PHM-2020-001

PHARMAMEL S.L.

Gran Vía 48, 7th floor, Granada, Spain, 18071

Germaine Escames, PHARMAMEL S.L. (Centro de Transferencia Tecnológica), 34 618 521 646, gescames@ugr.es

Germaine Escames, PHARMAMEL S.L. (Centro de Transferencia Tecnológica), 34 618 521 646, gescames@ugr.es

No

No

No

Final

26 Mar 2021

Yes

06 Feb 2021

Yes

06 Feb 2021

No

The primary objective was to evaluate whether intravenous (IV) melatonin treatment reduces mortality in patients with COVID-19 admitted to the Intensive care unit (ICU).

Patients were free to discontinue their participation in the study at any time. Withdrawal from the study did not affect or prejudice the patient’s further treatment. Patients could be withdrawn from study treatment and assessments at any time, if deemed necessary by the Investigator. Patients suspended study therapy and/or withdrew from the same for the following reasons: • Withdrawal of informed consent (decision of the patient to withdraw regardless of the reason). • Unacceptable toxicity • Disease progression which, in the investigator's opinion, did not allow the patient to continue in the study. • The patient did not comply with the protocol, treatment or monitoring requirements. • Any other reason to interrupt the treatment which, in the opinion of the investigator, was the best for the patient. • Any clinical adverse event, test anomaly or breakthrough disease which, in the opinion of the investigator, indicated that continuing treatment with such therapy and with participation in the study was not in the best interest of the patient. • Completion of the study by the research team.

15 Aug 2020

No

No

Spain: 18

18

18

0

0

0

0

0

0

12

6

0

Study period (overall period)

Randomised - controlled

Non-study staff prepared the unmasked randomization codes, designed so that patients were assigned proportionally 2:1 to the experimental group or the control group respectively. They also prepared sealed envelopes containing the unmasked randomization code. The research team was provided with a list of masked randomization codes, so that the research staff assigned each eligible patient, in order of inclusion, a masked randomization code.

Yes

Melatonin

Solution for injection

Intravenous use

The experimental treatment was melatonin 6 mg/mL solution for injection/infusion. The study medication was administered intravenously by the ICU health personnel in charge of the patient. Melatonin was administered according to the established guideline based on weight: 5 mg/kg current weight/day divided into 4 doses a day (1 dose/6hrs) and with a maximum daily dose of 500 mg. After the first 3 days of treatment, three intensive care physicians in charge of the patient decided whether to extend the treatment until day 6 of the study (total of 7 days of treatment) based on the patient's clinical evaluation.

Placebo

Solution for injection

Intravenous use

Patients included in the placebo group received placebo according to their weight: 5 mg/kg current weight/day divided into 4 doses a day (1 dose/6hrs). The study medication was administered intravenously by the ICU health personnel in charge of the patient. After the first 3 days of treatment, three intensive care physicians in charge of the patient decided whether to extend the treatment until day 6 of the study (total of 7 days of treatment) based on the patient's clinical evaluation.

Melatonin

Placebo

Melatonin

Placebo

The absolute and relative frequency of deaths in the study was tabulated by treatment group with the 95%CI of the percentages. There were a total of 6 deaths, 5 deaths in the melatonin group and 1 death in the placebo group. Three of them (2 in the melatonin group and 1 in the placebo group) occurred out of the study period.

Primary

From ICF signature until the end of the study.

Fisher's exact test was used to investigate whether there was a difference between treatment groups in the proportion of deaths.

Melatonin v Placebo

18

Pre-specified

Primary

From ICF signature until the end of the study.

The Kaplan-Meyer method for overall survival (OS) was performed to test the differences of the experimental treatment over placebo. OS was calculated in days as the time from the day of administration of the first dose of IV melatonin or IV placebo until the date of death due to any cause. For patients alive at the time of the analysis or if lost to follow up, the date of death was censored on the last date the patients were known to be alive.

Primary

From ICF signature until the end of the study.

Log rank test was performed to test the differences between the treatment groups.

Melatonin v Placebo

18

Pre-specified

ICUBSS= ICU admission time before the study start in days; ICUT=Total ICU admission time in days.

Secondary

ICUBSS, period from date of ICU admission until the date of first treatment study administration; ICUT, from the ICU admission date until the end of the study.

THA= Total time of hospital admission in days. It has to be noted that if the last patient is excluded from analysis (i.e., the last patient was hospitalized during a long time), the mean total time of hospital admission among survivors was numerically lower in the melatonin group than the placebo group (44.8 vs 59.6 days).

Secondary

From the calendar day of hospitalization until the date of hospital discharge.

TMVBSS = Time with mechanical ventilation before the start of the study in days; TFMV = Time free of mechanical ventilation in days. The total time with MV was tabulated by the type of MV.

Secondary

TMVBSS, from the date with MV before the 1st administration of study drug until the date of 1st administration of study drug. TFMV, cumulative time during study. Total time with MV, start/end dates reported in the ‘Mechanical ventilation’ CRF module.

The SOFA scale score numerically quantified the number and severity of failed organs. Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.

Secondary

Score on the SOFA scale at days 0, 1, 3, 7, 14, 21 and 28.

Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.

Secondary

Score on the MURRAY scale at days 0, 1, 3, 7, 14, 21 and 28.

Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.

Secondary

Score on the GCS at days 0, 1, 3, 7, 14, 21 and 28.

Too few patients had available assessments, being most of them from the screening visit. Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.

Secondary

Score on the APACHE II scale at days 0, 1, 3, 7, 14, 21 and 28.

Number of events, location and severity (affected organ and vascular territory) of thromboembolic events caused by COVID-19. It was not possible to assess whether IV melatonin treatment was associated with a reduction in the frequency and severity of thromboembolic processes caused by COVID-19, as only one single thromboembolic event was observed during the study (Respiratory, thoracic and mediastinal disorders > Pulmonary embolism > Moderate).

Secondary

From ICF signature until the end of the study.

The systemic inflammatory response was assessed through the change observed from baseline, presented as the percentage value from baseline (calculated as [Visit X value / Screening value]*100), in ferritin, D-dimer, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) on days 1, 3, 7, 14, 21 and 28. Please see documents attached.

Secondary

Systemic inflammatory parameters on days 0, 1, 3, 7, 14, 21 and 28.

The change in the haematological parameters was evaluated through the variation from baseline in the levels of erythrocytes, Hb, platelets, fibrinogen, cephalin time, prothrombin time, antithrombin III, ADAMTS13 and Factor Xa (see Table 1 attached). Moreover, levels of basophils, eosinophils, haematocrit, lymphocytes, mean corpuscular haemoglobin concentration (MCHC), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), monocytes, neutrophils and leucocytes were also evaluated throughout the study (see Table 2 attached).

Secondary

Haematological parameters on days 0, 1, 3, 7, 14, 21 and 28.

The change in the biochemical parameters was evaluated through the variation from baseline in the levels of creatine kinase (CK), lactate dehydrogenase (LDH), glutamate-oxalacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), bilirubin, vitamin D and 1,25-OH-Vit D (calcitriol), calcium, albumin, blood urea nitrogen (BUN), creatinine and troponin on days 1, 3, 7, 14, 21 and 28. Please see documents attached.

Secondary

Biochemical parameters on days 0, 1, 3, 7, 14, 21 and 28.

The change in the arterial blood gas parameters and electrolytes was evaluated through the variation from baseline in pH, SaO2, PaCO2, PO2, HCO3, glucose, Na, K, chlorine, lactate, anion gap and PaO2/FiO2 on days 1, 3, 7, 14, 21 and 28. Please see document attached.

Secondary

Arterial blood gas parameters and electrolytes on days 0, 1, 3, 7, 14, 21 and 28.

The collection of information on AEs should start on the basis of obtaining informed consent. All serious AEs must be reported to the sponsor within 24 hours of investigator’s awareness, regardless of their relationship to the experimental drug.

All identified AEs should be noted and described in the patient's medical history. The following information must be collected for all AEs: date of onset , intensity, causal relationship with the study drug in the opinion of the investigator, treatment required for the AE, serious criteria of the AE and information on its resolution or outcome.

23.1

Melatonin

Placebo