HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome

Postresuscitation Syndrome Clinical Trial

— HYVAPRESS  

Official title:

HYdrocortisone and VAsopressin in Post-REsuscitation Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04591990
• Other study ID #: APHP200033
• Secondary ID: 2020-001620-33
• Status: Recruiting
• Phase: Phase 3
• Start date: May 27, 2021
• Est. completion date: August 2024

Study information

• Verified date: November 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Guillaume GERI, MD, PhD
• Phone: +33 (0) 6 69 24 22 47
• Email: dr.guillaume.geri[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 380
• Est. completion date: August 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Postresuscitation Syndrome
• Syndrome

Intervention

Drug:
• Administration of AVP
Administration of AVP
• Administration of placebo AVP
Administration of placebo AVP
• Administration of placebo hydrocortisone
Administration of placebo hydrocortisone
• Administration of hydrocortisone
Administration of hydrocortisone

Locations

Country	Name	City	State
France	Intensive care unit, CHU Amiens- Picardie	Amiens
France	Intensive care unit, CHU Angers	Angers
France	Intensive care unit, CHI Robert Ballanger	Aulnay-sous-Bois
France	Medical Intensive Care Unit, Ambroise Paré hospital, APHP	Boulogne-Billancourt
France	Intensive care unit, CH public du Cotentin	Cherbourg
France	Intensive care unit, CHU Dijon	Dijon
France	Intensive care unit, Hospices civils de Lyon	Lyon
France	Intensive care unit, Hôpital Jacques Cartier	Massy
France	Intensive care unit, CHU Montpellier	Montpellier
France	Intensive care unit, Brabois hospital	Nancy
France	Intensive care unit, Hotel Dieu hospital	Nantes
France	Intensive care unit, Clinique Ambroise Paré	Neuilly-sur-Seine
France	Intensive care unit, Cochin hospital, APHP	Paris
France	Intensive care unit, André Mignot hospital	Versailles

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neurological outcome	The primary endpoint will be the good neurological outcome at day-30. This will be evaluated using the Glasgow Outcome Scale (GOS, addendum 18.5.1) dichotomized as follow: good neurological outcome for categories 4 and 5 and poor neurological outcome or death for categories 3, 2 and 1. The GOS will be obtained at day-30 from an in-hospital visit if the patient is still hospitalized or from telephone contact with patients, relatives or general practitioners.	at day-30
Secondary	All-cause mortality	Vital status at day-30.	at day-30
Secondary	Mortality attributed to irreversible hemodynamic failure	Time to irreversible cardiovascular failure defined as death in pharmacologically uncontrollable hypotension (mean arterial blood pressure < 60 mmHg) despite maximal ICU care, or withdrawal of care based on same, as previously defined (Witten L, Resuscitation 2019).	at day-30
Secondary	Mortality attributed to neurological withdrawal of care	Time to neurological withdrawal of care. Withdrawal of care will be based on expectations of a poor neurological recovery based on most recent guidelines (Sandroni C, ICM 2015).	at day-30
Secondary	Mortality attributed to comorbid withdrawal of care	Time to comorbid withdrawal of care. Comorbid withdrawal of care or refusal of life-sustaining therapy based on the expectation of a poor quality of life. This may be related to a preexisting or newly discovered terminal illness or other serious medical condition (e.g. dementia or cancer).	at day-30
Secondary	Day-30 brain death	Time to brain death (according to French legislation)	at day-30
Secondary	mortality attributed to recurrent cardiac arrest	Time to recurrent cardiac arrest	at day-30
Secondary	Other causes	Proportion of patients dead from a cause not listed above.	at day-30
Secondary	Neurological recovery at day-30	Glasgow outcome score - extended at day-30. This score will be evaluated similarly to the primary endpoint	at day-30
Secondary	Brain damage	Neuron-specific enolase (NSE) blood level measured 48 and 72 hours after CA	at 48 hours and at 72hours