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Losartan and Spironolactone Treatment for ICU Patients With COVID-19 Suffering From ARDS (COVIDANCE)

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ClinicalTrials.gov Identifier: NCT04643691
Recruitment Status : Recruiting
First Posted : November 25, 2020
Last Update Posted : November 25, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille

Brief Summary:

Coronavirus disease (COVID-19) is a current pandemic infection caused by an RNA virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Severe forms of COVID-19 are most often responsible for isolated respiratory failure in the form of acute respiratory distress syndrome (ARDS), which accounts for most of the mortality. Angiotensin converting enzyme 2 (ACE2) has been shown to be a co-receptor for the entry of SARS-CoV-2 into cells and is likely to play a prolonged role in the pathogenesis of COVID-19. ACE2 and angiotensin (1-7) have been shown to be protective in a number of different lung lesion models. In a mouse model of acidic lung injury, negative regulation of ACE2 by COVID, the SARS virus responsible for the 2003 SARS outbreak, worsened the lung injury which was improved by treatment with ARBs.

We believe that blocking the first RAS pathway at the end of the chain on the AT1r angiotensin 2 receptor may prevent the initiation of this chain reaction and limit decompensation secondary to the disruption of the equilibrium of the renin-angiotensin system. We have several molecules that block the AT1r angiotensin-2 receptor (ARBs) as well as a molecule that blocks the secretion of aldosterone (spironolactone). The main objective is to demonstrate the value of losartan and spironolactone therapy in the regulation of the renin-angiotensin system in improving the prognosis of patients infected with COVID-19 and suffering from acute respiratory distress syndrome.

This is a prospective, multicenter, randomized, open-label, controlled, therapeutic trial studying two parallel groups. The population included in this study is any major patient in acute respiratory distress hospitalized in intensive care requiring oxygen support of at least 6L/min and suffering from a PCR-confirmed SARS-cov2 infection. The control group will benefit from the usual resuscitation management of COVID19 , and the experimental group will benefit from losartan and spironolactone treatment in addition to the usual management, according to the study protocol. The number of subjects required has been calculated and 45 patients for each group, for a total of 90 patients.

The SOFA score at D7 will be compared between the "experimental" versus "control" groups using a mean comparison method. The comparison of this criterion and all secondary criteria of judgments between the 2 groups will be performed using a Student or Mann-Whitney test based on the normality of the distribution. The significance threshold will be set at 0.05. No intermediate analysis is scheduled. The analysis will be blinded.

The main expected outcome is an improved prognosis with a decrease in the SOFA severity score at 7 days in resuscitation patients, resulting in an improvement in organ failure. The expected secondary results will be to show the interest of ARA2/Spironolactone treatment on oxygenation based on the PaO2/FiO2 ratio, mechanical ventilation duration and mortality.


Condition or disease Intervention/treatment Phase
COVID-19 ARDS Drug: Losartan 50 mg and Spironolactone 25 mg pillules oral use Phase 2

Detailed Description:

Coronavirus disease (COVID-19) is a current pandemic infection caused by an RNA virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Severe forms of COVID-19 are most often responsible for isolated respiratory failure in the form of acute respiratory distress syndrome (ARDS), which accounts for most of the mortality. Angiotensin converting enzyme 2 (ACE2) has been shown to be a co-receptor for the entry of SARS-CoV-2 into cells and is likely to play a prolonged role in the pathogenesis of COVID-19. ACE2 and angiotensin (1-7) have been shown to be protective in a number of different lung lesion models. In a mouse model of acidic lung injury, negative regulation of ACE2 by COVID, the SARS virus responsible for the 2003 SARS outbreak, worsened the lung injury which was improved by treatment with ARBs.

We believe that blocking the first RAS pathway at the end of the chain on the AT1r angiotensin 2 receptor may prevent the initiation of this chain reaction and limit decompensation secondary to the disruption of the equilibrium of the renin-angiotensin system. We have several molecules that block the AT1r angiotensin-2 receptor (ARBs) as well as a molecule that blocks the secretion of aldosterone (spironolactone). The main objective is to demonstrate the value of losartan and spironolactone therapy in the regulation of the renin-angiotensin system in improving the prognosis of patients infected with COVID-19 and suffering from acute respiratory distress syndrome.

This is a prospective, multicenter, randomized, open-label, controlled, therapeutic trial studying two parallel groups. The population included in this study is any major patient in acute respiratory distress hospitalized in intensive care requiring oxygen support of at least 6L/min and suffering from a PCR-confirmed SARS-cov2 infection. The control group will benefit from the usual resuscitation management of COVID19 , and the experimental group will benefit from losartan and spironolactone treatment in addition to the usual management, according to the study protocol. The number of subjects required has been calculated and 45 patients for each group, for a total of 90 patients.

The SOFA score at D7 will be compared between the "experimental" versus "control" groups using a mean comparison method. The comparison of this criterion and all secondary criteria of judgments between the 2 groups will be performed using a Student or Mann-Whitney test based on the normality of the distribution. The significance threshold will be set at 0.05. No intermediate analysis is scheduled. The analysis will be blinded.

The main expected outcome is an improved prognosis with a decrease in the SOFA severity score at 7 days in resuscitation patients, resulting in an improvement in organ failure. The expected secondary results will be to show the interest of ARA2/Spironolactone treatment on oxygenation based on the PaO2/FiO2 ratio, mechanical ventilation duration and mortality.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Benefit of Treatment With Losartan and Spironolactone on the Regulation of the Renin-angiotensin System in the Prognosis of Patients Infected With COVID-19 and Suffering From Acute Respiratory Distress Syndrome
Actual Study Start Date : September 11, 2020
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : October 30, 2022


Arm Intervention/treatment
Experimental: losartan / spironolactone
Losartan 50 mg and Spironolactone 25 mg pillules oral use
Drug: Losartan 50 mg and Spironolactone 25 mg pillules oral use
Losartan 50 mg and Spironolactone 25 mg pillules oral use during 10 days

No Intervention: usual care
Usual care of COVID-19 infection in intensive care



Primary Outcome Measures :
  1. SOFA score [ Time Frame: 7 days (J7) ]
    Organ failures will be assessed on the SOFA score on day 7 post-inclusion.


Secondary Outcome Measures :
  1. Pa02/Fi02 [ Time Frame: day 3; day 7; day 14; day 21 and day 28 ]
    Oxygenation will be assessed using the PaO2/FiO2 ratio on the 3rd, 7th, 14th, 21st, 28th day after inclusion

  2. Duration of mechanical ventilation [ Time Frame: 28 days ]
    The duration of mechanical ventilation will be evaluated by the number of days of ventilation, the number of days without ventilation between inclusion and death or D28

  3. Death [ Time Frame: 28 days ]
    Mortality will be measured by: mortality at D28, hospital mortality, ICU mortality.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patient
  • Patient with respiratory distress requiring oxygen support of 6 liters per minute or more.
  • News-Score greater than 6 PCR SARS-CoV-2 positive in a pharyngeal or respiratory specimen,
  • Informed Consent

Exclusion Criteria:

  • Minor patient,
  • Patient deprived of liberty,
  • Refusal of the patient to participate in the study,
  • Patient for whom measures of therapeutic limitation have been issued justifying the absence of recourse to mechanical ventilation,
  • Patient of 80 years or older,
  • Pregnant or breastfeeding woman,
  • Patient with prior treatment with ARA2 or ACE inhibitors,
  • Hypotension justifying treatment with norepinephrine,
  • Acute renal failure with a clearance of less than 60ml/min,
  • Severe liver failure.
  • Intolerance or contraindication to losartan or spironolactone

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): NCT04643691


Contacts
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Contact: Pierre SIMEONE 06 59 24 03 13 ext +33 pierre.simeone@ap-hm.fr
Contact: Claire MORANDO 04 91 38 21 83 ext +33 claire.morando@ap-hm.fr

Locations
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France
Assistance Publique Hôpitaux de Marseille Recruiting
Marseille, France, 13005
Contact: Pierre SIMEONE         
Sponsors and Collaborators
Assistance Publique Hopitaux De Marseille
Investigators
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Study Director: Emilie GARRIDO-PRADALIE Assistance Publique Hôpitaux de Marseille
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Responsible Party: Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier: NCT04643691    
Other Study ID Numbers: 2020-24
2020-001766-11 ( EudraCT Number )
First Posted: November 25, 2020    Key Record Dates
Last Update Posted: November 25, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Hopitaux De Marseille:
COVID-19
ARDS
Additional relevant MeSH terms:
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Stress, Psychological
Behavioral Symptoms
Losartan
Spironolactone
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents