Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina (RENEW)

A Prospective, Randomized, Double-blinded, Active-control and Unblinded Standard of Care (SOC) Controlled Study to Determine the Efficacy and Safety of Targeted Intramyocardial Delivery of Autologous CD34+ Cells (Auto-CD34+ Cells) for Increasing Exercise Capacity During Standardized Exercise Testing in Subjects With Refractory Angina Pectoris and Chronic Myocardial Ischemia

The purpose of the study is to assess the safety and efficacy of targeted intramyocardial delivery of Auto-CD34+ cells for increasing exercise time and amelioration of anginal symptoms in subjects with refractory angina and chronic myocardial ischemia.

Study Overview

• Status: Completed
• Conditions: Refractory Angina Pectoris; Chronic Myocardial Ischemia; Advanced Coronary Heart Disease
• Intervention / Treatment: Biological: Auto-CD34+ cells; Biological: Placebo: Diluent used to suspend Auto-CD34+ cells; Other: Standard of care

• Study Type: Interventional
• Enrollment (Actual): 291
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Gilbert, Arizona, United States
    • Phoenix, Arizona, United States
  • California
    • La Jolla, California, United States
    • Los Angeles, California, United States
    • Oxnard, California, United States
    • San Diego, California, United States
    • Stanford, California, United States
  • Florida
    • Boynton Beach, Florida, United States
    • Daytona Beach, Florida, United States
    • Gainesville, Florida, United States
    • Jacksonville, Florida, United States
    • Miami, Florida, United States
    • Orlando, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Augusta, Georgia, United States
  • Illinois
    • Chicago, Illinois, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Saginaw, Michigan, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
    • Rochester, Minnesota, United States
  • New Jersey
    • Haddon Heights, New Jersey, United States
    • Newark, New Jersey, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
    • Durham, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Cleveland, Ohio, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
    • Pittsburgh, Pennsylvania, United States
  • Tennessee
    • Germantown, Tennessee, United States
  • Texas
    • Dallas, Texas, United States
    • Houston, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Washington
    • Seattle, Washington, United States
  • Wisconsin
    • Madison, Wisconsin, United States
    • Milwaukee, Wisconsin, United States

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

Main Inclusion Criteria:

• Male or female participants who are 21 to 80 years of age at the time of signing the informed consent.
• Participants with Canadian Cardiovascular Society (CCS) class III or IV chronic refractory angina.
• Participants without control of their angina symptoms in spite of maximal tolerated doses of anti-angina drugs. Participants must be on optimal therapy for their angina and must have been on a stable anti-anginal medication regimen for at least 4 weeks before signing the informed consent form.
• Participants with obstructive coronary disease unsuitable for conventional revascularization due to unsuitable anatomy or comorbidity as determined at the site and confirmed by an independent adjudication committee.
• Participants must have evidence of inducible myocardial ischemia.
• Participants must experience angina episodes.
• Participants must be able to complete 2 exercise tolerance tests on the treadmill within 3 weeks of randomization.
• If female of childbearing potential, subject must not be pregnant and agree to employ adequate birth control measures for the duration of the study.

Main Exclusion Criteria:

• Cardiovascular hospitalization within 60 days prior to potential study enrollment. Participant has had a successful or partially successful coronary artery bypass graft (CABG) within 6 months or PCTA within 60 days of potential study enrollment.
• Participant has had a placement of a bi-ventricular pacemaker for cardiac resynchronization therapy (CRT) for heart failure within 180 days of potential study enrollment.
• Participant has documented stroke or transient ischemic attacks (TIAs) within 60 days of potential study enrollment.
• Participant has a history of moderate to severe aortic stenosis; or severe aortic insufficiency; or severe mitral stenosis; or severe mitral insufficiency.
• Participant has a prosthetic aortic valve or a mechanical mitral valve replacement.
• Participant has severe co-morbidity associated with a reduction in life expectancy to less than 3 years as a result of chronic medical illnesses.

• Participants with cancer are excluded with the following exceptions:

  • Subjects with in-situ non-melanoma skin cancer or in-situ cervical cancer are not excluded.
  • Participants that have been cancer free for >= 5 years as determined by their oncologist are not excluded. Subjects with a prior history of stem cell transplant for cancer are excluded no matter how long they have been cancer-free.
• Participants with a history of leukemia or other bone marrow disease.
• Participant has sickle cell disease or sickle cell trait.
• Participants with proliferative retinopathy.
• Participants with Hb A1c > 9%.
• Participant has platelet counts >10% above the upper limit of normal (ULN) or platelet counts < 70,000.
• Participant has a hematocrit < 30% prior to potential study enrollment.
• Participant has a serum creatinine > 2.5 mg/dL prior to potential study enrollment.
• Participant tests positive for HIV, hepatitis B, or hepatitis C, or is on chronic immunosuppressive medications, or has had a previous stem cell transplant.
• Participant has a known contraindication to Neupogen (filgrastim) or G-CSF.
• Participant was previously enrolled in an active treatment group of cell therapy trials for cardiovascular disease including any phase of CD34+ stem cell trials.
• Left ventricular (LV) thickness of < 7 mm in the target areas of injection as measured by during a 2-D echocardiogram (ECHO).
• Atrial fibrillation, atrial flutter, or other uncontrolled arrhythmias that would prohibit accurate electromechanical mapping and NOGA-guided intramyocardial injection.
• Bleeding diathesis with an INR > 1.8 when not receiving anti-thrombotic therapy.
• Hepatic dysfunction as evidenced by elevated AST or ALT levels > 2.5 x ULN.
• Any previous transplant requiring immunosuppression.
• Disease state requiring chronic immunosuppression.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm; Targeted intramyocardial delivery of 1 x 10^5 Auto-CD34+ cells after granulocyte-colony stimulating factor (G-CSF) mobilization and apheresis	Biological: Auto-CD34+ cells; 10 intramyocardial injections of 0.2 mL per injection site of Auto-CD34+ cells
Placebo Comparator: Active Control Arm; Targeted intramyocardial delivery of placebo after G-CSF mobilization and apheresis	Biological: Placebo: Diluent used to suspend Auto-CD34+ cells; 10 intramyocardial injections of 0.2 mL per injection site of placebo
Other: Unblinded Standard of Care (SOC) Arm; No study-related procedures will be performed.	Other: Standard of care; Standard of care for refractory angina

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol	Baseline (BL) is the average of the two total exercise times measured during the screening period.	Baseline and 12 month visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit	Participants self-reported angina episodes utilizing an electronic diary for 4 weeks at baseline (screening period) and in the 4 weeks before the 3, 6 and 12 month follow-up visits.	Baseline and 12 month visit
Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit	Baseline (BL) is the average of the two total exercise times measured during the screening period.	Baseline and 6 month visit
Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit		6 month visit
Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period	Major adverse cardiac events (MACE) defined as death, cardiac hospitalization, non-fatal myocardial infarction and stroke, as adjudicated by an independent clinical endpoint classification (CEC) committee. The category Total MACE includes death, cardiovascular hospitalization, myocardial infarction or stroke.	From randomization until the end of the 24 month follow-up period
Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period		From randomization until the end of the 24 month follow-up period

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Povsic TJ, Henry TD, Traverse JH, Fortuin FD, Schaer GL, Kereiakes DJ, Schatz RA, Zeiher AM, White CJ, Stewart DJ, Jolicoeur EM, Bass T, Henderson DA, Dignacco P, Gu Z, Al-Khalidi HR, Junge C, Nada A, Hunt AS, Losordo DW; RENEW Investigators. The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina. JACC Cardiovasc Interv. 2016 Aug 8;9(15):1576-85. doi: 10.1016/j.jcin.2016.05.003.
• Povsic TJ, Junge C, Nada A, Schatz RA, Harrington RA, Davidson CJ, Fortuin FD, Kereiakes DJ, Mendelsohn FO, Sherman W, Schaer GL, White CJ, Stewart D, Story K, Losordo DW, Henry TD. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am Heart J. 2013 Jun;165(6):854-861.e2. doi: 10.1016/j.ahj.2013.03.003. Epub 2013 Apr 19.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: January 10, 2012
• First Submitted That Met QC Criteria: January 11, 2012
• First Posted (Estimate): January 12, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2018
• Last Update Submitted That Met QC Criteria: November 29, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ischemia; Angina Pectoris
• Other Study ID Numbers: 901001; RENEW Study (Other Identifier: Caladrius Biosciences, Inc.)