Evaluating Neuroprotection in Aneurysm Coiling Therapy

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo-controlled, single-dose, design investigating the safety, tolerability and efficacy of NA-1, a peptide designed to reduce ischemic brain damage. Up to 200 male and female patients undergoing endovascular repair of brain aneurysm will be dosed with 2.60 mg/kg of NA-1 or placebo as a 10 minute intravenous infusion after completion of the endovascular procedure on Day 1 of the study period. Subjects will undergo interim procedures Days 2-4 and end-of study procedures on Day 30. Standard safety criteria will be analysed. Efficacy endpoints include the ability of NA-1 to: 1) reduce the volume of ischemic embolic strokes, 2) reduce the number of ischemic embolic strokes, 3) reduce vascular cognitive impairment, and 4) reduce the frequency of large strokes induced by the endovascular procedure. The plasma concentrations of NA-1 will also be analyzed.

Official Title
-----------------
A Phase II, Multicenter, Randomized, Fasting, Double-Blind, Placebo-Controlled, Safety, Tolerability and Efficacy Study Evaluating a Single Dose of Intravenous NA-1 in Male and Female Patients Undergoing Endovascular Repair of Brain Aneurysms

Conditions
-----------------
Stroke

Intervention / Treatment
-----------------
* Drug: NA-1
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria A diagnosis of a ruptured or unruptured brain aneurysm deemed suitable for repair by neuroendovascular techniques involving intraluminal occlusion by detachable platinum coils, stent-assisted coiling, pipeline stent, balloon-assisted coiling, covered stent only, neck-bridge device, re-coiling, or re-treatment of a previously coiled/treated aneurysm. There are no restrictions on adjunctive devices. For patients with a ruptured aneurysm, endovascular repair must take place within 72 hours of the ictal haemorrhage. If the aneurysm has ruptured, patient should be Grade I-III on the World Federation of Neurological Surgeons (WFNS) grading scale for subarachnoid hemorrhage. If the patient is intubated but alert and able to follow commands (at least a 2-step command), and is not kept intubated for neurological status (i.e., WFNS Grade IV or V), the patient is considered WFNS Grade III and is eligible for the trial. Absence of ongoing ischemic symptoms such as transient ischemic attacks, minor strokes, stroke-in-evolution, or clinical evidence of cerebral vasospasm within 2 weeks prior to randomization. (If a CT scan, cerebral angiogram, or other imaging performed during the 2 weeks prior to randomization shows radiological vasospasm deemed by the treating physician to be potentially clinically significant, the subject is excluded.) Brain MRI imaging (DWI and FLAIR sequences) within 2 weeks prior to the endovascular aneurysm repair procedure as detailed in Section 8.2. Imaging must not demonstrate any focal ischemic stroke defined as a new region of restricted diffusion and/or a focal area of reduced perfusion on a relative mean transit time (rMTT) or relative time to peak (rTTP) map Male or female with a minimum age of 18 years on the day of enrolment. Female subjects of childbearing potential: Negative pregnancy test. After enrolment, blood will be drawn from women of childbearing potential for a confirmatory test of pregnancy as evaluated by a serum B-hCG test. The definition of non-childbearing potential includes the following: Surgically sterile (e.g., hysterectomy with or without oophorectomy; fallopian tube ligation; endometrial ablation), at least 30 days prior to signature of the Informed Consent form At least 5 years post-menopause (i.e., 6 years post last menstrual period), or menopause confirmed by follicle-stimulating hormone (FSH) testing. Non-surgically sterile females or females with undocumented post-menopausal status must be willing to use a medically approved method of birth control for 3 months after completion of dosing. Non-surgically sterile males or males with partners of childbearing potential must be willing to use condoms with spermicide for 3 months after completion of dosing. Body weight less than or equal to 180 kg. Normal or abnormal but not clinically significant findings in the non-neurological physical examination 12-lead ECG PQ or PR interval less than or equal to 210 msec; In unruptured aneurysm cases, QTc interval less than 450 msec for males or 470 msec for females. For ruptured aneurysm cases, QTc interval is not restricted. vital signs blood pressure between 80-180/50-100 mm Hg, body temperature less than or equal to 38.5oC Informed consent and availability of the subject for the entire study period and willingness of the subject to adhere to protocol requirements, as evidenced by a signed Informed Consent Form. Exclusion Criteria Dissecting or mycotic brain aneurysm. Fusiform or atherosclerotic intracerebral aneurysms may be eligible for the trial if endovascular treatment is planned with a goal of exclusion of the aneurysm from the circulation. Planned endovascular vessel sacrifice as the primary modality for aneurysm treatment. Known history of life-threatening allergic reaction to any medication. Chronic renal disease defined as a baseline serum creatinine > 150 umol/L. Women who are pregnant, or have a positive urine or blood (β-hCG) pregnancy test. Women who are breastfeeding. Any clinically significant psychiatric or psychological disease, which would preclude the patient from completing the protocol. Pre-morbid (estimated) modified Rankin scale score of greater than 2. Previous serious traumatic brain injury that would preclude the patient from completing the protocol or preclude MRI analysis of small strokes. Patients with known HIV infection. Patients who are unable to have an MRI scan for any reason. Participation in a clinical trial with an investigational drug within 30 days preceding this study. Previous participation in the ENACT trial (e.g,, to treat a prior aneurysm), participation in another trial involving NA-1 or prior receipt of NA-1. Any other medical condition that the site investigator deems would put the patient at excessive risk of participation in the study or an expected life expectancy less than 1 year or that would result in inability to collect clinical outcomes at 30 days.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NA-1<br>20 amino acid peptide that consists of a 9 amino acid domain that inhibits PSD-95 and a 11 amino acid domain than enables the peptide to cross the blood-brain barrier. | Drug: NA-1<br>* single intravenous dose of 2.6 mg/kg of NA-1 administered as a 10-minute infusion<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volume of New FLAIR Lesions(MRI) | Volume of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose | Enrolment, Days 2-4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of New DWI Lesions (MRI) | Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose. | Enrolment, Day 2-4 | 
| Number of New FLAIR Lesions (MRI) | Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose. | Enrolment, Days 2-4 | 
| Volume of New DWI Lesions (MRI) | Volume of new DWI lesions as defined by MRI at 12-95 hours postdose. | Enrolment, Days 2-4 | 
| National Institutes of Health Stroke Scale (NIHSS). | The NIHSS is a standardized neurological method to measure disability and recovery after stroke. Scores range from 0 to 42, with higher scores indicating increasing severity. Scores were dichotomized into 0-1 (good outcome) versus 2 or above. The number of participants scoring 0-1 on the NIHSS at Day 30 was compared for both groups. | Enrolment, Day 30 | 
| Modified Rankin Scale (mRS). | The mRS is a measure of global disability that has been widely applied for evaluating recovery from stroke. Scores range from 0 to 6, with higher scores indicating greater disability. A score of 0 indicates no residual symptoms; 1 = no significant disability/able to carry out all usual activities, despite some symptoms; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability; 5 = severe disability; 6 = death. The number of participants scoring 0-2 on the mRS at Day 30 was compared in both treatment groups. | Enrolment, Day 30 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Vascular cognitive impairment, Coiling, Endovascular repair, Brain aneurysm, NA-1