COVID-19 trials registries data warehouse

https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001420-34/DK

Aarhus University - www.Clinicaltrials.gov

us@biomed.au.dk

2020-04-01

Completed

RCT

Randomized

Parallel

Open label

multi-center

Treatment

1) COVID-19 2) Age ≥18 years 3) Respiratory insufficiency 4) ICU admission COVID-19 will be defined as a positive polymerase chain reaction (PCR) test for SARS-CoV-2, either from a nasal or throat swab or from tracheal suctioning, within the last 14 days prior to ICU admission. Respiratory insufficiency will be defined as a need for supplemental oxygen of at least 10 L/min in patients without a need for mechanical ventilation or invasive or non-invasive mechanical ventilation with a FiO2 ≥ 40%. An ICU will be defined per local practices.

1) Severe heart failure (ejection fraction < 30%) 2) Severe renal insufficiency (eGFR < 30 mL/min/1.73m2) 3) Severe hemodynamic instability (noradrenalin dose > 0.3 μg/kg/min) 4) Prior enrollment in the trial 5) Pregnancy 6) Allergy to senicapoc 7) Inability to take enteral medication 8) More than 24 hours since ICU admission 9) Limitations of care 10) Anticipated death within 24 hours Severe heart failure will pragmatically be defined solely on the basis of the latest measured or estimated ejection fraction obtained via echocardiography (or other image modalities). If no ejection fraction is available, it will be assumed that the patient does not have severe heart failure. Renal insufficiency will be defined based on the latest estimated glomerular filtration rate (eGFR). If a patient is receiving renal replacement therapy, this will likewise be considered severe renal insufficiency. Hemodynamic instability will be defined based on a need for high-dose continuous vasopressor therapy specifically a noradrenalin dose > 0.3 μg/kg/min. If the patient is receiving other vasopressors instead of or in addition to noradrenalin, a noradrenaline-equivalent dose will be estimated based on prior formulas.39 In fertile women (age < 50 years) a negative urine-hCG or plasma-hCG must be present before enrolment. In order to optimize the chances of patients surviving to 72 hours (the time of the primary outcome), patients with limitations of care (including limitations related to mechanical ventilation and renal replacement therapy but not cardiopulmonary resuscitation) and patients with anticipated death within 24 hours, as judged by the treating clinician, will be excluded.

2

Aarhus University

18

None

Denmark

Critical disease at enrollment

8: Critical disease at enrollment

46

The primary outcome will be the PaO2/FiO2 ratio 72 hours after randomization. The PaO2/FiO2 ratio will be calculated based on the arterial gas closest to the time-point of 72 hours after randomization. If no clinically-indicated arterial gas is performed or planned within ± 2 hours of the time-point, an arterial gas will be performed. The ratio will be calculated based on the PaO2 from the arterial gas and the FiO2 at the same time point. If the patient is receiving mechanical ventilation (invasive or non-invasive) or is receiving oxygen through a high-flow nasal cannula, the FiO2 will be obtained directly from the ventilator. If the patient is receiving oxygen through a regular nasal cannula, the FiO2 will be calculated based on the following: FiO2 = 21% + 4%/(l/min) x O2 flow in l/min. For face masks, with or without reservoir, the FiO2 will be estimated based on the approach used in EPIC2.40,41 Patients who dies prior to the 72-hour time point will be handled as described in Section 6.2.3. The PaO2/FiO2 ratio is a commonly used measure of illness severity in patients with acute lung injury and ARDS and is used to define these two conditions.17 Furthermore, the PaO2/FiO2 ratio is associated with mortality17,20 making it a potential useful surrogate outcome for phase II trials. Although data is sparse, a lower PaO2/FiO2 ratio has also been associated with worse outcomes in patients with COVID-19.10,42 Furthermore, animal studies in mice have shown that Senicapoc improves the PaO2/FiO2 ratio in experimentally induced ARDS (Section 1.3.2). Based on these considerations, and the fact that hypoxemic respiratory failure is the hallmark of severe COVID-19 infection, the PaO2/FiO2 ratio is a reasonable primary outcome for a phase II trial. The primary measure of the PaO2/FiO2 ratio will be done 72-hours after randomization. This time-point was chosen to allow adequate time for the intervention to work while avoiding missing data due to deaths.

nan

Phase 2

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