Efficacy of Intravenous Almitrine in Reducing the Need for Mechanical Ventilation in Patients With Hypoxemic Acute Respiratory Failure Due to Covid-19-related Pneumonia

Phase 3

Completed

• Conditions: Hypoxemic Respiratory Failure; Covid 19
• Interventions: Drug: Almitrine; Drug: Placebo

• Registration Number: NCT04357457
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

The COVID-19 outbreak is associated with a surge in ICU bed requirement and substantial mortality (estimated between 0.5% and 1%). Admission in the intensive care unit (ICU) and need for mechanical ventilation is reportedly associated with an estimated hospital mortality of more than 30%. Furthermore, the surge in ICU bed requirement is a worldwide-shared issue, leading to sub-optimal ICU management.

In acute respiratory failure due to COVID-19-related pneumonia, vasoplegia with vascular enlargement inside the lung lesions and dilation of small vessels seen on chest CT scan largely account for severe hypoxemia whose physiological response is hyperventilation leading to hypocapnia. Almitrine, initially described to reduce intrapulmonary shunt by enhancement of hypoxic pulmonary vasoconstriction in combination with inhaled nitric oxide (iNO), redistributes pulmonary blood flow from shunt areas to lung units with normal ventilation/perfusion (VA/Q) ratio. Low dose of intravenous almitrine (2 µg.kg-1.min-1) alone also improves oxygenation (without combination with iNO) by selective pulmonary vasoconstriction of precapillary pulmonary arteries perfusing lung areas exposed to a hypoxic challenge with a slight increase in mean arterial pulmonary. Therefore, our hypothesis is that 5 days of low dose of almitrine therapy may improve the ventilation-perfusion (VA/Q) ratio at a relatively early stage of this specific lung disease and limit respiratory worsening and subsequent need for mechanical ventilation.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-04-20
• Study First Submitted QC: 2020-04-20
• Study First Posted: 2020-04-22
• Study Start: 2020-09-03
• Primary Completion: 2021-10-01
• Study Completion: 2021-12-17
• Status Verified: 2022-04
• Last Update Submitted: 2022-05-02
• Last Update Posted: 2022-05-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 181

Inclusion Criteria

• Adults patients aged 80 years or less
• COVID-19 diagnosis defined as either positive RT-PCR for SARS-CoV-2 or COVID-19 compatible or typical chest CT pattern or positive serology for COVID-19 antibodies
• Hypoxemic acute respiratory failure with the following criteria: oxygen saturation level of 92% or less, as measured by pulsed oximetry (SpO2) under oxygen therapy with an oxygen rate of 6L/min or more.
• Hospital admission for COVID-19 within 14 days
• Patients affiliated

Exclusion Criteria

• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy or breastfeeding woman
• Known Hepatic failure (PT <50%, Factor V < 50%)
• Last known Plasma total bilirubin > 21 μmol/L
• Lactate level > 4 mmol/L
• ALT and AST levels greater than 3 times the upper limit
• Pulmonary hypertension (PAPs ≥37 mmHG and/or VmaxIT ≥ 2,9 m/s) or right ventricular dysfunction
• History of pulmonary embolism
• Diagnosis of pulmonary embolism during the current hospitalization or on-going anticoagulant therapy at curative dose for thromboembolism when hospitalized
• PaCO2 > 45 mmHg
• Exacerbation of asthma or chronic respiratory failure
• Cardiogenic pulmonary oedema
• Systolic blood pressure of 90 mmHg or less, or use of vasopressors
• Urgent need for endotracheal intubation at the discretion of the treating physician
• Do-not-intubate order or estimated life expectancy less than 6 months
• Participation in another interventional research

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Almitrine	Almitrine	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Rate of endotracheal intubation	7 days	Endotracheal intubation within 7 days after randomization Death will be considered as a failure (endotracheal intubation).

Secondary Outcome Measures

Name	Time	Method
Number of ventilator-free days	28 days
28-day mortality	28 days
In-hospital mortality	28-day
Number of days in the hospital	28 days
Discontinuation rate of the treatment	28 days	safety assessment: discontinuation rate of the treatment for arterial lactate more than 4 mmol/L, ALT/AST levels greater than 3 times the upper limit, and diagnosis of pulmonary arterial hypertension or acute cor pulmonale documented by echocardiography.
Number of days in the ICU	28 days

Trial Locations

Locations (1)

Hospital Pitié-Salpêtrière; 🇫🇷 Paris, France