HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome (HYVAPRESS)

Assistance Publique - Hôpitaux de Paris

Status and phase: Enrolling; Phase 3

Conditions: Postresuscitation Syndrome

Treatments: Drug: Administration of placebo hydrocortisone; Drug: Administration of hydrocortisone; Drug: Administration of AVP; Drug: Administration of placebo AVP

Study type: Interventional

Funder types: Other

Identifiers

NCT04591990

2020-001620-33 (EudraCT Number)

APHP200033

Details and patient eligibility

About

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.

Full 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.

Enrollment: 380 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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380 participants in 4 patient groups

AVP + placebo hydrocortisone

Experimental group

Description:

REVERPLEG® 40 IU/2mL+ Placebo of hydrocortisone.

Treatment:

Drug: Administration of AVP

Drug: Administration of placebo hydrocortisone

placebo AVP + hydrocortisone

Experimental group

Description:

Placebo of REVERPLEG® 40 IU/2mL + Hydrocortisone 100mg UPJOHN®.

Treatment:

Drug: Administration of placebo AVP

Drug: Administration of hydrocortisone

AVP + hydrocortisone

Experimental group

Description:

REVERPLEG® 40 IU/2mL + Hydrocortisone 100mg UPJOHN®.

Treatment:

Drug: Administration of hydrocortisone

Drug: Administration of AVP

placebo AVP + placebo hydrocortisone

Experimental group

Description:

Placebo of REVERPLEG® 40 IU/2mL + placebo of hydrocortisone

Treatment:

Drug: Administration of placebo AVP

Drug: Administration of placebo hydrocortisone