ENACT: Evaluating Neuroprotection in Aneurysm Coiling Therapy

• Sponsor: NoNO Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00728182
• Collaborator: Arbor Vita Corporation (Industry)
• Enrollment: 185
• Locations: 14
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 13.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: NA-1; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 185 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2008
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: NA-1; single intravenous dose of 2.6 mg/kg of NA-1 administered as a 10-minute infusion
Placebo Comparator: Placebo	Drug: Placebo; single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Volume of New DWI Lesions (MRI) [Enrolment, Days 2-4]

   Volume of new DWI lesions as defined by MRI at 12-95 hours postdose.

4. 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.

5. 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 Outcome Measures

1. 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)

2. 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)

3. 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)

4. 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)

5. 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).

6. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barrow Neurological Institute	Phoenix	Arizona	United States	85013
2	Stanford University Medical Center	Stanford	California	United States	94305
3	Oregon Health and Science University	Portland	Oregon	United States	97239
4	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
5	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
6	QEII Health Sciences Centre - Halifax Infirmary	Halifax	Nova Scotia	Canada	B3H 3A7
7	Hamilton Health Sciences General Site	Hamilton	Ontario	Canada	L8X 2S2
8	London Health Sciences Centre	London	Ontario	Canada	N6A 5A5
9	The Ottawa Hospital - Civic Campus	Ottawa	Ontario	Canada	K1Y 4E9
10	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 2W8
11	Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8
12	Hôpital Notre-Dame du Centre Hospitalier de l'Université de Montréal (CHUM)	Montréal	Quebec	Canada	H2L 4M1
13	Hopital de l'Enfant Jesus	Quebec City	Quebec	Canada	G1J 1Z4
14	Royal University Hospital	Saskatoon	Saskatchewan	Canada	S7N0W8

Sponsors and Collaborators

• NoNO Inc.
• Arbor Vita Corporation

Investigators

• Principal Investigator: Michael Hill, M.D., Foothills Medical Centre, University of Calgary

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NoNO Inc.
• ClinicalTrials.gov Identifier: NCT00728182
• Other Study ID Numbers: 3302 (NA-1-002)
• First Posted: Aug 5, 2008
• Last Update Posted: Oct 17, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by NoNO Inc.: Stroke; Vascular cognitive impairment; Coiling; Endovascular repair; Brain aneurysm; NA-1
• Additional relevant MeSH terms: Aneurysm

Study Results

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 Detail	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.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Period Title: Overall Study
STARTED	92	93
COMPLETED	89	90
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	1 NA-1	2 Placebo	Total
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion	Total of all reporting groups
Overall Participants	92	93	185
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	70 76.1%	78 83.9%	148 80%
>=65 years	22 23.9%	15 16.1%	37 20%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.72 (10.6)	56.05 (10.3)	56.88 (10.5)
Sex: Female, Male (Count of Participants)
Female	64 69.6%	68 73.1%	132 71.4%
Male	28 30.4%	25 26.9%	53 28.6%
Region of Enrollment (participants) [Number]
United States	12 13%	15 16.1%	27 14.6%
Canada	80 87%	78 83.9%	158 85.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All study patients who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	91	93
Mean (Standard Deviation) [mm^3]	915 (5598)	477 (1611)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Comparison of the summed volume of new FLAIR lesions in the NA-1 and placebo treated groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.445
	Comments
	Method	ANCOVA
	Comments	Data were cubic root transformed and modelled with multiple linear regression.

2. Secondary Outcome

Title	Number of New DWI Lesions (MRI)
Description	Number of new ischemic lesions as defined by DWI MRI at 12-95 hours postdose.
Time Frame	Enrolment, Day 2-4

Outcome Measure Data

Analysis Population Description

All patients who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	91	93
Mean (Standard Deviation) [Lesions]	4.1 (6.8)	7.3 (12.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Comparison of the total number of new ischemic lesions on DWI for NA-1 versus placebo treated groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Generalized linear model
	Comments	With log link and negative bnomial distribution.
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of New FLAIR Lesions (MRI)
Description	Number of new ischemic lesions as defined by FLAIR MRI at 12-95 hours postdose.
Time Frame	Enrolment, Days 2-4

Outcome Measure Data

Analysis Population Description

All patients who received study drug and an analyzable MRI scan at 12-95 hours postdose.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	91	93
Mean (Standard Deviation) [Lesions]	3.0 (4.4)	4.8 (7.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Comparison of the total number of new FLAIR lesions in the NA-1 versus placebo treated groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Generalized linear model
	Comments	With log link and negative binomial distribution.
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Volume of New DWI Lesions (MRI)
Description	Volume of new DWI lesions as defined by MRI at 12-95 hours postdose.
Time Frame	Enrolment, Days 2-4

Outcome Measure Data

Analysis Population Description

All patients who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	91	93
Mean (Standard Deviation) [mm^3]	966 (5266)	645 (1382)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Comparison of the summed volume of new ischemic lesions on DWI.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.306
	Comments
	Method	ANCOVA
	Comments	Data were cubic root transformed and modelled with multiple linear regresion.

5. Secondary Outcome

Title	National Institutes of Health Stroke Scale (NIHSS).
Description	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

Outcome Measure Data

Analysis Population Description

All patients who received study drug and outcome assessment at Day 30.

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	92	93
Number [No. of participants with NIHSS 0-1]	86 93.5%	83 89.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Number of patients obtaining a score on the NIHSS of 0-1 at Day 30.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Modified Rankin Scale (mRS).
Description	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

Outcome Measure Data

Analysis Population Description

All patients who received study drug and an outcome assessment at Day 30

Arm/Group Title	1 NA-1	2 Placebo
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	92	93
Number [No. of participants with mRS 0-2]	86 93.5%	87 93.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments	Comparison of the number of patients with mRS scores of 0-2 at Day 30 for NA-1 and placebo treated groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Volume of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Mean (Standard Deviation) [mm^3]	205 (495)	1575 (3229)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	ANCOVA
	Comments

8. Other Pre-specified Outcome

Title	Number of New DWI Lesions (MRI) - Ruptured Aneuryms Subjects
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Mean (Standard Deviation) [Lesions]	3.4 (5.9)	9.47 (11.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Adjusted Incidence Rate Ratio
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Other Pre-specified Outcome

Title	Number of New FLAIR Lesions (MRI) - Ruptured Aneurysm Subjects
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Mean (Standard Deviation) [Lesions]	2.4 (4.7)	6.58 (7.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	Generalized linear model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Other Pre-specified Outcome

Title	Volume of New DWI Lesions (MRI) - Ruptured Aneurysm Subjects
Description	Volume of new DWI lesions as defined by MRI at 12-95 hours postdose(pre-specified subgroup analysis)
Time Frame	Enrolment, Day 2-4

Outcome Measure Data

Analysis Population Description

All subjects who entered the study with a ruptured aneurysm, who received study drug and an analyzable MRI at 12-95 hours postdose.

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Mean (Standard Deviation) [mm^3]	277 (528)	1373 (2267)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	ANCOVA
	Comments

11. Other Pre-specified Outcome

Title	National Institutes of Health Stroke Scale (NIHSS) - Ruptured Aneurysm Subjects
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who entered the study with a ruptured aneurysm, who received study drug and outcome assessment at Day 30.

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Number [No. of participants with NIHSS 0-1]	18 19.6%	13 14%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 1.1 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Other Pre-specified Outcome

Title	Modified Rankin Scale (mRS)- Ruptured Aneurysm Subjects
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 NA-1 - Subjects With Ruptured Aneurysms	2 Placebo - Subjects With Ruptured Aneurysms
Arm/Group Description	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	Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
Measure Participants	18	19
Number [No. of participants with mRS 0-2]	17 18.5%	14 15.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 NA-1, 2 Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	1 NA-1		2 Placebo
Arm/Group Description	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		Placebo : single intravenous dose of 2.6 mg/kg of placebo administered as a 10-minute infusion
All Cause Mortality
	1 NA-1		2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	1 NA-1		2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/92 (9.8%)		14/93 (15.1%)
Gastrointestinal disorders
Gastrointestinal	0/92 (0%)	0	2/93 (2.2%)	2
General disorders
Administration site	1/92 (1.1%)	1	0/93 (0%)	0
Injury, poisoning and procedural complications
Procedural complications	1/92 (1.1%)	1	2/93 (2.2%)	2
Nervous system disorders
Nervous system	3/92 (3.3%)	3	9/93 (9.7%)	14
Renal and urinary disorders
Genitourinary	1/92 (1.1%)	1	1/93 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory	1/92 (1.1%)	2	1/93 (1.1%)	2
Vascular disorders
Vascular	3/92 (3.3%)	3	3/93 (3.2%)	3
Other (Not Including Serious) Adverse Events
	1 NA-1		2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/92 (90.2%)		85/93 (91.4%)
Eye disorders
Eye pain	1/92 (1.1%)	1	5/93 (5.4%)	5
Gastrointestinal disorders
Nausea	33/92 (35.9%)	33	27/93 (29%)	28
Vomiting	12/92 (13%)	12	8/93 (8.6%)	8
Constipation	4/92 (4.3%)	4	7/93 (7.5%)	7
General disorders
Fatigue	1/92 (1.1%)	1	7/93 (7.5%)	7
Puncture site pain	5/92 (5.4%)	5	5/93 (5.4%)	5
Infections and infestations
Urinary tract infection	7/92 (7.6%)	7	3/93 (3.2%)	3
Injury, poisoning and procedural complications
Procedural pain	2/92 (2.2%)	2	10/93 (10.8%)	10
Metabolism and nutrition disorders
Hypocalcaemia	4/92 (4.3%)	4	5/93 (5.4%)	5
Hypokalaemia	6/92 (6.5%)	6	4/93 (4.3%)	4
Musculoskeletal and connective tissue disorders
Back pain	6/92 (6.5%)	6	7/93 (7.5%)	7
Nervous system disorders
Headache	42/92 (45.7%)	47	37/93 (39.8%)	39
Dizziness	6/92 (6.5%)	6	2/93 (2.2%)	3
Hypoaesthesia	4/92 (4.3%)	4	5/93 (5.4%)	5
Psychiatric disorders
Anxiety	3/92 (3.3%)	3	7/93 (7.5%)	8
Renal and urinary disorders
Haematuria	5/92 (5.4%)	5	4/93 (4.3%)	4
Skin and subcutaneous tissue disorders
Alopecia	5/92 (5.4%)	5	2/93 (2.2%)	2
Vascular disorders
Hypotension	9/92 (9.8%)	10	6/93 (6.5%)	6
Hypertension	4/92 (4.3%)	4	7/93 (7.5%)	7
Haematoma	6/92 (6.5%)	6	7/93 (7.5%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Investigator shall have the right to publish any information after prior submittal to NoNO, where NoNO can request a hold for up to 60 days, provided that no publication shall disclose Proprietary Information other than Data containing the results of the Study. Investigators may not publish in the first 18 months after the close of the trial except within a publication representing all participating clinical sites.