Hydrocorticose and vasopressin in post-resuscitation syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

18 Jul 2021 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS

External identifiers

EU CT number

2024-516373-77-00

EudraCT number

2020-001620-33

ClinicalTrials.gov

NCT04591990

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

to demonstrate the superiority of AVP and hydrocortisone compared with placebo regarding day-30 survival and neurological recovery in post-cardiac arrest patients with hemodynamic failure.

Secondary objectives 17

1. Day-30 all-cause mortality-Day-30 mortality attributed to irreversible hemodynamic failure
2. Day-30 mortality attributed to neurological withdrawal of care
3. Day-30 mortality attributed to comorbid withdrawal of care
4. Day-30 brain death
5. Day-30 mortality attributed to recurrent cardiac arrest Other causes
6. Neurological recovery at day-30
7. Brain damage
8. Number of days between inclusion and day-30 without - catecholamines - norepinephrine - AVP - inotropic support
9. Number of patients successfully weaned from vasopressor support at day-3, -5 and -7
10. Atrial fibrillation (new onset) between inclusion and day-30
11. Left ventricular systolic function assessed at day- 1, 2, 3 and 7
12. Number of days free of mechanical ventilation between inclusion and day-30
13. Number of days between inclusion and day-30 free of renal replacement therapy
14. Acute kidney injury at day- 7 and day-30
15. Safety related to AVP use: - acute coronary syndrome - mesenteric ischemia - digital ischemia and diabetes insipidus at AVP weaning
16. Safety related to hydrocortisone use: gastrointestinal bleeding up to day-30, episodes of hyperglycemia up to day 7
17. ICU and hospital length of stay

Conditions and MedDRA coding

Adult cardiac arrest patients with sustained ROSC and hemodynamic failure due to post-resuscitation syndrome

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult patients (≥18y)
2. Cardiac arrest (in-hospital or out-of-hospital) with sustained ROSC (> 30 minutes) admitted to the ICU
3. 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 tartrate/epinephrine continuous infusion at a dose greater or equal to 0.2μg/kg/min for at least 3 hours
4. A maximal delay between the start of norepinephrine infusion and randomization of 9 hours;
5. Informed written consent of a legally authorized close relative, or emergency procedure

Exclusion criteria 14

1. Evidence for a traumatic or a neurological cause of cardiac arrest
2. In-ICU cardiac arrest
3. Shock due to uncontrolled haemorrhage
4. Previously known adrenal insufficiency
5. Limitation of life-sustaining therapies
6. Ongoing treatment by any steroids, at a daily dose greater or equal to 7.5mg/d equivalent prednisone for at least 3 weeks
7. Ongoing extra-corporeal circulatory assistance
8. Gastrointestinal bleeding in the past 6 weeks
9. Pregnant or breastfeeding women
10. inclusion in another randomized trial involving a drug that could interact with either interventional drug
11. Hypersensitivity to argipressin and to its excipients
12. Hypersensitivity to hydrocortisone and to its excipients
13. Legal protection (i.e. incompetence to provide consent, guardianship, curator or incarceration)
14. No affiliation with the French health care system

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 21

1. Vital status at day-30 Time to day-30 caused by 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)
2. Time to day-30 caused by 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).
3. Time to day-30 by comorbid withdrawal of care. Comorbid withdrawal of care or refusal of lifesustaining 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).
4. Time to brain death (according to French legislation)
5. Time to recurrent cardiac arrest-Proportion of patients dead from a cause not listed above
6. Glasgow outcome score –extended at day-30. This score will be evaluated similarly to the primary endpoint
7. Neuron-specific enolase (NSE) blood level measured 48 and 72 hours after CA
8. Number of days between inclusion and day-30 without :catecholamines - norepinephrine - AVP - inotropic support
9. Number of patients alive and free of norepinephrine at day-3, -5 and -7 Number of patients alive and free of AVP at day-3, - 5 and -7
10. Proportion of patients with new onset of atrial fibrillation at day-30
11. Left ventricular ejection fraction at day-1, 2, 3 and 7. Left ventricular ejection fraction will be evaluated using echocardiography (either trans-thoracic or trans-esophageal)
12. Number of mechanical ventilation free days at day- 30
13. Number of renal replacement therapy free days at day-30
14. KDIGO classification at day-7 and day-30. The day- 30 KDIGO classification will be estimated on the creatinine criteria as theurine criteria will be unlikely available. The estimated glomerular filtration rate will becalculated using the MDRD equation.
15. Proportion of patients with acute coronary syndrome defined according to the international guidelines (2015 ESC guidelines) as to know: the detection of an increase and/or a decrease of cardiac troponin and at least one of the following: (1) symptoms of ischemia, (2) new or presumed new significant ST-T wave changes or left bundle branch block on 12-lead ECG; (3) development of pathological Q waves on ECG, (4) imaging evidence of new or presumed new loss of viable myocardium or regional wall mot
16. Proportion of patients with mesenteric ischemia at day-30, diagnosed on clinical assessment and a computed tomography angiography or endoscopy
17. Proportion of patients with clinically diagnosed digital ischemia at day-30
18. Proportion of patients with central diabetes insipidus at argipressin (AVP) weaning. Central diabetes insipidus is defined by a polyuria (> 50mL/kg/24h) associated with an increased plasmatic osmolality (> 300mOsm/L) and a decreased urinary osmolality (< 300mOsm/L)
19. Proportion of patients with gastro-intestinal bleeding at day-30. Gastrointestinal bleeding will be diagnosed as a clinical gastrointestinal bleeding simultaneously with a drop of blood hemoglobin level
20. Proportion of patients with hyperglycemia occurrence, defined as the number of episodes of blood glucose level higher than 11mmol/L between inclusion and day- 7
21. ICU and hospital lengths of stay (in days)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Guillaume GERI

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Mme Wafa FETHALLAH

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications