana, 261, 28046 Madrid.Ref: ' '47/027899.9/20, June 11^th 2020.Informed consent will be obtained ' 'before conducting any study-specific procedures.Eligible subjects will be ' 'informed before the beginning of the study about the objectives and procedures, ' 'as well as the potential risks derived from their study participation.The ' 'process of obtaining informed consent will be documented in the subject source ' 'documents.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'GE and DA-C are Scientific Advisors of Pharmamel LTD, the Sponsor of the ' 'clinical trial.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '699'}