Intramyocardial Transplantation of Bone Marrow Stem Cells in Addition to Coronary Artery Bypass Graft (CABG) Surgery (PERFECT)

• ClinicalTrials.gov Identifier: NCT00950274
• Recruitment Status: Terminated
• First Posted: July 31, 2009
• Last Update Posted: July 15, 2020
• Sponsor: Miltenyi Biotec B.V. & Co. KG
• Collaborator: German Federal Ministry of Education and Research
• Information provided by (Responsible Party): Miltenyi Biomedicine GmbH ( Miltenyi Biotec B.V. & Co. KG )

Tracking Information

• First Submitted Date: July 30, 2009
• First Posted Date: July 31, 2009
• Last Update Posted Date: July 15, 2020
• Study Start Date: July 2009
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 30, 2009): Left ventricular ejection fraction at rest, measured by MRI [ Time Frame: 6 months ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 22, 2010)

• Change in LVEF as assessed by MRI and echocardiography [ Time Frame: early postoperatively and 6 months ]
• Regional contractility in the AOI / Change in LV dimensions (left ventricular end systolic diameter [LVESD], left ventricular end diastolic diameter [LVEDD]) as assessed by echocardiography [ Time Frame: early postoperatively (discharge), 6 months ]
• Physical exercise capacity determined by 6 minute walk test [ Time Frame: early postoperatively (discharge), 6 months ]
• NYHA and CCS class [ Time Frame: early postoperatively (discharge), 6 months ]
• MACE (cardiac death, myocardial infarction, secondary intervention/reoperation, ventricular arrhythmia) [ Time Frame: 6 months ]
• QoL-score: Minnesota Living with Heart Failure Questionnaire, SF36 Questionnaire, EQ-5D Questionnaire [ Time Frame: 3 months, 6 months post-OP ]

Original Secondary Outcome Measures (submitted: July 30, 2009)

• Change in LVEF as assessed by MRI and echocardiography [ Time Frame: early postoperatively and 6 months ]
• Regional contractility in the AOI / Change in LV dimensions (left ventricular end systolic diameter [LVESD], left ventricular end diastolic diameter [LVEDD]) as assessed by echocardiography [ Time Frame: early postoperatively (discharge), 6 months ]
• Physical exercise capacity determined by 6 minute walk test [ Time Frame: early postoperatively (discharge), 6 months ]
• NYHA and CCS class [ Time Frame: early postoperatively (discharge), 6 months ]
• MACE (cardiac death, myocardial infarction, secondary intervention/reoperation, ventricular arrhythmia) [ Time Frame: 6 months ]
• QoL-score: Minnesota Living with Heart Failure Questionnaire, SF36 Questionnaire [ Time Frame: 3 months, 6 months post-OP ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intramyocardial Transplantation of Bone Marrow Stem Cells in Addition to Coronary Artery Bypass Graft (CABG) Surgery
• Official Title: Intramyocardial Transplantation of Bone Marrow Stem Cells for Improvement of Post-infarct Myocardial Regeneration in Addition to CABG Surgery: a Controlled, Prospective, Randomized, Double Blinded Multicenter Trial (PERFECT)

Brief Summary

In spite of the fact that the post-myocardial infarction survival rate has improved with recent medical advances, reduced heart function attributed to irreversible loss of viable cardiomyocytes is still a major clinical problem.

The aim of the current study is to determine whether intramyocardial injection of autologous CD133+ bone marrow stem cells yields a functional benefit in addition to coronary artery bypass graft (CABG) surgery in patients with chronic ischemic coronary artery disease.

Detailed Description

Beginning in 2001, a phase-1 equivalent feasibility and safety evaluation of intramyocardial injection of autologous CD133+ bone marrow cells during elective CABG surgery was conducted at Rostock University. No procedure-related adverse events were observed and there was some improvement of myocardial contractility and perfusion. It was decided to proceed with a controlled efficacy testing, comparing the outcome of standard CABG surgery with that after CABG and CD133+ cell injection. The results of that study indicate that the additional cell injection yields a better left ventricular contractility than CABG alone (LVEF = 47.1±8% vs. 41.3±9% at 6 months). Although this result is encouraging, the trial had several limitations that hamper interpretation of the data. Most notably, no sham-injection of placebo material was performed in the control group, and standard 2D echocardiography served as the only measurement of global LV contractility.

However, there were no procedure-related complications up to 18 months postoperatively, especially no new ventricular arrhythmia or neoplasia.

Therefore, a prospective, double blinded, randomized, and placebo-controlled multi-center trial will be conducted in Germany, employing current state-of-the art measurement of global and regional LV contractility by cardiac MRI. The following hypothesis will be tested: "Patients who undergo CABG & CD133+ cell injection do not have a higher LV ejection fraction than patient who undergo CABG alone, measured 6 months after the operation". A power analysis based on the previous trial results indicated that 71 patients per group need to be enrolled so as to reject the null-hypothesis with sufficient statistical power. A total of 142 patients will therefore be enrolled in the study. Patients will be randomized in a 1:1 ratio to undergo CABG surgery in conjunction with either intramyocardial injection of autologous CD133-enriched bone marrow cells or placebo. Bone marrow will be harvested one or two days prior to surgery and a CD133-enriched cell product (or placebo) will be prepared at a central cell processing GMP unit. Bypass surgery will be performed and the investigational product will be injected in the border zone of the infarcted myocardium. Random allocation will be performed in the cell production facility, so that neither the patient nor the surgeon nor any of the personnel involved in follow-up examinations will know whether the cell product or placebo was administered. The primary outcome parameter (LVEF at 6 months) will be measured by cardiac MRI, and secondary outcome parameters include physical exercise capacity, cardiac function, safety and Quality of Life (QoL).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Myocardial Ischemia
• Coronary Artery Disease

Intervention

• Drug: CD133+ autologous bone marrow stem cell
  Intramyocardial injection of 5 mL CD133+ cells (0.5-5x10e6 cells) suspended in physiological saline + 10% autologous serum intramyocardially during CABG surgery
• Drug: Placebo
  Intramyocardial injection of 5 mL of physiological saline + 10% autologous serum intramyocardially during CABG surgery

Study Arms

• Active Comparator: CD133+ autologous bone marrow stem cells
  Intervention: Drug: CD133+ autologous bone marrow stem cell
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Publications *

• Wolfien M, Klatt D, Salybekov AA, Ii M, Komatsu-Horii M, Gaebel R, Philippou-Massier J, Schrinner E, Akimaru H, Akimaru E, David R, Garbade J, Gummert J, Haverich A, Hennig H, Iwasaki H, Kaminski A, Kawamoto A, Klopsch C, Kowallick JT, Krebs S, Nesteruk J, Reichenspurner H, Ritter C, Stamm C, Tani-Yokoyama A, Blum H, Wolkenhauer O, Schambach A, Asahara T, Steinhoff G. Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3. EBioMedicine. 2020 Jul;57:102862. doi: 10.1016/j.ebiom.2020.102862. Epub 2020 Jul 4.
• Steinhoff G, Nesteruk J, Wolfien M, Kundt G; PERFECT Trial Investigators Group; Borgermann J, David R, Garbade J, Grosse J, Haverich A, Hennig H, Kaminski A, Lotz J, Mohr FW, Muller P, Oostendorp R, Ruch U, Sarikouch S, Skorska A, Stamm C, Tiedemann G, Wagner FM, Wolkenhauer O. Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction. EBioMedicine. 2017 Aug;22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.
• Donndorf P, Kaminski A, Tiedemann G, Kundt G, Steinhoff G. Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials. 2012 Jul 2;13:99. doi: 10.1186/1745-6215-13-99.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 14, 2016): 81
• Original Estimated Enrollment (submitted: July 30, 2009): 142
• Actual Study Completion Date: September 2017
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Coronary artery disease after myocardial infarction with indication for CABG surgery
• Currently reduced global LVEF assessed at site by cardiac MRI at rest (25% ≤ LVEF ≤ 50%)
• Presence of a localized akinetic/hypokinetic/hypoperfused area of LV myocardium for defining the target area
• Informed consent of the patient
• 18 years ≤ Age < 80 years
• Are not pregnant and do not plan to become pregnant during the study. Females with childbearing potential must provide a negative pregnancy test within 1-7 days before OP and must be using oral or injectable contraception (non-childbearing potential is defined as post-menopausal for at least 1 year or surgical sterilization or hysterectomy at least 3 months before study start).

Exclusion Criteria:

• Emergency operation
• Presence of any moderate-severe valvular heart disease requiring concomitant valve replacement or reconstruction
• Medical History of recent resuscitation in combination with ventricular arrhythmia classified by LOWN ≥ class II
• Acute myocardial infarction within last 2 weeks
• Debilitating other disease: Degenerative neurologic disorders, psychiatric disease, terminal renal failure requiring dialysis, previous organ transplantation, active malignant neoplasia, or any other serious medical condition that, in the opinion of the Investigator is likely to alter the patient's course of recovery or the evaluation of the study medication's safety
• Impaired ability to comprehend the study information
• Absent informed written consent
• Treatment with any investigational drug within the previous 30 days
• Apparent infection (c-reactive protein [CRP] ≥ 20 mg/L, fever ≥ 38.5° C)
• Contraindication for MRI scan
• Immune compromise including active infection with Hepatitis B, C, HIV virus or seropositivity for Treponema pallidum
• Pregnant or breast feeding
• Childbearing potential with unreliable birth control methods
• Have previously been enrolled in this study, respectively phase I and phase II
• Known hypersensitivity or sensitization against murine products and human-anti-mouse-antibody-titer ≥ 1:1000
• Contraindication to bone marrow aspiration
• Known hypersensitivity against iron dextran

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 79 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT00950274
• Other Study ID Numbers: PERFECT 001; M-2006-144 ( Other Identifier: Sponsor )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Miltenyi Biomedicine GmbH ( Miltenyi Biotec B.V. & Co. KG )
• Original Responsible Party: Miltenyi Biotec GmbH
• Current Study Sponsor: Miltenyi Biotec B.V. & Co. KG
• Original Study Sponsor: Miltenyi Biomedicine GmbH
• Collaborators: German Federal Ministry of Education and Research

Investigators

• Principal Investigator: Gustav Steinhoff, M.D.; Universitiy of Rostock

• PRS Account: Miltenyi Biomedicine GmbH
• Verification Date: August 2018