Cardiomyopathy Due to Anthracyclines
Conditions
Keywords
Cardiomyopathy, AIC, Anthracyclines, Chemotherapy, Allogeneic, Mesenchymal stem cells, MSCs, Cancer survivors, Breast Cancer, Leukemia, Lymphoma, Sarcoma
Brief summary
The primary purpose of this study is to examine the safety and feasibility of delivering allogeneic human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC). The secondary purpose of this study is to obtain preliminary evidence for therapeutic efficacy of allo-MSCs delivered by transendocardial injection to cancer survivors with LV dysfunction secondary to AIC.
Detailed description
This phase I, randomized, placebo-controlled, trial will evaluate the safety and feasibility of allo-MSCs administered by transendocardial injection in thirty-seven subjects with anthracycline-induced cardiomyopathy (AIC). The first six subjects received allo-MSC therapy (open label) and were assessed for safety and feasibility of the study procedures. Following 1 month data review of each of the six subjects by the National Heart, Lung, and Blood Institute Gene and Cell Therapy Data Safety Monitoring Board; this was followed by a randomized, double-blind clinical trial enrolling thirty-one subjects. These subjects were randomized 1:1 to receive allo-MSCs or placebo. All subjects underwent cardiac catheterization and study product administration using the NOGA Myostar catheter injection system. Subjects are being followed at 1 day, 1 week, 1 month, 6 months, and 12 months post study product injection. All endpoints are assessed at the 6 and 12 month visits which will occur 180 ±30 days and 365 ±30 days, respectively, after the day of study product injection (Day 0). For the purpose of the safety evaluations and endpoint analysis, the Investigators will utilize an intention-to-treat study population. In addition, because this phase I study is the first cell therapy study in this population, at 12 months available standard-of-care medical records for cancer surveillance will be reviewed for cancer recurrence.
Interventions
BIOLOGICALAllo-MSCs
20 transendocardial injections of 0.4ml allo-MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure)
BIOLOGICALPlacebo
20 transendocardial injections of 0.4ml Buminate solution administered to the left ventricle via NOGA Myostar injection catheter (single procedure)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
To participate, a subject MUST: 1. Be ≥ 18 and \< 80 years of age 2. Be a cancer survivor with diagnosis of AIC 3. Have an LVEF ≤ 45% by cMRI 4. Be in NYHA class II-III 5. Have received the initial diagnosis of AIC at least six months earlier and be on stable, optimally-tolerated therapy with beta-blockers, ACE inhibitors/ARBs, and/or aldosterone antagonists for 3 months, unless contraindicated 6. Have a period of at least two years of clinical cancer-free state\* and low likelihood of recurrence (a five-year risk of recurrence estimated at 30% or less), as determined by an oncologist, based on tumor type, response to therapy, and negative metastatic work-up at the time of diagnosis (\*exceptions to this are carcinoma in situ or fully resected basal and squamous cell cancer of the skin.) 7. Be a candidate for cardiac catheterization
Exclusion criteria
To participate, a subject MUST NOT HAVE: 1. A life expectancy \<12 months 2. A CT scan or baseline cardiac MRI showing new tumor or suspicious lymphadenopathy raising concern of malignancy 3. Presence of obstructive CAD as determined via imaging within 5 years prior to study enrollment provided there have been no symptoms or evidence of CAD since the test 4. Had a previous myocardial infarction 5. A history of radiation therapy AND evidence of constrictive physiology and/or evidence of other patterns of non-ischemic cardiomyopathy on cardiac MRI (e.g., amyloidosis, sarcoidosis, hemochromatosis, pure radiation-induced cardiomyopathy, etc.) not consistent with AIC being the dominant etiology of heart failure 6. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe valvular (any valve) insufficiency/regurgitation within 12 months of consent. 7. Aortic stenosis with valve area ≤ 1.5cm2 8. A history of LV reduction surgery or cardiomyoplasty 9. Evidence of cardiogenic shock 10. A history of ischemic or hemorrhagic stroke within 90 days of baseline testing 11. Liver dysfunction during baseline testing, as evidenced by enzymes (e.g., AST, ALT, alkaline phosphatase) greater than 3 times upper limit of normal 12. Diabetes with poorly controlled blood glucose levels (HbA1c \> 8.5%) 13. An underlying autoimmune disorder or current immunosuppressive therapy (e.g., chronic corticosteroid, rheumatologic or immune modulating therapy) or likelihood of use of immunosuppressive therapy during participation in the trial (medications will be considered on a case by case basis) 14. A baseline eGFR \<35 ml/min/1.73m2 15. A contrast allergy that cannot adequately be managed by premedication 16. Received gene or cell-based therapy from any source within the previous 12 months 17. A hematologic abnormality during baseline testing as evidenced by hemoglobin \< 9 g/dl; hematocrit \< 30%; absolute neutrophil count \< 2,000 or total WBC count more than 2 times upper limit of normal; or platelet values \< 100,000/ul 18. Evidence of active systemic infection at time of study product delivery 19. HIV and/or active HBV or HCV 20. Coagulopathy (INR \> 1.5) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors) (see Section 6.4 re: injection procedure and anticoagulation therapy) Note: Subjects who cannot be withdrawn from anticoagulation will be excluded. 21. Presence of LV thrombus 22. Presence of a pacemaker and/or ICD generator with any of the following limitations/conditions: * manufactured before the year 2000 * leads implanted \< 6 weeks prior to consent * non-transvenous epicardial or abandoned leads * subcutaneous ICDs * leadless pacemakers * any other condition that, in the judgment of device-trained staff, would deem an MRI contraindicated 23. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded) 24. A cardiac resynchronization therapy (CRT) device implanted \< 3 months prior to consent 25. Other MRI contraindications (e.g. patient body habitus incompatible with MRI) 26. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent 27. Ventricular tachycardia ≥ 20 consecutive beats without an ICD within 3 months of consent, or symptomatic Mobitz II or higher degree atrioventricular block without a functioning pacemaker within 3 months of consent 28. A history of drug abuse (use of illegal street drugs except marijuana, or prescription medications not being used appropriately for a pre-existing medical condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months 29. Cognitive or language barriers that prohibit obtaining informed consent or any study elements (interpreter permitted) 30. Participation (currently or within the previous 30 days) in a cardiac related investigational therapeutic (including stem cell based therapies) or device trial 31. Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to use acceptable forms of birth control during study participation 32. Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Major Adverse Cardiac Events (MACE) | Baseline to 12 months | Proportion of adjudicated events including death, hospitalization for worsening heart failure, and/or other exacerbation of heart failure (non-hospitalization). |
| Proportion of Other Significant Clinical Events | Baseline to 12 months | Proportion of other significant adjudicated clinical events including: non-fatal stroke, non-fatal MI, coronary artery revascularization, ventricular tachycardia/fibrillation, pericardial tamponade, infectious myocarditis, hypersensitivity reaction, neoplasm, and/or other potential deleterious late effects. |
| Subjects With Events Precluding Their Receipt of Product | Randomization to SPI | Number and percent of subjects with events between randomization and study product injection (SPI) that preclude the subject from receiving product. |
| Subjects Who Receive Less Than 20 Injections During SPI | During SPI procedure | Number and percent of subjects who receive less than 20 injections during SPI |
| Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo) | During SPI procedure | Number and percent of subjects who did not receive the study product (either 100 million cells or placebo) |
| Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable | Baseline to 12 months | Number and percent of subjects who have at least one cardiac MRI endpoint measure that is uninterpretable due to issues related to the device, including, but not limited to, inability to undergo the procedure. |
| Subjects Who Fail to Complete Follow-up | Baseline to 12 months | Number and percent of subjects who fail to complete follow up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) | Baseline to 12 months | Change in left ventricular end systolic volume index as assessed via cardiac MRI |
| Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Left Ventricular Sphericity Index | Baseline to 12 months | Change in Left Ventricular Sphericity Index as assessed by cardiac MRI. Sphericity index is the ratio of the long and short axis measurements of the left ventricle. |
| Change From Baseline in Left Ventricular Sphericity Index-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. Sphericity index is the ratio of the long and short axis measurements of the left ventricle. |
| Change From Baseline in Area of Injury | Baseline to 12 months | Change in the scar percent (scar mass normalized to left ventricular mass) as assessed via cardiac MRI. |
| Change From Baseline in Area of Injury-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | Baseline to 12 months | Change in left ventricular ejection fraction as assessed via cardiac MRI. |
| Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | Change in the distance walked (in feet) as measured by the six minute walk test. Two walk tests were completed at each endpoint visit (separated by 30 min). The average distance of the two walk tests will be used for analysis. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score | Baseline to 12 months | Change in the quality of life summary score as measured by the Minnesota Living with Heart Failure Questionnaire. Minimum and maximum scores for scale are 0 and 105 respectively. Lower scores indicative of better outcome. |
| Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. Minimum and maximum scores for scale are 0 and 105 respectively. Lower scores indicative of better outcome. |
| Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | Baseline to 12 months | Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured via laboratory blood draw |
| Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Cumulative Days Alive and Out of Hospital for Heart Failure | Baseline to End of 12 Month Visit Window (i.e. 395 days after intervention) | Days alive and out of hospital for heart failure during the study evaluation period. Subjects were allotted a visit window extending 30 days past their anticipated 12-month visit (i.e., 395 days). |
| Change From Baseline in Exercise Tolerance (Six Minute Walk Test) | Baseline to 12 months | Change in the distance walked (in meters) as measured by the six minute walk test. Two walk tests were completed at each endpoint visit (separated by 30 min). The average distance of the two walk tests will be used for analysis. |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Global Strain (HARP MRI) | Baseline to 12 months | Change in global circumferential strain as assessed via cardiac MRI |
| Change From Baseline in Global Strain (HARP MRI)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Regional Strain (HARP MRI) | Baseline to 12 months | Change in regional longitudinal strain as assessed via cardiac MRI |
| Change From Baseline in Regional Strain (HARP MRI)-Trajectory | Assessed as a trajectory (baseline, 6 months, and 12 months) | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. |
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) | Baseline to 12 months | Change in left ventricular end diastolic volume index as measured via cardiac MRI |
Countries
United States
Participant flow
Recruitment details
Enrollment took place at seven CCTRN centers between September 2016 and October 2018. The main centers are located in Texas, Florida (2 locations), Minnesota, Kentucky, Indiana, and California. Recruitment methods included www.clinicaltrials.gov, cancer survivorship organization websites, and local cancer center physician outreach.
Pre-assignment details
46 subjects consented to participate; 37 completed baseline testing and met eligibility criteria. This includes 6 (open label) and 31 (randomized) subjects. Reasons for failed eligibility (n=9) include elevated LVEF, failure to complete baseline testing, MRI contraindications, and investigator discretion.
Participants by arm
| Arm | Count |
|---|---|
| Allo-MSCs Target dose of 100 million allo-MSCs
Allo-MSCs: 20 transendocardial injections of 0.4ml allo-MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure) | 14 |
| Placebo Buminate solution
Placebo: 20 transendocardial injections of 0.4ml Buminate solution administered to the left ventricle via NOGA Myostar injection catheter (single procedure) | 17 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomized Phase | Death | 1 | 0 |
| Randomized Phase | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Allo-MSCs | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 12.8 | 56.6 years STANDARD_DEVIATION 11.8 | 58.2 years STANDARD_DEVIATION 11.2 |
| AIC exposure | 353.0 mg/m^2 STANDARD_DEVIATION 351.3 | 346.2 mg/m^2 STANDARD_DEVIATION 254.2 | 339.5 mg/m^2 STANDARD_DEVIATION 113.6 |
| Angina | 3 Participants | 8 Participants | 5 Participants |
| Body Mass Index | 30.2 kg/m^2 STANDARD_DEVIATION 9 | 30.3 kg/m^2 STANDARD_DEVIATION 7.6 | 30.4 kg/m^2 STANDARD_DEVIATION 6.5 |
| Breast cancer | 6 Participants | 15 Participants | 9 Participants |
| Daunorubicin | 2 Participants | 2 Participants | 0 Participants |
| Diabetes | 3 Participants | 8 Participants | 5 Participants |
| Diastolic blood pressure | 68.9 mmHg STANDARD_DEVIATION 18.6 | 67.9 mmHg STANDARD_DEVIATION 14.7 | 67.1 mmHg STANDARD_DEVIATION 11.2 |
| Doxorubicin | 11 Participants | 28 Participants | 17 Participants |
| Epirubicin | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 25 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Heart rate | 74.4 beats per minute STANDARD_DEVIATION 9 | 75.4 beats per minute STANDARD_DEVIATION 10.1 | 76.1 beats per minute STANDARD_DEVIATION 11.2 |
| Hodgkin's disease | 0 Participants | 1 Participants | 1 Participants |
| Hypertension | 6 Participants | 16 Participants | 10 Participants |
| Left ventricular ejection fraction | 33.7 percentage of blood ejected STANDARD_DEVIATION 3.4 | 33.0 percentage of blood ejected STANDARD_DEVIATION 5.3 | 32.5 percentage of blood ejected STANDARD_DEVIATION 6.5 |
| Leukemia | 3 Participants | 3 Participants | 0 Participants |
| Multiple cancers | 3 Participants | 5 Participants | 2 Participants |
| New York Heart Association class II | 13 Participants | 26 Participants | 13 Participants |
| New York Heart Association class III | 1 Participants | 5 Participants | 4 Participants |
| Non-Hodgkin's lymphoma | 1 Participants | 6 Participants | 5 Participants |
| Presence of a cardiac device | 6 Participants | 18 Participants | 12 Participants |
| Previous emergency department visit for heart failure | 4 Participants | 7 Participants | 3 Participants |
| Previous hospitalization for heart failure | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 21 Participants | 13 Participants |
| Region of Enrollment United States | 14 participants | 31 participants | 17 participants |
| Sarcomas | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 8 Participants | 21 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 4 Participants |
| Smoking (lifetime) | 5 Participants | 8 Participants | 3 Participants |
| Sustained ventricular arrhythmia | 5 Participants | 12 Participants | 7 Participants |
| Systolic blood pressure | 118.6 mmHg STANDARD_DEVIATION 21.6 | 116.8 mmHg STANDARD_DEVIATION 16.4 | 115.4 mmHg STANDARD_DEVIATION 11 |
| Time from Cancer Diagnosis | 16.4 years STANDARD_DEVIATION 9.5 | 17.7 years STANDARD_DEVIATION 8.9 | 18.8 years STANDARD_DEVIATION 8.5 |
| Time from last anthracycline treatment | 13.3 years STANDARD_DEVIATION 9.3 | 15.2 years STANDARD_DEVIATION 8.4 | 16.8 years STANDARD_DEVIATION 7.6 |
| Time since AIC diagnosis | 6.1 years STANDARD_DEVIATION 5.9 | 7.5 years STANDARD_DEVIATION 5.5 | 8.7 years STANDARD_DEVIATION 5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 0 / 17 |
| other Total, other adverse events | 4 / 20 | 4 / 17 |
| serious Total, serious adverse events | 5 / 20 | 11 / 17 |
Outcome results
Primary
Proportion of Major Adverse Cardiac Events (MACE)
Proportion of adjudicated events including death, hospitalization for worsening heart failure, and/or other exacerbation of heart failure (non-hospitalization).
Time frame: Baseline to 12 months
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects (n=31).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allo-MSCs | Proportion of Major Adverse Cardiac Events (MACE) | 3 events |
| Placebo | Proportion of Major Adverse Cardiac Events (MACE) | 6 events |
Primary
Proportion of Other Significant Clinical Events
Proportion of other significant adjudicated clinical events including: non-fatal stroke, non-fatal MI, coronary artery revascularization, ventricular tachycardia/fibrillation, pericardial tamponade, infectious myocarditis, hypersensitivity reaction, neoplasm, and/or other potential deleterious late effects.
Time frame: Baseline to 12 months
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects (n=31).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allo-MSCs | Proportion of Other Significant Clinical Events | 0 events |
| Placebo | Proportion of Other Significant Clinical Events | 1 events |
Primary
Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo)
Number and percent of subjects who did not receive the study product (either 100 million cells or placebo)
Time frame: During SPI procedure
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects who were participating at the time of study product injection (n=30). Note: one placebo patient withdrew after randomization but prior to injection visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-MSCs | Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo) | 0 Participants |
| Placebo | Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo) | 0 Participants |
Primary
Subjects Who Fail to Complete Follow-up
Number and percent of subjects who fail to complete follow up
Time frame: Baseline to 12 months
Population: Population for safety and feasibility analysis include open label lead-in participants (n=6)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-MSCs | Subjects Who Fail to Complete Follow-up | 2 Participants |
| Placebo | Subjects Who Fail to Complete Follow-up | 1 Participants |
Primary
Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable
Number and percent of subjects who have at least one cardiac MRI endpoint measure that is uninterpretable due to issues related to the device, including, but not limited to, inability to undergo the procedure.
Time frame: Baseline to 12 months
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects (n=31). Analysis population includes only participants who completed an MRI at 12 months (n=32).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-MSCs | Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable | 1 Participants |
| Placebo | Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable | 4 Participants |
Primary
Subjects Who Receive Less Than 20 Injections During SPI
Number and percent of subjects who receive less than 20 injections during SPI
Time frame: During SPI procedure
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects who were participating at the time of study product injection (n=30). Note: one placebo patient withdrew after randomization but prior to injection visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-MSCs | Subjects Who Receive Less Than 20 Injections During SPI | 1 Participants |
| Placebo | Subjects Who Receive Less Than 20 Injections During SPI | 0 Participants |
Primary
Subjects With Events Precluding Their Receipt of Product
Number and percent of subjects with events between randomization and study product injection (SPI) that preclude the subject from receiving product.
Time frame: Randomization to SPI
Population: Population for safety and feasibility measures include open label lead-in participants (n=6) as well as randomized subjects (n=31).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-MSCs | Subjects With Events Precluding Their Receipt of Product | 0 Participants |
| Placebo | Subjects With Events Precluding Their Receipt of Product | 1 Participants |
Secondary
Change From Baseline in Area of Injury
Change in the scar percent (scar mass normalized to left ventricular mass) as assessed via cardiac MRI.
Time frame: Baseline to 12 months
Population: Participants who had available analyzable scar percent at baseline and 12 month.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Area of Injury | -1.06 percentage of mass | Standard Deviation 2.44 |
| Placebo | Change From Baseline in Area of Injury | -0.41 percentage of mass | Standard Deviation 2.76 |
Comparison: The change in scar percent was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.99395% CI: [-3.05, 1.74]ANCOVA
Secondary
Change From Baseline in Area of Injury-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable scar percent at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Area of Injury-Trajectory | -0.56 percentage of mass | Standard Error 0.41 |
| Placebo | Change From Baseline in Area of Injury-Trajectory | -0.27 percentage of mass | Standard Error 0.43 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.151Repeated Measures Linear Regression
Secondary
Change From Baseline in Exercise Tolerance (Six Minute Walk Test)
Change in the distance walked (in meters) as measured by the six minute walk test. Two walk tests were completed at each endpoint visit (separated by 30 min). The average distance of the two walk tests will be used for analysis.
Time frame: Baseline to 12 months
Population: Participants who had available analyzable walk tests at baseline and 12 month.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Exercise Tolerance (Six Minute Walk Test) | 34.96 meters | Standard Deviation 61.62 |
| Placebo | Change From Baseline in Exercise Tolerance (Six Minute Walk Test) | -3.07 meters | Standard Deviation 42.9 |
Comparison: The change in distance walked was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.05695% CI: [-5.84, 81.89]ANCOVA
Secondary
Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory
Change in the distance walked (in feet) as measured by the six minute walk test. Two walk tests were completed at each endpoint visit (separated by 30 min). The average distance of the two walk tests will be used for analysis. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable six minute walk test data at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory | 9.81 meters | Standard Error 7.53 |
| Placebo | Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory | -3.43 meters | Standard Error 5.72 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.583Repeated Measures Linear Regression
Secondary
Change From Baseline in Global Strain (HARP MRI)
Change in global circumferential strain as assessed via cardiac MRI
Time frame: Baseline to 12 months
Population: Participants with available analyzable global circumferential strain at baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Global Strain (HARP MRI) | -0.83 percent | Standard Deviation 1.7 |
| Placebo | Change From Baseline in Global Strain (HARP MRI) | -0.12 percent | Standard Deviation 2.86 |
Comparison: The change in global strain was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.32895% CI: [-2.68, 1.26]ANCOVA
Secondary
Change From Baseline in Global Strain (HARP MRI)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable global strain at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Global Strain (HARP MRI)-Trajectory | -0.49 percent | Standard Error 0.24 |
| Placebo | Change From Baseline in Global Strain (HARP MRI)-Trajectory | -0.04 percent | Standard Error 0.36 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.261Repeated Measures Linear Regression
Secondary
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
Change in left ventricular ejection fraction as assessed via cardiac MRI.
Time frame: Baseline to 12 months
Population: Participants who had available analyzable LVEF at baseline and 12 month.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 3.47 percentage of end diastolic volume | Standard Deviation 6 |
| Placebo | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 2.68 percentage of end diastolic volume | Standard Deviation 6.85 |
p-value: 0.74695% CI: [-4.52, 6.11]ANCOVA
Secondary
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable LVEF at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory | 1.81 percentage of end diastolic volume | Standard Error 0.86 |
| Placebo | Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory | 1.33 percentage of end diastolic volume | Standard Error 0.95 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.024Repeated Measures Linear Regression
Secondary
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
Change in left ventricular end diastolic volume index as measured via cardiac MRI
Time frame: Baseline to 12 months
Population: Participants with available analyzable LVEDVI at baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) | -2.30 ratio- unitless | Standard Deviation 16.97 |
| Placebo | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) | -3.36 ratio- unitless | Standard Deviation 15.18 |
Comparison: The change in LVEDVI was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.93595% CI: [-12.33, 14.45]ANCOVA
Secondary
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable LVEDVI at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory | -0.94 ratio-unitless | Standard Error 2.38 |
| Placebo | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory | -1.98 ratio-unitless | Standard Error 1.95 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.325Repeated Measures Linear Regression
Secondary
Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)
Change in left ventricular end systolic volume index as assessed via cardiac MRI
Time frame: Baseline to 12 months
Population: Participants with available analyzable LVESVI at baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) | -3.62 ratio- unitless | Standard Deviation 15.66 |
| Placebo | Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) | -4.28 ratio- unitless | Standard Deviation 14.18 |
Comparison: The change in LVESVI was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.91995% CI: [-11.75, 13.08]ANCOVA
Secondary
Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable LVESVI at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory | -2.05 ratio- unitless | Standard Error 2.14 |
| Placebo | Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory | -2.34 ratio- unitless | Standard Error 1.81 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.183Repeated Measures Linear Regression
Secondary
Change From Baseline in Left Ventricular Sphericity Index
Change in Left Ventricular Sphericity Index as assessed by cardiac MRI. Sphericity index is the ratio of the long and short axis measurements of the left ventricle.
Time frame: Baseline to 12 months
Population: Participants who had available analyzable LV sphericity index at baseline and 12 month LV.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular Sphericity Index | 0.01 ratio- unitless | Standard Deviation 0.08 |
| Placebo | Change From Baseline in Left Ventricular Sphericity Index | -0.07 ratio- unitless | Standard Deviation 0.09 |
Comparison: The change in LV sphericity index was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.12495% CI: [0.003, 0.15]ANCOVA
Secondary
Change From Baseline in Left Ventricular Sphericity Index-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. Sphericity index is the ratio of the long and short axis measurements of the left ventricle.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable sphericity index at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Left Ventricular Sphericity Index-Trajectory | 0.005 ratio-unitless | Standard Error 0.013 |
| Placebo | Change From Baseline in Left Ventricular Sphericity Index-Trajectory | -0.037 ratio-unitless | Standard Error 0.012 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. A time by treatment interaction was assessed.
Secondary
Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score
Change in the quality of life summary score as measured by the Minnesota Living with Heart Failure Questionnaire. Minimum and maximum scores for scale are 0 and 105 respectively. Lower scores indicative of better outcome.
Time frame: Baseline to 12 months
Population: Participants who had available analyzable MLHFQ summary score at baseline and 12 month.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score | -25.45 score on a scale | Standard Deviation 25.65 |
| Placebo | Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score | -12.63 score on a scale | Standard Deviation 14.59 |
Comparison: The change in MLHFQ summary score was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.04895% CI: [-30.49, 4.84]ANCOVA
Secondary
Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model. Minimum and maximum scores for scale are 0 and 105 respectively. Lower scores indicative of better outcome.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable MLHFQ data at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory | -10.15 score on a scale | Standard Error 2.94 |
| Placebo | Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory | -6.05 score on a scale | Standard Error 1.92 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.0002Repeated Measures Linear Regression
Secondary
Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured via laboratory blood draw
Time frame: Baseline to 12 months
Population: Participants who had available analyzable NT-proBNP results at baseline and 12 month. Log transformation used. p-values were obtained from transformed data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | -392.58 pg/ml | Standard Deviation 953.71 |
| Placebo | Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | -76.76 pg/ml | Standard Deviation 410.48 |
Comparison: The change in NT-proBNP was compared using ANCOVA analyses adjusting for baseline values. Data log transformed. p-values were obtained from transformed data.p-value: 0.19995% CI: [-947.5, 315.8]ANCOVA
Secondary
Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable NT-proBNP results at baseline, 6 month, and 12 month. Log transformation used for the regression. p-values were obtained from transformed data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory | -184.18 pg/ml | Standard Error 113.16 |
| Placebo | Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory | -58.58 pg/ml | Standard Error 49.41 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported. Log transformation used for the regression. p-values were obtained from transformed data.p-value: 0.229Repeated Measures Linear Regression
Secondary
Change From Baseline in Regional Strain (HARP MRI)
Change in regional longitudinal strain as assessed via cardiac MRI
Time frame: Baseline to 12 months
Population: Participants with available analyzable regional longitudinal strain at baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Regional Strain (HARP MRI) | -1.20 percent | Standard Deviation 3.34 |
| Placebo | Change From Baseline in Regional Strain (HARP MRI) | 0.38 percent | Standard Deviation 3.73 |
Comparison: The change in regional strain was compared using ANCOVA analyses adjusting for baseline values.p-value: 0.07195% CI: [-4.51, 1.35]ANCOVA
Secondary
Change From Baseline in Regional Strain (HARP MRI)-Trajectory
The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). If there is no interaction between change over time and treatment a single calculated value is the slope (the change per six months) from the model. If there is an interaction, the p-value for interaction is presented along with two calculated values representing the slope (the change per six months) for each treatment arm from the model.
Time frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
Population: Participants who had available analyzable regional strain at baseline, 6 month, and 12 month.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Change From Baseline in Regional Strain (HARP MRI)-Trajectory | -0.58 percent | Standard Error 0.42 |
| Placebo | Change From Baseline in Regional Strain (HARP MRI)-Trajectory | 0.21 percent | Standard Error 0.52 |
Comparison: Repeated-measures linear regression models were used to address trajectories (upward or downward trends) over time within each of the treatment groups. If there was no significant interaction, only one trajectory (slope) was reported.p-value: 0.689Repeated Measures Linear Regression
Secondary
Cumulative Days Alive and Out of Hospital for Heart Failure
Days alive and out of hospital for heart failure during the study evaluation period. Subjects were allotted a visit window extending 30 days past their anticipated 12-month visit (i.e., 395 days).
Time frame: Baseline to End of 12 Month Visit Window (i.e. 395 days after intervention)
Population: Comparison of the two groups on days alive and out of the hospital for heart failure during the 12 month study evaluation period. Analysis includes all study subjects (including the 6 open label patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allo-MSCs | Cumulative Days Alive and Out of Hospital for Heart Failure | 368 days | Standard Deviation 25.8 |
| Placebo | Cumulative Days Alive and Out of Hospital for Heart Failure | 363 days | Standard Deviation 31.9 |