From Bench to Bedside
Step 1: First-time application of DESWT in a rodent model of ischemic HF
(pilot trial); redesign of device
Step 2: In-vitro validation
Step 3: Reproduction of results of pilot trial in a rodent large scale trial
(320 rodents); human fitting studies
Step 4: Reproduction of the results of the rodent large scale trial in a large
animal (pig) model; human fitting studies
Step 5: Phase I clinical trial with external data monitoring
Pilot Trials
Trials show promising
results, exceeding comparable stem cell trials.
Main problem: size of the
applicator
8 Weeks Later: Cardiac Shock Wave Applicator
CardioGold® CG050
CRT – Cardiac Regeneration Technologies, Woodstock, USA
(manufactured by MTS-Europe GmbH, Konstanz, Germany)
Electro-hydraulic, focused, ECG-triggering facility
EFD: 0.38 mJ/mm2
Frequency: 1-5 Hz
35mm
In-vitro Experiments
distance bar
adapter
temp. sensor
Shock Wave Devices
Water bath – prototype
appl. fixation
Degassed water, temperature 37°C
DermaGold® CP155 (TRT, USA)
heater
300 impulses at 0.15 mJ/mm2, 5 Hz
In-vitro Experiments
Mean cell duplication time
Connexine 43 = cell contact, communication
Cardiomyocytes (= heart muscle cells)
Endothelial cells (= vessel cells)
Fibroblasts (= cells of connective tissue)
Rodent Large Scale Trial – Results from 320 rats!
___ SWT
___ Controls
‡
80
70
60
†
FS %
50
40
*
30
*
‡
†
*
20
10
0
prae MI
*
post MI
* p<.05 to pre MI
SWT Group vs. Controls
*
6-week FUP
†p<.05 to post MI
*
14 week FUP
‡ p<.05
Next Step: Large Animal Trial
25 Domestic pigs:
Myocardial infarction by LAD ligation
3 Groups: Sham = healthy subjects
SWT = LAD ligation with SWT
Control = LAD ligation without SWT
Timeline:
d0
week 4
▼_______________
LAD lig./sham OP
week 8
▼ _______________▼
SWT/sham OP
Termination
Ventricular Function
LVEF
SWT
control
LV ejection fraction %
100
75
+
68 ± 0.7%
62 ±
9.1%
*
50
43 ± 2.5%
25
46 ± 5%
*
*
week 4
week 8
0
d0
* p<.05 vs. pre MI
+ p<.05 vs. 4 weeks post MI
First Human Application – Study Design
Title: DESWT - Safety of Myocardial Regeneration by Direct
Epicardial Shock Wave Therapy in Combination with Coronary
Artery Bypass Grafting
Design: Prospective, Phase I
Enrollment: Commenced September 2008, 10 Patients – last patient
enrolled June 2009
Primary Endpoint:
Safety
Secondary Endpoint:
Efficacy
Study outline:
CABG+DESWT
8-week FUP
6-month FUP
▼_______________▼______________▼
First Human Application (Sep. 23, 2008)
First Human Application (Sep. 23, 2008)
First Human Application (Sep. 23, 2008)
First Human
Application
(Sep. 23, 2008)
Primary Endpoint - Safety
 Death
 Myocardial infarction
 Bleeding, including pericardial tamponade
 Ventricular arrhythmias
 Bacteriaemia / sepsis
 Respiratory failure
 CPR
 Lesions related to DESWT (cardiac, intrathoracic)
 Renal failure
 Liver failure
 Low cardiac output syndrome
 CVA (Stroke/Bleeding/TIA)
 Re-hospitalization
 Other non-anticipated events fulfilling the definition for AEs/SAEs
Secondary Endpoint - Efficacy
 Myocardial contractility
 Cardiac MRI
 Symptoms of heart failure
 Minnesota Heart Failure Questionnaire
 Six-minute walk test
 Serum levels of proBNP
 Device failures and malfunctions
Primary Endpoint AE/SAE´s
Perioperative
1 Pat. ventricular arrhytmia 1st. to 3rd p.o. day
1 Pat. prolonged ICU stay, mediastinitis
1 Pat. post-op bleeding (no surgical revision)
Follow-Up
3 Pat. rehospitalization (embolism, pneumonia, pacemaker implant)
None of the complications device related!
Left Ventricular Ejection Fraction
*
55.00
*
LVEF %
50.00
45.00
40.00
35.00
30.00
25.00
Improvement of wall motion in all patients
less late enhancement in all patients
20.00
baseline
* P < 0.05 to baseline
8 week FUP
6 month FUP
Gavira JJ JTCVS 2006
Left Ventricular Wall Motion
Global
*
Treated areas = infarct
*
* P < 0.05 to baseline
*
*
Left Ventricular Volumes
End Diastolic Volume
*
End Systolic Volume
*
* P < 0.05 to baseline
*
*
6-Minute Walk Test
*
* P < 0.05 to baseline
Minnesota Heart Failure Questionnaire
*
* P < 0.05 to baseline
Conclusion
 DESWT is SAFE
 Neo – Angiogenesis
 VEGF, PIGF, Flt-1
 Endogenous angiogenetic pathway activation ?
 Stem cell homing ?
 Improvement of LV function
 Global and regional LV function
 proBNP surrogate for heart failure
 Improvement of Symptoms
 6-MWT gold standard of symtom assessment in heart failure
 Patients feel the difference – Minesota Heart Failure Questionnaire
Conclusion
 Safe and simple method for myocardial regeneration
 Bench to bedside completed
 Next logical step – prospective randomized trial
 Continuation of basic research (working mechanism)
 Continuation of human trials (histology, stem cells)
 Continuation of animal trials (dose-reaction, working mechanism)
 Customized device, disposable therapy head
 Cell cultivation, cell seeding on scaffolds ………