1. David Liebeskind (UCLA) Imaging
Pre-Ischemic Conditioning for Intracranial AtheroSclerotic StrOke PICASSO TRIAL
Marc Chimowitz (MUSC)
David C Hess (GRU)
Renee Martin (MUSC)
David Liebeskind (UCLA) Imaging

2. Need For Better Rxs For High-Risk Patients With ICAS
ICAS may be most common cause of stroke in the world % of strokes in China Pu et al Stroke. 2013;44(8):
Despite aggressive medical management (AMM) in SAMMPRIS, 1-year rate of symptomatic cerebral infarction (new AHA / ASA stroke definition) in subjects whose qualifying event was a symptomatic infarct (74% of the SAMMPRIS cohort) was still very high (19.7%)
Alternative or Adjunctive Therapies Needed

5. Scientific Premise For A Trial To Evaluate Remote Ischemic Conditioning (RIC) For ICAS
Cardiac trials and other organs (renal)
Long term benefit with single RIC
Chinese chronic conditioning trials in ICAS
Reduction of stroke
SPECT studies suggesting increase of CBF
Preclinical data
Neuroprotective in multiple models
Increases CBF in multiple models
Effective in Bilateral carotid artery stenosis model (BCAS)

6. RIC
Most studies have treated with RIC once with 4 to 5 cycles of 5 minute inflation above 200 mmHg, then deflation for 5 minutes
Two studies with long term follow-up have shown long term effects on Major Adverse Cardiac and Cerebrovascular Events (MACCE)

7. CONDI long term Prehospital trial of RIC in STEMI before PCI Sloth et al European Heart Journal (2014) 35, 168–175

8. Upper Limb Ischemic Preconditioning For Preventing Stroke in ICAS Meng et al. Neurology 2012
Randomized Trial (n=68):
Brief Repetitive Cycles of Occluding Both Brachial Arteries With a BP Cuff BID x 300 Days
vs.
Usual Care
300 Day Stroke Rate: 7.9% vs. 26.7% (p<0.01)
Second trial in patients over age 80 (180 days of RIC) with similar “positive” results (under peer review)
Regarding Non-surgical treatments, Meng et al from China recently reported a small randomized trial in which THEY compared brief repetitive cycles of occluding both brachial arteries with a BP cuff twice daily for 300 days vs. usual care and found a remarkably lower rate of stroke at 300 days with this treatment. The mechanisms of action of this ischemic preconditioning are uncertain but could involve improved cerebral perfusion and collaterals as well as platelet inhibition. These remarkable findings warrant a..

9. Bilateral Carotid Artery Stenosis Model (adapted from Shibata M, Stroke. 2004;35:2598-2603)

10. Chronic daily RIC in a mouse BCAS model
Increases CBF, improves cognitive function reduces cell death and myelin loss
(Hoda et al, Trans Stroke Res 2014)
High plasma nitrite

11. How Does Chronic RIC Work in ICAS?
Increase CBF in areas where it is decreased
Cytoprotection (protects neurons, glia)
Platelet activation, plaque stability
Improve recovery from stroke

12. Pleiotropic with multiple mechanisms
A key mediator is nitrite
RIC increases nitrite (NO) in blood of
mice and men
Nitrite likely related to increased CBF
Bilateral carotid artery stenosis model in mice with plasma nitrite
measured at 30 days. Mice with Remote Ischemic Postconditioning
(RIPostC) had significant elevations of nitrite (P<.001)

13. Biomarkers
IMAGING- CBF-MRI ASL in collaboration with David Liebeskind, UCLA and Max Wintermark, Stanford
Plasma/serum biomarkers
Nitrite
Platelet activation
Inflammatory-CRP, TNFa
Anti-inflammatory, IL-10
SDF-1

14. Arterial spin-labeled perfusion MRI (ASL)
Noninvasive
Obviates exogenous contrast agents
Enables serial acquisition
Provides absolute quantification of changes in cerebral blood flow (CBF) mapped to template
hypoperfusion or serial worsening of perfusion
hyperperfusion or serial increases in perfusion
Multiparametric perfusion also informative about changes over time in a given patient
Courtesy of David Liebeskind

15. Arterial spin-labeled perfusion MRI (ASL)
Courtesy of David Liebeskind

16. Questions That Need Answers Before a Phase III Trial
? Dose – bilateral vs. unilateral; bid vs. qd
? Duration
? Rx Adherence
? Potential Efficacy
(? Correlation Between Biomarkers And Clinical Outcome)

17. PICASSO Ischemic Conditioning Trial Design
Phase 1 Phase 2
Bilateral bid + AMM
N= 30
Unilateral qd +AMM
N=30
AMM alone
N=20
Rx Adherence, ASL MRI, Blood biomarkers, Clinical Endpt.
at Baseline, 30d, 4m, 9m (no ASL MRI), 12m.
Dose for Phase 2 based on Adherence, Blood biomarkers and ASL MRI at 4m
AMM alone -
Validation Gp.
N= Phase 1
Chosen Dose + AMM
N= Phase 1
Rx Adherence, clinical endpoints
30d, 4m, 9m, 12m
Clinical Endpt.
30d, 4m, 9m, 12m

18. The Doctormate Device FDA IDE G140239
Automating RIC
Safely, Accurately, Non-Invasively
It is so simple, even I could use it…..
Cuff
Sized S, M, L
Rechargeable Controller
Device charger
The 18 18 18

19. Phase I Baseline 30 days 4 months 9 months 12 months
MRI ASL
Blood biomarkers
Adherence
MRI ASL
Blood biomarkers
Adherence
MRI ASL
Blood biomarkers
Determine dose for Phase 2
MRI ASL
Blood biomarkers
Bilateral, bid
Unilateral, qd
Aggressive med management (AMM)
Dose decision based on:
Adherence
MRI ASL (CBF)
Blood biomarkers

20. Phase 2 30 subjects from Phase 1 74 subjects 20 subjects
MRI ASL
Biomarkers
74 subjects
20 subjects
20 subjects from Phase 1
MRI ASL
Biomarkers
9 months
12 months
Symptomatic
infarct
Optimal dose from phase 1
AMM

21. Key Inclusion Criterion
Non-disabling symptomatic cerebral infarction within 30 days of enrollment attributed to 70-99% stenosis of a major intracranial artery (carotid artery, MCA stem (M1), vertebral artery, or basilar artery) that is documented by any of the following: MRA, CTA, or catheter angiography

22. EXTRA SLIDES

23. No Go for Phase III Trial
GO/NO GO for PHASE III Clinical Trial
Do 1. the Intent-to-Treat Efficacy Analysis in Phase 2 Show A Significantly Lower 1-Year Rate of Symptomatic Cerebral Infarction Than 20% (The High-Risk Rate in SAMMPRIS?), and 2. the ASL MRI or Blood Biomarker Studies in Phase 1 Suggest a Favorable Response to RLIC?
Yes No
Does the 95% CI of the Observed 1-Year Rate of Symptomatic Cerebral Infarction in the Control Group Include the Observed Rate for Similar High-Risk Patients in SAMMPRIS?
Do 1. Pre-specified Secondary Efficacy Analyses Suggest a Subgroup With A Significantly Lower 1-Year Rate of Symptomatic Cerebral Infarction Than the Rate Observed in That Subgroup in SAMMPRIS and 2. the ASL MRI or Blood Biomarker Studies in Phase 1 Suggest a Favorable Response to RLIC in this Subgroup?
Yes No
Is the Rate in the RLIC Group Sufficiently Lower Than the Control Group to Suggest Moving Forward With The Phase III Trial? No
Yes
Go for Phase III Trial
Yes No
No Go for Phase III Trial

24. Relative Risk Reduction
SAMPLE SIZE
Phase 2: The primary efficacy hypothesis to be tested in Phase 2 is that subjects treated with RLIC plus AMM in this trial will have a significantly lower rate of symptomatic cerebral infarction at 1 year compared with the rate observed in high-risk patients treated with AMM alone in SAMMPRIS.
In those subjects, the 1-yr rate of symptomatic cerebral infarction was 19.7%. For the primary endpoint, the hypothesis is that the percent of subjects with this outcome will be less than 20%. Let p be the true percent of subjects with the outcome by 1 year. The statistical hypothesis is: Ho: p > or = 20% versus H1: p < 20%. The sample size was calculated to provide at least 80% power for p = 13% in subjects treated with RLIC plus AMM. This corresponds to a 35% relative risk reduction. Using a one-sided exact binomial test with a Type I error of 15%, the required sample size is 100 subjects. The power with 100 subjects for several values of p is shown in the table. p
Relative Risk Reduction
Power with
n=100
10%
50%
0.97
11%
45%
0.93
12%
40%
0.88
13%
35%
0.80
14%
30%
0.70
15%
25%
0.59