Non-Ischemic Heart Failure
Conditions
Keywords
Non-ischemic Heart Failure, Stem Cells
Brief summary
A phase IIa study to assess the safety and preliminary efficacy of intravenous dose of ischemia-tolerant Allogeneic Mesenchymal Bone Marrow Cells in subjects with non-ischemic heart failure.
Detailed description
A phase IIa, single-blind, placebo-controlled, crossover, multi-center, randomized study to assess the safety, tolerability, and preliminary efficacy of a single intravenous dose of ischemia-tolerant allogeneic mesenchymal bone marrow cells to subjects with heart failure of non-ischemic etiology.
Interventions
DRUGAllogeneic Mesenchymal Bone Marrow Cells (aMBMC)
One time infusion Allogeneic Mesenchymal Bone Marrow Cells (aMBMC) 1.5 million cells/kg.
One time infusion 1.5mL/kg
Sponsors
Stemedica Cell Technologies, Inc.
CardioCell LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females ≥18 years of age 2. LVEF ≤35% on echocardiogram within 12 months of randomization to undergo MRI 3. Screening cardiac MRI at baseline with: Ejection fraction ≤40% No significant hyper enhancement on MRI scan in the opinion of the central imaging lab reviewer 4. Patients with non-ischemic heart failure etiology, as documented by absent or non-obstructive coronary artery disease on x-ray angiography or coronary computed tomography 5. Patients with history of heart failure and treated for at least three months with GDMT 6. NYHA class II-III symptoms 7. Ability to understand and provide signed informed consent 8. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled safety follow-up visits
Exclusion criteria
1. Pregnant or nursing women or those of childbearing age and not using an effective method of contraception 2. History of stroke within 3 months 3. Cardiac surgery within 3 months prior to randomization or the likelihood of a requirement for such procedures during the study period 4. Current ICD or CRT or implantation planned within 6 months of infusion 5. Presence of clinically significant, uncorrected valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension 6. History of cardiac arrest or life-threatening arrhythmias within 3 months 7. Treatment with parenteral inotropic agents within 1 month of randomization 8. Anticipated cardiac transplantation within 1 year 9. Illness other than heart failure with life expectancy less than 1 year 10. Received an experimental drug or device within 30 days of randomization 11. Left ventricular assist device or implantation planned in the next 6 months 12. Patients with complex congenital heart disease 13. Uncontrolled seizure disorder 14. Presence of immune deficiency 15. Clinically significant hematologic, hepatic, or renal impairment as determined by screening clinical laboratory tests: * Liver disease = ALT or AST \> 3x normal, alkaline phosphatase or bilirubin \>2x normal) * Renal disease = estimated glomerular filtration rate as assessed by the MDRD formula \<30 ml/min * Hematologic = Unexplained leukocytosis \>10 or hemoglobin \< 9gm/dl 16. Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory abnormality, that in the judgment of the investigator or sponsor for which participation in the study would pose a safety risk to the subject 17. Inability to comply with the conditions of the protocol 18. Malignancy within the previous five years, except adequately treated basal cell carcinoma, provided that it is neither infiltrating nor sclerosing, and carcinoma in situ of the cervix 19. Active myocarditis or early postpartum cardiomyopathy (within six months). 20. Systemic corticosteroids, cytostatics, immunosuppressive drug therapy (cyclophosphamide, methotrexate, cyclosporine, azathioprine, etc.), and DNA depleting or cytotoxic drugs taken within four weeks prior to study treatment 21. Porphyria 22. Allergy to sodium citrate or any caine type of local anesthetic 23. Any contraindication for gadolinium use for MRI 24. Patient scheduled for hospice care 25. Clinically relevant abnormal findings in the clinical history, physical examination, ECG, or laboratory tests at the screening assessment that would interfere with the objectives of the study or would preclude safe completion of the study. Abnormal findings could include: known HIV infection or other immunodeficiency state, chronic active viral infection (such as hepatitis B or C), acute systemic infections (defined as patients undergoing treatment with antibiotics), gastrointestinal tract bleeding, or any severe or acute concomitant illness or injury 26. Any other medical, social, or geographical factor that would make it unlikely that the patient could comply with study procedures (e.g., alcohol abuse, lack of permanent residence, severe depression, disorientation, distant location, or noncompliance)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Will be Evaluated by Number of AE | Total AEs and SAEs within 450 days post-infusion | As identified in the SAP, the safety analysis was the primary objective and was evaluated by the number of AEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in LVEF From Baseline to Day 90 Post-initial Infusion. | Baseline to Day 90 | The secondary efficacy endpoint was the change in LVEF from baseline to Day 90 post-initial infusion. Participants with data available at each time point. |
Countries
United States
Participant flow
Recruitment details
34 patients have been screened for eligibility between June, 2014 and April, 2016 at Emory University Medical Center, Atlanta, GA, Northwestern University Medical Center, Chicago, IL, University of Pennsylvania Medical Center, Philadelphia, PA, and Stony Brook University Medical Center, Stony Brook, NY.
Pre-assignment details
23 out of 34 patients have been randomized and 22 received the study intervention. Of those not randomized, 10 did not meet inclusion criteria and 1 could not tolerate CMR.
Participants by arm
| Arm | Count |
|---|---|
| Study Population itMSC, then Placebo: Participants first received itMSC 1.5 million per kilogram of weight, infused in the corresponding hospital facility at speed of 1 mL/minute (cell concentration 1 million/mL). After 90 days patients completed treatment at 90 days, and thus constituted the control treatment. After 90 day follow-up testing patients received Placebo and followed up for another 90 days. Total efficacy follow-up - 180 days. Safety follow-up - 240 days.
Placebo, then itMSC: Participants first received Placebo, infused in the corresponding hospital facility at speed of 1 mL/minute. After 90 days patients completed Placebo Control and related testing, and received itMSC treatment 1.5 million per kilogram of weight, and thus constituted the itMSC treated group for another 90 days.Total efficacy follow-up - 180 days. Safety follow-up - 240 days. and thus constituted the control treatment. | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Study Population |
|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 12.8 |
| Alanine Aminotransferase (ALT) | 21.82 IU/L STANDARD_DEVIATION 9.57 |
| Albumin | 4.2 g/dL STANDARD_DEVIATION 0.36 |
| angiotensin converting enzyme inhibitors (ACEI) or Angiotensin II Receptor Blockers (ARB) medication | 22 Participants |
| Aspartate Aminotransferase (AST) | 21.86 International Units/milliliter (IU/mL) STANDARD_DEVIATION 8.64 |
| Beta-blocker | 22 Participants |
| BMI | 32.24 kg/m^2 STANDARD_DEVIATION 7.56 |
| Diastolic Blood Pressure | 74 mmHg STANDARD_DEVIATION 9.6 |
| Heart Rate | 78 bpm STANDARD_DEVIATION 14.2 |
| History of Atrial Fibrillation | 2 Participants |
| History of Diabetes | 3 Participants |
| History of Hypertension | 5 Participants |
| History of Kidney Disease | 1 Participants |
| Left Ventricular Ejection Fraction (LVEF) | 31.6 % STANDARD_DEVIATION 9.8 |
| Left Ventricular End-Diastolic Volume (LVEDV) | 264.9 mL STANDARD_DEVIATION 120.4 |
| Left Ventricular End Systolic Volume (LVESV) | 189.6 mL STANDARD_DEVIATION 114.2 |
| Loop diuretic medication | 16 Participants |
| Mineralocorticoid Receptor Antagonist medication | 18 Participants |
| New York Heart Association (NYHA) Class Class II | 21 Participants |
| New York Heart Association (NYHA) Class Class III | 1 Participants |
| N-terminlal-proB-type Natriuretic Peptide (NT-proBNP) | 212 pg/mL STANDARD_DEVIATION 841 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Serum Creatinine | 0.96 mg/dL STANDARD_DEVIATION 0.23 |
| Serum Sodium | 138 mmol/L STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
| Systolic Blood Pressure | 120 mmHg STANDARD_DEVIATION 17.1 |
| Total bilirubin | 0.8 mg/dL STANDARD_DEVIATION 0.4 |
| Troponin I | 0.0009 ug/mL STANDARD_DEVIATION 0.0003 |
| Weight | 92.5 kg STANDARD_DEVIATION 19.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 18 / 22 | 15 / 20 |
| serious Total, serious adverse events | 1 / 22 | 1 / 20 |
Outcome results
Primary
Safety Will be Evaluated by Number of AE
As identified in the SAP, the safety analysis was the primary objective and was evaluated by the number of AEs
Time frame: Total AEs and SAEs within 450 days post-infusion
Population: All 22 participants that received itMSC treatment were included. All adverse events are divided into serious and non-serious.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental | Safety Will be Evaluated by Number of AE | Adverse Events | 38 number of events |
| Experimental | Safety Will be Evaluated by Number of AE | Cell related adverse events | 1 number of events |
| Experimental | Safety Will be Evaluated by Number of AE | All-cause hospitalization | 0 number of events |
| Experimental | Safety Will be Evaluated by Number of AE | All-cause death | 0 number of events |
| Experimental | Safety Will be Evaluated by Number of AE | Serious Adverse Events | 1 number of events |
| Placebo | Safety Will be Evaluated by Number of AE | All-cause death | 0 number of events |
| Placebo | Safety Will be Evaluated by Number of AE | Adverse Events | 35 number of events |
| Placebo | Safety Will be Evaluated by Number of AE | Serious Adverse Events | 1 number of events |
| Placebo | Safety Will be Evaluated by Number of AE | All-cause hospitalization | 0 number of events |
| Placebo | Safety Will be Evaluated by Number of AE | Cell related adverse events | 0 number of events |
Secondary
Change in LVEF From Baseline to Day 90 Post-initial Infusion.
The secondary efficacy endpoint was the change in LVEF from baseline to Day 90 post-initial infusion. Participants with data available at each time point.
Time frame: Baseline to Day 90
Population: The secondary efficacy endpoint according to the protocol was the change in LVEF from baseline to Day 90 post-initial infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental | Change in LVEF From Baseline to Day 90 Post-initial Infusion. | Baseline (%) | 34.3 percentage of ejection volume | Standard Deviation 7.91 |
| Experimental | Change in LVEF From Baseline to Day 90 Post-initial Infusion. | 90 days (%) | 34.1 percentage of ejection volume | Standard Deviation 9.7 |
| Placebo | Change in LVEF From Baseline to Day 90 Post-initial Infusion. | Baseline (%) | 34.5 percentage of ejection volume | Standard Deviation 7.49 |
| Placebo | Change in LVEF From Baseline to Day 90 Post-initial Infusion. | 90 days (%) | 36.7 percentage of ejection volume | Standard Deviation 5.42 |