E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult cardiac arrest patients with sustained ROSC and hemodynamic failure due to post-resuscitation syndrome |
Patients adultes présentant une récupération d’activité circulatoire spontanée après avoir été réanimés d’un arrêt cardiaque et ayant une insuffisance circulatoire aigue dans le cadre d’un état de choc post-ressuscitation |
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E.1.1.1 | Medical condition in easily understood language |
Post-RESuscitation Syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to demonstrate the superiority of AVP and hydrocortisone compared with norepinephrine regarding day-30 survival and neurological recovery in post-cardiac arrest patients with hemodynamic failure |
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E.2.2 | Secondary objectives of the trial |
D-30 : all-cause mortality, mortality attributed to irreversible hemodynamic failure, mortality attributed to neurological withdrawal of care, mortality attributed to comorbid withdrawal of care, brain death, mortality attributed to recurrent cardiac arrest, Neurological recovery, Brain damage N° of free days between inclusion and D-30 for norepinephrine, AVP, inotropes N° of patients successfully weaned from vasopressor support at D-3, -5 and -7 Atrial fibrillation new onset between inclusion and D-30 Left ventricular ejection fraction assessed at D-1, 2, 3 and 7 N° of days between inclusion and D-30 free of mechanical ventilation N° of days between inclusion and D-30 free of renal replacement therapy Acute kidney injury at D-7 and D-30 Safety related to AVP use: acute coronary syndrome, mesenteric ischemia, digital ischemia Safety related to hydrocortisone use: gastrointestinal bleeding up to D-30, episodes of hyperglycemia up to D 7 ICU and hospital length of stay |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 or emergency procedure
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E.4 | Principal exclusion criteria |
- Traumatic and 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 mechanical circulatory assistance - Gastrointestinal bleeding in the past 6 weeks - Pregnant or breastfeeding women - Hypersensitivity to arginin-vasopressin and to its excipients - Hypersensitivity to hydrocortisone and to its excipients - 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 - Legal protection (i.e. incompetence to provide consent, guardianship, curator or incarceration) - No affiliation to a social security system
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be a good neurological outcome at day-30. This will be evaluated using the Glasgow Outcome Scale (GOS, addendum 18.5.1) dichotomized as follows: 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Vital status 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:2019fy} Time to neurological withdrawal of care. Withdrawal of care will be based on expectations of a poor neurological recovery based on brain imaging, a neurologic exam, or a formal opinion of a neurologist stating that the prognosis for neurologic recovery is very poor. If an assessment off sedation is not done, there must be other evidence of severe neurologic injury (e.g. severe cerebral edema or herniation). 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). Time to brain death Time to recurrent cardiac arrest Proportion of patients dead from a cause not listed above Glasgow outcome score – extended at day-30. This score will be evaluated similarly to the primary endpoint Neuron-specific enolase (NSE) blood level measured 48 and 72 hours after CA Number of days between inclusion and day-30 without - catecholamines - norepinephrine - AVP - inotropic support 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 Proportion of patients with new onset of atrial fibrillation at day-30 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) Number of mechanical ventilation free days at day-30 Number of renal replacement therapy free days at day-30 KDIGO classification at day-7 and day-30. The day-30 KDIGO classification will be estimated on the creatinine criteria as the urine criteria will be unlikely available. The estimated glomerular filtration rate will be calculated using the MDRD equation. - 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 motion abnormality and (5) intracoronary thrombus detected on angiography or autopsy. These findings should be differentiated with the potential initial coronary cause of cardiac arrest. - Proportion of patients with mesenteric ischemia at day-30, diagnosed on clinical assessment and a computed tomography angiography or endoscopy - Proportion of patients with clinically diagnosed digital ischemia at day-30 - Proportion of patients with gastro-intestinal bleeding at day-30. Gastrointestinal bleeding will be diagnosed as a clinical gastro-intestinal bleeding simultaneously with a drop of blood hemoglobin level. - 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 ICU and hospital lengths of stay (in days)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1 Day 2 Day 3 Day 5 Day 7 Day 30 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 25 |
E.8.9.1 | In the Member State concerned days | |