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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)

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ClinicalTrials.gov Identifier: NCT04357457
Recruitment Status : Not yet recruiting
First Posted : April 22, 2020
Last Update Posted : May 13, 2020
Sponsor:
Collaborator:
Centre Hospitalier de Chartres
Information provided by (Responsible Party):
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 3.6%). 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.


Condition or disease Intervention/treatment Phase
Covid 19 Hypoxemic Respiratory Failure Drug: Almitrine Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 212 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : May 2020
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Almitrine Drug: Almitrine
Intravenous almitrine at a dose of 2 µg.kg-1.min-1 during 5 days

Placebo Comparator: Placebo Drug: Placebo
Intravenous glucose 5% during 5 days




Primary Outcome Measures :
  1. Rate of endotracheal intubation [ Time Frame: 7 days ]
    Endotracheal intubation within 7 days after randomization Death will be considered as a failure (endotracheal intubation).


Secondary Outcome Measures :
  1. 28-day mortality [ Time Frame: 28 days ]
  2. In-hospital mortality [ Time Frame: 28-day ]
  3. Number of ventilator-free days [ Time Frame: 28 days ]
  4. Number of days in the ICU [ Time Frame: 28 days ]
  5. Number of days in the hospital [ Time Frame: 28 days ]
  6. Discontinuation rate of the treatment [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults patients aged 75 years or less
  • COVID-19 diagnosis in the past 14 days 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 within 14 days
  • Patients affiliated to French social security ("AME" excepted)

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%)
  • Known Plasma total bilirubin > 21 µmol/L during hospitalization
  • Lactate level > 4 mmol/L
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04357457


Contacts
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Contact: Yonathan FREUND, PU-PH 00 33 663 549 017 yonathman@gmail.com
Contact: Pierre KALFON, MD 00 33 237 303 073 pkalfon@ch-chartres.fr

Locations
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France
Hospital Pitié-Salpêtrière
Paris, France
Contact: Yonathan Freund, PU-PH    00 33 663 549 017    yonatman@gmail.com   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Centre Hospitalier de Chartres
Investigators
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Principal Investigator: Yonathan FREUND, PU-PH Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04357457    
Other Study ID Numbers: APHP200461
2020-001909-22 ( EudraCT Number )
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: May 13, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Almitrine
HYPOXEMIC ACUTE RESPIRATORY FAILURE
COVID-19
COVID-19 pneumonia
Additional relevant MeSH terms:
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Pneumonia
Respiratory Insufficiency
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiration Disorders
Almitrine
Respiratory System Agents