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Supplementary webappendix
This webappendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Hill MD, Martin RH, Mikulis D, et al, for the 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; published online Oct 8. http://dx.doi.org/10.1016/S14744422(12)70225-9.
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eTable 6 – Laboratory Values
Day 0
Day 1
Day 2-4
Day 30
NA-1
Control
NA-1
Control
NA-1
Control
NA-1
Control
Hemoglobin (g/L)
137 (13)
139 (14)
122 (16)
121 (13)
118 (14)
117 (13)
134 (15)
136 (13)
Hematocrit (%)
0.40 (0.04)
0.41 (0.04)
0.36 (0.04)
0.35 (0.04)
0.34 (0.04)
0.34 (0.04)
0.39 (0.04)
0.40 (0.04)
WBC (x 109/L)
7.7 (2.9)
8.0 (2.9)
9.1 (3.0)
9.4 (2.6)
8.8 (3.1)
8.7 (2.6)
6.7 (2.2)
6.9 (1.7)
Plt (x 109/L)
261 (76)
252 (61)
222 (62)
213 (62)
222 (68)
209 (55)
263 (79)
257 (66)
Na+ (mM)
139 (2.7)
139 (2.4)
139 (2.4)
140 (2.8)
139 (2.5)
139 (3.0)
140 (2.9)
139 (3.0)
K+ (mM)
4.0 (0.4)
4.0 (0.4)
3.9 (0.4)
3.8 (0.4)
3.8 (0.4)
3.8 (0.4)
4.1 (0.4)
4.0 (0.3)
Cl- (mM)
105 (2.9)
105 (3.0)
109 (3.3)
110 (3.6)
108 (2.8)
108 (3.8)
105 (3.1)
104 (3.2)
Creatinine
(umol/L)
72 (19)
71 (16)
65 (18)
63 (17)
64 (16)
62 (15)
72 (18)
71 (15)
BUN (mM)
5.0 (2.0)
5.2 (1.5)
4.0 (1.7)
4.2 (1.2)
3.7 (1.7)
3.5 (1.1)
5.2 (2.1)
5.1 (1.6)
Ca2+ (mM)
2.3 (0.1)
2.3 (0.1)
2.0 (0.1)
2.0 (0.1)
2.1 (0.1)
2.1 (0.1)
2.4 (0.1)
2.4 (0.1)
Glucose (mM)
5.9 (1.3)
6.1 (2.5)
6.3 (2.1)
6.6 (2.0)
6.5 (2.6)
6.2 (1.6)
5.6 (1.4)
5.7 (1.7)
All values are presented as mean (sd). Plt = platelets; Na = sodium; K = potassium; Cl = chloride; BUN = blood urea nitrogen, CA = calcium
There were no differences in values between treatment and control groups for any of the serum blood tests.
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eTable 7 - Day 30 Neurocognitive Outcomes
All Randomised Subjects (Day 30)
Unruptured Subjects
(Day 30)
NA-1
Control
Mean (SD)
Mean (SD)
P Value
Ruptured Subjects
(Day 30)
NA-1
Control
Mean (SD)
Mean (SD)
Test
Direction of
better score
NA-1
Mean (SD )
Control
Mean (SD)
P Value
P Value
Trails A
Lower
37.6 (18.5)
48.1 (34.2)
0.08
36.0 (19.1)
46.2 (32.8)
0.12
45.1 (13.7)
61.6 (45.5)
0.38
Trails B
Lower
101.1 (75.1)
115.3 (77.8)
0.40
96.6 (73.5)
107.9 (72.4)
0.52
123.7 (85.1)
168.6 (103.0)
0.43
Phonemic Verbal
Fluency
Semantic Verbal
Fluency
Digit Symbol
Higher
34.8 (12.0)
36.2 (13.1)
0.47
34.7 (12.4)
37.7 (12.0)
0.15
35.3 (10.9)
27.9 (16.3)
0.15
Higher
16.4 (4.9)
17.8 (5.5)
0.08
16.1 (4.7)
18.3 (4.6)
0.01
17.2 (5.6)
14.8 (8.7)
0.35
Higher
60.6 (21.1)
65.0 (22.4)
0.19
62.1 (21.1)
66.9 (21.7)
0.20
54.9 (20.7)
54.9 (24.1)
0.99
HVLT-R Total
Recall
HVLT-R Delayed
Recall
HVLT-R
Retention %
HVLT-R RDI
Higher
22.7 (6.3)
23.2 (5.2)
0.56
23.1 (6.0)
23.7 (5.0)
0.53
21.1 (7.1)
20.5 (6.1)
0.82
Higher
7.4 (3.3)
8.1 (2.6)
0.11
7.4 (3.2)
8.3 (2.5)
0.06
7.2 (3.7)
6.8 (2.6)
0.74
Higher
76.6 (26.9)
85.1 (18.7)
0.03
76.2 (25.7)
86.7 (18.2)
0.01
78.3 (31.9)
76.1 (19.5)
0.83
Higher
9.6 (2.6)
10.0 (1.7)
0.24
9.7 (2.6)
10.0 (1.8)
0.37
9.4 (2.6)
10.1 (1.3)
0.43
MMSE
Higher
28.5 (2.6)
28.5 (1.7)
1.00
28.7 (2.3)
28.5 (1.7)
0.66
27.4 (3.8)
28.5 (1.3)
0.60
NPI-Q Severity
Lower
1.8 (2.3)
3.5 (4.7)
0.01
1.6 (2.0)
3.0 (4.2)
0.05
2.5 (3.1)
5.1 (6.0)
0.16
NPI-Q Distress
Score
CES-D
Lower
1.6 (2.5)
3.2 (5.2)
0.03
1.3 (2.1)
2.6 (4.4)
0.07
2.4 (3.5)
5.1 (7.1)
0.21
Lower
10.8 (8.1)
11.6 (11.2)
0.56
9.6 (7.8)
11.4 (11.0)
0.27
15.3 (7.8)
13.2 (12.2)
0.56
This neurocognitive battery was comprised of tests derived from the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network
vascular cognitive impairment harmonization standards18 as well as the MMSE and Trails A and B tests.
HVLT-R: Hopkins Verbal Learning Test-Revised; MMSE: Mini-Mental Status Examination; NPI-Q: Neuropsychiatric Inventory Questionnaire; CESD: Centre for Epidemiological Studies – Depression scale;
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eTable 8 – Detailed Selection Criteria
Inclusion Criteria
1.
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 subjects with a ruptured aneurysm, endovascular repair must take place within 72 hours of the ictal hemorrhage.
2.
If the aneurysm has ruptured, subject should be Grade I-III on the World Federation of Neurological Surgeons (WFNS) grading scale for subarachnoid hemorrhage. If the subject 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 subject is considered WFNS Grade III and is
eligible for the trial.
3.
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.)
4.
Brain MR 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.
5.
Male or female with a minimum age of 18 years on the day of enrolment.
6.
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 bphCG 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.
7.
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.
8.
Body weight less than or equal to 180 kg.
9.
Normal or abnormal but not clinically significant findings in the
a.
non-neurological physical examination
b.
12-lead ECG
i. PQ or PR interval less than or equal to 210 msec;
ii. 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.
c.
vital signs
i. blood pressure between 80-180/50-100 mm Hg,
ii. body temperature less than or equal to 38.5oC
Exclusion Criteria
11. 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.
12. Planned endovascular vessel sacrifice as the primary modality for aneurysm treatment.
13. Known history of life-threatening allergic reaction to any medication.
14. Chronic renal disease defined as a baseline serum creatinine > 150 µmol/L
15. Women who are pregnant, or have a positive urine or blood (!-hCG) pregnancy test.
16. Women who are breastfeeding.
17. Any clinically significant psychiatric or psychological disease, which would preclude the subject from completing the protocol.
18. Pre-morbid (estimated) modified Rankin scale score of greater than 2. A subject is not excluded if they have a pre-morbid modified Rankin scale of greater than 2 but the disability does not
interfere with the subject’s ability to complete the primary outcome (MRI) and the cognitive evaluations.
19. Previous serious traumatic brain injury that would preclude the subject from completing the protocol or preclude MRI analysis of small strokes.
20. Subjects with known HIV infection.
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21.
22.
23.
Subjects 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 subject 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.
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Appendix 1
The following Investigators participated in the ENACT trial: Steering Committee:
Roberta Anderson, Ottawa, Canada (Chair), Michael D. Hill, Calgary, Canada (Principal
Investigator), Michael Tymianski, Toronto, Canada (Sponsor representative), Peter S. Lu,
Sunnyvale, CA (Co-sponsor representative), Renee Martin, Charleston, SC (Lead
Statistician); Data and safety monitoring board. Gary Redekop, Vancouver, Canada
(Chair), Gord Gubitz, Halifax, Canada, Dean Johnston, Halifax, Canada, Randomization:
Wenle Zhao, Charleston, SC; Plasma Concentration Analysis: Charles River, Senneville,
Canada; Histamine Analysis: Gamma Dynacare, Brampton, Canada; Clinical
Monitoring: NoNO Inc., Ottawa, Canada, PRC, Inc, Calgary, Canada. and Study Hall
Inc., Hudson, MA; Drug Manufacturing: The University of Iowa Pharmaceuticals, Iowa
City, Iowa; Data Management: BioClinica, Audubon, PA and Hotchkiss Brain Institute –
Clinical Research Unit, Calgary, Canada. Medical Monitors: Michael D. Hill (all sites
other than Calgary), Michael Tymianski (Calgary Site). MRI Assessment: David Mikulis,
Toronto, ON. Julien Poublanc, Toronto, ON. Timo Krings, Toronto, ON. Mayank Goyal,
Calgary, AB. Andrew M. Demchuck, Calgary, AB. Clinical Sites: Calgary, AB – John H.
Wong. Edmonton, AB – Mike Chow. Saskatoon, SK – Michael E. Kelly. Toronto, ON
(St Michael Hospital) – R. Loch MacDonald. Toronto, ON (Toronto Western Hospital) –
Frank L. Silver, Karel terBrugge. London, ON – Melford Boulton. Ottawa, ON –
Cheemun Lum. Hamilton, ON – Thorsteinn Gunnarsson. Quebec, QC – Genevieve Milot.
Halifax, NS – Ian Fleetwood. Phoenix, AZ – Cameron McDougall. Palo Alto, CA –
Robert Dodd. Portland, OR – Wayne Clark.