Transcript Document

Final Results of a Phase II-a, Randomized,
Open-Label Trial to Evaluate Intramyocardial
Autologous Skeletal Myoblast Transplantation
in Congestive Heart Failure Patients:
The SEISMIC Trial
Patrick W. Serruys, MD PhD
Eric J Duckers, MD PhD
on behalf of the BIOHEART
European SEISMIC study investigators
American College of Cardiology Late-Breaking Clinical Trials
April 1, 2008, 11:15 – 11:25 am
Patrick W. Serruys, MD PhD
Declares no conflicts of interest relating to
this presentation
Percutaneous Intramyocardial
Transplantation of Autologous Myoblasts:
BIOHEART SEISMIC* Trial
–
Phase II-a, open-label, 2:1 randomized, controlled,
multi-center study
–
–
P.I.:
Patrick W. Serruys
Sponsor: Bioheart, Inc. Sunrise, Florida, USA
–
Blinded analysis by core facilities
–
–
–
–
Health Decisions – Data Management / Statistics, CRO
Synarc – Echo, MUGA Core-Lab
Spacelabs – Holter Core-Lab
Pivotal – Haematology / Viral Core-Lab
* Safety and Effects of Implanted (Autologous) Skeletal Myoblasts
(MyoCell®) using an Injection Catheter = SEISMIC Trial
Bioheart EU Phase II-a Trial – SEISMIC
Overall Objective:
To assess the safety and efficacy of MYOCELL® therapy on myocardial
function in CHF patients post MI(s).
Primary Safety Endpoint
– Defined Serious Adverse Events (SAEs) at 3 & 6 mos
• fatal or life-threatening events
• prolonged or required hospitalization
Secondary
Safety Endpoints
• sustained arrhythmia for > 30 seconds
– Holter monitoring, 12-lead ECG data, frequency of
• documented worsening of congestive heart failure
ventricular
arrhythmias
• resulting in permanent impairment
or surgical intervention
– Safety
of the use of the MyoCath® injection
catheter by
to
preclude
permanent
impairment
of
a
body
function
Adverse Event (AE) assessment
Numberand
andscientific
mean length
of staybyfor
hospitalizations
–– Medical
judgment
the
DSMB committee
was exercised when classifying events as serious
Relation between an adverse event and the test article was determined
by the Investigator on the basis of his or her clinical judgment
Bioheart EU Phase II-a Trial – SEISMIC
Overall Objective:
To assess the safety and efficacy of MYOCELL® therapy
on myocardial function in CHF patients post MI(s).
Primary Efficacy Endpoint:
– Change in LVEF at 3 & 6 mos. by MUGA compared
with baseline
Secondary Efficacy Endpoints:
– QOL assessment, 6-min. walk, NYHA class
– Hospitalization, readmissions or the need for
medical treatment outside of hospitalizations
– Global and regional contractility by contrast aidedDobutamine Stress Echo and Tissue Doppler
Imaging
Bioheart EU Phase II-a Trial – SEISMIC
Screening:
62 ICD Patients
Baseline Evaluation
15 Screen Fails
47 Patients Randomized:
®
ICD Patients: 31 MyoCell , 16 Standard Medical Therapy
5 Withdrawals*
Treatment Arm
6
(MyoCell ® 150-800 x 10 )
26 ICD Patients
2 Withdrawals**
Control Arm
(Standard Medical Therapy)
14 ICD Patients
* All 5 treated patients withdrew due to changes in German biopsy regulations.
** Both control patients withdrew after knowledge of randomization allocation.
SEISMIC Trial Investigators
1.
Pr. Patrick Serruys, Rotterdam, the Netherlands (PI)
3.
6.
Pr.
Legrand,
Belgium The Netherlands
– Victor
J. Tijssen,
ChairLiege,
– Amsterdam,
– Walter
G. StegVan
– Paris,
FranceGenk, Belgium
Dr.
Mieghem,
– F. Verheugt – Nijmegen, The Netherlands
Pr. Christoph Nienaber, Rostock, Germany
– H. Wellens – Maastricht, The Netherlands
Pr. Joachim Schofer, Hamburg, Germany
7.
Pr. Christoph Hehrlein, Freiburg, Germany
DataAalst,
Safety
& Monitoring
2. Independent
Dr. Jozef Bartunek,
Belgium
4.
5.
Board
Steering
Committee
8. SEISMIC
Dr. Johannes
Waltenberger,
Maastricht, the Netherlands
9.
Dr. Carlos Macaya, Madrid, Spain
– P.W. Serruys, Chair – Rotterdam, The Netherlands
10. Dr.
Gershlick,
– Anthony
J. Bartunek
– Aalst,Leicester,
Belgium UK
– Nicholas
A. Gershlick
– Leicester,
11. Pr.
Peters,
London, UK
UK
– N.
PetersSiminiak,
– London,
UnitedPoland
Kingdom
12. Pr.
Tomasz
Poznan,
13. Dr. Peter Smits, Rotterdam, the Netherlands
13 investigative sites, 6 European countries
SEISMIC Eligibility Criteria
EXCLUSION Criteria
INCLUSION Criteria
•
MI within 12 weeks of scheduled
implant
NYHA Class II – III
•
NYHA class I or IV
•
Need for revascularization ruled out
within 30 days of screening
•
CABG within 3 months or
PCI within 6 months of cell implant
•
Optimal pharmacological therapy for
> 60 days prior to screening
•
Any cardiac valve replacement or
significant aortic stenosis
•
Prior MI > 90 days
•
Heart failure secondary to valvular
disease
•
Placement of ICD > 180 days prior
to implant
•
Severe tortuosity of aorta, iliac or
femoral arteries
•
Target region wall thickness of > 5
mm by echocardiography
•
Prior angiogenic therapy or
myocardial laser therapy
•
LVEF > 20% and < 45% by MUGA
•
End stage renal disease
•
Age > 18 and < 75 years old
•
SEISMIC Study Flow
ICD
implant
Holter
ICD
QOL
Viral
Echo
MUGA
Holter
ICD
ECG
Echo
Holter
ICD
ECG
Holter Holter
ICD
ICD
QOL QOL
Echo
MUGA
Holter
ICD
QOL
Echo
MUGA
Biopsy
Holter
-6M
ICD
-4w -3w -2w -1w
SCREENING
0 7d 14d 21d 1M
INJECTION
1-M FU
3M
3-M FU
QOL comprises Minnesota Living with Heart Failure Questionnaire,
NYHA Heart Failure Classification and 6-minute walk test.
6M
6-M FU
SEISMIC Baseline Characteristics
6-Month Analysis (n=40)
TREATMENT (n=26)
CONTROL (n=14)
Mean
Range
Mean
Range
Age (years)
59
32-72
62
44-75
Years since last MI
8.3
1-21
7.1
1-17
Years ICD in place
1.9
1-5
2.6
1-5
Race: caucasian (%)
100 %
100 %
Prior MI (%)
100 %
100%
Male (%)
92 %
71 %
Prior history of VT (%)
69 %
64 %
Diabetes type II (%)
31 %
14 %
NYHA class III (%)
39 %
21 %
LVEF (%)
30.9  9.2
19-53
32.6 + 11.2 15-55
SEISMIC Skeletal Myoblasts Harvest
and Culture
Biopsy Weight (gr)
9.1 ± 2.8
Cell harvest (x106)
888 ± 319
Cells injected (x106)
592 ± 184
Number of injections
24 + 7
CD56 staining > 50%
100%
Volume of cell transplant (mL)
11.8 ± 3.7
Number of cells injected based on infarct size;
Non-ionic contrast media may be mixed with cells
SEISMIC
Kaplan Meier Survival Curve for
Time to Onset First SAE or Death
Probability Freedom from SAE / Death
Control Tx
d5
VT term by ICD
d6, d8, d9 VT term by ATP
d11
VT term by ICD
BB/ Amiodarone/ Flecainide 
arrhythmia control 2 wks with
status improvement
27-30 d
deterioration CHF
death
Myoblast Tx
One patient died in the treatment arm (3.8%), no deaths in the control arm.
SEISMIC
Serious Adverse Events
MyoCell ® Tx
Control Tx
(n=26)
(n=14)
no. of pts. no. of no. of pts. no. of
w SAE episodes w SAE episodes
Cardiovascular-related SAEs
Arrhythmias
Timing of the episodes of tachyarrhythmia
Bradyarrhythmias
1
1
2
on
sequential
holter
monitoring
Ventricular fibrillation
1
2
0
(no.
of
patients
and
no.
of
episodes
in
brackets)
Ventricular tachyacardia
5
8
3
Idioventricular rhythm
0
0
2
MyoCell
Worsening of congestive
heart failureTx
3 Control
3 Tx 1
Hypotension
0
0
1
Cardiogenic shock
1
0
periproc
1/26 (3.8 %, 1 eps) 1
<Pulmonary
1 wk Edema
2/26 (7.7 %, 3 eps) 1 1/14 1(7.1 %,0 1
Pericarditis
1
1
0
1-4
wks
2/26
(7.7
%,
3
eps)
3/14
(21.4
%,
Aortic dissection [procedural]
1
1
0
1-6 mo
2/26 (7.7 %, 3 eps)
Non-cardiovascular SAEs
Total Cardiovascular SAEs
All SAEs
No. of subject experiencing SAEs
2
0
10
2
1
1
0
eps)0
0
10 eps)
0
1/14 (7.1 %, 1 eps)
2
2
2
18
20
13/26 (50%)
2
16
18
5/14 (35.7%)
SEISMIC
NYHA Heart Failure Class
100%
90%
80%
70%
Myoblast Therapy
NYHA Class I
60%
NYHA Class II
50%
NYHA Class III
40%
NYHA Class IV
30%
20%
10%
0%
BL
N=26
1 mo
N=23
3 mo
N=22
6 mo
N=20
100%
90%
80%
Control Therapy
70%
NYHA Class I
60%
NYHA Class II
50%
NYHA Class III
40%
NYHA Class IV
30%
20%
10%
0%
BL
1 mo
3 mo
6 mo
N=14
N=9
N=12
N=13
SEISMIC
MUGA Global LV Ejection Fraction
60
32.6 %
32.5 %
MUGA LVEF (%)
50
40
30
20
Control
10
0
LVEF baseline
N=14
60
LVEF 3 month
N=13
30.9 %
LVEF 6 month
N=14
31.2 %
MUGA LVEF (%)
50
40
30
20
Treatment
10
0
LVEF baseline
N=26
LVEF 3 month
N=23
LVEF 6 month
N=23
SEISMIC
6-Minute Walk Test
1200
6MWT (m)
1000
448 m
Control
Control
Difference Between
Baseline and 6 Months
441 m
800
-0.2 m ± 177.1
600
400
200
0
6MW Tbaseline
N=14
700
406 m
6MWT 3 month
N=12
Treatment
6MWT 6 month
N=13
466 m
600
6MWT (m)
500
+60.3 m + 54.1
400
300
200
100
0
6MWT baseline
N=26
6MWT 3 month
N=21
6MWT 6 month
N=19
SEISMIC
Minnesota Living With Heart Failure QOL Score
MyoCell Tx
Control Tx
80
60
50
.8
6
39
.3
6
.0
0
38
10
38
.3
0
.2
9
38
20
41
30
.8
8
40
40
MLWHF Score
70
0
QOL Score base line QOL Score 3 month QOL Score 6 month
Baseline
N=26
N=14
3-month
N=21
N=12
6-month
N=19
N=13
SEISMIC
Response to Treatment
NYHA HF / 6MWT / MLFQ / LVEF
Improved
58% 94% 31% 84% 57% 67% 50% 56%
or
No Change
Worsened 42% 6% 69% 16% 43% 33% 50% 44%
NYHA HF
6MWT
MLFQ
LVEF
Percutaneous Intramyocardial
Transplantation of Autologous Myoblasts:
BIOHEART SEISMIC Trial
–
The SEISMIC trial is a phase II-a, open-label, placebocontrolled, randomized, multi-center study.
–
Primary Safety Endpoint:
In this heart failure population previously fitted with an ICD,
myoblast cell therapy was not associated with an increased
incidence of arrhythmia, as documented by holter tape and
ICD recordings, and appeared to be safe.
–
Primary Efficacy Endpoint:
The MUGA global LVEF remained unchanged, without
overall sign of deterioration.
Percutaneous Intramyocardial
Transplantation of Autologous Myoblasts:
BIOHEART SEISMIC Trial
–
Secondary Efficacy Endpoint:
6-minute walk test showed an improvement not seen in the control group,
which was corroborated by a change in NYHA classification, while further
deterioration in these parameters was observed in the control group.
–
However, none of these changes were statistically significant, and may be
the result of a placebo effect in the absence of a true blind placebocontrol group with sham treatment.
–
Further investigation in double-blind (sham treatment), placebo-controlled
studies to evaluate autologous myoblasts in patients with CHF is
warranted (MARVEL, CAUSMIC II).
SEISMIC
Response to Treatment
6 MWT / NYHA HF / LVEF
Improved
31% 84% 58% 94% 50% 56%
or
No Change
Worsened
69% 16% 42%
6MWT
6%
NYHA HF
50% 44%
LVEF
Percutaneous Intramyocardial
Transplantation of Autologous Myoblasts:
BIOHEART SEISMIC Trial
Secondary efficacy end point:
6 min walking test shows an improvement not seen in the
control group, corroborated by a change in the NYHA
classification in the cell-treated group, while a further
deterioration was seen in the control group.
However, none of these changes were statistically significant,
and may be the result of a placebo effect in the absence of a
true blind placebo control group with sham treatment.
SEISMIC
Serial echocardiographic analysis of
dimension in the myoblast treated group (n=26)
LVESD
LVESD (mm)
100
90
80
70
60
50
40
30
20
10
0
LVESD baseline
N=22
LVESD 3 month
N=15
LVESD 6 month
N=13
120
LVEDD
LVEDD (mm)
100
80
60
40
20
0
LVEDD baseline
N=22
LVEDD 3 month
N=15
LVEDD 6 month
N=15