Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR)

Randomized, Double-Blind, Placebo-Controlled Phase I/II Study of the Safety and Efficacy of Intracoronary Delivery of Allogeneic Cardiosphere-Derived Cells in Patients With a Myocardial Infarction and Ischemic Left Ventricular Dysfunction

The purpose of this study is to determine whether Allogeneic Cardiosphere-Derived Cells (CAP-1002) is safe and effective in decreasing infarct size in patients with a myocardial infarction.

Study Overview

• Status: Terminated
• Conditions: Myocardial Infarction
• Intervention / Treatment: Drug: Placebo; Biological: CAP-1002 Allogeneic Cardiosphere-Derived Cells

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Cardiology, P.C.
    • Huntsville, Alabama, United States, 35801
      • Heart Center Research
  • California
    • La Jolla, California, United States, 92037
      • Scripps
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Shands Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Springfield, Illinois, United States, 62712
      • Prairie Heart - St. John's Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Kansas University Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Umass Memorial Medical Center
  • Michigan
    • Saginaw, Michigan, United States, 48602
      • Michigan CardioVascular Institute
  • Minnesota
    • Coon Rapids, Minnesota, United States, 55433
      • Metropolitan Heart and Vascular Institute / Mercy Hospital
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • New York
    • Buffalo, New York, United States, 14203
      • University at Buffalo
    • New York, New York, United States, 10075
      • Lenox Hill Hospital
  • North Carolina
    • Charlotte, North Carolina, United States
      • Carolinas Healthcare System
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital
    • Raleigh, North Carolina, United States, 27607
      • NC Heart & Vascular Research
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Health System
    • Cincinnati, Ohio, United States, 45219
      • Lindner Center for Research and Education at the Christ Hospital
    • Columbus, Ohio, United States, 43201
      • Ohio State University
    • Columbus, Ohio, United States, 43214
      • OhioHealth Research Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital
  • Texas
    • Austin, Texas, United States, 78756
      • Austin Heart
    • Houston, Texas, United States, 77030
      • University of Texas Memorial Hermann Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center - Heart and Vascular Research
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53233
      • Aurora Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. History of MI (STEMI or NSTEMI) within the prior 12 months due to a coronary artery event and evidenced by at least two of the following: typical ischemic symptoms, serial ST-T changes (new ST elevation or new left bundle block) and/or elevated troponin or Creatine phosphokinase MB isoenzyme (CK-MB) >5 times the upper limit of normal. Also at least one of the following: development of pathological Q wave ECG changes, imaging evidence of new loss of viable myocardium, or new regional wall motion abnormalities.
2. History of percutaneous coronary intervention (PCI), with stent placement resulting in Thrombolysis in Myocardial Infarction (TIMI) flow = 3, in the coronary artery supplying the infarcted, dysfunctional territory and through which the treatment will be infused.

3. At least one assessment of left ventricular ejection function (LVEF) <=0.45 as determined by any one of the standard modalities (echocardiography, ventriculography, nuclear imaging, CT and/or MRI) prior to or during the screening period.

   • For participants that fulfill the criteria of Recent MI (i.e., within 90 days of MI) at time of screening visit: assessment must be post-reperfusion after index MI and the most recent test prior to or during the screening period.
   • For participants that fulfill the criteria of Chronic MI (i.e., greater than 90 days from MI) at the time of screening visit: assessment must be at least 21 days post-reperfusion after index MI and the most recent test prior to or during the screening period.

   Note: participants may screen as a Recent MI but be randomized into the Chronic MI strata if the infusion date is > 90 days post-MI.

4. Left ventricular infarct size of >= 15% of left ventricular mass in the qualifying infarct-related region to be infused as determined by centrally read screening MRI, with associated thinning and/or hypokinesis, akinesis, or dyskinesis, with no large aneurysmal area in the infarcted regions.
5. No further revascularization clinically indicated at the time the participants is assessed for participation in the clinical trial.
6. Ability to provide informed consent and follow-up with protocol procedures.
7. Age >= 18 years.

Exclusion Criteria

1. Participants with a history of coronary artery bypass surgery, and a patent graft (arterial or saphenous vein graft) attached to the coronary artery to be infused.
2. Diagnosed or suspected myocarditis.
3. History of cardiac tumor, or cardiac tumor demonstrated on screening MRI.
4. History of acute coronary syndrome in the 4 weeks prior to study infusion.
5. History of previous stem cell therapy.
6. History of radiation treatment to the central or left side of thorax.
7. Current or history (within the previous 5 years) of systematic auto-immune or connective tissue disease including, but not limited to, giant cell myocarditis, cardiac or systemic sarcoidosis, Dressler's syndrome, chronic recurrent or persistent pericarditis.
8. History of or current treatment with immunosuppressive, anti-inflammatory, or other agents to treat manifestations of systemic immunologic reactions, including chronic systemic corticosteroids, biologic agents targeting the immune system, anti-tumor and anti-neoplastic drugs, anti-vascular endothelial growth factor, or chemotherapeutic agents within 3 months prior to enrollment.

9. Prior implantable cardioverter defibrillator (ICD) and/or pacemaker placement where study imaging site has not been trained and certified specifically for this protocol to conduct cardiac MRI in participants with ICD and/or pacemaker placement.

   a. Presence of a pacemaker and/or ICD generator with any of the following limitations/conditions are excluded: i. Manufactured before the year 2000, ii. Leads implanted < 6 weeks prior to signing informed consent, iii. Non-transvenous epicardial, abandoned, or no-fixation leads, iv. Subcutaneous ICDs, v. Leadless pacemakers, vi. Any other condition that, in the judgement of device-trained staff, would deem an MRI contraindicated.

   b. Pacemaker dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded).

   c. A cardiac resynchronization therapy (CRT) device implanted < 3 months prior to signing informed consent.

10. Estimated glomerular filtration rate < 30 mL/min.
11. Participation in an on-going protocol studying an experimental drug or device, or participation in an interventional clinical trial within the last 30 days.
12. Diagnosis of arrhythmogenic right ventricular cardiomyopathy.
13. Current alcohol or drug abuse.
14. Pregnant/nursing women and women of child-bearing potential that do not agree to use at least two forms of active and highly reliable method(s) of contraception. Acceptable methods of contraception include contraceptive pills, depo-progesterone injections, a barrier contraceptive such as a condom with or without spermicide cream or gel, diaphragms or cervical cap with or without spermicide or gel, or an intrauterine device (IUD).
15. Human Immunodeficiency Virus (HIV) infection.
16. Viral hepatitis.
17. Uncontrolled diabetes (HbA1c>9%).
18. Abnormal liver function (Serum Glutamic Pyruvic Transaminase/Alanine aminotransferase > 3 times the upper reference range) and/or abnormal hematology (hematocrit < 25%, White Blood Cell < 3000 µl, platelets < 100,000 µl) studies without a reversible, identifiable cause.
19. Sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia > 30 beats, not associated with the acute phase of a previous MI (> 48 hours after the MI onset) or a new acute ischemic episode.
20. Ventricular fibrillation not associated with a new acute ischemic episode.
21. New York Heart Association (NYHA) Class IV congestive heart failure.
22. Evidence of tumor on screening chest/abdominal/pelvic (body) CT scan.
23. Any prior transplant.
24. Known hypersensitivity to dimethyl sulfoxide (DMSO).
25. Known hypersensitivity to bovine products.
26. Any malignancy within 5 years (except for in-situ non-melanoma skin cancer and in-situ cervical cancer) of signing the informed consent form.
27. Any condition or other reason that, in the opinion of the Investigator or Medical Monitor, would render the participants unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Single, blinded, intracoronary infusion of a placebo solution
Active Comparator: CAP-1002 Allogeneic Cardiosphere-Derived Cells	Biological: CAP-1002 Allogeneic Cardiosphere-Derived Cells; Single dose, blinded, intracoronary infusion of 25 Million cardiosphere-derived cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Any of the Adjudicated Events	Adjudicated Events reported included: Acute myocarditis; Death due to ventricular tachycardia (VT) or ventricular fibrillation (VF); Sudden unexpected death (defined as occurring within one hour of symptom onset, or un- witnessed death); and Major adverse cardiac event (MACE) (defined as the composite incidence of death, non- fatal recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure, left ventricular assist device [LVAD] placement or heart transplant).	Within 1-month post-infusion
Percent Change From Baseline in Myocardium Mass Infarct Size at Month 12	Infarct size, expressed as a percentage, was calculated by dividing the sum of infarct areas from all sections by the sum of left ventricular (LV) areas from all sections (including those without infarct scar) and multiplying by 100. Percent improvement in infarct size defined by scar as a percent of LV mass was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Any of the Adjudicated Events	Adjudicated Events reported included: Acute myocarditis; Death due to VT or VF; Sudden unexpected death (defined as occurring within one hour of symptom onset, or un- witnessed death); MACE (defined as the composite incidence of death, non- fatal recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure, LVAD placement or heart transplant); New cardiac tumor formation on MRI imaging; Any hospitalization due to cardiovascular cause; Any inter-current cardiovascular illness or one related to CAP-1002 or placebo infusion, which prolongs hospitalization; New thrombolysis in myocardial infarction (TIMI) flow <=1; Development of, or an increase in frequency of VT; Development of increased anti-human leukocyte antigen (anti-HLA) antibody levels (mean fluorescence intensity [MFI] >= 1000; 5000) with development of sensitization to HLA antigens specific to CAP-1002 cardiosphere-derived cells donor.	Up to Month 12 post-infusion
Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Month 6 and 12	LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). LVEF expressed as percentage ejection fraction was assessed by magnetic resonance imaging. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Month 6 and 12	LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). Percent change in LVEF was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Absolute Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) at Month 6 and 12	LVEDV is the amount of blood in the heart's left ventricle just before the heart contracts. LVEDV was assessed by magnetic resonance imaging. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) at Month 6 and 12	LVEDV is the amount of blood in the heart's left ventricle just before the heart contracts. Percent change in LVEDV was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Absolute Change From Baseline in Left Ventricular End Systolic Volume (LVESV) at Month 6 and 12	LVESV is the amount of blood remaining in the ventricle at the end of systole, after the heart has contracted. LVESV was assessed by magnetic resonance imaging. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Left Ventricular End Systolic Volume (LVESV) at Month 6 and 12	LVESV is the amount of blood remaining in the ventricle at the end of systole, after the heart has contracted. Percent change in LVESV was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Myocardium Mass Infarct Size at Month 6 and 12	Infarct size, expressed as a percentage, was calculated by dividing the sum of infarct areas from all sections by the sum of LV areas from all sections (including those without infarct scar) and multiplying by 100. Improvement in infarct size as a percent of LV mass was assessed by magnetic resonance imaging.	Baseline, Month 6 and Month 12
Absolute Change From Baseline in Infarct Size (Scar Tissue Mass) at Month 6 and 12	Infarct size in grams was assessed by magnetic resonance imaging. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Infarct Size (Scar Tissue Mass) at Month 6 and 12	Percent change in infarct size was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Absolute Change From Baseline in Viable Mass at Month 6 and 12	Viable mass expressed in grams was assessed by magnetic resonance imaging. Myocardial viable mass refers to myocardial cells that are alive after myocardial injury, according to cellular, metabolic and contractile functions. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Viable Mass at Month 6 and12	Percent change in viable mass was assessed by magnetic resonance imaging. Myocardial viable mass refers to myocardial cells that are alive after myocardial injury, according to cellular, metabolic and contractile functions. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Absolute Change From Baseline in Function of the Region Receiving CAP-1002 Therapy at Month 6 and 12	The regions assessed of the heart were: Anterior, Lateral, Inferior and Septal. Tissue mass recovery in the function of region receiving therapy expressed as percentage improvement was assessed by magnetic resonance imaging. Absolute change was calculated as: post-baseline value-Baseline value.	Baseline, Month 6 and Month 12
Percent Change From Baseline in Function of the Region Receiving CAP-1002 Therapy at Month 6 and 12	The regions assessed of the heart were: Anterior, Lateral, Inferior and Septal. Tissue mass recovery in the function of region receiving therapy expressed as percentage improvement was assessed by magnetic resonance imaging. Percent change from Baseline was calculated as: Percent change = (post-baseline value-Baseline value)/Baseline value *100%.	Baseline, Month 6 and Month 12
Change From Baseline in Six-Minute Walk Test at Month 6 and 12	The six-minute walk test measures the distance a participant is able to walk over a total of six minutes on a hard, flat surface. The goal is for the participant to walk as far as possible in six minutes. The participant is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. The total distance walked, in meters, was recorded for each participant. Longer distances indicate better outcomes.	Baseline, Month 6 and Month 12
Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Total Score at Month 6 and 12	Health related quality of life is measured using the Minnesota Living with Heart Failure questionnaire (MLHFQ). The MLHFQ is a patient-reported outcome to measure the patient's perceptions of the influence of heart failure on physical and emotional aspects of life. The questionnaire has 21 items to assess the impact of frequent physical symptoms of heart failure and the effects of heart failure on physical and emotional functions. Responses are recorded on six-point Likert scales, ranging from 0 (none) to 5 (very much). Total Scores are summed to a range of 0-105, in which with higher scores indicate worse health-related quality of life.	Baseline, Month 6 and Month 12
Change From Baseline in Short Form (36) (SF-36) Scale Score at Month 6 and 12	The Short Form (36) Health Survey is a 36-item, patient-reported survey of participant health. The SF-36 consists of eight scaled scores (Physical Function, Physical Health, Emotional Problems, Energy/Fatigue, Emotional Well-Being, Social Functioning, Pain Scale and General Health) which are the weighted sums of the questions in their section. Each component on the SF-36 Item Health Survey is scored from 0-100 with higher scores reflecting better participant status.	Baseline, Month 6 and Month 12
Change From Baseline in Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) Score at Month 6 and 12	WPAI:SHP is a self-administered questionnaire that measures the effect of general health and symptom severity on work productivity and regular activities during the last 7 days. Four scores are derived as percent: Absenteeism, Presenteeism, Work Productivity Loss, Activity Impairment. Each of 4 scores expressed as impairment percentages with a total possible score range of 0 to 100, high percentage= more impairment, less productivity.	Baseline, Month 6 and Month 12
Number of Participants With Change From Baseline in Patient Global Assessment (PGA) Score at Month 6 and 12	PGA will ask participants to assess how their overall status has changed since prior to receiving the therapy. Possible PGA responses are "0=none", "1=mild", "2=moderate", "and 3=severe". Change from Baseline was calculated as lowest PGA score on scheduled visits minus PGA score at Baseline which resulted in possible ranges from -3 to +3. Decreasing scores indicate improvement.	Baseline, Month 6 and Month 12
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Class at Month 6 and 12	New York Heart Association (NYHA) Classification: Class I Subject with cardiac disease but without resulting limitations of physical activity. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Change from Baseline was calculated as lowest NYHA score on scheduled visits minus NYHA score at Baseline which resulted in possible ranges from -3 to +3. Decreasing scores indicate improvement.	Baseline, Month 6 and Month 12
Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) Biomarker at Month 6 and 12	NT-proBNP was the cardiac biomarkers assessed through serum sample.	Baseline, Month 6 and Month 12
Change From Baseline in Log Transformed N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) Biomarker at Month 6 and 12	NT-proBNP was the cardiac biomarkers assessed through serum sample.	Baseline, Month 6 and Month 12

Collaborators and Investigators

• Sponsor: Capricor Inc.
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); California Institute for Regenerative Medicine (CIRM)
• Investigators: Study Director: Frank Litvack, MD, Capricor Inc.

Publications and helpful links

General Publications

• Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marban L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marban E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial. Eur Heart J. 2020 Sep 21;41(36):3451-3458. doi: 10.1093/eurheartj/ehaa541.
• Ostovaneh MR, Makkar RR, Ambale-Venkatesh B, Ascheim D, Chakravarty T, Henry TD, Kowalchuk G, Aguirre FV, Kereiakes DJ, Povsic TJ, Schatz R, Traverse JH, Pogoda J, Smith RD, Marban L, Marban E, Lima JAC. Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial. Open Heart. 2021 Jul;8(2):e001614. doi: 10.1136/openhrt-2021-001614.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2012
• Primary Completion (Actual): July 3, 2017
• Study Completion (Actual): February 28, 2019

Study Registration Dates

• First Submitted: October 20, 2011
• First Submitted That Met QC Criteria: October 21, 2011
• First Posted (Estimated): October 24, 2011

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Left ventricular dysfunction; Myocardial Infarction; Stem cell; Heart Attack; Congestive heart failure
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Ventricular Dysfunction
• Other Study ID Numbers: 1002-01; RC3HL103356-01 (U.S. NIH Grant/Contract)