Acute Stroke ManagementPart 2 Michael D Hill, MD MSc FRCPC Professor, Neurology Calgary Stroke Program Western Canada Stroke Day 1 dec 2012, Vancouver, BC Rosewood Georgia Hotel
Disclosure Slide • In the last 5 years: • I have been funded by CIHR, HSF Alberta/NWT/Nunavut, CSN, AHFMR/AIHS, NINDS (NIH) • I have received speaker fees/honouraria from Hoffmann-La Roche Canada Ltd., Sanofi Canada, Boehringer-Ingelheim Canada, Novo-Nordisk Canada • I have been an advisor/consultant to NovoNordisk Canada, Genentech Ltd, Stem Cell Therapeutics, Vernalis Group Ltd., Sanofi Canada, Portola Therapeutics, Hoffmann-La Roche Canada, Covidien Inc. • I hold no stock or direct investment in any pharmaceutical or device company (except those possibly in mutual funds) • I am the vice-chair of the advisory board of the Heart & Stroke Foundation of Alberta • I am on the steering committee for the IMS3 trial, coPI of ALIAS, PI of ENACT • Covidien has provided seed funding for ESCAPE
Outline • Neuroprotection • ALIAS trial • NA-1 trial • IMS 1, 2, 3 • ESCAPE trial
ALIAS Part 2 Vancouver, BC 1 dec 2012 Western Canada Stroke Day Rosewood Georgia Hotel
Human serum albumin • Safety and feasibility study • Dose-finding • Based upon strong pre-clinical evidence of efficacy
Characteristics of an Ideal Neuroprotectant • Exhibits proven and robust efficacy • Targets multiple injury mechanisms • Has minimal risk of adverse effects • Is acceptable both to patients and to medical personnel • Can be easily administered without complicated laboratory tests Funded by NINDS
Mechanisms (cont’d) These properties include: • prolonged circulatory half-life; • prominent role in the binding and transport of plasma fatty acids; • ability to bind to many other metabolites and drugs; • major role as a plasma antioxidant and scavenger of oxygen radicals; • ability to bind copper and other metal ions; • multiple actions on vascular endothelium, influencing trans- and endocytosis, vascular tone, and erythrocyte aggregation; • prominent metabolic effects on astrocytes Funded by NINDS
In vivo confocal microscopy of ALB therapy in focal ischemia • We used laser-scanning confocal microscopy to image the cortical vasculature through a closed cranial window. Plasma was labeled with FITC-dextran, and FITC-labeled erythrocytes were also injected. Rats received 2-h MCA suture-occlusion followed by recirculation. • During the first 15-30 minutes of postischemic recirculation, prominent foci of vascular stasis developed within cortical venules, with thrombus-like stagnant foci and adherent intra-venular corpuscular structures (believed to be adherent neutrophils) (LEFT). Saline administration did not affect these phenomena, while i.v. albumin therapy (2.5 g/kg) led to prompt improvement of venular flow and disappearance of adherent corpuscules and thrombotic material (RIGHT). Funded by NINDS
Saline Alb 4 h Therapeutic window 4-5h after stroke onset (Belayev et al, Stroke 32: 553-60, 2001) Funded by NINDS
Outcome by Dose-Tier RR good outcome (mRS 0-1 OR NIHSS 0-1) at 90d compared to NINDS trial historical controls tPA group: 2.0 (1.4-2.7) Non-tPA group: 1.9 (1.1-3.2)
ALIAS trial • 1800 patients • 900 in tPA cohort, 900 Non-tPA cohort • Large simple trial • ALB 2.0 g/kg vs. saline control • 5 hour treatment window
DSMB • Stopped the trial in Dec 2007 due to: • Excess mortality in the treatment group • We were asked to redesign the trial focussing on safety and efficacy • [Details published in Stroke]
Adverse Events and Death Stroke. 2011;42:119-127
Revisions to Protocol • Exclude patients > 83 years old • Cannot have had their 84th birthday one the day of enrolment • Troponin levels • Troponin I, troponin T - 0.1 ng/ml (ug/L) as upper limit • Universal definition of MI requires one value of acute troponin above the 99% percentile norm • Repeat troponin levels at 24h and 48h
Exclusion • Historical modified Rankin Scale (mRS) >2. Patients who live in a nursing home or who are not fully independent for activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.), immediately prior to the stroke are not eligible for the trial • In-patient stroke. Patients with stroke occurring as a complication of hospitalization for another condition, or as a complication of a procedure.
Fluid Management • Maximum 4200 cc over the first 48h • 100 cc tPA • 650 cc study drug (note maximum dose is 750 cc) • 3450 cc saline (0.9%) = 75ml/h x 46h • TOTAL = 4200 cc • Furosemide (Lasix) 20 mg at about 18 h from treatment as the default treatment • May explicitly withhold if the patient is doing particularly well
Training Training of all site investigators, sub-investigators, and study coordinators is mandatory; the instruction should emphasize vigilant diagnosis and management of fluid overload, electrolytes and cardiorespiratory signs. It is the responsibility of the local study-site principal investigator to ensure that ALL staff who could potentially be involved in the treatment of an ALIAS subject receive in-servicing in the Trial. All personnel listed on FDA form 1572 must complete re-training and the credentialing examination before being allowed to participate in the Trial.
Major Statistical Changes • Total sample size: 1,100 (instead of 1,800 – 900 thrombolysis and 900 non-thrombolysis subjects) • Randomization: stratified by thrombolysis, in addition to site (instead of two separate cohorts by thrombolysis status) • Primary analysis: adjusted for thrombolysis and baseline NIHSS score (instead of unadjusted)
Major Statistical Changes • Primary analysis: one-sided test at alpha=0.025 (instead of two-sided test at 0.05) – affects only the interim futility analysis boundaries • Developed statistical safety monitoring guidelines based on CI around the adjusted* RR of death within 30 days of randomization • Planned meta analysis of Part 1 and 2 data at the end *Adjusted for thrombolysis, age and baseline NIHSS score
10 September 2012 • DSMB meeting • Study recruitment was halted for futility • Decision based upon 732 randomized subjects with complete 3 month data • In addition, there were increased numbers of adverse events in the ALB arm • The study is now in data collection and final follow-up and further information will be available in the late spring
Stopping Boundaries Funded by NINDS
ENACTEvaluating Neuroprotection in Aneurysm Coiling Therapy MD Hill, JH Wong, FL Silver, G Milot, L MacDonald, WM Clark, R Martin, R Anderson, J Bishop, D Garman, M Tymianskion behalf of the ENACT investigators.
Disclosures • The study was funding by NoNO Inc. and Arbor Vita Corporation • The study reports on the use a novel agent – NA-1 – which is not licensed for clinical use • R Anderson, J Bishop, D Garman, M Tymianski are employed by or have an ownership interest in NoNO Inc. • M Hill is funded by Alberta Innovates Health Solutions and the Heart & Stroke Foundation of Alberta, NWT, NU
A Phase 2, double-blinded, placebo-controlled, randomized trial in Canada (11 sites) and the USA (3 sites)
Neuroprotection • Neuroprotection has been “proven” in animal models of stroke for multiple agents and paradigms. • None has been translated to humans N Engl J Med 2007;357:562-71.
STAIR • What are the reasons for failure? • Primate models • Fidelity of reproduction of the experimental paradigm in humans • Time, dose, correct diagnosis • Variability in human stroke • Variability in collaterals and blood supply • Trial design and execution
Novel Trial Design • Endovascular coiling associated with small embolic strokes • Measureable on MR • Controlled setting under anesthesiology control • Time of drug delivery – within minutes to hours of stroke onset
N N 1 1 3 3 4 4 PDZ PDZ N N 2 2 PDZ PDZ PDZ PDZ SH3 SH3 C C GK GK C C NO PDZ PDZ N N C C nNOS nNOS Cell Death due to Free Radicals PSD-95 Plays Key Role in Neurotoxicity Link Between NMDARs and Neurotoxicity via PSD-95 Treatment with PSD-95 Antisense PSD-95/SAP90 PSD-95/SAP90 No Nitric Oxide, No Cell Death
N 1 3 4 PDZ N 2 PDZ PDZ SH3 GK C PDZ N C nNOS Treatment with PDZ interacting peptides + Active drug = Drug Carrier PSD-95/SAP90 No Nitric Oxide No Cell Death
RCT • Ho: Treatment with NA-1 does not result in any reduction in the number of volume of peri-procedural ischemic strokes measured by MR Inclusion Criteria • Aneurysm suitable for coiling • Unruptured • Ruptured with WFNS Grade III or less Exclusion • Contraindication to MR • Dissecting, mycotic aneurysm • Major chronic illness
RCT • 1:1 randomization, central, stratified by aneurysm status (ruptured v. unruptured) • MR pre-treatment • Endovascular procedure • Treatment with NA-1 – IV infusion over 10 minutes - at the end of the procedure • MR at 2-4 days • Clinical outcomes at 30 days
Safety • No serious adverse events attributable to NA-1 • 2 adverse events, consisting of transient (15 min) mild hypotension were considered possibly related to NA-1
Lesion reduction in UNRUPTURED aneurysm subjects Two patients with in the NA-1 group suffered large strokes by volume secondary to complications of the endovascular procedure. *P values reflect a test of the differences between the means. **Adjusted P values represent the effect of treatment, adjusted for age, ruptured vs. unruptured aneurysm status, the use of adjunctive devices (eg. stent assisted coiling), groin puncture to infusion time, and the use of antiplatelet agents. Counts data were modeled using negative binomial regression. Volume data were cubic root transformed and modeled using multiple linear regression.
Lesion reduction in patients without large stroke *P values reflect a test of the differences between the means. **Adjusted P values represent the effect of treatment, adjusted for age, ruptured vs. unruptured aneurysm status, the use of adjunctive devices (eg. stent assisted coiling), groin puncture to infusion time, and the use of antiplatelet agents. Counts data were modeled using negative binomial regression. Volume data were cubic root transformed and modeled using multiple linear regression.
Reduced Lesion Number Proportions of patients with DWI lesions, binned at the 90th percentile. More NA-1 patient have 0 or 1 lesion; less NA-1 patients have more than 15 lesions (p=0.012).
Conclusions • ENACT is a novel approach to assessing neuroprotection in humans • NA-1 is safe and without serious adverse event in patients with ruptured and unruptured aneurysms • NA-1 reduces the number and volume of ischemic stroke lesions in a human model of iatrogenic embolic stroke
Implications • Ischemic neuroprotection is possible in aged humans • Multiple endovascular procedures may be amenable to treatment with NA-1 to treat stroke • Testing of NA-1 in human community acquired stroke is a priority • NA-1 may be a useful treatment for ruptured aneurysm patients