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

NCT04357457 | Completed Phase 3 DMC

• 2 other identifiers: APHP2004612020-001909-22
• Study Type: interventional
• Target: 181
• Locations: 1 country
• Sites: 1

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

Keywords

Almitrine; HYPOXEMIC ACUTE RESPIRATORY FAILURE; COVID-19; COVID-19 pneumonia

Outcome Measures

Primary Outcomes (1)

• Rate of endotracheal intubation

  Endotracheal intubation within 7 days after randomization Death will be considered as a failure (endotracheal intubation).

  7 days

Secondary Outcomes (6)

• 28-day mortality

  28 days

• In-hospital mortality

  28-day

• Number of ventilator-free days

  28 days

• Number of days in the ICU

  28 days

• Number of days in the hospital

  28 days

Study Arms (2)

Almitrine

EXPERIMENTAL

Drug: Almitrine

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Almitrine DRUG

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

Almitrine

Placebo DRUG

Intravenous glucose 5% during 5 days

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hospital Pitié-Salpêtrière

Paris, France

Location

Related Publications (1)

• 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.

  PMID: 36157895 DERIVED

MeSH Terms

Conditions

COVID-19; Respiratory Insufficiency

Interventions

Almitrine

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Triazines

Study Officials

• Yonathan FREUND, PU-PH

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2020
• First Posted: April 22, 2020
• Study Start: September 3, 2020
• Primary Completion: October 1, 2021
• Study Completion: December 17, 2021
• Last Updated: May 3, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share

Locations

FR (1)