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

• ClinicalTrials.gov Identifier: NCT04344730
• Recruitment Status: Unknown
• First Posted: April 14, 2020
• Last Update Posted: February 9, 2021
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Hypoxemic Respiratory Failure; COVID-19	Drug: Dexamethasone injection; Drug: placebo; Procedure: conventional oxygen; Procedure: CPAP; Procedure: HFNO; Procedure: mechanical ventilation	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 550 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: In non-mechanically ventilated patients, a 2x2 factorial design will be used to assess the two interventions, separately.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The masking label is available only for the treatment assignation
• Primary Purpose: Treatment
• Official Title: Dexamethasone and Oxygen Support Strategies in ICU Patients With Covid-19 pneumonia_COVIDICUS
• Actual Study Start Date: April 10, 2020
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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	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 Name: experimental treatment; 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: 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 Name: 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 Name: 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 Name: 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)

Outcome Measures

Primary Outcome Measures :

1. The time-to-death from all causes [ Time Frame: day-60 ]
   The time-to-death from all causes within the first 60 days after randomization.
2. The time to need for mechanical ventilation (MV) [ Time Frame: day-28. ]
   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.

Secondary Outcome Measures :

1. The viral load in the respiratory tract [ Time Frame: day-10 ]
   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)
2. Number of patient with at least one episode of healthcare-associated infections [ Time Frame: day-28 ]
   Proportion of patients with at least one episode of any healthcare-associated infection between randomization and D28
3. Number of days alive without mechanical ventilation [ Time Frame: day-28 ]
   To compare the exposition to mechanical ventilation
4. Measure of SOFA score [ Time Frame: day-1 to day 3, day 7, day 10, day 21, day 28 ]
   Changes in SOFA (Sepsis-related Organ Failure Assessment) score. (min = 0 for normal status max = 24 for worse status)
5. Number of days alive without renal replacement therapy [ Time Frame: day-28 ]
   to compare the exposition to renal replacement therapy
6. Lengths of ICU-stay [ Time Frame: day-60 ]
   To compare the lengths of ICU
7. Lengths of hospital-stay [ Time Frame: day-60 ]
   To compare the lengths of hospital-stay
8. Number of patients with severe hypoxemia, [ Time Frame: day 60 ]
   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
9. Proportion of patients with cardiac arrest within 1 hour after intubation [ Time Frame: day 60 ]
   Proportion of patients with cardiac arrest within 1 hour after intubation
10. Overall survival [ Time Frame: day 60 ]
    To compare Overall survival after randomization

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

France

Hopital Bichat - Aphp

Paris, France, 75018

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT04344730
• Other Study ID Numbers: APHP200388; 2020-001457-43 ( EudraCT Number )
• First Posted: April 14, 2020
• Last Update Posted: February 9, 2021
• Last Verified: February 2021

• 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:

COVID-19; acute hypoxemic respiratory failure (AHRF)

Additional relevant MeSH terms:

COVID-19; Pneumonia; Respiratory Insufficiency; Respiratory Tract Infections; Infections; Pneumonia, Viral; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Dexamethasone; Dexamethasone acetate; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents