HYVAPRESS: HYdrocortisone and VAsopressin in Post-RESuscitation Syndrome

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT04591990

Collaborator

(none)

380

Enrollment

Location

Arms

23.1

Anticipated Duration (Months)

16.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Postresuscitation Syndrome	Drug: Administration of AVP Drug: Administration of placebo AVP Drug: Administration of placebo hydrocortisone Drug: Administration of hydrocortisone	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

380 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

HYdrocortisone and VAsopressin in Post-REsuscitation Syndrome

Actual Study Start Date :

May 27, 2021

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AVP + placebo hydrocortisone REVERPLEG® 40 IU/2mL+ Placebo of hydrocortisone.	Drug: Administration of AVP Administration of AVP Drug: Administration of placebo hydrocortisone Administration of placebo hydrocortisone
Experimental: placebo AVP + hydrocortisone Placebo of REVERPLEG® 40 IU/2mL + Hydrocortisone 100mg UPJOHN®.	Drug: Administration of placebo AVP Administration of placebo AVP Drug: Administration of hydrocortisone Administration of hydrocortisone
Experimental: AVP + hydrocortisone REVERPLEG® 40 IU/2mL + Hydrocortisone 100mg UPJOHN®.	Drug: Administration of AVP Administration of AVP Drug: Administration of hydrocortisone Administration of hydrocortisone
Experimental: placebo AVP + placebo hydrocortisone Placebo of REVERPLEG® 40 IU/2mL + placebo of hydrocortisone	Drug: Administration of placebo AVP Administration of placebo AVP Drug: Administration of placebo hydrocortisone Administration of placebo hydrocortisone

Outcome Measures

Primary Outcome Measures

Neurological outcome [at day-30]
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.

Secondary Outcome Measures

All-cause mortality [at day-30]
Vital status at day-30.
Mortality attributed to irreversible hemodynamic failure [at day-30]
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).
Mortality attributed to neurological withdrawal of care [at day-30]
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).
Mortality attributed to comorbid withdrawal of care [at day-30]
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).
Day-30 brain death [at day-30]
Time to brain death (according to French legislation)
mortality attributed to recurrent cardiac arrest [at day-30]
Time to recurrent cardiac arrest
Other causes [at day-30]
Proportion of patients dead from a cause not listed above.
Neurological recovery at day-30 [at day-30]
Glasgow outcome score - extended at day-30. This score will be evaluated similarly to the primary endpoint
Brain damage [at 48 hours and at 72hours]
Neuron-specific enolase (NSE) blood level measured 48 and 72 hours after CA

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Intensive Care Unit, Ambroise Paré Hospital, APHP	Boulogne-Billancourt		France	92100

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Principal Investigator: Guillaume GERI, MD, PhD, Medical Intensive Care Unit, Ambroise Paré Hospital, APHP
Study Director: Alain CARIOU, MD, PhD, Medical Intensive Care Unit, Cochin Hospital, APHP