Transcript Trial Overview - Clinical Trial Results

Vasodilator Induced Stress In
CONcordance with Adenosine
Binodenoson Pivotal Clinical Trial Program
James E. Udelson, Bruce Iteld, Fred Weiland,
Jack Foster, Robert Bonow, Edward Ficaro,
Raymond Gibbons, Gary Heller, Frans Wackers,
Richard Barrett, Glenn Pixton
for the VISION 302 and 305 Investigators
Disclosures
 Drs. Udelson, Iteld, Weiland, Foster,
Bonow, Ficaro, Gibbons, Heller and
Wackers received research grant
support and/or consulting honoraria
from King Pharmaceuticals R&D
 All investigators and/or their institutions
received research grant support from
King Pharmaceuticals R&D
 Drs. Barrett and Pixton are employees of
King Pharmaceuticals R&D
Background
 Vasodilator stress is widely used in lieu of
exercise for SPECT MPI
 Mechanism: stimulation of adenosine A2a
receptors
coronary arteriolar dilation,
decreased resistance and increased CBF
 Stimulation of other adenosine receptors
(A1, A2b, A3)
high incidence of side effects
(>80%), including 2o/3o AVB, CP, SOB, flushing
 More selective A2a receptor stimulation
desirable
Background (con’t)
 Binodenoson is a highly selective A2a
agonist
 In Phase 2 cath lab studies, CBFR with
I.V. binodenoson was similar to that
seen with I.C. adenosine
 Phase 2 studies suggested SPECT
image concordance with adenosine,
and fewer/less severe side effects than
adenosine in single-blind studies
VISION Pivotal Trial Program:
Primary Objective
 To demonstrate that SPECT MPI
acquired during binodenoson-stress
and adenosine-stress detect similar
magnitudes of ischemia in the same
patients
Secondary Objectives
 To evaluate and compare side effects
between binodenoson and adenosine:
• Incidence of 2nd or 3rd degree AV block
• Incidence, intensity of reported side effects,
patient preference
Study Design
 Two multi-center trials: VISION 302
(40 sites), VISION 305 (39 sites)
 Randomized, active-controlled
(adenosine), crossover design
 Double-blind, double-dummy drug
dosing
 Enrolled pts were risk-stratified by ACC
pre-test LK for CAD, to ensure broad pt
representation
Inclusion/Exclusion Criteria
 Inclusion:
• Referred for clinical pharm stress MPI
• Age ≥ 30 years
• Typical or atypical anginal pain
• Provide informed consent
 Exclusion:
• Pregnancy
• Very low pre-test LK for CAD
• MI within 30 days, PCI or CABG within 3 years,
•
•
unless new angina
Contraindications for adenosine
LVEF < 0.35, or NYHA HF Class IV
Study Design: VISION 302 and 305
Eligible Patients Randomized to Sequence
VISION
305
1st Scan
“MPI #1”
adenosine
2nd Scan
“MPI #2”
binodenoson
binodenoson
adenosine
2-7Days
Days
2-7
adenosine
adenosine
Identical image protocols, camera, isotope, doses, acquisition times and image
time post-dose, time of day, background anti-anginal meds held
Double-Blind, Double-Dummy Drug
Administration
placebo
0.06 mL/kg
in 30 secs
adenosine, 140 g/kg/min x 6 min
or
binodenoson
1.5 g/kg
in 30 secs
-30 sec
RP = radiopharmaceutical
RP
placebo, 0.047 mL/kg/min x 6 min
0
1
2
Time (min)
3
4
5
6
Demographics
Gender (M / F)
Age (Years, SD)
BMI (kg/m2, SD)
Reason for referral:
Chest Pain
Prior MI
Prior CABG/PCI
VISION 302
n=415
37% / 63%
63.3 (12.0)
31.4 (7.0)
94%
4%
9%
VISION 305
n=427
46% / 54%
62.9 (11.9)
31.3 (6.5)
97%
7%
15%
Demographics
Gender (M / F)
Age (Years, SD)
BMI (kg/m2, SD)
Reason for referral:
Chest Pain
Prior MI
Prior CABG/PCI
Low LK
Intermed LK
High LK
Known CAD
VISION 302
n=415
37% / 63%
63.3 (12.0)
31.4 (7.0)
94%
4%
9%
Target
5%
45%
25%
25%
Actual
6%
45%
24%
26%
VISION 305
n=427
46% / 54%
62.9 (11.9)
31.3 (6.5)
97%
7%
15%
Target
5%
45%
10%
40%
Actual
5%
44%
10%
41%
Data Analysis and Results
 Efficacy: SPECT image
concordance
• Methodology
• Results
 Side effects
• Methodology
• Results
Methods: SPECT Image Reviews
 Compliant: with FDA Guidelines
 Independent Readers: No other
involvement with studies or
development program, no knowledge of
other readers’ interpretations
 Blinded: to all treatment data
 Separated: Reader reviews of both MPI
studies from same patient were
separated by 2 weeks or ≥ 50 studies
Methods: Segmental Scoring of MPI
Each segment at stress/rest from 0=NL, to 4=severe defect
Derived global scores:
SSS: sum of stress scores = total abn myocardium at stress
SRS: sum of rest scores = extent of infarct
SDS = SSS - SRS = extent/severity of ischemia
Circulation 2002
Analysis of SDS
Stress
Stress
Rest
Rest
Binodenoson
SDS = 9
Adenosine
SDS = 8
Difference between studies =
SDSbino – SDSadeno = 1 SDS unit
Primary Efficacy Endpoint Hypothesis
 Mean paired difference between SDS
(extent/severity of ischemia) of
binodenoson images and adenosine
images is within 1.5 SDS units in either
direction,
and
 Fewer than 10% pts with highly
discordant results (severe ischemia on
one, no ischemia on alternate image)
Primary Endpoint Analysis of SDS
Difference
Hypothesis: 95% CI of mean SDS Bino – Adeno difference
is within +/- 1.5 SDS units
Mean SDS
Difference
Bino - Adeno
-3
VISION 302
-2
-1
0
1
2
3
VISION 305
-1.5
1.5
SDS units
Data Analysis and Results
 Efficacy: SPECT image concordance
• Methodology
• Results
 Side effects
• Methodology
• Results
Assessment of Side Effects:
Methodology
 When side effects occurred, pts were
asked to rate severity on a 1 – 10
point VAS scale
 At follow-up, while still blinded, pts
were asked which study they
preferred
 Order of analysis of individual side
effects was pre-specified for
sequential testing, to account for
multiplicity
Frequency (%) of Pre-Specified Side
Effects
VISION 302
2-3o AVB
Flushing
Chest Pain
Dyspnea
Nausea
Headache
Abdm Discmft
Dizziness
*p<0.05 in sequential testing
Bino
N=402
0*
32*
38*
42*
18
43
25
19
Adeno
N=404
3%
50
61
51
22
35
28
17
VISION 305
Bino
N=419
0*
38*
38*
45*
16*
47
34
19
Adeno
N=421
1%
58
61
54
22
42
28
19
Patient-Rated Intensity of Side Effects:
1-10 Visual Analog Scale
VISION 302
Flushing
Chest Pain
Dyspnea
Nausea
Headache
Abdm Discmft
Dizziness
*p<0.05 in sequential testing
Bino
N=402
1.4*
1.7*
2.0*
0.8
1.9
0.9
0.7
Adeno
N=404
2.8
3.6
2.9
1.1
1.8
1.3
0.8
VISION 305
Bino
N=419
1.4*
1.5*
2.0*
0.7*
2.0
1.4
0.7
Adeno
N=421
2.8
3.3
2.9
1.2
2.0
1.4
0.9
Blinded Patient Responses to
“Which Treatment Did You Prefer?”
VISION 302
VISION 305
80
70
71%
Percent
60
68%
P=0.004
P=0.001
20%
21%
50
40
30
20
10
0
11%
9%
Bino
Adeno No Pref
Bino
Adeno No Pref
Summary
Efficacy
 In both trials, the extent and
severity of SPECT MPI
reversible perfusion defects
(ischemia) were similar with
binodenoson as with adenosine
Summary
Side effects
 The incidence and intensity of
flushing, chest pain and dyspnea
were significantly reduced with
binodenoson
 Patients preferred binodenoson
in a blinded analysis
 AV block was not observed with
binodenoson
Conclusions
 Selective adenosine A2a receptor
stimulation with binodenoson for
pharmacologic stress MPI:
• Can be performed safely with 30 sec
bolus dosing
• Provides similar clinical information
on the extent/severity of ischemia as
adenosine
• Is associated with a significant
reduction in the incidence and
intensity of many side effects