Metoprolol in Acute Respiratory Distress Syndrome (MAIDEN)

Sponsor

Consorcio Centro de Investigación Biomédica en Red (CIBER) (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05847517

Collaborator

European Commission (Other), Instituto de Salud Carlos III (Other)

350

Enrollment

Locations

Arms

Anticipated Duration (Months)

31.8

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy of intravenous metoprolol in patients with Acute Respiratory Respiratory Distress Syndrome (ARDS).

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome (ARDS)	Drug: Metoprolol Injection Drug: saline 0.9%	Phase 3

Detailed Description

This is a placebo-controlled, randomised, double-blind, multicentre, Phase III clinical trial to assess the efficacy of IV metoprolol in newly intubated ARDS patients, assessing survival and days free of invasive mechanical ventilation during the first 28 days. Eligible participants shall have had orotracheal intubation (OTI) and mechanical ventilation within 72 hours prior to randomisation, moderate-severe ARDS (PaO2/FiO2: ≤200 mmHg under standardised conditions (PEEP≥5 cm H2O), a heart rate ≥ 60 bpm and invasive systolic blood pressure ≥ 110 mmHg.The trial will include a total of n=350 patients, with two treatment arms: metoprolol vs. placebo (1:1). Each of the 7 days of treatment, participants will be receive 15 mg of iv metoprolol tartrate or matching placebo in 100 ml of saline for 10 minutes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

350 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomization (1:1) will be stratified according to the severity of ARDS and by participating centre: Moderate (PaO2/FiO2 of 100-200 mmHg). Severe (PaO2/FiO2 ≤100 mmHg).Randomization (1:1) will be stratified according to the severity of ARDS and by participating centre:Moderate (PaO2/FiO2 of 100-200 mmHg). Severe (PaO2/FiO2 ≤100 mmHg).

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Both metoprolol and saline are supplied in 5 ml ampoules of the same shape, structure and colour

Primary Purpose:

Treatment

Official Title:

Randomised, Double-blind, Placebo-controlled Clinical Trial to Evaluate the to Assess the Efficacy of Intravenous Metoprolol in Patients With Acute Respiratory Distress Syndrome (ARDS).

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2025

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Metoprolol Participants will be administered IV Metoprolol tartrate 15 mg (3 ampoules of 5 ml) diluted in 100 ml of saline.	Drug: Metoprolol Injection A dilution of 15 mg Metoprolol tartrate in 100 ml saline shall be performed and infused for 10 minutes. No dose reduction or increase is allowed. Systolic blood pressure and heart rate shall be measured 3 and 6 minutes after starting the infusion. In case of a consistent drop in systolic blood pressure or heart rate, the infusion shall be stopped and the infusion noted.
Placebo Comparator: Saline Participants will be administered IV saline (0.9% sodium chloride) (3 ampoules of 5 ml) diluted in 100 ml of saline.	Drug: saline 0.9% A dilution of 0.9% sodium chloride in 100 ml saline shall be performed and infused for 10 minutes. No dose reduction or increase is allowed. Systolic blood pressure and heart rate shall be measured 3 and 6 minutes after starting the infusion. In case of a consistent drop in systolic blood pressure below 110 mmHg or heart rate below 60 bpm, the infusion shall be stopped and the infusion noted.

Arm

Intervention/Treatment

Active Comparator: Metoprolol

Participants will be administered IV Metoprolol tartrate 15 mg (3 ampoules of 5 ml) diluted in 100 ml of saline.

Drug: Metoprolol Injection

A dilution of 15 mg Metoprolol tartrate in 100 ml saline shall be performed and infused for 10 minutes. No dose reduction or increase is allowed. Systolic blood pressure and heart rate shall be measured 3 and 6 minutes after starting the infusion. In case of a consistent drop in systolic blood pressure or heart rate, the infusion shall be stopped and the infusion noted.

Placebo Comparator: Saline

Participants will be administered IV saline (0.9% sodium chloride) (3 ampoules of 5 ml) diluted in 100 ml of saline.

Drug: saline 0.9%

A dilution of 0.9% sodium chloride in 100 ml saline shall be performed and infused for 10 minutes. No dose reduction or increase is allowed. Systolic blood pressure and heart rate shall be measured 3 and 6 minutes after starting the infusion. In case of a consistent drop in systolic blood pressure below 110 mmHg or heart rate below 60 bpm, the infusion shall be stopped and the infusion noted.

Outcome Measures

Primary Outcome Measures

days alive and free of invasive mechanical ventilation during the first 28 days. [28 days]
Hierarchical composite outcome "Alive and ventilator-free days at 28 days" (win ratio approach)

Secondary Outcome Measures

All-cause death at day 28 after randomization [28 days]
cumulative incidence of death from any cause
Ventilator-free days at 28 days [28 days]
number of days without mechanical ventilation during the firs 28 days
Intensive care unit days of admission [3 months]
Number of days admitted at the intensive care unit
Quality of life score [at 3 months]
Mean quality of life score according to the SF 36 questionnaires
Arterial oxygenation [on day 8]
Mean arterial oxygen saturation (PaO2/FiO2)
Change in arterial oxigenation [8 days]
Mean difference in arterial oxygen saturation (PaO2/FiO2) between baseline and day 8

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients (≥18 years and <80 years) with a clinical diagnosis of ARDS of any aetiology (pneumonia, including SARS-CoV-2, sepsis, pancreatitis, bronchospasm and trauma) admitted to the ICU.
Orotracheal intubation (OTI) and mechanical ventilation within 72 hours prior to randomisation.
Moderate-severe ARDS (PaO2/FiO2: ≤200 mmHg under standardised conditions (PEEP≥5 cm H2O).
Heart rate ≥ 60 bpm.
Invasive systolic blood pressure ≥ 110 mmHg.

Exclusion Criteria:

Prolonged hospital admission prior to randomisation (i.e. ≥7 days at the time of randomisation).
Reduced left ventricular ejection fraction (LVEF <50%).
Life expectancy due to other processes (cancer, degenerative diseases, etc.) of less than 6 months.
Right ventricular (RV) systolic dysfunction.
Concomitant acute heart failure (cardiac index ≤2.5 L/m2 or pulmonary capillary pressure ≥15 mmHg or clinical suspicion).
Second-degree atrioventricular block, 2:1 AV block, high-grade/advanced AV block and third-degree AV block. Also significant sinus bradycardia, which would be implied by having a heart rate >60 bpm as an inclusion criterion.
Pregnant or breastfeeding women.
Cardiogenic shock.
Persistent invasive blood pressure <110 mmHg despite vasopressor agents.
Use of noradrenaline at concentrations greater than 0.2 µg/kg/min at the time of the randomisation.
Use of dobutamine within 48 hours before randomisation.
Concomitant pulmonary embolism.
Known severe peripheral arterial disease.
Known asthma before admission (with active bronchodilator therapy).
Active beta-blocker treatment prior to admission (i.e. within 3 months prior to admission).

Contacts and Locations

Locations

	Site	City	State	Country
1	Hospital SAS de Jerez	Jerez De La Frontera	Andalucía	Spain
2	Hospital Universitario de Toledo	Toledo	Castilla-La Mancha	Spain
3	Hospital Clinic	Barcelona	Cataluña	Spain
4	Hospital Parc Taulí	Barcelona	Cataluña	Spain
5	Fundación Jiménez Díaz University Hospital	Madrid		Spain
6	Hospital Clínico San Carlos	Madrid		Spain
7	Hospital de Getafe	Madrid		Spain
8	Hospital General de Villalba	Madrid		Spain
9	Hospital La Paz	Madrid		Spain
10	Hospital Ramón y Cajal	Madrid		Spain
11	Hospital Rey Juan Carlos	Madrid		Spain