Clinical trial NCT04591990: HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome
Official title: HYdrocortisone and VAsopressin in Post-REsuscitation Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Postresuscitation Syndrome
Keywords: intensive care
hydrocortisone
vasopressin
post-resuscitation syndrome
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-10-19
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The primary objective is to demonstrate the superiority of arginine-vasopressin (AVP) and hydrocortisone compared with norepinephrine regarding day-30 survival and neurological recovery in post-cardiac arrest patients with hemodynamic failure.

Detailed description: For patients successfully resuscitated who got restoration of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR), the course is usually marked by a post-resuscitation syndrome including multiple organ failures of various intensity and anoxic brain damage. The cardiocirculatory failure usually dominates the clinical picture, and it often leads to multiorgan failure. This hemodynamic failure is multifactorial, including at various levels vasoplegia, myocardial dysfunction, endotoxin release and adrenal dysfunction and is at least partly related to a hormonal defect that could be counteracted by hormonal supplementation. Such a substitutive opotherapy by hydrocortisone and AVP could improve hemodynamic failure and decrease overall mortality in this setting.

This trial is a superiority multicentric trial and patients will be randomized in a 1:1:1:1 ratio using an electronic CRF.

Investigational medicinal products:

- Arginin-vasopressin or AVP (REVERPLEG) The solution for infusion is prepared by diluting 40 I.U. REVERPLEG® with sodium chloride 9 mg/ml (0.9%) solution. The total volume after dilution should be 50 ml (equivalent to 0.8 I.U. AVP per ml).

AVP will be administered according to mean arterial pressure to target a 65mmHg blood pressure for max 3 days.

- HYDROCORTISONE HEMISUCCINATE Vials with lyophilisate (100mg hydrocortisone) are provided by SERB laboratory. Hydrocortisone hemisuccinate will be administered as a 50mg intravenous bolus every 6 hours after an initial dose of 100mg, for 7 consecutive days. Stop of treatment by hydrocortisone will be performed without tapering.

Comparator treatment: placebos.

17 ICU centers in France will participate to this study targetting 380 patient's enrollment in the study.

Eligibility criteria: Inclusion Criteria:

* Adult patients (\>18y)
* Cardiac arrest (in-hospital or out-of-hospital) with sustained ROSC (\> 30 minutes) admitted to the ICU
* Post-resuscitation shock defined as arterial hypotension (SAP \< 90 mmHg or MAP \< 65 mmHg) unresponsive to adequate fluid loading, which occurred within the first 24 hours after ROSC and requiring norepinephrine/epinephrine continuous infusion at a dose greater or equal to 0.2µg/kg/min for at least 3 hours
* A maximal delay between the start of norepinephrine infusion and randomization of 9 hours
* Informed written consent of the patient or a legally authorized close relative.

Exclusion Criteria:

* Evidence for a traumatic or a neurological cause of cardiac arrest
* Shock due to uncontrolled haemorrhage
* Previously known adrenal insufficiency
* Limitation of life-sustaining therapies
* Ongoing treatment by any steroids, whatever the dose
* Ongoing extra-corporeal circulatory assistance
* Gastrointestinal bleeding in the past 6 weeks
* Pregnant or breastfeeding women
* Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants, if applicable
* Hypersensitivity to arginin-vasopressin and to its excipients
* Hypersensitivity to hydrocortisone and to its excipients
* Legal protection (i.e. incompetence to provide consent, guardianship, curator or incarceration)
* No affiliation with the French health care system.

Primary outcomes:
measure: Neurological outcome
timeFrame: at day-30
Secondary outcomes:
measure: All-cause mortality
timeFrame: at day-30
measure: Mortality attributed to irreversible hemodynamic failure
timeFrame: at day-30
measure: Mortality attributed to neurological withdrawal of care
timeFrame: at day-30
measure: Mortality attributed to comorbid withdrawal of care
timeFrame: at day-30
measure: Day-30 brain death
timeFrame: at day-30
measure: mortality attributed to recurrent cardiac arrest
timeFrame: at day-30
measure: Other causes
timeFrame: at day-30
measure: Neurological recovery at day-30
timeFrame: at day-30
measure: Brain damage
timeFrame: at 48 hours and at 72hours
Other outcomes:
Locations:
city: Amiens
country: France
facility: Intensive care unit, CHU Amiens- Picardie
city: Angers
country: France
facility: Intensive care unit, CHU Angers
city: Aulnay-sous-Bois
country: France
facility: Intensive care unit, CHI Robert Ballanger
city: Boulogne-Billancourt
country: France
facility: Medical Intensive Care Unit, Ambroise Paré hospital, APHP
city: Cherbourg
country: France
facility: Intensive care unit, CH public du Cotentin
city: Dijon
country: France
facility: Intensive care unit, CHU Dijon
city: Lyon
country: France
facility: Intensive care unit, Hospices civils de Lyon
city: Massy
country: France
facility: Intensive care unit, Hôpital Jacques Cartier
city: Montpellier
country: France
facility: Intensive care unit, CHU Montpellier
city: Nancy
country: France
facility: Intensive care unit, Brabois hospital
city: Nantes
country: France
facility: Intensive care unit, Hotel Dieu hospital
city: Neuilly-sur-Seine
country: France
facility: Intensive care unit, Clinique Ambroise Paré
city: Paris
country: France
facility: Intensive care unit, Cochin hospital, APHP
city: Versailles
country: France
facility: Intensive care unit, André Mignot hospital
Study officials:
affiliation: Intensive Care Unit, Clinique Ambroise Paré, 92200 Neuilly sur seine
name: Guillaume GERI, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Intensive Care Unit, Cochin Hospital, APHP, 75014 Paris
name: Alain CARIOU, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Witten L, Gardner R, Holmberg MJ, Wiberg S, Moskowitz A, Mehta S, Grossestreuer AV, Yankama T, Donnino MW, Berg KM. Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest. Resuscitation. 2019 Mar;136:93-99. doi: 10.1016/j.resuscitation.2019.01.031. Epub 2019 Jan 30.