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

Efficacy of Intravenous Almitrine in Reducing the Need for Mechanical Ventilation in Patients With Hypoxemic Acute Respiratory Failure Due to Covid-19-related Pneumonia: a Randomized Controlled Double-blind Study From the Skip-icu Consortium

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.

Study Overview

• Status: Completed
• Conditions: Covid 19; Hypoxemic Respiratory Failure
• Intervention / Treatment: Drug: Almitrine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hospital Pitie-Salpetriere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Intravenous glucose 5% during 5 days
EXPERIMENTAL: Almitrine	Drug: Almitrine; Intravenous almitrine at a dose of 2 µg.kg-1.min-1 during 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of endotracheal intubation	Endotracheal intubation within 7 days after randomization Death will be considered as a failure (endotracheal intubation).	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality		28 days
Number of ventilator-free days		28 days
In-hospital mortality		28-day
Number of days in the ICU		28 days
Number of days in the hospital		28 days
Discontinuation rate of the treatment	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.	28 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Kalfon P, Payen JF, Rousseau A, Chousterman B, Cachanado M, Tibi A, Audibert J, Depret F, Constantin JM, Weiss E, Remerand F, Freund Y, Simon T, Riou B. Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial. EClinicalMedicine. 2022 Oct;52:101663. doi: 10.1016/j.eclinm.2022.101663. Epub 2022 Sep 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 3, 2020
• Primary Completion (ACTUAL): October 1, 2021
• Study Completion (ACTUAL): December 17, 2021

Study Registration Dates

• First Submitted: April 20, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (ACTUAL): April 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 3, 2022
• Last Update Submitted That Met QC Criteria: May 2, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; COVID-19 pneumonia; Almitrine; HYPOXEMIC ACUTE RESPIRATORY FAILURE
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Lung Diseases; COVID-19; Respiratory Insufficiency; Pneumonia; Respiratory System Agents; Almitrine
• Other Study ID Numbers: APHP200461; 2020-001909-22 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Yes, upon request, after approval by the primary investigator and clinical research platform of East Paris. For the purpose of IPD meta-analysis, or secondary analysis. Unidentifying data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No