For ICAS

Report
Pre-Ischemic Conditioning for
Intracranial AtheroSclerotic StrOke
PICASSO TRIAL
Marc Chimowitz (MUSC)
David C Hess (GRU)
Renee Martin (MUSC)
David Liebeskind (UCLA) Imaging
Need For Better Rxs For High-Risk
Patients With ICAS
• ICAS may be most common cause of stroke in the world- 4250% of strokes in China Pu et al Stroke. 2013;44(8):2109-14
• 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
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)
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)
CONDI long term
Prehospital trial of RIC in STEMI before PCI
Sloth et al European Heart Journal (2014) 35, 168–175
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)
Bilateral Carotid Artery Stenosis Model
(adapted from Shibata M, Stroke. 2004;35:2598-2603)
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
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
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)
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
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
Arterial spin-labeled perfusion MRI (ASL)
Courtesy of David Liebeskind
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)
PICASSO Ischemic Conditioning Trial Design
Phase 1
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
Phase 2
Chosen Dose + AMM
N=74 + 30 Phase 1
Rx Adherence, clinical endpoints
30d, 4m, 9m, 12m
AMM alone Validation Gp.
N=20 + 20 Phase 1
Clinical Endpt.
30d, 4m, 9m, 12m
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
1818
18
Phase I
Baseline
MRI ASL
Blood biomarkers
30 days
Adherence
MRI ASL
Blood biomarkers
4 months
Adherence
MRI ASL
Blood biomarkers
Determine dose for Phase 2
Bilateral, bid
Unilateral, qd
Aggressive med management (AMM)
Dose decision based on:
Adherence
MRI ASL (CBF)
Blood biomarkers
9 months
12 months
MRI ASL
Blood biomarkers
Phase 2
30 subjects from Phase 1
MRI ASL
Biomarkers
20 subjects from Phase 1
MRI ASL
Biomarkers
74 subjects
20 subjects
9 months
Optimal dose from phase 1
AMM
12 months
Symptomatic
infarct
Key Inclusion Criterion
• Non-disabling symptomatic cerebral infarction
within 30 days of enrollment attributed to 7099% 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
EXTRA SLIDES
GO/NO GO for PHASE III Clinical Trial
Yes
Does the 95% CI of the Observed 1Year Rate of Symptomatic Cerebral
Infarction in the Control Group
Include the Observed Rate for
Similar High-Risk Patients in
SAMMPRIS?
No
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?
No
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
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
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.
Relative Risk
Power with
p
10%
11%
12%
13%
14%
15%
Reduction
50%
45%
40%
35%
30%
25%
n=100
0.97
0.93
0.88
0.80
0.70
0.59

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