Evaluation of Peripheral Dilute Norepinephrine for Functional Independence in Acute Progressive Perforating Artery Stroke

The primary objective of the PRESSURE trial is to evaluate the impact of **peripheral dilute norepinephrine** in conjunction with standard care on the 90-day functional independence rate, as measured by the modified Rankin Scale (mRS), in patients experiencing acute progressive perforating artery stroke. This objective is clinically significant as it aims to determine whether the addition of norepinephrine can enhance recovery and functional outcomes in stroke patients, potentially leading to improved long-term quality of life and reduced disability.

Secondary objectives include:

• Assessing the efficacy of standard care plus norepinephrine on 90-day functional outcomes, early neurological improvement, mortality, and psychological conditions such as post-traumatic stress disorder, anxiety, depression, and cognitive disorders.
• Identifying predictive factors for achieving 90-day functional independence and early neurological improvement, with a focus on maintaining target blood pressure levels.
• Evaluating the safety profile of the treatment combination, specifically regarding symptomatic intracerebral hemorrhage, drug extravasation, congestive heart failure, acute coronary syndrome, and tachyarrhythmia.
• Comparing the length of hospital stays and the proportion of patients requiring rehabilitation between the treatment groups.

The clinical trial involves participants diagnosed with **stroke**, specifically focusing on acute progressive perforating artery stroke. The study population includes both male and female subjects, aged 18 years and older. Participants are required to have experienced an acute ischemic stroke within 72 hours in a perforating artery territory, as confirmed by brain MRI. The trial targets individuals who have shown early neurological deterioration or fluctuation, as evidenced by a significant increase in the NIHSS score. The selection process ensures that participants are randomized within 6 hours of early neurological deterioration. The trial includes a vulnerable population, and all participants must be beneficiaries of a health insurance system. Contraception is mandated for women of childbearing potential. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **norepinephrine** in improving the prognosis of patients experiencing neurological deterioration during the acute phase of an **ischemic stroke**. This is a Phase III, randomized, double-blind, controlled trial. The study aims to compare the 90-day functional independence rate, as measured by the modified Rankin Scale (mRS), between patients receiving standard care plus peripheral dilute norepinephrine and those receiving standard care alone. The trial is expected to commence recruitment on October 1, 2024, and conclude by October 1, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as acute ischemic stroke within 72 hours, early neurological deterioration, and age of at least 18 years. Following randomization, participants will receive the investigational treatment or placebo. Follow-up visits will be conducted to monitor early neurological improvement, adverse events, and other secondary outcomes, including mortality and cognitive assessments, at specified intervals up to 90 days post-treatment. The end-of-study visit will assess the primary endpoint of functional independence.

The expected duration of participant involvement is approximately 90 days, with the possibility of early termination if significant adverse events occur, such as symptomatic intracerebral hemorrhage or norepinephrine extravasation requiring medical intervention. Participants may also be withdrawn if they no longer meet the inclusion criteria or if they choose to discontinue participation. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study period.

The clinical trial involves the administration of **NORADRENALINE RENAUDIN 2 mg/ml SANS CONSERVATEUR**, a **solution for infusion**. The active substance in this experimental medication is **noradrenaline tartrate**, a chemical compound. The pharmaceutical form is a solution intended for dilution prior to intravenous infusion. The maximum daily dose is 0.6 mg/kg/h, with the same maximum total dose amount, and the treatment period is limited to a maximum of 3 days. The administration route is strictly intravenous, ensuring direct delivery into the bloodstream. This medication is not formulated for pediatric use and is provided by **Laboratoire Renaudin**.

In addition to the experimental treatment, the study includes a standard-of-care therapy as a comparator. The trial aims to evaluate the efficacy of peripheral dilute norepinephrine in conjunction with standard care, compared to standard care alone, in patients with acute progressive perforating artery stroke. The primary outcome measure is the 90-day functional independence rate, assessed using the modified Rankin Scale (mRS). Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Induced hypertension in acute PRogrESsive perforating artery Stroke Using peripheral dilute noREpinephrine" will be assessed primarily through the evaluation of functional independence at 90 days, using the **modified Rankin Scale (mRS)**. The primary endpoint is defined as achieving a mRS score of 0-2, or a return to pre-stroke mRS, at 90 days. This will be compared between patients receiving standard care plus peripheral dilute norepinephrine and those receiving standard care alone. The primary analysis will focus on the adjusted odds ratio of achieving this endpoint, regardless of intercurrent events during follow-up.

Secondary endpoints include several measures to assess 90-day functional outcomes: the ordinal (shift) mRS at 90 days, the rate of excellent functional outcome (mRS 0-1), and early neurological improvement, which is defined as a reduction of at least 3 points on the National Institutes of Health Stroke Scale (NIHSS) at the end of norepinephrine infusion and at 7 days, or a NIHSS score of 0 or 1 at these timepoints. Additional secondary endpoints include mortality from any cause at 90 days, assessments using the Primary Care Post-Traumatic Stress Disorder Screen for DSM-5 (PC-PTSD-5), the Hospital Anxiety and Depression (HAD) Scale, and the Montreal Cognitive Assessment (MOCA), all at 90 days. Other secondary measures include symptomatic intracerebral hemorrhage, norepinephrine extravasation, acute coronary syndrome, congestive heart failure, tachyarrhythmia, and various symptoms during norepinephrine infusion, as well as the length of in-hospital stay and rehabilitation needs.