Post on 16-Jan-2016
description
Michael JB Kutryk, Michael JB Kutryk, MD PhDMD PhD
Terrence Donnelly Heart Centre, Terrence Donnelly Heart Centre, St Michael’s Hospital, St Michael’s Hospital, University of Toronto, University of Toronto,
Ontario, CanadaOntario, Canada
on behalf of the NORTHERN investigatorson behalf of the NORTHERN investigators
Duncan J Stewart, Duncan J Stewart, MDMD
Ottawa Health Research Institute, Ottawa Health Research Institute, The Ottawa Hospital, The Ottawa Hospital, University of Ottawa, University of Ottawa,
Ontario, CanadaOntario, Canada
The NORTHERN Trial:A Prospective, Randomized, Double Blind
Placebo-Controlled Evaluation of Intramyocardial VEGF165 Plasmid Gene
Transfer in Patients with Refractory Angina
Disclosure Statement of Financial Interest
Within the past 12 months, I have had a financial interest/ arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship Company
Grant/Research support Johnson & Johnson
Introduction• Angiogenesis represents a potential novel
therapy for patients with refractory angina due to chronic coronary artery disease
• Despite the promise of the preclinical and early clinical trials, larger “proof-of-concept” studies have failed to show convincing benefit – but, previous studies have limitations:
Use of unstable protein factors – FIRST, VIVA Delivery strategies (i.e. intracoronary
administration) – AGENT trials Lack of blinding – REVASC Suboptimal gene “dose” – EURO-INJECT-1
The NORTHERN trial
• The NORTHERN trial was designed to overcome these limitations by: Intramyocardial gene transfer to achieve
a high level of local cardiac VEGF165 expression
Percutaneous navigational and mapping injection catheter (NOGA, Cordis – Biosense, Webster) to allow double blind trial design
Delivery of an “optimal dose” of plasmid DNA equivalent to preclinical studies
NORTHERN TrialQuebec City
Laval -Dr. G. Proulx-Dr. E. Larose
-Mr. G. Rossignol TorontoSt. Michael’s Hospital
-Dr. M. Kutryk -Dr. M. Freeman-Dr. H. Leong-Poi-Dr. D. Fitchett-Ms. R. Dunne-Ms. N. Camack
Sunnybrook Health SC-Dr. S. Radhakrishnan-Dr. A. Dick-Ms. I. Taibert -Ms. L. Balleza
EdmontonU of Alberta
-Dr. J. Burton-Dr. W. Tymchak-Ms. L. Lindholm
-Ms. N. Hogg
VictoriaHeart Institute
-Dr. D. Hilton -Dr. P. Klinke
-Dr. A. Della Siega-Ms. N. Lounsbury
MontrealHeart Institute - Dr. L. Bilodeau- Dr. S. Doucet- Ms. N. St.Jean
• VEGF165 plasmid DNA (2,000 g total dose) vs. saline – 10 injections targeted to ischemic region
• Io EP: persantine sesta MIBI SSS at 3 and 6 months• Secondary EPs: SDS, ETT, CCS class, SAQ, SF-36
7 “NOGA” sites across Canada7 “NOGA” sites across Canada
Mt. Sinai Hospital -Dr. A. Barolet -Ms. D. Locke
NOGA Catheter Mapping
Group 1 (n=72) – “no option” patients: severe,
advanced CAD;CCS Class III or IV
7 day F/U: ECG, Office visit
3 and 6 monthsExercise test/Sestamibi
CCS/SAQ/SF-36
Primary Outcome Assessment
30 day F/U: ECG, Office Visit, CCSA score SAQ, AE
Randomization
Sham (saline) NOGA Injection (n=45)
NORTHERN Study Flow ChartNORTHERN Study Flow Chart
Active VEGF165 DNA NOGA Injection (n=48)
Group 2 (n=21) - Single vessel disease: diffuse in-stent restenosis or single
occlusion
Baseline Characteristics
P-value from Fisher’s Exact Test
CardiacRFs
Past MedicalHistory
VEGF 165 Placebon=48 (%) n=45(%)
Age 63±7 64±8 0.58
Male sex 40 (83%) 42 (93%) 0.20
Hyperlipidemia 46 (96%) 41 (91%) 0.43
Hypertension 35 (73%) 33 (73%) 1
DM 18 (38%) 14 (31%) 0.66
Smoking 18 (38%) 13 (29%) 0.51
MI 41 (85%) 38 (84%) 1
CABG 42 (88%) 39 (87%) 1
PCI 30 (63%) 33 (73%) 0.28
Stroke 7 (15%) 3 ( 7%) 0.32
TIA 3 ( 6%) 3 ( 7%) 1
PVD 12 (25%) 12 (27%) 1
P-value
Myocardial Perfusion by SPECT imaging
Summed Stress Score
0
5
10
15
20
25
30
Base 3M 6M
Placebo
VEGF165
P=0.26 P=0.48 P=0.8
P-value from Wilcoxon Test
38 45 47 42 40 42
Summed Difference Score
02468
1012141618
Base 3M 6M
P=0.78 P=0.19 P=0.87
38 45 47 42 40 42
Change in Myocardial Perfusion by SPECT imaging – the Primary analysis
Placebo
VEGF165
3M 6M 3M 6M
Summed Stress Score
-2.5
-2
-1.5
-1
-0.5
0
Summed Difference Score
P=0.98 P=0.95 P=0.16 P=0.93
P-value from Wilcoxon Test
-3
-2.5
-2
-1.5
-1
-0.5
0
††††
VEGF vs. placebo VEGF vs. placebo
†
† p=0.08 vs. baseline†† p=0.01 vs. baseline
Baseline Characteristics
CardiacRFs
Past MedicalHistory
AgeMale sex
HyperlipidemiaHypertensionDMSmoking
MICABGPCIStrokeTIAPVD
Group 1 Group 2n=72 (%) n=21 (%)
63±7 63±9 0.9965 (90%) 17 (81%) 0.26
67 (93%) 20 (95%) 152 (72%) 16 (76%) 0.7927 (38%) 5 (24%) 0.3024 (33%) 7 (33%) 1
59 (82%) 20 (95%) 0.2964 (89%) 17 (81%) 0.4649 (68%) 14 (67%) 18 (11%) 2 ( 10%) 15 ( 7%) 1 ( 5%) 1
19 (26%) 5 (24%) 1
P-value
Change in SSS and SDS:Group 1 and Group 2
Placebo VEGF165
-8
-6
-4
-2
0
Group 1 Group 26 months
SS
S
-6
-4
-2
0
SD
S
(31) (6)(35) (9)(N)
-6
-4
-2
0
*
(31) (6)(35) (9)(N)
SD
S
* = p<0.05; Wilcoxon sum-rank
3 months
-6
-4
-2
0
Group 1 Group 2
SS
S
Exercise treadmill Time (ETT)
Placebo
VEGF165
Change in ETT
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
(min
ute
s)
3M 6M
ETT
0
1
2
3
4
5
6
7
8
Base 3M 6M
(m
inu
tes)
†
†
P=0.46 P=0.74 P=0.78 P=0.49 P=0.96
P-value from Wilcoxon Test
† ††
† p<0.05 vs. baseline†† p<0.01 vs. baseline
CCS Functional Class
Placebo
100%
0%
20%
40%
60%
80%
Base 3M 6M
VEGF165 CCS Class
I
II
III
IV
P=1.0
3M 6M
P=0.23 P=0.48VEGF vs. Placebo:
†† †† †† ††
P values from Fisher’s Exact Test †† P<0.001 vs. baseline
Base
Adverse Events
* basal cell carcinomasP-value from Fisher Exact Test
VEGF 165 Placebon=48 (%) n=45 (%) P-value
Liver enzyme rise 4 (8%) 3 (7%) 0.68Headache 5 (10%) 8 (18%) 0.54Pericardial 7 (15%) 3 (7%) 0.32GI related 15 (31%) 11 (24%) 0.62Dizziness 6 (13%) 5 (11%) 1Dermatological 12 (25%) 11 (24%) 0.86Retinal 2 (4%) 1 (2%) 0.44Peripheral 9 (19%) 7 (16%) 0.89Muskuloskeletal 21 (44%) 11 (24%) 0.04Neurological 7 (15%) 9 (20%) 0.68Inflammation 5 (10%) 4 (9%) 1Hypotension 4 (8%) 3 (7%) 0.73Cancer* 1 (2%) 1 (2%) 1
0
1
2
3
4
5
6
7
8
Death/MI/Revascularization*
Ischemicevent
Cardiovascular Events - Major
Nu
mb
er
of p
atie
nts
P=0.16 P=0.49
Placebo n=45 VEGF165 n=48
P-value from Fisher Exact Test
* 2 deaths: 1 VEGF; 1 Placebo
Summary• Intramyocardial plasmid VEGF165 gene
transfer did not result in any improvement in myocardial perfusion, exercise tolerance or anginal symptom class compared with placebo
• Similar and significant improvement was seen in both the treatment and placebo groups in all endpoints: – 2 point decrease in SDS by SPECT imaging– ~1 minute improvement in total ETT– 40-50% of patients improved by at least 1 CCS
symptom class
Conclusion
• Intramyocardial plasmid VEGF165 gene transfer was ineffective for the treatment of refractory angina in patients who were not candidates for traditional revascularization procedures (Group 1) or for whom bypass surgery was deemed not appropriate (Group 2).
Discussion• The improvement in myocardial perfusion in
both placebo and treatment groups raises the possibility of spontaneous development of collaterals, which supports the biological plausibility pro-angiogenic therapeutic strategies despite the lack of efficacy of simple VEGF gene transfer
• This study suggests that more sophisticated strategies will be required in order to enhance collateralization in patients with severely symptomatic coronary disease– Combinations of genes or sequential delivery– Cell or combined cell and gene therapies
This trial was supported by:Canadian Institutes of Health ResearchHeart & Stroke Foundation of Ontario
St. Michael’s Hospital FoundationJohnson & Johnson
Acknowledgements
Study Limitations
• Limited power due to termination prior to reaching target enrolment of 110 patients– Given the lack of any trend in favor of VEGF, it
is unlikely that additional patients would have changed the result
• Transfection efficiency due to use of plasmid rather than viral vector– Cannot rule out that higher levels of
transfection might have been effective
Change SSS and SDS in VEGF Group Troponin +ve vs. Troponin –ve
Positive
Negative
P-value from Wilcoxon Test
-4
-3
-2
-1
0
1
2
3 Months 6 Months
Summed Difference Score
(37) (34)(7) (7)(N)
P=0.16 P=0.93
(37) (34)(7) (7)(N)-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
3 Months 6 Months
Summed Stress Score
P=0.98 P=0.95