Results
Patient Population
Overall, 93 patients were enrolled into the study at 16 investigational sites. Baseline demographic data are shown in Table 1. Importantly, the population as a whole was well treated per guideline directed therapy with >80% receiving ACE-I/ARB, >90% receiving β-blockade and >55% on mineralocorticoid receptor antagonists (MRAs). The three study groups demonstrate fairly well-matched baseline characteristics. Patients were predominantly male, with age in the mid-1960s, with an average duration since myocardial infarction of over 10 years. The median LVEF and LVESV were 29% and 154 mL, respectively, with two-thirds of the population being New York Heart Association (NYHA) Class III. Consistent with NYHA Class III population the average 6 MWD was ≤300 m and the MLWHFQ score averaged 50.8 points.
Safety
Pre-specified safety endpoint profile by treatment cohort as shown in Table 2 demonstrated that endomyocardial delivery of JVS-100 was well tolerated. Ninety-six per cent of the patients received the pre-specified 15 endomyocardial injections of 1 mL/injection, total 15 mL. As seen in our pre-clinical porcine studies and Phase I trial, there was a transient increase troponin I following the injection procedure that decreased over time through 3 days after injection (Table 3). The increase in troponin I was not different between cohorts. Four patients exhibited small pericardial effusions without haemodynamic impairment on the post-dosing safety echocardiogram that were resolved by the following day without intervention. No patients demonstrated any evidence of haemodynamic perturbation or arrhythmia following IP delivery.
Overall Results Primary Endpoint and Total Population
The effects of pSDF injections on the primary endpoint composite score at 4 and 12 months as well as the mean values measured for cardiac function (Figure 2B, LVEF). Cardiac structure (Figure 2C, LVESV) and NTproBNP (Figure 2D) are shown at baseline and 4 and 12 months after injection. Consistent with other contemporary trials testing invasive regenerative strategies in advanced HF patients, we observed a significant improvement in the composite score in the treated patients (P ≤ 0.001, Figure 2A); however, there was a significant placebo effect such that the primary endpoint of relative improvement in composite score at 4 months was not achieved. The median changes at 4 and 12 months in 6 MWD and MLWHQ were 46 ± 59, 44 ± 51, 62 ± 77 m and 60 ± 88, 52 ± 76, 50 ± 77 m and −10.7 ± 19.0 points, −9.2 ± 21.0 points, −17.0 ± 20.0 points and −12.5 ± 15.3 points, −9.2 ± 16 points, −13.2 ± 25 points, respectively, for the placebo, 15 and 30 mg cohorts, respectively.
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Figure 2.
Effect of stromal cell-derived factor-1 over-expression on structural, functional, and clinical measures in patients with chronic heart failure. Mean values of (A) composite score, (B) left ventricular ejection fraction (%), (C) left ventricular end-systolic volume (mL), (D) N-terminal pro BNP (pg/mL) and (D) N-terminal pro BNP at baseline, 4 and 12 months after treatment with placebo (open circles), 15 (grey circles), or 30 mg (black circles) of JVS-100. Box in (A) represents primary endpoint of trial. P-value represents treated vs. placebo at 4 months.
Left ventricular ejection fraction (Figure 2B) and LVESV (Figure 2C) demonstrated non-significant improvement, with a trend in median change from baseline relative to placebo in LVESV at 4 months (P = 0.24) and a further separation from median changes seen in the placebo cohort in LVEF at 12 months in the 30 mg pSDF cohort (P = 0.20). Median changes in NTproBNP did not demonstrate clinically meaningful changes from baseline.
Effect of Plasmid Stromal Cell-derived Factor-1 Based on Baseline Ejection Fraction
Based on our understanding of the mechanisms of action, we pre-specified an analysis of myocardial response to pSDF-1 as a function of three ranges of baseline EF (low-LVEF <26%, intermediate 26–31%, and high ≥32%). Baseline demographics for each tertile are shown in Table 4. With decreasing LVEF between tertiles, there was an increase in baseline LVESV, and there was no imbalance between treatment cohorts for LVEF and LVESV within each tertile.
The data in Figure 3 depict change in LVEF by cumulative tertile of EF at 4 and 12 months after treatment. These data demonstrate that in the patients with the greatest degree of LV dilation and systolic dysfunction pSDF-1-induced significant improvement in LVEF. In the lowest tertile of baseline LVEF (<26%), we observed an absolute increase in EF of 5% (P = 0.22) and 11% (P = 0.01) relative to placebo at 4 and 12 months, respectively. The data in Figure 4 quantify the changes in composite endpoint, LVESV, and NTproBNP for the lowest LVEF tertile at 4 and 12 months. In this tertile, there was a decrease in LVESV of 19 mL (P = 0.38) and 34 mL (P = 0.12) relative to placebo at 4 and 12 months, respectively. There was an inverse relationship between LVEF and change in LVESV such that the greatest reduction in LVESV was noted in the group with the lowest LVEF. We observed a trend towards a decrease in NTproBNP in the 30 mg treatment cohort relative to placebo at 4 and 12 months after treatment (4 months: −330 pg/mL, P = 0.15; 12 months: −784 pg/mL, P = 0.23).
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Figure 3.
Effect of stromal cell-derived factor-1 over-expression on ejection fraction at 4 and 12 months based on baseline ejection fraction. Data represent change in left ventricular ejection fraction in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo, (grey circle) 15, or (black circle) 30 mg treatment cohorts. (A) Patients with EF < 26% at baseline, (B) patients with EF < 32% at baseline, or (C) patients with EF < 40% at baseline. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.
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Figure 4.
Effect of stromal cell-derived factor-1 over-expression on parameters of chronic heart failure in high-risk heart failure patients. Data represent change in (A) composite endpoint, (B) left ventricular end-systolic volume, and (C) N-terminal pro BNP in the first tertile (left ventricular ejection fraction <26% at baseline) in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo, (grey circle) 15, or (black circle) 30 mg treatment cohorts. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.
In a post hoc analysis, we calculated stroke volume based on the difference between LVEDV and LVESV obtained by echocardiography. The data in Figure 5 demonstrate the dose-dependent changes in stroke volume (mL) in the total population and the first tertile (EF < 26%) of study subjects. These data demonstrate a non-significant increase in stroke volume in the total population and a trend of a dose-dependent increase in stroke volume in the high-risk cohort relative to placebo (P = 0.09). The findings suggest a differential effect of pSDF depending on baseline LVEF, with the best results noted in those with the lowest baseline LVEF.
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Figure 5.
Effect of stromal cell-derived factor-1 over-expression on stroke volume 12 months after treatment. Mean change in stroke volume from baseline to 12 months following administration of placebo or treatment with 15 or 30 mg of JVS-100 in all patients (open bar) or patients in the first tertile of EF (<26%) at baseline. Data represent mean ± SD.
Special Populations
Investigations in diabetic and aged populations suggest that bone marrow-derived stem cells are less functional than non-diabetic or young subjects. We wanted to begin to determine if there was less of a response to pSDF-1 in diabetic or older patients. Therefore, we compared the change in stroke volume in patients above and below the median age of the trial (66 years) (Figure 6A), as well as non-diabetic and diabetic patients (Figure 6B). This post hoc analysis suggests that aged and diabetic patients appear to be no less responsive to pSDF-1.
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Figure 6.
Effect of age and diabetes on change in stroke volume in response to stromal cell-derived factor-1 over-expression in chronic heart failure. Data represent change in left ventricular ejection fraction in patients from the first tertile of baseline left ventricular ejection fraction (<26%) in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo or (black circle) 30 mg treatment cohorts. (A) Analysis in patients based on median age and (B) analyses of patients based on presence or absence of diabetes mellitus. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.