Stroke
Conditions
Keywords
Stroke, Vascular cognitive impairment, Coiling, Endovascular repair, Brain aneurysm, NA-1
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.
Interventions
DRUGNA-1
single intravenous dose of 2.6 mg/kg of NA-1 administered as a 10-minute infusion
DRUGPlacebo
single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Sponsors
Arbor Vita Corporation
NoNO Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of New FLAIR Lesions(MRI) | Enrolment, Days 2-4 | Volume of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New DWI Lesions (MRI) | Enrolment, Day 2-4 | Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose. |
| Number of New FLAIR Lesions (MRI) | Enrolment, Days 2-4 | Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose. |
| Volume of New DWI Lesions (MRI) | Enrolment, Days 2-4 | Volume of new DWI lesions as defined by MRI at 12-95 hours postdose. |
| National Institutes of Health Stroke Scale (NIHSS). | Enrolment, Day 30 | 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. |
| Modified Rankin Scale (mRS). | Enrolment, Day 30 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | Enrolment, Days 2-4 | Volume of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose (pre-specified subgroup analysis) |
| Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects | Enrolment, Day 2-4 | Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose(pre-specified subgroup analysis) |
| Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | Enrolment, Day 2-4 | Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose(pre-specified subgroup analysis) |
| Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects | Enrolment, Day 2-4 | Volume of new DWI lesions as defined by MRI at 12-95 hours postdose(pre-specified subgroup analysis) |
| National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects | Enrolment, Day 30 | 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 participants with ruptured aneurysms in both treatment groups(pre-specified subgroup analysis). |
| Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects | Enrolment, Day 30 | 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 with ruptured aneurysms was compared in both treatment groups(pre-specified subgroup analysis). |
Countries
Canada, United States
Participant flow
Recruitment details
Between September 16, 2008 and March 30, 2011, subjects were recruited to 10 hospitals in Canada and 3 in the United States.
Pre-assignment details
12 subjects were randomized into study but did not receive drug:5 due to do endovascular aneurysm repair, 3 due to inability to obtain a pre-procedure MRI,2 due to pre-procedure ECG showing a QTc interval \> 450 ms, 1 due to a fatal aneurysm rupture before drug, and 1 due to refusal by anesthesiologist to give drug to a subject with severe COPD.
Participants by arm
| Arm | Count |
|---|---|
| 1 NA-1 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.
NA-1 : single intravenous dose of 2.6 mg/kg of NA-1 administered as a 10-minute infusion | 92 |
| 2 Placebo Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion | 93 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Protocol Noncompliance | 0 | 1 |
Baseline characteristics
| Characteristic | 1 NA-1 | 2 Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 15 Participants | 37 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 78 Participants | 148 Participants |
| Age Continuous | 57.72 years STANDARD_DEVIATION 10.6 | 56.05 years STANDARD_DEVIATION 10.3 | 56.88 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment Canada | 80 participants | 78 participants | 158 participants |
| Region of Enrollment United States | 12 participants | 15 participants | 27 participants |
| Sex: Female, Male Female | 64 Participants | 68 Participants | 132 Participants |
| Sex: Female, Male Male | 28 Participants | 25 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 83 / 92 | 85 / 93 |
| serious Total, serious adverse events | 9 / 92 | 14 / 93 |
Outcome results
Primary
Volume of New FLAIR Lesions(MRI)
Volume of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose
Time frame: Enrolment, Days 2-4
Population: All study patients who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Volume of New FLAIR Lesions(MRI) | 915 mm^3 | Standard Deviation 5598 |
| 2 Placebo | Volume of New FLAIR Lesions(MRI) | 477 mm^3 | Standard Deviation 1611 |
Comparison: Comparison of the summed volume of new FLAIR lesions in the NA-1 and placebo treated groups.p-value: 0.445ANCOVA
Secondary
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.
Time frame: Enrolment, Day 30
Population: All patients who received study drug and an outcome assessment at Day 30
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 NA-1 | Modified Rankin Scale (mRS). | 86 No. of participants with mRS 0-2 |
| 2 Placebo | Modified Rankin Scale (mRS). | 87 No. of participants with mRS 0-2 |
Comparison: Comparison of the number of patients with mRS scores of 0-2 at Day 30 for NA-1 and placebo treated groups.p-value: 195% CI: [0.9, 1.1]Chi-squared
Secondary
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.
Time frame: Enrolment, Day 30
Population: All patients who received study drug and outcome assessment at Day 30.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 NA-1 | National Institutes of Health Stroke Scale (NIHSS). | 86 No. of participants with NIHSS 0-1 |
| 2 Placebo | National Institutes of Health Stroke Scale (NIHSS). | 83 No. of participants with NIHSS 0-1 |
Comparison: Number of patients obtaining a score on the NIHSS of 0-1 at Day 30.p-value: 0.4395% CI: [0.9, 1.1]Chi-squared
Secondary
Number of New DWI Lesions (MRI)
Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose.
Time frame: Enrolment, Day 2-4
Population: All patients who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Number of New DWI Lesions (MRI) | 4.1 Lesions | Standard Deviation 6.8 |
| 2 Placebo | Number of New DWI Lesions (MRI) | 7.3 Lesions | Standard Deviation 12.6 |
Comparison: Comparison of the total number of new ischemic lesions on DWI for NA-1 versus placebo treated groups.p-value: 0.01895% CI: [0.38, 0.74]Generalized linear model
Secondary
Number of New FLAIR Lesions (MRI)
Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose.
Time frame: Enrolment, Days 2-4
Population: All patients who received study drug and an analyzable MRI scan at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Number of New FLAIR Lesions (MRI) | 3.0 Lesions | Standard Deviation 4.4 |
| 2 Placebo | Number of New FLAIR Lesions (MRI) | 4.8 Lesions | Standard Deviation 7.7 |
Comparison: Comparison of the total number of new FLAIR lesions in the NA-1 versus placebo treated groups.p-value: 0.04895% CI: [0.42, 0.83]Generalized linear model
Secondary
Volume of New DWI Lesions (MRI)
Volume of new DWI lesions as defined by MRI at 12-95 hours postdose.
Time frame: Enrolment, Days 2-4
Population: All patients who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Volume of New DWI Lesions (MRI) | 966 mm^3 | Standard Deviation 5266 |
| 2 Placebo | Volume of New DWI Lesions (MRI) | 645 mm^3 | Standard Deviation 1382 |
Comparison: Comparison of the summed volume of new ischemic lesions on DWI.p-value: 0.306ANCOVA
Other Pre-specified
Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects
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 with ruptured aneurysms was compared in both treatment groups(pre-specified subgroup analysis).
Time frame: Enrolment, Day 30
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 NA-1 | Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects | 17 No. of participants with mRS 0-2 |
| 2 Placebo | Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects | 14 No. of participants with mRS 0-2 |
p-value: 0.1895% CI: [0.95, 1.7]Chi-squared
Other Pre-specified
National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects
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 participants with ruptured aneurysms in both treatment groups(pre-specified subgroup analysis).
Time frame: Enrolment, Day 30
Population: All subjects who entered the study with a ruptured aneurysm, who received study drug and outcome assessment at Day 30.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 NA-1 | National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects | 18 No. of participants with NIHSS 0-1 |
| 2 Placebo | National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects | 13 No. of participants with NIHSS 0-1 |
p-value: 0.0295% CI: [1.1, 2]Chi-squared
Other Pre-specified
Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects
Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose(pre-specified subgroup analysis)
Time frame: Enrolment, Day 2-4
Population: All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects | 3.4 Lesions | Standard Deviation 5.9 |
| 2 Placebo | Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects | 9.47 Lesions | Standard Deviation 11.6 |
p-value: 0.02795% CI: [0.17, 0.73]Adjusted Incidence Rate Ratio
Other Pre-specified
Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose(pre-specified subgroup analysis)
Time frame: Enrolment, Day 2-4
Population: All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | 2.4 Lesions | Standard Deviation 4.7 |
| 2 Placebo | Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | 6.58 Lesions | Standard Deviation 7.5 |
p-value: 0.04695% CI: [0.17, 0.75]Generalized linear model
Other Pre-specified
Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects
Volume of new DWI lesions as defined by MRI at 12-95 hours postdose(pre-specified subgroup analysis)
Time frame: Enrolment, Day 2-4
Population: All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects | 277 mm^3 | Standard Deviation 528 |
| 2 Placebo | Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects | 1373 mm^3 | Standard Deviation 2267 |
p-value: 0.015ANCOVA
Other Pre-specified
Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
Volume of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose (pre-specified subgroup analysis)
Time frame: Enrolment, Days 2-4
Population: All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 NA-1 | Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | 205 mm^3 | Standard Deviation 495 |
| 2 Placebo | Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects | 1575 mm^3 | Standard Deviation 3229 |
p-value: 0.023ANCOVA