ACT34-CMI -- Adult Autologous CD34+ Cells

A DB, Randomized, Placebo-controlled Study of the Tolerability, Efficacy, Safety, and Dose Range of Intramyocardial CLBS14 for Reduction of Angina Episodes in Patients With Refractory Chronic Myocardial Ischemia (ACT34-CMI)

The purpose of this study is to evaluate the efficacy and safety of intramyocardial injections of CLBS14 in patients with refractory chronic myocardial ischemia.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia
• Intervention / Treatment: Biological: CLBS14 (low-dose); Biological: CLBS14 (high-dose); Biological: placebo injection

Detailed Description

This is a double-blind, prospective, randomized, placebo-controlled trial to determine the tolerability, efficacy, safety and dose range of intramyocardial injections of adult autologous CD34+ cells mobilized with granulocyte colony stimulating factor (G-CSF) for the reduction of angina episodes in patients with refractory chronic myocardial ischemia.

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Cardiology PC
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
    • Phoenix, Arizona, United States, 85005
      • Arizona Heart Institute
  • California
    • La Jolla, California, United States, 92037
      • Scripps Memorial Hospital
    • Stanford, California, United States, 94305
      • Stanford University Hospital and Clinics
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Science Center
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Center
    • Orlando, Florida, United States, 32803
      • Central Florida Cardiology Group
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Saint Joseph's Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern University Medical Center, Bluhm Cardiovascluar Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02135
      • Caritas Saint Elizabeth's Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern Hospital
  • New York
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital - Columbia University Medical Center
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital - Weill Cornell Medical College of Cornell University
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Heart & Vascular - Swedish Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Medical School
    • Milwaukee, Wisconsin, United States, 53223
      • Comprehensive Cardiovascular Care Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Canadian Cardiovascular Society (CCS) functional class III or IV chronic refractory angina
• subjects without control of their angina symptoms, in spite of maximal tolerated doses of anti-anginal drugs, must be on optimal therapy for their angina and on a stable anti-anginal medication regimen for at least 1 month prior to entering the screening period of the study
• identified as unsuitable for conventional revascularization
• recent coronary angiogram (within the last 12 months) to document the coronary anatomy and to verify the revascularization procedures
• subjects must have objective evidence of inducible ischemia or viable myocardium in the potential target injection zone
• a left ventricular ejection fraction equal to or greater than 25% by ECHO or single photon emission computed tomography (SPECT) at screening
• subjects must experience at minimum an average of 7 angina or anginal equivalent episodes per week
• subjects must be able to complete a minimum of 3 minutes but nor more than 10 minutes on a treadmill following the Modified Bruce Protocol
• subjects must experience angina or anginal equivalent episodes during the screening exercise treadmill test
• female subjects must either be no longer capable of reproduction or using medically valid contraception to prevent pregnancy during the study
• subjects must be willing and able to comply with specified follow-up evaluations

Exclusion Criteria:

• predominant congestive heart failure
• myocardial infarction within 60 days of treatment
• successful or partially successful coronary revascularization procedures (any vessel) within 6 months of study enrollment
• placement of a bi-ventricular pacemaker for cardiac resynchronization therapy (CRT) for heart failure in the past 90 days
• documented stroke or transient ischemic attack (TIA) within 60 days of study enrollment
• history of moderate to severe aortic stenosis or severe aortic insufficiency; severe mitral stenosis or severe mitral insufficiency
• prosthetic aortic valve replacement
• evidence of any life-threatening arrhythmia that requires intervention on the 24-hour Holter monitor. Life-threatening arrhythmia that is successfully treated with an implantable cardioverter defibrillator (ICD) is not exclusionary.
• splenomegaly and/or severe co-morbidity associated with a reduction in life expectancy of less than 1 year, such as chronic medical illness (ie, severe chronic obstructive pulmonary disease, renal failure or cancer [exceptions: in-situ skin cancer or fully removed skin cancer other than melanoma, in-situ cervical cancer, or cancer free for 5 years with no history of a stem cell transplant])
• sickle cell disease or sickle cell trait
• platelet count greater than 10% above the upper limit of normal or a platelet count below 100,000 if on Clopidogrel or 50,000 without Clopidogrel
• hematocrit <30%
• serum creatinine >2.5 mg/dL
• any clinically significant laboratory abnormality on screening laboratories
• currently enrolled in another IDE or IND that has not completed the protocol required primary follow-up period (excludes 15 year follow up of gene therapy trials)
• history of alcohol or drug abuse within 3 months of screening
• joint or peripheral vascular disease or neurologic disease that severely limits treadmill walking
• chronic obstructive pulmonary disease that severely limits walking or FEV1 <30% predicted
• females who are pregnant or lactating
• female subjects who are capable of reproduction and will not use medically valid contraception to prevent pregnancy during the study
• subjects who test positive for HIV, hepatitis B or hepatitis C, or are on chronic immunosuppressive medications or have had a prior stem cell transplant
• subjects with a known hypersensitivity to E. coli-derived proteins, or to any component of Neupogen (Filgrastim) or G-CSF
• subjects who have a significant psychiatric disorder or mental disability that could interfere with the subject´s ability to provide informed consent and/or comply with protocol procedures

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CLBS14: Low-Dose Group; 10 intramyocardial injections of 0.2 mL each of auto-CD34+ cells at a dose of 1 x 10^5 (=100000) cells/kg bodyweight	Biological: CLBS14 (low-dose); Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+ cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Autologous CD34+ cells will be delivered in 10 intramyocardial injections of 0.2 mL at a dose of 1 x 10^5 (=100000) cells/kg bodyweight each using the MyoStar injection catheter (Biosense Webster, Inc.) into the target areas of myocardial ischemia.; Other Names: G-CSF mobilized, autologous CD34+ cells
Experimental: CLBS14: High-Dose Group; 10 intramyocardial injections of 0.2 mL each of auto-CD34+ cells at a dose of 5 x 10^5 (=500000) cells/kg bodyweight	Biological: CLBS14 (high-dose); Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Autologous CD34+ cells will be delivered in 10 intramyocardial injections of 0.2 mL at a dose of 5 x 10^5 (=500000) cells/kg bodyweight each using the MyoStar injection catheter (Biosense Webster, Inc.) into the target areas of myocardial ischemia.; Other Names: G-CSF mobilized, autologous CD34+ cells
Placebo Comparator: Placebo injection; 10 intramyocardial injections of 0.2 mL each of 0.9% NaCl (saline) in 5% autologous plasma	Biological: placebo injection; Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+ cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Placebo will be delivered in 10 intramyocardial injections of 0.2 mL each of 0.9% NaCl (saline) in 5% autologous plasma into the target areas of myocardial ischemia.; Other Names: 0.9% NaCl (saline) in 5% autologous plasma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Angina Episodes Per Week at 6 and 12 Months	The number of angina episodes were collected via an electronic subject diary for four weeks at Baseline and at 6 and 12 months. The four-week angina episodes (per week mean) were used as the frequency for each visit. A lower number represents fewer angina episodes. A lower number is better.	6 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exercise Treadmill Test According to Modified Bruce Protocol: Mean Change From Baseline in Duration of Exercise	A modified Bruce Protocol Exercise Treadmill Test was used to evaluate duration of exercise in all subjects.	Change from Baseline to 6 months and change from baseline to 12 months after treatment
Number of Participants With Change in Canadian Cardiovascular Society Anginal Classification Levels	The Canadian Cardiovascular Society (CCS) Functional Classification of Angina is as follows: Class I - Angina only during strenuous or prolonged physical activity; Class II - Slight limitation, with angina only during vigorous physical activity; Class III - Symptoms with everyday living activities, i.e., moderate limitation; Class IV - Inability to perform any activity without angina or angina at rest, i.e., severe limitation	Baseline and 12 months after treatment
Changes From Baseline in Seattle Angina Questionnaire (SAQ) Scores at 6 Months	Angina symptoms were evaluated based on the Seattle Angina Questionnaire (SAQ), which was used to analyze the following: physical limitations, angina stability, angina frequency, treatment satisfaction, and disease perception. The SAQ consisted of 11 questions with 5 or 6 possible responses. Responses were ordinal values (1-7, 10, 11, 97, depending on the type of question; no uniform ranges throughout); responses that corresponded to the lowest level of functioning (worse outcomes) were assigned values of 1, while responses that corresponded to higher functioning levels (better outcome) were assigned a higher ordinal value. If the response to any of these questions was 97 it was recoded as a missing value. Each scale can have a scored value ranging from 0 to 100. A larger number is better.	Baseline to 6 months after treatment
Changes From Baseline to 6 Months in Short Form 36 (SF-36) Parameters	The Short Form 36 (SF-36) health survey form was used to analyze physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, general mental health, and health transition. Responses were coded as ordinal numbers going from worst (=1) to best (=highest number). These ordinal scores were transformed into scales ranging from 0 to 100. Higher numbers are generally considered better.	Baseline to 6 months after treatment
Change in Anti-anginal Medication (ie, Nitroglycerin) Use	The mean nitroglycerin use per week was analyzed at baseline and 6 months	Baseline to 6 months

Collaborators and Investigators

• Sponsor: Lisata Therapeutics, Inc.
• Investigators: Study Director: Caladrius Study DIrector, Lisata Therapeutics, Inc.

Publications and helpful links

General Publications

• Losordo DW, Henry TD, Davidson C, Sup Lee J, Costa MA, Bass T, Mendelsohn F, Fortuin FD, Pepine CJ, Traverse JH, Amrani D, Ewenstein BM, Riedel N, Story K, Barker K, Povsic TJ, Harrington RA, Schatz RA; ACT34-CMI Investigators. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011 Aug 5;109(4):428-36. doi: 10.1161/CIRCRESAHA.111.245993. Epub 2011 Jul 7.
• Henry TD, Schaer GL, Traverse JH, Povsic TJ, Davidson C, Lee JS, Costa MA, Bass T, Mendelsohn F, Fortuin FD, Pepine CJ, Patel AN, Riedel N, Junge C, Hunt A, Kereiakes DJ, White C, Harrington RA, Schatz RA, Losordo DW; ACT. Autologous CD34+ Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study. Cell Transplant. 2016;25(9):1701-1711. doi: 10.3727/096368916X691484. Epub 2016 May 4.
• Povsic TJ, Losordo DW, Story K, Junge CE, Schatz RA, Harrington RA, Henry TD. Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: an analysis from ACT34-CMI. Am Heart J. 2012 Nov;164(5):689-697.e3. doi: 10.1016/j.ahj.2012.06.022.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: March 6, 2006
• First Submitted That Met QC Criteria: March 6, 2006
• First Posted (Estimate): March 8, 2006

Study Record Updates

• Last Update Posted (Actual): January 26, 2021
• Last Update Submitted That Met QC Criteria: January 8, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: angina
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Ischemia; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Lenograstim
• Other Study ID Numbers: 24779