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

NCT ID: NCT04357457

Last Updated: 2022-05-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 181 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-03
• Study Completion Date: 2021-12-17

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.

Conditions

Covid 19; Hypoxemic Respiratory Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Almitrine

Group Type: EXPERIMENTAL

Almitrine

Intervention Type: DRUG

Intravenous almitrine at a dose of 2 µg.kg-1.min-1 during 5 days

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Intravenous glucose 5% during 5 days

Interventions

Almitrine

Intravenous almitrine at a dose of 2 µg.kg-1.min-1 during 5 days

Intervention Type: DRUG

Placebo

Intravenous glucose 5% during 5 days

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yonathan FREUND, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Hospital Pitié-Salpêtrière

Paris, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 36157895 (View on PubMed)

Other Identifiers

2020-001909-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

APHP200461

Identifier Type: -

Identifier Source: org_study_id