Gene Therapy in Chronic Ischaemic Heart Failure Patients
Gene Therapy in Chronic Ischaemic Heart Failure Patients
A total of 196 patients with a known history of systolic dysfunction due to prior myocardial infarction and symptomatic but stable HF were screened for participation in the STOP-HF trial (ClinicalTrials.gov—NCT01643590), under approval by the local institutional review boards. Potential study subjects who met all inclusion and exclusion criteria and granted written informed consent to participate were entered in the study. All subjects were on stable optimal medical therapy defined as ACE-I/ARB, β-blocker, aspirin (ASA), statin and diuretic with <50% change in dose over the previous 30 days (unless contraindicated) and had an ICD or cardiac resynchronization therapy-defibrillator present for over 3 months at the start of the trial. Study inclusion criteria also included left ventricular ejection fraction (LVEF) ≤40% (as read by the Cleveland Clinic C5 Research echo core lab), MLWHFQ score ≥20 points, and 6 MWD ≤400 m. Primary exclusion criteria were a minimum wall thickness of <0.3 cm for any segment, estimated glomerular filtration rate <30 mL/min, HgbA-1C > 9 mg/dL, a history of moderate or severe aortic valve regurgitation and aortic stenosis with valve area <1.5 cm, any history of cancer (excluding curable non-melanoma skin malignancy or resection with no recurrence in 5 years), presence of LV thrombus, or persistent atrial fibrillation). A total of 93 subjects were enrolled and randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of plasmid stromal cell-derived factor-1 (pSDF-1) or placebo via a series of 15 endomyocardial injections with the BioCardia Helix as previously described. Subjects were not considered enrolled until they entered the laboratory in preparation for the injection procedure (Figure 1).
(Enlarge Image)
Figure 1.
Consort diagram of patients screened and enrolled between May 2012 and September 2013.
STOP-HF was a double-blind, randomized, placebo-controlled trial in which subjects were randomized 1 : 1 : 1 to receive investigational product (IP), either JVS-100 (15 or 30 mg) or placebo. Before delivery of IP, the infarct zones were identified using baseline echocardiography. The peri-infarct zones that were ≥0.6 cm in thickness were identified for injection. Following study agent delivery, all subjects were monitored overnight for at least 18 h, which included echocardiography within 6 h post-injection procedure to exclude evidence of myocardial perforation. Post-hospital discharge each subject had scheduled visits at 3 and 7 days post-injection to ensure that there were no safety concerns, with subsequent follow-up visits at ~30 days (1 month), 120 days (4 months), and 360 days (12 months) to assess safety and cardiac function. Cardiac function was assessed by contrast enhanced surface echocardiography with results read by the same independent Cleveland Clinic Echo Core Lab. Contrast and non-contrast images were attempted to be collected in all patients. Images were obtained in three-beat cycles in multiple views and measurements were performed at the core laboratory. All sonographers from C5 reading studies were blinded to subject randomization allocation. Adverse events were tracked for each subject throughout the study. Safety was monitored by an independent Drug Safety Monitoring Committee.
Cardiovascular interventionists participated in pre-clinical training on the use of the Helix per BioCardia standard operating procedures. Subjects were placed under conscious sedation and access to the femoral artery was obtained using standard techniques to enable insertion of an arterial sheath. An 8 Fr arterial sheath was then introduced and advanced into the artery to enable passage of delivery catheters. Left ventriculography was performed in both the left and right anterior oblique views and the contour of the heart was recorded onto two clear acetate sheets. BioCardia's Helix was used for all endomyocardial injections. For the procedure, unfractionated heparin was administered IV in single or multiple doses as needed to achieve an activated clotting time of ≥250 s. The Helix was positioned within the left ventricle to facilitate 15, 1 mL injections. Each injection lasted 60 s with an additional 15 s dwell, and was targeted to the peri-infarct border zone. Total volume delivered was 15 mL per patient. Post-procedure all subjects were monitored in a clinical post-catheterization hospital unit with telemetry.
The primary efficacy endpoint was the difference in change of a composite endpoint consisting of the 6 MWD and MLWHFQ in the treated patients compared with placebo at 4 months. The composite score was calculated by dividing the change in 6 MWD by 30 m plus the change in MLWHFQ divided by −10. These values represent clinically significant changes in the respective measures. Additional endpoints included changes in left ventricular end-systolic volume (LVESV), left ventricular end-diastolic function (LVEDV), left ventricular ejection fraction (LVEF), and N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) at 4 and 12 months post-injection procedure. For echocardiographic volumes and LVEF, contrast echocardiographic measurements are reported for each patient unless, for a given patient, either a readable baseline contrast echo was not obtained, (n = 9) or an incomplete set (missing time point) of contrast echo was collected and the patient had complete set of non-contrast echocardiograms (n = 4). In these cases, non-contrast echocardiograms were used for all time points.
Safety endpoints included major adverse clinical events (MACE), significant adverse events (SAEs), as well as complete metabolic panel, complete blood count, physical exam, vitals, safety echocardiogram after injection procedure, HF assessment, and anti-nuclear antibody.
Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was randomized and blinded at the clinical site level 1 : 1 : 1. Descriptive statistics were used to compare continuous efficacy variables between each dose group and the control and across dosing groups. For the complete data set, if the parameter was normally distributed, parametric statistics (mean and SD) were used for comparison; if it was not, non-parametric statistics were used. For subgroup analyses, non-parametric statistics were used for analysis. Safety parameters were collected and assessed qualitatively or summarized quantitatively by descriptive statistics where appropriate. The data from each efficacy parameter was assessed at each time point as either raw values or calculated as change from baseline for each subject. A P-value of 0.05 was considered significant and a P-value of <0.25 was considered evidence of a trend.
The primary efficacy endpoint was the composite endpoint of 6 MWD and MLWHFQ at 4 months post-dosing. All data were also analysed at the 1 year endpoint.
Baseline characteristics are presented as mean ± SD for continuous variables and percentages for categorical variables. Changes from baseline are presented as median values for each treatment group. Continuous variable difference between the groups was compared with a t-test for two samples with equal variance with a P-value of 0.05 considered significant. For differences in categorical variables, the Wilcoxon rank-sum test was used, with a P-value of 0.05 considered significant. The primary endpoint was analysed using a one-way analysis of variance (ANOVA) model.
Based on previous data from our Phase I study delivering JVS-100 to HF subjects via the same route of administration, we estimated an improvement of at least two points in the primary endpoint with an SD of ~2.1; enrolment of 93 subjects would be sufficient to detect such a difference with 80% power and α of 0.05. We included in our analyses the complete data set for all randomized subjects who received at least one injection of study drug or placebo, and who had a baseline and at least one post-baseline measurement by intent-to-treat analysis. The endpoint was analysed using all observed data with no imputation for missing data. For safety endpoints, the safety population was used, consisting of all randomized subjects.
There were several pre-specified analyses that included sub-set analysis by LVEF as well as LVESV, with change from baseline by absolute and percentage change from baseline values to results at 4 and 12 months post-delivery of study agent. In addition to comparisons of the entire study population, a pre-specified analysis was undertaken to compare patients in three different groups defined by baseline LVEF. The thresholds were divided by the lowest (LVEF < 26%), mid-range (LVEF 26–32%), and highest tertiles (LVEF > 32%) for all patient baseline LVEF values. Baseline and change from baseline statistics were then compared across treatment groups within each of these sub-groups.
Methods
Patient Population
A total of 196 patients with a known history of systolic dysfunction due to prior myocardial infarction and symptomatic but stable HF were screened for participation in the STOP-HF trial (ClinicalTrials.gov—NCT01643590), under approval by the local institutional review boards. Potential study subjects who met all inclusion and exclusion criteria and granted written informed consent to participate were entered in the study. All subjects were on stable optimal medical therapy defined as ACE-I/ARB, β-blocker, aspirin (ASA), statin and diuretic with <50% change in dose over the previous 30 days (unless contraindicated) and had an ICD or cardiac resynchronization therapy-defibrillator present for over 3 months at the start of the trial. Study inclusion criteria also included left ventricular ejection fraction (LVEF) ≤40% (as read by the Cleveland Clinic C5 Research echo core lab), MLWHFQ score ≥20 points, and 6 MWD ≤400 m. Primary exclusion criteria were a minimum wall thickness of <0.3 cm for any segment, estimated glomerular filtration rate <30 mL/min, HgbA-1C > 9 mg/dL, a history of moderate or severe aortic valve regurgitation and aortic stenosis with valve area <1.5 cm, any history of cancer (excluding curable non-melanoma skin malignancy or resection with no recurrence in 5 years), presence of LV thrombus, or persistent atrial fibrillation). A total of 93 subjects were enrolled and randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of plasmid stromal cell-derived factor-1 (pSDF-1) or placebo via a series of 15 endomyocardial injections with the BioCardia Helix as previously described. Subjects were not considered enrolled until they entered the laboratory in preparation for the injection procedure (Figure 1).
(Enlarge Image)
Figure 1.
Consort diagram of patients screened and enrolled between May 2012 and September 2013.
Study Design
STOP-HF was a double-blind, randomized, placebo-controlled trial in which subjects were randomized 1 : 1 : 1 to receive investigational product (IP), either JVS-100 (15 or 30 mg) or placebo. Before delivery of IP, the infarct zones were identified using baseline echocardiography. The peri-infarct zones that were ≥0.6 cm in thickness were identified for injection. Following study agent delivery, all subjects were monitored overnight for at least 18 h, which included echocardiography within 6 h post-injection procedure to exclude evidence of myocardial perforation. Post-hospital discharge each subject had scheduled visits at 3 and 7 days post-injection to ensure that there were no safety concerns, with subsequent follow-up visits at ~30 days (1 month), 120 days (4 months), and 360 days (12 months) to assess safety and cardiac function. Cardiac function was assessed by contrast enhanced surface echocardiography with results read by the same independent Cleveland Clinic Echo Core Lab. Contrast and non-contrast images were attempted to be collected in all patients. Images were obtained in three-beat cycles in multiple views and measurements were performed at the core laboratory. All sonographers from C5 reading studies were blinded to subject randomization allocation. Adverse events were tracked for each subject throughout the study. Safety was monitored by an independent Drug Safety Monitoring Committee.
Injection Procedure
Cardiovascular interventionists participated in pre-clinical training on the use of the Helix per BioCardia standard operating procedures. Subjects were placed under conscious sedation and access to the femoral artery was obtained using standard techniques to enable insertion of an arterial sheath. An 8 Fr arterial sheath was then introduced and advanced into the artery to enable passage of delivery catheters. Left ventriculography was performed in both the left and right anterior oblique views and the contour of the heart was recorded onto two clear acetate sheets. BioCardia's Helix was used for all endomyocardial injections. For the procedure, unfractionated heparin was administered IV in single or multiple doses as needed to achieve an activated clotting time of ≥250 s. The Helix was positioned within the left ventricle to facilitate 15, 1 mL injections. Each injection lasted 60 s with an additional 15 s dwell, and was targeted to the peri-infarct border zone. Total volume delivered was 15 mL per patient. Post-procedure all subjects were monitored in a clinical post-catheterization hospital unit with telemetry.
Outcomes Measures
The primary efficacy endpoint was the difference in change of a composite endpoint consisting of the 6 MWD and MLWHFQ in the treated patients compared with placebo at 4 months. The composite score was calculated by dividing the change in 6 MWD by 30 m plus the change in MLWHFQ divided by −10. These values represent clinically significant changes in the respective measures. Additional endpoints included changes in left ventricular end-systolic volume (LVESV), left ventricular end-diastolic function (LVEDV), left ventricular ejection fraction (LVEF), and N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) at 4 and 12 months post-injection procedure. For echocardiographic volumes and LVEF, contrast echocardiographic measurements are reported for each patient unless, for a given patient, either a readable baseline contrast echo was not obtained, (n = 9) or an incomplete set (missing time point) of contrast echo was collected and the patient had complete set of non-contrast echocardiograms (n = 4). In these cases, non-contrast echocardiograms were used for all time points.
Safety endpoints included major adverse clinical events (MACE), significant adverse events (SAEs), as well as complete metabolic panel, complete blood count, physical exam, vitals, safety echocardiogram after injection procedure, HF assessment, and anti-nuclear antibody.
Statistical Analysis
Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was randomized and blinded at the clinical site level 1 : 1 : 1. Descriptive statistics were used to compare continuous efficacy variables between each dose group and the control and across dosing groups. For the complete data set, if the parameter was normally distributed, parametric statistics (mean and SD) were used for comparison; if it was not, non-parametric statistics were used. For subgroup analyses, non-parametric statistics were used for analysis. Safety parameters were collected and assessed qualitatively or summarized quantitatively by descriptive statistics where appropriate. The data from each efficacy parameter was assessed at each time point as either raw values or calculated as change from baseline for each subject. A P-value of 0.05 was considered significant and a P-value of <0.25 was considered evidence of a trend.
The primary efficacy endpoint was the composite endpoint of 6 MWD and MLWHFQ at 4 months post-dosing. All data were also analysed at the 1 year endpoint.
Baseline characteristics are presented as mean ± SD for continuous variables and percentages for categorical variables. Changes from baseline are presented as median values for each treatment group. Continuous variable difference between the groups was compared with a t-test for two samples with equal variance with a P-value of 0.05 considered significant. For differences in categorical variables, the Wilcoxon rank-sum test was used, with a P-value of 0.05 considered significant. The primary endpoint was analysed using a one-way analysis of variance (ANOVA) model.
Based on previous data from our Phase I study delivering JVS-100 to HF subjects via the same route of administration, we estimated an improvement of at least two points in the primary endpoint with an SD of ~2.1; enrolment of 93 subjects would be sufficient to detect such a difference with 80% power and α of 0.05. We included in our analyses the complete data set for all randomized subjects who received at least one injection of study drug or placebo, and who had a baseline and at least one post-baseline measurement by intent-to-treat analysis. The endpoint was analysed using all observed data with no imputation for missing data. For safety endpoints, the safety population was used, consisting of all randomized subjects.
There were several pre-specified analyses that included sub-set analysis by LVEF as well as LVESV, with change from baseline by absolute and percentage change from baseline values to results at 4 and 12 months post-delivery of study agent. In addition to comparisons of the entire study population, a pre-specified analysis was undertaken to compare patients in three different groups defined by baseline LVEF. The thresholds were divided by the lowest (LVEF < 26%), mid-range (LVEF 26–32%), and highest tertiles (LVEF > 32%) for all patient baseline LVEF values. Baseline and change from baseline statistics were then compared across treatment groups within each of these sub-groups.