Evaluating Neuroprotection in Aneurysm Coiling Therapy
Condition: Stroke
MeSH terms: Aneurysm
Intervention: NA-1; Placebo
Intervention description: single intravenous dose of 2.6 mg/kg of NA-1 administered as a 10-minute infusion; single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 185.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Stroke; Vascular cognitive impairment; Coiling; Endovascular repair; Brain aneurysm; NA-1

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.
    

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.