Download Slides - Clinical Trial Results

Safety and Preliminary Efficacy
of Intravenous Allogeneic
Mesenchymal Stem Cells in
Patients With Non-ischemic
Heart Failure
NCT02467387
Sponsor: CardioCell, LLC
Javed Butler, MD, MPH, MBA
Stephen E. Epstein, MD
Stephen J. Greene, MD
Arshed A. Quyyumi, MD
Sergey Sikora, PhD
Raymond J. Kim, MD, PhD
Allen S. Anderson, MD
Jane E. Wilcox, MD
Nikolai I. Tankovich, MD
Michael J. Lipinski, MD
Kenneth B. Margulies, MD
Robert T. Cole, MD
Hal A. Skopicki, MD, PhD
Mihai Gheorghiade, MD
Disclosures
• Javed Butler: Consultant, CardioCell
• Stephen E. Epstein, Arshed A. Quyyumi, and Mihai Gheorghiade:
Consultants and Stock Options, CardioCell
• Sergey Sikora, Nikolai I. Tankovich: Employees, CardioCell
• Stephen J. Greene, Raymond J. Kim, Allen S. Anderson, Jane E. Wilcox,
Michael J. Lipinski, Kenneth B. Margulies, Robert T. Cole, Hal A.
Skopicki: None
Introduction
• Initial trials with direct myocardial injections of mesenchymal stem cells
(MSCs) in patients with heart failure (HF) with reduced ejection fraction
(EF) have demonstrated safety with potential efficacy.
– Engraftment of directly injected MSCs is relatively modest and transient.
– Catheter or surgical based delivery techniques have practical limitations, especially for
multiple administrations.
• MSCs secrete a broad array of molecules with potential therapeutic
effects, including anti-inflammatory and immune-modulatory activities
that may be effective with intravenous delivery.
– Both allogeneic and autologous MSCs are available for human use.
– Allogeneic MSCs are well tolerated without rejection or autoimmune reactions.
Background
• Ischemia-tolerant bone marrow derived allogeneic MSCs (itMSC,
CardioCell Inc.) derived from a single young <25 year-old healthy
volunteer and grown under hypoxic conditions.
• Enhanced paracrine properties
• Preclinical studies with human itMSCs
in murine ischemic cardiomyopathy and
acute myocardial infarction models have
demonstrated safety, improvement in LV
function, and reduced inflammation.
From M.J. Lipinski, D. Luger, and S.E. Epstein ESC: 2016
Aims and Hypothesis
• Aim: To assess the safety and preliminary efficacy of
intravenous itMSC injection in patients with non-ischemic
HF
• Hypothesis: Intravenous itMSC injection will be safe and
well tolerated and will be associated with improvement in
symptoms and cardiac function
Key Eligibility Criteria
•
•
•
•
•
Non-ischemic cardiomyopathy
Ejection fraction ≤40%
NYHA class II-III symptoms
No evidence hyper-enhancement on MRI
Stable on evidence based medical therapy for at least 3
months.
Study Design
Design: Phase IIa, single-blind, placebo-controlled, crossover, multi-center, RCT
Subjects: 23 patients
Randomization: 1:1 itMSC or placebo injection with 90 day crossover
Intervention: itMSC group: Single dose 1.5 million cells/kg iv
Placebo group: 1 mL/kg Lactate Ringer’s solution iv.
itMSCs
itMSCs
All subjects
Placebo
Day 0
Randomization
Testing
Placebo
Day 90
Crossover
Day 180
Endpoints
Primary (Safety)
 Procedural complications
 Laboratory profile
 Liver function
 Renal function
 Troponin and CK
 Pulmonary function test
 Arrhythmias (Holter monitor)
 Clinical events (All-cause
mortality and hospitalization)
Secondary
 Left ventricular ejection fraction
and volumes by MRI
 Kansas City Cardiomyopathy
Questionnaire
 Clinical Summary Score
 Functional Status Score
 Six minute walk distance
 NYHA functional class
 Inflammatory and immune markers
Measured at baseline and 90 days after each treatment arm (itMSCs or placebo)
Trial Conduct
•
Steering Committee
– Javed Butler, MD - Principal Investigator and
Co-Chair
– Mihai Gheorghiade, MD - Co-Chair
– Arshed A. Quyyumi, MD
– Stephen E. Epstein, MD
• Data Safety Monitoring Board
– Barry Greenberg, MD- Chair
– James Fang, MD
– Gregory Daniels, MD, PhD
• MRI Core Lab
– Duke University (Raymond J. Kim, MD)
•
Enrolling Centers and Site PI:
– Emory University (R. Cole, MD)
– Northwestern University Feinberg School of
Medicine (A. Anderson, MD, J. Wilcox, MD)
– University of Pennsylvania (K. Margulies, MD)
– Stony Brook University (H. Skopicki, MD)
• Statistical Analysis
– Emory University (Yi An Ko PhD)
Screened (N = 34)
• Patients with stable non-ischemic
HFrEF and LVEF ≤ 40% by CMR
Enrollment
Screen Failure (n =11)
Randomized
(n=23)
itMSCs (n = 11)
Placebo (n= 12)
90-day endpoints
(N=10)
90-day endpoints
(N=12)
Placebo ( n = 8)
itMSC (n = 12)
180-day endpoints
(N=7)
180 day endpoints
(N=12)
Did not undergo infusion (n=1)
Did not undergo 180 day assessments
• 1 withdrawal after 90 day evaluation, before cross-over
infusion
• 1 Protocol violation after 90 day evaluation, before
cross-over infusion
• 1 Protocol violation after cross-over infusion – no show
10 visit.
for Day 180 tests. Tests performed on Day 240
Patient Population
Characteristics
Age, yr (SD)
Male, N (%)
Weight, kg (SD)
Body mass index (SD)
Race – White N (%)
NYHA Class II N (%)
Systolic BP, mmHg (SD)
Heart rate, bpm (SD)
NT-proBNP, pg/mL (IQR)
Troponin I, ug/mL (SD)
Serum sodium, mmol/L (SD)
Serum creatinine, mg/dL (SD)
47 (13)
13 (59%)
92·5 (19·9)
32·2 (7·5)
15 (68%)
21 (96%)
120 (17)
78 (14)
212 (841)
0·009 (0·003)
138 (2)
0·96 (0·23)
Medical History N (%)
Hypertension
5 (23%)
Diabetes
3 (14%)
Atrial fibrillation
2 (9%)
Chronic kidney disease
1 (5%)
Baseline Cardiac Magnetic Resonance Data
LVEF, % (SD)
31.6 (9.8)
LVESV, mL (SD)
189.6 (114.2)
LVEDV, mL (SD)
264.9 (120.4)
Baseline Medications
Loop diuretic N (%)
16 (73%)
ACEI or ARB N (%)
22 (100·0%)
MR Antagonist N (%)
18 (82%)
Beta-blockers N (%)
22(100·0%)
Safety
Placebo
itMSC
*Both infusion related; 1 superficial
(n=22)
(n=22)
thrombophlebitis; 1 bruising at iv site
Adverse events
33
40
Serious adverse events
0
0
Cell related adverse
0
2
All-cause hospitalization
1
0
All-cause death
0
0
events*
No significant changes in
1. Holter monitor
2. Liver function (ALT, AST, Alk
Phos, bilirubin, and albumin)
3. Renal function (creatinine, GFR)
4. Pulmonary function (FVC, FEV1,
FEV1/FVC, DLCO)
Six Minute Walk Distance
6 Minute Walk Test
Distance (m)
Distance
(% change from baseline)
Differences between groups,
itMSC minus placebo (95% CI)
P value
36·47 (5·98-66·97)
0·02
15·94 (1·63-30·24)
0·03
Kansas City Cardiomyopathy Questionnaire
KCCQ
Differences between groups,
itMSC minus placebo (95% CI)
P value
Functional Status Score
Clinical Summary Score
5·65 (-0·11-11·41)
5·22 (0·70-9·74)
0·06
0·02
Left Ventricular Function
Initial Injection: itMSC (N=10)
Variable
LVEF (%)
LVEDV (ml)
LVESV (ml)
Difference
2.31
-17.86
-16.60
95% CI
-0.09
4.71
-35.03
-0.69
-33.22
0.02
Initial Injection: Placebo (N=12)
P
0.06
0.04
0.05
Variable
LVEF (%)
LVEDV (ml)
LVESV (ml)
Difference
1.62
-10.56
-8.90
Initial Injection: difference itMSC - placebo
Variable
LVEF (%)
LVEDV (ml)
LVESV (ml)
Difference
-0.69
7.30
7.70
95% CI
-3.93
2.54
-18.02
32.61
-16.09
31.49
P
0.66
0.55
0.50
Second injection post crossover - 22 itMSC, 12 placebo
Variable
Difference
0·01
95% CI
-1.50
1.54
LVEF (%)
1·67
-8.60
11.93
0·67
-7.28
8.62
LVEDV (ml)
LVESV (ml)
P
0·99
0·75
0·87
95% CI
-0.82
4.05
-30.54
9.43
-27.40
9.60
P
0.17
0.27
0.31
New York Heart Association Class
Placebo (n=12)
itMSCs (n=22)
NYHA
Class
I
II
III
Baseline
itMSCs
P value
NYHA
Class
Baseline
Placebo
P value
0
19
5
15
0·014
II
11
12
0.32
1
0
III
1
0
The difference in improvement in 90 day NYHA functional class between
itMSC and placebo was not significant (p=0.33)
itMSC Treatment Reduces NK Cells
itMSC-induced decrease in natural killer (NK) cells correlates with improvement
in LV function
Summary
Single administration of IV itMSCs in patients with non-ischemic HFrEF was
• Safe (clinical, PFT, LFT, arrhythmias)
• Improved 6-minute walk test
• Improved KCCQ Clinical Summary score and trend for Functional Status score
• No significant change in LV function
• Significant reduction in NK cells that correlated with improvement in EF
Future studies
•
•
•
Confirm findings in larger non-ischemic cohort with hard endpoints
Explore effectiveness in ischemic cardiomyopathy
Explore whether multiple IV treatments lead to further improvement, including
changes in cardiac function