Induced Hypertension in Acute PRogrESsive Perforating Artery Stroke Using Peripheral Dilute noREpinephrine (PRESSURE)

PRESSURE is a multicenter, prospective, randomized, open, blinded end-point assessed (PROBE) trial, that aims to evaluate the efficacy and safety of drug-induced hypertension using peripheral dilute norepinephrine, in patients with acute ischemic stroke in a perforating artery territory and experiencing early neurological deterioration.

Study Overview

• Status: Recruiting
• Conditions: Stroke, Ischemic; Stroke, Acute
• Intervention / Treatment: Drug: Peripheral intravenous norepinephrine

Detailed Description

Perforating artery strokes represent 25% of all ischemic strokes and is a well-known cause of progressive symptoms : 12 to 36% of cases experience early neurological deterioration in hours or days after stroke onset. A possible mechanism is hypoperfusion due to lack of a rapid development of collateral flow because of the terminal distribution of perforating arteries. Moreover, arterioles are maximally dilated within penumbra region, resulting in a cerebral autoregulation failure and a passive dependence of cerebral blood flow on arterial pressure. Thus, induced-hypertension therapy by using vasopressive agents is an attractive therapy to increase the cerebral perfusion pressure and therefore restore blood flow in the ischemic penumbra.

• Study Type: Interventional
• Enrollment (Estimated): 358
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pauline RENOU; Phone Number: 05-56-79-55-20; Email: pauline.renou@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • CHU de Bordeaux
    • Contact: Pauline RENOU
    • Principal Investigator: Pauline RENOU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute ischemic stroke < 72 h in a perforating artery territory on brain MRI
• 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 or ataxia score, whether this deterioration is transient or permanent.
• Time between early neurological deterioration and randomization < 6 hours
• Age ≥ 18 years
• 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)
• Beneficiary of a health insurance system

Exclusion Criteria:

• - Pre-Stroke Modified Rankin Score > 3
• Contraindication to brain Magnetic Resonance Imaging (MRI)

• High risk of intracerebral hemorrhage:

  • 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
• Prior intravenous thrombolysis < 24 hours
• Requirement for anticoagulation in the first 7 days after randomization
• Systolic blood pressure (SBP) > 180mmHG and/or mean arterial pressure (MAP) ≥ 110mmHG at inclusion
• Large artery atherosclerosis (ipsilateral atherosclerotic stenosis > 50%), intra and extracranial dissection, or cardio-embolic stroke mechanisms
• Drugs with important interactions with norepinephrine: monoamine oxidase inhibitors (including reversible, non-selective agents such as linezolid), tricyclic antidepressants, entacapone.
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Induced hypertension using norepinephrine; Standard care and peripheral intravenous norepinephrine. Norepinephrine (dilution: 10µg/ml, initial dose: 0.04µg/kg/min) will be titrated until MAP is between 110 and 120mmHG (with a maximal systolic blood pressure of 210mmHG) Gradually decrease of norepinephrine will start after 24h of NIHSS stabilization. Standard care includes antithrombotic treatments according to the physician's choice and ESO recommendations	Drug: Peripheral intravenous norepinephrine; Norepinephrine (dilution: 10µg/ml, initial dose: 0.04µg/kg/min) will be titrated until MAP is between 110 and 120mmHG (with a maximal systolic blood pressure of 210mmHG) Gradually decrease of norepinephrine will start after 24h of NIHSS stabilization.
No Intervention: Standard care; Standard care includes antithrombotic treatments according to the physician's choice and ESO recommendations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin Scale (mRS)	Functional independence defined by modified Rankin scale 0-2 or return to pre-stroke modified Rankin scale, assessed at 90 days. The assessment of the clinical outcome at 90 (±15) days will be conducted by an independent qualified assessor (blinded to patient treatment allocation). The minimal value of the modified Rankin Scale is 0 (best outcome) and the maximum value is 6 (worst outcome).	Day 0
modified Rankin Scale (mRS)	Functional independence defined by modified Rankin scale 0-2 or return to pre-stroke modified Rankin scale, assessed at 90 days. The assessment of the clinical outcome at 90 (±15) days will be conducted by an independent qualified assessor (blinded to patient treatment allocation). The minimal value of the modified Rankin Scale is 0 (best outcome) and the maximum value is 6 (worst outcome).	Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		Day 90
modified Rankin Scale (mRS)	Functional outcomes as measured through the ordinal (shift) modified Rankin scale. The minimal value of the modified Rankin Scale is 0 (best outcome) and the maximum value is 6 (worst outcome).	Day 90
modified Rankin Scale (mRS)	Functional outcomes as measured through the rate of 90-day excellent functional outcome (mRS 0-1). The minimal value of the modified Rankin Scale is 0 (best outcome) and the maximum value is 6 (worst outcome).	Day 90
NIHSS Score	c. Early neurological improvement defined as a reduction (compared to the NIHSS at the time of randomization) of at least 3 points or a score of 0 or 1 on the NIHSS	Day 0
NIHSS Score	Early neurological improvement defined as a reduction (compared to the NIHSS at the time of randomization) of at least 3 points or a score of 0 or 1 on the NIHSS	Day 7
Primary Care PTSD Screen for DSM-5 (PC-PTSD-5)	The minimum value of the PC-PTSD-5 is 0 (best outcome) and the maximum value is 5 (worst outcome)	Day 90
Hospital Anxiety and Depression Scale	The HAD scale provides 2 sub-scores, one on depression, and one on anxiety. Both sub-scores range from 0 (best outcome) to 21 (worst outcome)	Day 90
Proportion of patients presenting Acute coronary syndrome	Acute Coronary Syndrome refers to ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. We will estimate the proportion of patients presenting at least one of these events until day 7.	Day 7
Proportion of patients presenting Congestive heart failure	We will estimate the proportion of patients presenting at least one episode of congestive heart failure until day 7.	Day 7
Proportion of patients presenting Tachyarrhythmia	Tachyarrythmia refers to a resting heart rate that exceeds 100 beats per minute. We will estimate the proportion of patients presenting at least one episode of tachyarrythmia until day 7.	Day 7

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Study Chair: Pauline RENOU, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2024
• Primary Completion (Estimated): August 28, 2027
• Study Completion (Estimated): November 28, 2027

Study Registration Dates

• First Submitted: May 26, 2023
• First Submitted That Met QC Criteria: September 22, 2023
• First Posted (Actual): September 28, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 7, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Ischemic Stroke; Stroke; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: CHUBX 2022/23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No