Advanced Coronary Heart Disease, Chronic Myocardial Ischemia, Refractory Angina Pectoris
Conditions
Brief summary
The purpose of the study is to assess the safety and efficacy of targeted intramyocardial delivery of Auto-CD34+ cells for increasing exercise time and amelioration of anginal symptoms in subjects with refractory angina and chronic myocardial ischemia.
Interventions
BIOLOGICALAuto-CD34+ cells
10 intramyocardial injections of 0.2 mL per injection site of Auto-CD34+ cells
BIOLOGICALPlacebo: Diluent used to suspend Auto-CD34+ cells
10 intramyocardial injections of 0.2 mL per injection site of placebo
OTHERStandard of care
Standard of care for refractory angina
Sponsors
Lisata Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Male or female participants who are 21 to 80 years of age at the time of signing the informed consent. * Participants with Canadian Cardiovascular Society (CCS) class III or IV chronic refractory angina. * Participants without control of their angina symptoms in spite of maximal tolerated doses of anti-angina drugs. Participants must be on optimal therapy for their angina and must have been on a stable anti-anginal medication regimen for at least 4 weeks before signing the informed consent form. * Participants with obstructive coronary disease unsuitable for conventional revascularization due to unsuitable anatomy or comorbidity as determined at the site and confirmed by an independent adjudication committee. * Participants must have evidence of inducible myocardial ischemia. * Participants must experience angina episodes. * Participants must be able to complete 2 exercise tolerance tests on the treadmill within 3 weeks of randomization. * If female of childbearing potential, subject must not be pregnant and agree to employ adequate birth control measures for the duration of the study. Main
Exclusion criteria
* Cardiovascular hospitalization within 60 days prior to potential study enrollment. Participant has had a successful or partially successful coronary artery bypass graft (CABG) within 6 months or PCTA within 60 days of potential study enrollment. * Participant has had a placement of a bi-ventricular pacemaker for cardiac resynchronization therapy (CRT) for heart failure within 180 days of potential study enrollment. * Participant has documented stroke or transient ischemic attacks (TIAs) within 60 days of potential study enrollment. * Participant has a history of moderate to severe aortic stenosis; or severe aortic insufficiency; or severe mitral stenosis; or severe mitral insufficiency. * Participant has a prosthetic aortic valve or a mechanical mitral valve replacement. * Participant has severe co-morbidity associated with a reduction in life expectancy to less than 3 years as a result of chronic medical illnesses. * Participants with cancer are excluded with the following exceptions: * Subjects with in-situ non-melanoma skin cancer or in-situ cervical cancer are not excluded. * Participants that have been cancer free for \>= 5 years as determined by their oncologist are not excluded. Subjects with a prior history of stem cell transplant for cancer are excluded no matter how long they have been cancer-free. * Participants with a history of leukemia or other bone marrow disease. * Participant has sickle cell disease or sickle cell trait. * Participants with proliferative retinopathy. * Participants with Hb A1c \> 9%. * Participant has platelet counts \>10% above the upper limit of normal (ULN) or platelet counts \< 70,000. * Participant has a hematocrit \< 30% prior to potential study enrollment. * Participant has a serum creatinine \> 2.5 mg/dL prior to potential study enrollment. * Participant tests positive for HIV, hepatitis B, or hepatitis C, or is on chronic immunosuppressive medications, or has had a previous stem cell transplant. * Participant has a known contraindication to Neupogen (filgrastim) or G-CSF. * Participant was previously enrolled in an active treatment group of cell therapy trials for cardiovascular disease including any phase of CD34+ stem cell trials. * Left ventricular (LV) thickness of \< 7 mm in the target areas of injection as measured by during a 2-D echocardiogram (ECHO). * Atrial fibrillation, atrial flutter, or other uncontrolled arrhythmias that would prohibit accurate electromechanical mapping and NOGA-guided intramyocardial injection. * Bleeding diathesis with an INR \> 1.8 when not receiving anti-thrombotic therapy. * Hepatic dysfunction as evidenced by elevated AST or ALT levels \> 2.5 x ULN. * Any previous transplant requiring immunosuppression. * Disease state requiring chronic immunosuppression.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol | Baseline and 12 month visit | Baseline (BL) is the average of the two total exercise times measured during the screening period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit | 6 month visit | — |
| Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Baseline and 12 month visit | Participants self-reported angina episodes utilizing an electronic diary for 4 weeks at baseline (screening period) and in the 4 weeks before the 3, 6 and 12 month follow-up visits. |
| Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit | Baseline and 6 month visit | Baseline (BL) is the average of the two total exercise times measured during the screening period. |
| Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | From randomization until the end of the 24 month follow-up period | Major adverse cardiac events (MACE) defined as death, cardiac hospitalization, non-fatal myocardial infarction and stroke, as adjudicated by an independent clinical endpoint classification (CEC) committee. The category Total MACE includes death, cardiovascular hospitalization, myocardial infarction or stroke. |
| Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period | From randomization until the end of the 24 month follow-up period | — |
Countries
United States
Participant flow
Recruitment details
The study started in May 2012 and completed in November 2015.
Pre-assignment details
291 participants provided informed consent and were screened. There were 179 screen failures. 112 participants were randomized and treated. Note that during treatment the number of arms increased from 3 to 4 to include Not Injected arm as 6 participants in Treatment and Active Control Arms did not have intramyocardial injections.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Targeted intramyocardial delivery of 1 x 10\^5 Auto-CD34+ cells after granulocyte-colony stimulating factor (G-CSF) mobilization and apheresis. | 57 |
| Active Control Arm Targeted intramyocardial delivery of placebo after granulocyte-colony stimulating factor (G-CSF) mobilization and apheresis. | 27 |
| Unblinded Standard of Care (SOC) Arm No study-related procedures will be performed. | 28 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment | Death | 2 | 3 | 2 | 0 |
| Treatment | Lost to Follow-up | 0 | 0 | 2 | 1 |
| Treatment | Sponsor Decision | 0 | 0 | 0 | 1 |
| Treatment | Withdrawal by Subject | 0 | 1 | 6 | 1 |
Baseline characteristics
| Characteristic | Treatment Arm | Active Control Arm | Unblinded Standard of Care (SOC) Arm | Total |
|---|---|---|---|---|
| Age, Continuous | 64 Years STANDARD_DEVIATION 8 | 64 Years STANDARD_DEVIATION 8 | 63 Years STANDARD_DEVIATION 10 | 64 Years STANDARD_DEVIATION 8 |
| Sex: Female, Male Female | 10 Participants | 4 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 47 Participants | 23 Participants | 24 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 50 | 26 / 28 | 23 / 28 | 5 / 6 |
| serious Total, serious adverse events | 31 / 50 | 17 / 28 | 22 / 28 | 3 / 6 |
Outcome results
Primary
Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol
Baseline (BL) is the average of the two total exercise times measured during the screening period.
Time frame: Baseline and 12 month visit
Population: Participants in the Intent to Treat population defined as participants randomized to Treatment or Active Control arms. For participants not receiving intramyocardial injections, the missing values were imputed i.e. replaced with substituted values from the baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Arm | Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol | 108.7 seconds | Standard Deviation 194.3 |
| Active Control Arm | Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol | 90.0 seconds | Standard Deviation 184.7 |
Secondary
Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit
Participants self-reported angina episodes utilizing an electronic diary for 4 weeks at baseline (screening period) and in the 4 weeks before the 3, 6 and 12 month follow-up visits.
Time frame: Baseline and 12 month visit
Population: Participants in the Intent to Treat population defined as participants randomized to Treatment or Active Control arms. For participants not receiving intramyocardial injections, the missing values were imputed i.e. replaced with substituted values from the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Arm | Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Number of weekly angina episodes at Month 12 visit | 7.7 angina episodes per week | Standard Deviation 9.5 |
| Treatment Arm | Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Number of weekly angina episodes at baseline | 20.1 angina episodes per week | Standard Deviation 13 |
| Active Control Arm | Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Number of weekly angina episodes at Month 12 visit | 5.4 angina episodes per week | Standard Deviation 7.4 |
| Active Control Arm | Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Number of weekly angina episodes at baseline | 16.5 angina episodes per week | Standard Deviation 9.4 |
Secondary
Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit
Time frame: 6 month visit
Population: Participants in the Intent to Treat population defined as participants randomized to Treatment or Active Control arms. For participants not receiving intramyocardial injections, the missing values were imputed i.e. replaced with substituted values from the baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Arm | Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit | 8.0 angina episodes per week | Standard Deviation 9.6 |
| Active Control Arm | Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit | 8.4 angina episodes per week | Standard Deviation 9.8 |
Secondary
Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit
Baseline (BL) is the average of the two total exercise times measured during the screening period.
Time frame: Baseline and 6 month visit
Population: Participants in the Intent to Treat population defined as participants randomized to Treatment or Active Control arms. For participants not receiving intramyocardial injections, the missing values were imputed i.e. replaced with substituted values from the baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Arm | Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit | 126.5 seconds | Standard Deviation 161.1 |
| Active Control Arm | Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit | 93.5 seconds | Standard Deviation 138.6 |
Secondary
Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period
Time frame: From randomization until the end of the 24 month follow-up period
Population: Safety Population as Treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm | Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period | 62.0 percent |
| Active Control Arm | Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period | 60.7 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period | 78.6 percent |
| Not Injected Arm | Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period | 50.0 percent |
Secondary
Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period
Major adverse cardiac events (MACE) defined as death, cardiac hospitalization, non-fatal myocardial infarction and stroke, as adjudicated by an independent clinical endpoint classification (CEC) committee. The category Total MACE includes death, cardiovascular hospitalization, myocardial infarction or stroke.
Time frame: From randomization until the end of the 24 month follow-up period
Population: Participants in the safety population as Treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Cardiovascular Hospitalization | 42.0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Ventricular Arrhythmia | 2.0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Stroke | 0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Infarction | 10.0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Death | 4.0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Perforation | 4.0 percent |
| Treatment Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Total MACE (see outcome measure description) | 46.0 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Death | 10.7 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Perforation | 0 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Cardiovascular Hospitalization | 32.1 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Infarction | 10.7 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Stroke | 0 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Total MACE (see outcome measure description) | 42.9 percent |
| Active Control Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Ventricular Arrhythmia | 7.1 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Infarction | 7.1 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Death | 7.1 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Total MACE (see outcome measure description) | 67.9 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Perforation | 0 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Ventricular Arrhythmia | 3.6 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Cardiovascular Hospitalization | 64.3 percent |
| Unblinded Standard of Care (SOC) Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Stroke | 0 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Cardiovascular Hospitalization | 33.3 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Infarction | 33.3 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Death | 0 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Ventricular Arrhythmia | 0 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Stroke | 0 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Myocardial Perforation | 16.7 percent |
| Not Injected Arm | Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Total MACE (see outcome measure description) | 33.3 percent |