Hypertension induced by intravenous administration of norepinephrine to improve the prognosis of patients with neurological deterioration in the acute phase of an ischemic stroke

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Bordeaux

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Nov 2024 → ongoing

Decision date (initial)

2024-07-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ministry of Health (PHRC National 2021 – N° PHRC-21-0096)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

The main objective of PRESSURE trial is to compare the 90-day functional independence rate (modified Rankin Scale [mRS]) between standard care and peripheral dilute norepinephrine and standard care alone in patients with acute progressive perforating artery stroke.

The estimand referred to this main objective, to the primary outcome measure, and to the primary analysis is the adjusted odds ratio of the modified Rankin Scale (mRS) 0-2, or return to pre-stroke mRS, at 90 days, between standard care plus peripheral dilute norepinephrine and standard care alone in patients with acute progressive perforating artery stroke, whatever the intercurrent events occurring during follow-up (treatment policy strategy).

Secondary objectives 4

1. 1. To assess the efficacy of standard care plus peripheral dilute norepinephrine in stroke patients with acute progressive perforating artery stroke compared to standard care alone on: - 90-day functional outcomes - Early neurological improvement - Mortality at 90 days - Post-traumatic stress disorder, anxiety and depression, cognitive disorder secondary to early neurological deterioration
2. 2. To identify predictive factors of 90-day functional independence (modified Rankin Scale [mRS] score 0-2) and return to pre-stroke mRS and early neurological improvement among patients randomized in the norepinephrine group. The main predictive factor of interest is the achievement of the target pressure (at least 24h with a PAM between 110 and 120mmH)
3. 3. To assess the safety of standard care plus peripheral dilute norepinephrine in stroke patients with acute progressive perforating artery stroke compared to standard care alone on: - Symptomatic intracerebral hemorrhage - Drug extravasation associated with tissue injury - Congestive heart failure - Acute coronary syndrome - Tachyarythmia
4. 4. To compare, between standard care plus peripheral dilute norepinephrine and standard care alone in patients with acute progressive perforating artery stroke: - The length of in-hospital stays - The proportion of patients admitted to a rehabilitation center

Conditions and MedDRA coding

Stroke

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. - Acute ischemic stroke < 72 h in a perforating artery territory on brain MRI
2. - Early neurological deterioration or fluctuation, attested by the neurologist in charge, defined by a ≥ 3-point increase in global NIHSS score OR a 2-point increase on motor (including hand motricity) or ataxia score, whether this deterioration is transient or permanent
3. - Time between the last neurological deterioration and randomization < 6 hours
4. - Age ≥ 18 years
5. - Contraception required in women of childbearing potential (Intra-uterine device, hormonal contraception associated with inhibition of ovulation (combined or progestogen-only; oral, intravaginal or transdermal), Female Sterilization, Vasectomised partner, sexual abstinence)
6. - Beneficiary of a health insurance system

Exclusion criteria 12

1. - Pre-Stroke Modified Rankin Score > 3
2. - Drugs with important interactions with norepinephrine: monoamine oxidase inhibitors (including reversible, non-selective agents such as linezolid), tricyclic antidepressants, entacapone. Pregnancy or breastfeeding
3. - Significant arrhythmia including atrial fibrillation, acute coronary syndrome, significant congestive heart failure, hypertrophic cardiomyopathy
4. - Pregnancy or breastfeeding.
5. - Contraindication to brain Magnetic Resonance Imaging (MRI)
6. - High risk of intracerebral hemorrhage defined on brain magnetic resonance imaging (MRI) by the presence of the following isolated or associated criteria:  cerebral microbleeds >10  non traumatic focal superficial siderosis  hemorrhagic transformation of the present ischemic stroke  previous history of intracerebral hemorrhage (symptomatic or asymptomatic identified on brain MRI)  intracranial vascular malformation or tumor with suspected risk of rupture or bleeding
7. - Prior intravenous thrombolysis < 24 hours and 24h post-thrombolysis required brain imaging (CT or MRI) to exclude haemorrhagic transformation of acute ischemic stroke
8. - Requirement for anticoagulation in the first 7 days after randomization (except subcutaneous low molecular weight heparins for prevention of deep venous thrombosis)
9. - Systolic blood pressure (SBP) > 200 mmHG and/or mean arterial pressure (MAP) ≥ 110mmHG at inclusion
10. - Large artery atherosclerosis (ipsilateral atherosclerotic stenosis > 50%), intra and extracranial dissection, or cardio-embolic stroke mechanisms
11. - Known hypersentivity to norepinephrine
12. - Poor venous access not allowing norepinephrine administration in accordance with the protocol’s administration criteria (except if indication for placement of a long catheter as part as routine care)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Functional independence defined as modified Rankin Scale (mRS) 0-2, or return to pre-stroke mRS, assessed at 90 days

Secondary endpoints 19

1. - Two outcomes will be used to assess 90-day functional outcomes: Ordinal (shift) modified Rankin scale at 90 days, and rate of 90-day excellent functional outcome (mRS 0-1)
2. - Early neurological improvement defined as a reduction of at least 3 points on the National Institutes of Health Stroke Scale (NIHSS) at the end of NorEpinephrine (NE) infusion and at 7 days compared to the NIHSS at the NE initiation, or a NIHSS score of 0 or 1 at the end of NE infusion and at 7 days, evaluated by a stroke neurologist
3. - Mortality from any cause at 90 days
4. - Primary Care Post-Traumatic Stress Disorder Screen for DSM-5 (PC-PTSD-5) at 90 days
5. - Hospital Anxiety and Depression (HAD) Scale at 90 days
6. - Montreal Cognitive Assessment (MOCA) at 90 days
7. - The main predictive factor of interest is the achievement of the target pressure (at least 24h with a PAM between 110 and 120mmH).
8. - Symptomatic intracerebral hemorrhage defined by parenchymal hematoma type 2 combined with an increase in the NIHSS score of at least 4 points.
9. - Norepinephrine (NE) extravasation associated with tissue injury requiring medical or surgical intervention (cf 10. Management of adverse events): peripheral intravenous must be assessed on initiation and every 1 hour while NE administration by nurses.
10. - Acute coronary syndrome at 7 days
11. - Congestive heart failure at 7 days
12. - Tachyarrhythmia at 7 days
13. - Headache, during NE infusion.
14. - Chest pain during NE infusion.
15. - Bradycardia
16. - Dysuria during NE infusion.
17. - Dyspnea during NE infusion.
18. - The length of in-hospital stay will be measured from the date of admission in the emergency unit and the date of hospital discharge.
19. - Rehabilitation will comprise need of hospitalization and length of stay in rehabilitation centers.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Bordeaux

Sponsor organisation

Centre Hospitalier Universitaire De Bordeaux

Address

12 Rue Dubernat, Cs 91286 Cs 91286

City

Talence

Postcode

33400

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Investigateur Coordonnateur

Public contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Investigateur Coordonnateur

Locations

1 EU/EEA country · 15 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 12 files

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

Application history

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