Clinical trial NCT00728182: Evaluating Neuroprotection in Aneurysm Coiling Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Stroke
Keywords: Stroke
Vascular cognitive impairment
Coiling
Endovascular repair
Brain aneurysm
NA-1
Lead sponsor: NoNO Inc.
Sponsor class: INDUSTRY
Collaborators: name: Arbor Vita Corporation
First posted: 2008-08-05
Enrollment: 185
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Volume of New FLAIR Lesions(MRI)
timeFrame: Enrolment, Days 2-4
Secondary outcomes:
measure: Number of New DWI Lesions (MRI)
timeFrame: Enrolment, Day 2-4
measure: Number of New FLAIR Lesions (MRI)
timeFrame: Enrolment, Days 2-4
measure: Volume of New DWI Lesions (MRI)
timeFrame: Enrolment, Days 2-4
measure: National Institutes of Health Stroke Scale (NIHSS).
timeFrame: Enrolment, Day 30
measure: Modified Rankin Scale (mRS).
timeFrame: Enrolment, Day 30
Other outcomes:
measure: Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
timeFrame: Enrolment, Days 2-4
measure: Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects
timeFrame: Enrolment, Day 2-4
measure: Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
timeFrame: Enrolment, Day 2-4
measure: Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects
timeFrame: Enrolment, Day 2-4
measure: National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects
timeFrame: Enrolment, Day 30
measure: Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects
timeFrame: Enrolment, Day 30
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Halifax
country: Canada
facility: QEII Health Sciences Centre - Halifax Infirmary
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences General Site
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montréal
country: Canada
facility: Hôpital Notre-Dame du Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Quebec City
country: Canada
facility: Hopital de l'Enfant Jesus
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: Foothills Medical Centre, University of Calgary
name: Michael Hill, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, Milot G, Clark WM, Macdonald RL, Kelly ME, Boulton M, Fleetwood I, McDougall C, Gunnarsson T, Chow M, Lum C, Dodd R, Poublanc J, Krings T, Demchuk AM, Goyal M, Anderson R, Bishop J, Garman D, Tymianski M; ENACT trial investigators. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012 Nov;11(11):942-50. doi: 10.1016/S1474-4422(12)70225-9. Epub 2012 Oct 8.
citation: Ganesh A, Goyal M, Wilson AT, Ospel JM, Demchuk AM, Mikulis D, Poublanc J, Krings T, Anderson R, Tymianski M, Hill MD; ENACT Trial Investigators. Association of Iatrogenic Infarcts With Clinical and Cognitive Outcomes in the Evaluating Neuroprotection in Aneurysm Coiling Therapy Trial. Neurology. 2022 Apr 5;98(14):e1446-e1458. doi: 10.1212/WNL.0000000000200111. Epub 2022 Feb 15.