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V asodilator I nduced S tress I n C ON cordance with Adenosine Binodenoson Pivotal Clinical Trial Program.

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Vasodilator Induced Stress In CONcordance with AdenosineBinodenoson 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 Pixtonfor the VISION 302 and 305 Investigators


Disclosures

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

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

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

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

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

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/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

Study Design: VISION 302 and 305

VISION 305

adenosine

adenosine

Eligible Patients Randomized to Sequence

1st Scan

“MPI #1”

adenosine

binodenoson

2-7 Days

2-7 Days

2nd Scan

“MPI #2”

binodenoson

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

Double-Blind, Double-Dummy Drug Administration

adenosine, 140 g/kg/min x 6 min

placebo, 0.047 mL/kg/min x 6 min

placebo

0.06 mL/kg

in 30 secs

RP

or

binodenoson

1.5 g/kg

in 30 secs

-30 sec0 1 2 3 4 5 6

Time (min)

RP = radiopharmaceutical


Demographics

Demographics

VISION 302 VISION 305

n=415 n=427

Gender (M / F) 37% / 63%46% / 54%

Age (Years, SD) 63.3 (12.0) 62.9 (11.9)

BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5)

Reason for referral:

Chest Pain 94% 97%

Prior MI 4% 7%

Prior CABG/PCI 9% 15%


Demographics1

Demographics

VISION 302 VISION 305

n=415 n=427

Gender (M / F) 37% / 63%46% / 54%

Age (Years, SD) 63.3 (12.0) 62.9 (11.9)

BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5)

Reason for referral:

Chest Pain 94% 97%

Prior MI 4% 7%

Prior CABG/PCI 9% 15%

Target

5%

45%

25%

25%

Actual

6%

45%

24%

26%

Target

5%

45%

10%

40%

Actual

5%

44%

10%

41%

Low LK

Intermed LK

High LK

Known CAD


Data analysis and results

Data Analysis and Results

  • Efficacy: SPECT image concordance

    • Methodology

    • Results

  • Side effects

    • Methodology

    • Results


Methods spect image reviews

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

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

Analysis of SDS

Stress

Stress

Rest

Rest

Binodenoson Adenosine

SDS = 9 SDS = 8

Difference between studies =

SDSbino – SDSadeno = 1 SDS unit


Primary efficacy endpoint hypothesis

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)


Paired difference vision 302 binodenoson adenosine sds

Paired Difference VISION 302Binodenoson-Adenosine SDS

Mean SDS difference = -0.09

140

N=374

120

100

80

Number of patients

60

40

20

0

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

SDS Difference Bino - Adeno


Paired difference vision 305 binodenoson adenosine sds

Paired Difference VISION 305Binodenoson-Adenosine SDS

160

140

120

100

80

60

40

20

Mean SDS difference = -0.68

N=391

Number of patients

0

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

14

16

SDS Difference Bino - Adeno


Primary endpoint analysis of sds difference

Primary Endpoint Analysis of SDS Difference

VISION 302

VISION 305

-1.5

1.5

Hypothesis: 95% CI of mean SDS Bino – Adeno difference

is within +/- 1.5 SDS units

Mean SDS

Difference

Bino - Adeno

-3 -2 -1 0 1 2 3

SDS units


Disclosures

197

38

14

6

38

13

7

2

9

8

9

5

5

7

6

10

Binodenoson vs. Adenosine AgreementPer-Patient Basis, Reader-Defined SDS VISION 302

Adenosine

Binodenoson

Normal(SDS: 0-1)

Mild(SDS: 2-4)

Moderate(SDS: 5-8)

Severe(SDS: >8)

Normal (SDS: 0-1)

Mild(SDS: 2-4)

Moderate(SDS: 5-8)

Severe(SDS: >8)

Patients in Extreme Off-Diagonal Cells: 11/374 (3%)

Exact categoricalagreement: 229/374 (61%)


Data analysis and results1

Data Analysis and Results

  • Efficacy: SPECT image concordance

    • Methodology

    • Results

  • Side effects

    • Methodology

    • Results


Assessment of side effects methodology

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

Frequency (%) of Pre-Specified Side Effects

VISION 302

VISION 305

Bino

N=402

0*

32*

38*

42*

18

43

25

19

Adeno

N=404

3%

50

61

51

22

35

28

17

Bino

N=419

0*

38*

38*

45*

16*

47

34

19

Adeno

N=421

1%

58

61

54

22

42

28

19

2-3o AVB

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

*p<0.05 in sequential testing


Patient rated intensity of side effects 1 10 visual analog scale

Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale

VISION 302

VISION 305

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

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

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

*p<0.05 in sequential testing


Blinded patient responses to which treatment did you prefer

Blinded Patient Responses to“Which Treatment Did You Prefer?”

VISION 302

VISION 305

80

71%

70

68%

60

P=0.004

P=0.001

50

Percent

40

30

20

21%

20%

10

11%

9%

0

Adeno

No Pref

Bino

Adeno

No Pref

Bino


Summary

Summary

Efficacy

  • In both trials, the extent and severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine


Summary1

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

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


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