Dexamethasone and Oxygen Support Strategies in ICU Patients With Covid-19 Pneumonia (COVIDICUS)

Dexamethasone and Oxygen Support Strategies in ICU Patients With Covid-19 pneumonia_COVIDICUS

The main manifestation of COVID-19 is acute hypoxemic respiratory failure (AHRF). In patients with AHRF, the need for invasive mechanical ventilation is associated with high mortality.

Two hypotheses will be tested in this study. The first hypothesis is the benefit of corticosteroid therapy on severe COVID-19 infection admitted in ICU in terms of survival.

The second hypothesis is that, in the subset of patients free of mechanical ventilation at admission, either Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) allows to reduce intubation rate safely during COVID-19 related acute hypoxemic respiratory failure.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Acute Hypoxemic Respiratory Failure
• Intervention / Treatment: Drug: placebo; Procedure: conventional oxygen; Drug: Dexamethasone injection; Procedure: CPAP; Procedure: HFNO; Procedure: mechanical ventilation

Detailed Description

The main manifestation of COVID-19 is acute hypoxemic respiratory failure (AHRF). In patients with AHRF, the need for invasive mechanical ventilation is associated with high mortality.

Two hypotheses will be tested in this study. The first hypothesis is the benefit of corticosteroid therapy on severe COVID-19 infection admitted in ICU in terms of survival.

The second hypothesis is that, in the subset of patients free of mechanical ventilation at admission, either Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) allows to reduce intubation rate safely during COVID-19 related acute hypoxemic respiratory failure.

The main objective is to assess the impact of dexamethasone on overall mortality at day-60 after randomization in patients admitted in ICU for severe COVID-19 infection.

In non mechanical ventilation (MV) patients, the additional objective is to assess whether oxygen support based on either HFNO or CPAP modality in COVID-19 related AHRF reduces the need for mechanical ventilation at day-28.

An ancillary study CACAO (COVIDICUS air contamination) will be performed in 4 centers aiming at assessing the environmental contamination by SARS-CoV-2 according to the oxygen support modality. Additional funding will be searched for these analyses (submitted for ANR call).

A metanalysis on individual data will be performed using patients enrolled in the 3 PHRC flash exploring the activity of corticosteroids.

• Study Type: Interventional
• Enrollment (Actual): 550
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75018
    • Hôpital Bichat - APHP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Admitted to ICU within 48 hours
3. Confirmed or highly suspected COVID-19 infection
4. Acute hypoxemic respiratory failure (PaO2 <70 mmHg or SpO2<90% on room air or tachypnea>30/min or labored breathing or respiratory distress; need for oxygen flow >=6L/min)
5. Any treatment intended to treat the SARS-CoV-2 infection in the absence of contraindications (either as a compassionate use or in the context of a clinical trial, i.e remdesivir, lopinavir/ritonavir, favipiravir, hydroxychloroquine and any other new drug with potential activity).

Non-inclusion Criteria:

1. Moribund status
2. Pregnancy or breastfeeding
3. Long term corticotherapy at a dose of 0.5mg/kg/j or higher
4. Active and untreated bacterial, fungal or parasitic infection
5. Not Written informed consent from the patient or a legal representative if appropriate . If absence a legal representative the patient may be included in emergency procedure
6. hypersensitivity to dexamethasone or to any of the excipients
7. Not Affiliation to the French social security

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard oxygen 1; Standard oxygen and placebo of Dexamethasone	Drug: placebo; Box of 10 NaCl 0,9% , solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Procedure: conventional oxygen; The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2)
Experimental: Standard oxygen 2; Standard oxygen and Dexamethasone	Procedure: conventional oxygen; The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2); Drug: Dexamethasone injection; Box of 10 DEXAMETHASONE 20 mg / 5 ml, solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Other Names: experimental treatment
Experimental: CPAP 1; CPAP and placebo of Dexamethasone	Drug: placebo; Box of 10 NaCl 0,9% , solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Procedure: CPAP; Patients assigned to the CPAP plus oxygen group will receive periods of CPAP in addition to the standard treatment.The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2)
Experimental: CPAP 2; CPAP and Dexamethasone	Drug: Dexamethasone injection; Box of 10 DEXAMETHASONE 20 mg / 5 ml, solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Other Names: experimental treatment; Procedure: CPAP; Patients assigned to the CPAP plus oxygen group will receive periods of CPAP in addition to the standard treatment.The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2)
Experimental: HFNO 1; HFNO and placebo of Dexamethasone	Drug: placebo; Box of 10 NaCl 0,9% , solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Procedure: HFNO; TIn the high-flow-nasal cannula group, oxygen will be delivered through a heated humidifier (Airvo-2, Fisher and Paykel Healthcare) and applied continuously through large-bore binasal prongs, with a gas flow rate of 30 liters per minute and adjusted based on the clinical response. FiO2 will be adjusted for the target SpO2
Experimental: HFNO 2; HFNO and Dexamethasone	Drug: Dexamethasone injection; Box of 10 DEXAMETHASONE 20 mg / 5 ml, solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Other Names: experimental treatment; Procedure: HFNO; TIn the high-flow-nasal cannula group, oxygen will be delivered through a heated humidifier (Airvo-2, Fisher and Paykel Healthcare) and applied continuously through large-bore binasal prongs, with a gas flow rate of 30 liters per minute and adjusted based on the clinical response. FiO2 will be adjusted for the target SpO2
Placebo Comparator: mechanically ventilated 1; placebo	Drug: placebo; Box of 10 NaCl 0,9% , solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Procedure: mechanical ventilation; The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2)
Experimental: mechanically ventilated 2; Dexamethasone	Drug: Dexamethasone injection; Box of 10 DEXAMETHASONE 20 mg / 5 ml, solution for injection in ampoule of 5mL. Each allocated box contains complete treatment from D1 to D10 for one patient.; Other Names: experimental treatment; Procedure: mechanical ventilation; The oxygen flow will be adjusted to maintain an oxygen saturation level of 92% or more, as measured by means of pulse oximetry (SpO2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time-to-death from all causes	The time-to-death from all causes within the first 60 days after randomization.	day-60
The time to need for mechanical ventilation (MV)	the time to need for mechanical ventilation (MV), as defined by any of the 3 criteria for intubation within the first 28 days after randomization.	day-28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The viral load in the respiratory tract	The cycle threshold for SARS-CoV-2 PCR at baseline, day 7+/-1 and day 10 +/- in samples of the same origin (preferably subglottic i.e. bronchoalveolar lavage or tracheal aspiration, otherwise nasopharyngeal swab)	day-10
Number of patient with at least one episode of healthcare-associated infections	Proportion of patients with at least one episode of any healthcare-associated infection between randomization and D28	day-28
Number of days alive without mechanical ventilation	To compare the exposition to mechanical ventilation	day-28
Measure of SOFA score	Changes in SOFA (Sepsis-related Organ Failure Assessment) score. (min = 0 for normal status max = 24 for worse status)	day-1 to day 3, day 7, day 10, day 21, day 28
Number of days alive without renal replacement therapy	to compare the exposition to renal replacement therapy	day-28
Lengths of ICU-stay	To compare the lengths of ICU	day-60
Lengths of hospital-stay	To compare the lengths of hospital-stay	day-60
Number of patients with severe hypoxemia,	Proportion of patients with severe hypoxemia, which is defined as an oxygen saturation of less than 80% during the same interval during the interval between induction and 2 minutes after tracheal intubation	day 60
Proportion of patients with cardiac arrest within 1 hour after intubation	Proportion of patients with cardiac arrest within 1 hour after intubation	day 60
Overall survival	To compare Overall survival after randomization	day 60

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Jean François TIMSIT, Pr, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Bouadma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Megarbane B, Garcon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Sep 1;182(9):906-916. doi: 10.1001/jamainternmed.2022.2168.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2020
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: April 9, 2020
• First Submitted That Met QC Criteria: April 13, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: February 6, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; acute hypoxemic respiratory failure (AHRF)
• 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; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Dexamethasone acetate
• Other Study ID Numbers: APHP200388; 2020-001457-43 (EudraCT Number)

Drug and device information, study documents

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