Building Clinical Trials that Will Positively Impact an ...
Transcript of Building Clinical Trials that Will Positively Impact an ...
UCLA Stroke Center
Building Clinical Trials that Will Positively Impact an Emerging Field
Jeffrey L. Saver, MD, Professor of Neurology
Director, UCLA Comprehensive Stroke Center
NIH RCTs of First Generation Neurothrombectomy Devices
• IMS 3 (NIH) » Multicenter, phase 3,
900 patients » IV TPA vs IV TPA + IA
(Merci or IA lytic or IA lytic + US), < 3h
• MR RESCUE (NIH) » Multicenter, phase 2,
120 patients » Merci Retriever vs best
medical care, 3-8h
UCLA Stroke Center
Potential Reasons for IMS 3 Nonpositivity
• Concomitant therapy » Low dose of TPA in active arm
• Confounding therapy » IA lytics > mechanical thrombectomy
• Early technology » First generation mechanical thrombectomy
• Patients without target occlusions » Spontaneous lysis, penetrators, M3s, etc » IV TPA worked too well – esp M2 MCAs
• Patients without target penumbra » No penumbral imaging selection
• Patients with high expected response treated outside of trial » Equipoise less in community before IMS 3 results known
• Infarct progression before intervention » Long door to arterial puncture times
UCLA Stroke Center
Potential Reasons for IMS 3 Nonpositivity
• Concomitant therapy » Low dose of TPA in active arm
• Confounding therapy » IA lytics > mechanical thrombectomy
• Early technology » First generation mechanical thrombectomy
• Patients without target occlusions » Spontaneous lysis, penetrators, M3s, etc » IV TPA worked too well – esp M2 MCAs
• Patients without target penumbra » No penumbral imaging selection
• Patients with high expected response treated outside of trial » Equipoise less in community before IMS 3 results known
• Infarct progression before intervention » Long door to arterial puncture times
UCLA Stroke Center
JL Saver, R Jahan, E Levy, T G Jovin, B Baxter, R Nogueira, W Clark, R Budzik, OO Zaidat, for the
SWIFT Trialists
Lancet, Aug 26, 2012
Primary Trial Endpoint Outcomes Among Randomized
Patients
Randomized Solitaire FR
N=58
Randomized Merci N=55
Non-inferiority P value1
Superiority P value1
Successful recanalization without SICH2 (Core Lab)
60.7% (34/56) 24.1% (13/54) <0.0001 0.0001
Successful recanalization study device (Core Lab)
68.5% (37/54) 30.2% (16/53) <0.0001 0.0001
Successful recanalization study device (Site Assessed)
83.3% (45/54) 48.1% (26/54) <0.0001 0.0002
Use of rescue therapy 20.7% (12/58) 43.6% (24/55) <0.0001 0.015
End of procedure successful recanalization (Site)
88.9% (48/54) 67.3% (37/55) <0.0001 0.010
End of procedure successful recanalization (Core Lab)
80.4% (45/56) 57.4% (31/54) <0.0001 0.013
1. Noninferiority by Wald’s method, superiority by Fisher’s Exact test 2. Symptomatic Intracranial Hemorrhage - Any PH1, PH2, RIH, SAH, or IVH associated with a decline in NIHSS ≥ 4 within 24hrs.
Global Disability at 90 Days (Modified Rankin Score)
12.7%
10.4%
12.7%
8.3%
10.9%
10.4%
20.0%
8.3%
21.8%
16.7%
3.6%
2.1%
18.2%
43.8%
SOLITAIREFR
MERCI
0 1 2 3 4 5 6
•CMH, p = 0.04
Hemorrhagic Transformation Outcomes
Outcomes Among Randomized Patients
Randomized Solitaire FR
N=58
Randomized Merci N=55
Non-inferiority P value1
Superiority P value1
SICH 1.7% (1/58) 10.9% (6/55) <0.0001 0.057
All ICH 17.2% (10/58) 38.2% (21/55) 0.0001 0.020
1. Fisher’s Exact
10 |
Rankin Shift
6.30%
15.10%
8.60%
12.00%
6.90%
12.90%
16.10%
9.40%
29.90%
14.10%
8.00%
2.40%
24.10%
34.10%
0.00% 20.00% 40.00% 60.00% 80.00% 100.00%
Merci™ Device
Trevo™ Device 0123456
•*Presented at European Stroke Congress 2102. Lisbon, Portugal by Dr. Raul Nogueira
Complete Recanalization Rates in Multicenter Trials
• IV TPA » Complete – 5%
• IA Lysis » Complete – 20%
• Merci/Multi-Merci » Complete – 23%
• Penumbra » Complete – 23%
Complete Recanalization Rates in Multicenter Trials
• IV TPA » Complete – 5%
• IA Lysis » Complete – 20%
• Merci/Multi-Merci » Complete – 23%
• Penumbra » Complete – 23%
• Solitaire » Complete – 51%
Favorable outcome and mortality at 90d and onset-to-reperfusion time 480 patients from 7 studies
Mazighi M et al. Circulation 2013;127:1980-1985
Copyright © American Heart Association
Favorable Outcome
Mortality
SWIFT-PRIME: Designing for Success
Desirable Feature Design Element Highly effective device SolitaireTM FR device √
Clots to attack CTA/MRA √
Clots distinctively responsive ICA/M1 √
Brain to save Small core (ASPECTS) √
Patients who will respond Randomize all eligible √
Minimize progression Imaging to puncture optimization √
Concomitant therapy Full dose TPA √
The SOLITAIRE™ FR Revascularization Device is intended for use as adjunctive therapy to improve neurological outcomes and decrease mortality in patients experiencing an acute ischemic stroke in large intracranial vessels within 6 hours of symptom onset. The SOLITAIRE™ FR Revascularization Device is also indicated for removing thrombus from a large intracranial vessel and restoring blood flow in patients, who are ineligible for or have failed IV tPA therapy, experiencing ischemic stroke within 8 hours of symptom onset. Solitaire is a trademark of a Covidien company.
Features of Second Generation Embolectomy Trials Current
N Planned Max N
Intervention CTA/ MRA
Time TPA Imaging Status
MR CLEAN
500 500 Variable (97% SR)
+ 6 hr Y or Inel <1/3 MCA
Positive
ESCAPE 316 500 Solitaire + 12 hr Y or Inel Collat < 50%
Positive
EXTEND IA
~70 100 Solitaire + 6 hr Y RAPID Mismatch
Positive
REVASCAT ~200 690 Solitaire + 8 hr Inel or Failed
A ≥ 6/7 Pending
SWIFT PRIME
195 833 Solitaire + 6 hr Y A ≥ 6 RAPID
Pending
THERAPY 109 692 Penumbra HVS≥8mm Y < 1/3 MCA
Halt
PISTE ~40 800 Variable + 6 hr Y CT hypo ?
THRACE ~450 480 Variable + R 4h Y ?
UCLA Stroke Center
How Many of the Dominoes Will Fall?
UCLA Stroke Center
MR CLEAN
REVASCAT
SWIFT PRIME
ESCAPE
EXTEND IA
How Many of the Dominoes Will Fall?
UCLA Stroke Center
MR CLEAN
REVASCAT
THRACE
SWIFT PRIME
THERAPY
ESCAPE
EXTEND IA
MR CLEAN Design
• Netherlands Hospitals • Medical therapy (w/o or w/ TPA) vs medical
therapy (w/o or w/ TPA) plus endovascular • Key entry criteria
» NIHSS ≥ 2 » Age ≥ 18 » CTA/MRA occlusion in ICA, MCA (M1/M2), or ACA
(A1/A2) » Embolectomy within 6hr » < 1/3 MCA or 100 cc
UCLA Stroke Center
Are We Done Yet?
•UCLA Stroke Center
Unable to return to work (mRS 2-6): 88% Permanent symptoms (mRS 1-6): 97%
Building Next Generation of Clinical Trials that Will Positively Impact an Emerging Field
Intervention Type
Special Trial Aspects
Example Comparisons
Target Patients
Reperfusion Strategies
Active Comparator
IVT+ERT vs ERTalone ICA occlusions IVT+IERT vs IVT alone M2 occlusions
Systems of Care Cluster randomization
EMS routing – PSCs first versus CSCs first
Severe deficits
Prehospital Neuroprotection
ED imaging endpoints
NA1, hypothermia, nitroglycerin vs control
EMS transported patients
Deter Reperfusion Injury
IA admin Free radical scavengers vs control
Post-successful TICI 2b/3 reperfusion
Neurothrombectomy Devices
Reperfusion 2b/3 as primary surrogate endpoint
Device A vs B Large artery occlusions
Imaging Selection
6-24h ERT vs no ERT Wake-up and late
UCLA Stroke Center
Symptoms Primary Stroke Center Neuroprotectants EMS 911
Comp Stroke Center EMS IV Lytic
Imaging
Imaging
IA Mechanical or Lytic
Angiogram
Cath Lab Reperfusion
Neuroprotectants Stroke Unit
Acute Ischemic Stroke Treatment 2.0: Fast and Furious