Conges've Heart Failure Cardiopoie'c Regenera've Therapy (CHART-1): Clinical Trial Primary Outcomes Jozef Bartunek On behalf of CHART-1 Inves<gators and Study Group
Conflict Of Interest Jozef Bartunek is member of an ins<tu<on which has been a co-founder of Cardio3Biosciences (now Celyad) All consultancy/speakers fees and research contracts are directed to Cardiovasculair Onderzoek and Cardiac Research Ins<tute, Aalst, BE
Background Advanced ischemic heart failure with cardiac enlargement leads to poor • outcomes Cell therapy is a paradigm-shiMing interven<on that targets organ • restora<on Cardiopoie<c cells, derived by lineage specifica<on of pa<ent own • mesenchymal stem cells, show clinical promise as next genera<on therapy
Objec've To validate the efficacy and safety of cardiopoie<c cells delivered via a reten<on-enhanced injec<on catheter in advanced ischemic heart failure
CHART-1 Trial Design Prospec<ve, mul<center, randomized, sham-controlled, pa<ent/evaluator- • blinded clinical trial executed in 39 centers Pa<ents with ischemic heart failure on standard-of-care randomized to: • Ø Ac#ve arm: endomyocardial cardiopoie<c cell therapy Ø Control arm: sham procedure Cell Product: C3BS-CQR-1, Celyad, Mont St Guibert, BE • Delivery Catheter: C-Cath ez , Celyad, Mont St Guibert, BE •
CHART-1 Trial Criteria Main Inclusion Criteria Major Exclusion Criteria ≥18 and <80 years Recent myocardial infarc<on or • • revasculariza<on prior to screening • Ischemic heart failure with LVEF ≤35% Severe uncontrolled heart failure • • Heart failure hospitaliza<on or within past 1 month worsening within 12 months LeM ventricular thrombus or aneurysm • • NYHA class >II at inclusion with NYHA class III/IV or INTERMACS class >4 LeM ventricular wall thickness < 8 mm • within 12 months in > 50% of ventricular segments • On guideline heart failure therapy
CHART-1 Clinical Trial End-points at 39 Weeks Primary efficacy end-point: Finkelstein Schoenfeld hierarchical composite where each pa<ent • was compared to every other pa<ent with respect to: All cause mortality: days alive out of 39 weeks (LVAD and Tx counted as cardiac death) Number of worsening heart failure events : 0, 1, or ≥ 2 Change in MLHFQ: ≥10 point improvement, ≥10 point deteriora<on, no change Change in 6MWD: ≥40m improvement, ≥40m deteriora<on, no change Change in LV ESV: ≥15mL improvement, ≥15mL deteriora<on, no change Change in LV EF: ≥4% improvement, ≥4% deteriora<on, no change Sta#s#cal power: 120 pa#ents per group to provide 87% power for Mann-Whitney es#mator, probability of beGer response in ac#ve, of 0.61 (value >0.5 favors ac#ve treatment) Safety assessment: all-cause mortality, aborted sudden death, cardiac transplanta<on, • myocardial infarc<on, stroke, hospitaliza<ons and incidence of adverse events
CHART-1 Pa'ent Flow 315 randomised 158 control 157 ac<ve 10 died 6 died 18 not mee<ng release criteria, 6 contraindicated 1 withdrew consent 1 contraindicated 2 withdrew consent 151 with baseline 120 with baseline 19 with baseline sham procedure* ac<ve procedure* sham procedure* Treated set: 271 pa<ents analyzed for efficacy (120 ac<ve vs 151 sham control) Safety set: 290 pa<ents (120 ac<ve vs 170 sham procedure = 151 sham control + 19 sham procedure) *3 months between randomiza<on and baseline procedure
CHART-1 Clinical Trial: Baseline Characteris'cs Ac've (N = 120) Control (N = 151) 61.6±8.6 62.1±8.7 Age (years) 107 (89.2 %) 136 (90.1%) Male sex, n (%) NYHA class II, n (%) 23 (19.2 %) 36 (23.8 %) NYHA class III, n (%) 96 (80.0 %) 114 (75.5 %) NYHA class IV, n (%) 1 (0.8 %) 1 ( 0.7 %) Time from HF diagnosis to screening (months) 44.11 (12.32 - 100.10) 46.27 (15.96 - 97.73) LV Ejec'on frac'on (%) 27 (23-32) 28 (24-32) LV end-diastolic volume (mL) 239.9 (197.4-294.0) 246.4 (198.2-285.6) MLWHFQ score 48.8 (39.8-64.8) 46.5 (37-60) 332.5 (282.0-366.8) 332.5 (282.5-367.0) 6 min walk distance (m) NT-proBNP pg/mL 1083.1 (450-2648.1) 1077.6 (483.7-2260.6) ACE or AR1 blockers, n (%) 109 (90.8) 137 (90.7) Betablockers, n (%) 107 (89.2) 135 (89.4) Loop diure'cs, n (%) 104 (86.7) 123 (81.5) Aldosterone blockers, n (%) 94 (78.3) 109 (72.2) Vitamin K antagonists, n (%) 42 (35) 60 (39.7) ICD/AICD, n (%) 46 (38.3) 63 (41.7) 25 (16.6) CRT, n (%) 25 (20.8)
CHART-1 Clinical Trial Primary Efficacy Outcome at 39 weeks
Components of the Primary Outcome in Overall Study Pa'ents Ac've (N = 120) Control (N = 151) P-value All-cause mortality, n (%) 11 (9.2%) 12 (7.9%) 0.696 Number of WHF events, n (%) 0.724 0 100 (83.3%) 128 (84.8%) 1 11 (9.2%) 14 (9.3%) ≥ 2 9 (7.5%) 9 (6.0%) Change in MLHFQ score from baseline, n (%) 0.116 ≥ 10-point improvement 64 (59.3%) 66 (48.5%) No change 37 (34.3%) 60 (44.1%) ≥ 10-point deteriora'on 7 (6.5%) 10 (7.4%) Change in 6MW distance from baseline, n (%) 0.070 ≥ 40 m improvement 50 (46.3%) 40 (30.5%) No change 39 (36.1%) 69 (52.7%) ≥ 40 m deteriora'on 19 (17.6%) 22 (16.8%) Change in LV ESV from baseline, n (%) 0.259 ≥ 15 mL improvement 51 (50.0%) 56 (45.2%) No change 33 (32.4%) 36 (29.0%) ≥ 15 mL deteriora'on 18 (17.6%) 32 (25.8%) Change in LV EF from baseline, n (%) 0.730 ≥ 4% absolute improvement 69 (67.6%) 82 (66.1%) No change 28 (27.5%) 33 (26.6%) ≥ 4% absolute deteriora'on 5 (4.9%) 9 (7.3%)
Safety Assessment Through 39 Weeks Ac've (N = 120) Control (N = 170) Total deaths (n, Kaplan Meier %) 10 (8.3%)* 14 (8.2%) Peri-procedural death Cardiovascular – Aor<c dissec<on 1 (0.8%) 0 Post-procedural death Cardiovascular Death (n, Kaplan Meier %) 9 (7.6%) 12 (7.1%) Heart Failure or Cardiogenic Shock( n, Kaplan Meier %) 6 (5.0%) 7 (4.2%) Sudden Cardiac Death (n, Kaplan Meier %) 0 4 (2.4%) Acute Myocardial Infarc<on (n), Kaplan Meier %) 1 (0.9%) 0 Stroke (n, Kaplan Meier %) 1 (0.9%) 0 Undetermined Cause (n, Kaplan Meier %) 1 (0.9%) 1 (0.6%) Non Cardiovascular Death (n, Kaplan Meier %) 0 2 (1.2%) Peri-procedural unblinded adverse events (n, Kaplan Meier %) 25 (20.8%) 9 (5.3%) Post-procedural blinded adverse events (n, Kaplan Meier %) 62 (52.5%) 90 (53.0%) Safety endpoints Cardiac transplanta<on (n, Kaplan Meier %) 1 (0.9%) 0 Myocardial infarc<on (n, Kaplan Meier %) 1 (0.9%) 1 (0.6%) Stroke (n, Kaplan Meier %) 3 (2.6%) 2 (1.2%) Aborted sudden death (n, Kaplan Meier %) 1 (0.9%) 5 (3.0%) Sudden or aborted sudden death: HR 0.16, 95% CI 0.02-1.23, p = 0.04 * One LVAD not counted for safety
CHART-1 Clinical Trial Exploratory Analyses • Modifying effect of baseline markers of heart failure severity • Impact of treatment intensity (number of Injec<ons)
CHART-1 Clinical Trial: Exploratory Analyses Primary Outcome according to Baseline Markers of HF Severity
Exploratory Analysis using the HF Severity Marker Subpopula'on Treatment Effect Pahern Plot by Baseline LVEDV STEPP Analysis: subpopula#on treatment effect paGern plot using progressive subgroups of 70 pa#ents with 25 pa#ent overlap .
Exploratory Analysis Primary Outcome as a Func'on of HF Severity Marker
Components of the Primary Outcome in Pa'ents with Baseline LV EDV 200-370 mL Ac've (N = 66) Control (N = 96) P-value All-cause mortality, n (%) 3 (4.5) 6 (6.2) 0.658 Number of WHF events, n (%) 0 58 (87.9) 79 (82.3) 0.342 1 4 (6.1) 9 (9.4) ≥ 2 4 (6.1) 8 (8.3) Change in MLHFQ score from baseline, n (%) ≥ 10-point improvement 43 (68.3) 44 (49.4) 0.043 No change 15 (23.8) 39 (43.8) ≥ 10-point deteriora'on 5 (7.9) 6 (6.7) Change in 6MWT distance from baseline, n (%) ≥ 40 m improvement 27 (42.9) 21 (24.7) 0.116 No change 25 (39.7) 51 (60.0) ≥ 40 m deteriora'on 11 (17.5) 13 (15.3) Change in LV ESV from baseline, n (%) ≥ 15 mL improvement 36 (57.1) 41 (48.2) 0.168 No change 18 (28.6) 23 (27.1) ≥ 15 mL deteriora'on 9 (14.3) 21 (24.7) Change in LVEF from baseline, n (%) ≥ 4% absolute improvement 42 (66.7) 56 (65.9) 0.759 No change 19 (30.2) 22 (25.9) ≥ 4% absolute deteriora'on 2 (3.2) 7 (8.2)
Exploratory Analysis Change in LV ESV as a Func'on of Treatment Intensity (number of Injec'ons) 5 0 Change from Baseline, mL -5 -10 -15 P=0.03 -20 -25 -30 Study Week 0 13 26 39 C3BS-CQR-1 (N=120) C3BS-CQR-1 (Inject. <= 19) (N=64) C3BS-CQR-1 (Inject. >19) (N=56)
Exploratory Analysis Primary Efficacy Outcome as a Func'on of Baseline LV EDV and Treatment Intensity ≤ < ≤
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