Appendix 1
The objective of the “Randomized controlled trial to compare the effects of single versus
repeated intracoronary application of autologous bone marrow-derived progenitor cells on allcause and SHFM-predicted mortality in patients with chronic post-infarction heart failure”
(REpetitive Progenitor cEll therapy in Advanced chronic hearT failure -REPEAT trial) trial is
to investigate whether mononuclear cells, isolated from bone marrow the same way as in
REPAIR-AMI 1, may improve clinical outcome when reinfused into the previous-infarctrelated coronary artery.
Study design
The REPEAT trial (NCT 01693042) is an investigator-initiated, open-label, randomized,
controlled, multicenter clinical trial. The design of the study is shown in Figure 1. A total of
668 patients who suffer from chronic post-infarction heart failure due to an at least 3 months
old myocardial infarction will be randomized to receive either one or two sequential
applications of mononuclear cells within 4 months via intracoronary infusion into the open
previously infarct-related artery.
End points
The single primary endpoint of the REPEAT trial is all-cause mortality at 2 years after the
first intracoronary application of autologous BM-MNC.
All secondary endpoints are listed in supplemental table 2. Of note, a secondary endpoint is
the comparison between observed and SHFM-predicted mortality in the repeated treatment
group.
Patient population
Patients with chronic post-infarction heart failure are eligible for trial inclusion if their most
recent myocardial infarction is older than 3 months, they have an open coronary vessel or
bypass supplying the most recent infarcted area, are stable functional NYHA class equal or
greater than 2 under constant optimal heart failure-directed medication with a LV ejection
fraction equal or smaller than 45% on routine echocardiography, and are above 18 years old
with a life expectancy of at least 1 year. In addition, participants have to provide written
informed consent. Major exclusion criteria are clinically significant renal failure and
hemodynamically relevant valvular disease. The complete list of exclusion criteria are
provided in supplemental table 2.
1
Bone marrow aspiration and cell preparation
Bone marrow aspiration will be performed the same way as in the REPAIR-AMI 1 and BAMI
trial.
Randomization
Patients will be randomized centrally by the cell processing center in a 1:1 ratio to the single
or repeated treatment group, by means of a sealed randomization list.
Intracoronary cell application
Intracoronary infusion of the isolated autologous bone marrow-derived cells will be
performed within 48 hours from the time of bone marrow aspiration, in order to ensure full
functionality of the isolated cells. Cells will be infused using the “stop-flow-techniques” with
either a conventional over-the-wire balloon or a specific cell infusion catheter. The final cell
product suspension will be infused in three portions of 3.3 ml each, with 3 min occlusion time
for each infusion. After the first portion of the cell suspension has been administered, the
balloon will be deflated for 3 min before reocclusion, to avoid extensive ischemia. Balloon
occlusion is intended to enhance the adhesion and migration of the infused cells in the infarct
area.
Importantly, only the use of bivalirudin is allowed for anticoagulation during the cell infusion
catheter procedure 2.
Statistics
The primary statistical aim is to compare survival until 2 years follow-up between the two
treatment arms with Kaplan-Meier analysis and a two-sided log-rank test. The global
significance level is set to =5%. For sample size calculation, we assume survival rates of 85
and 92%, respectively, after 2 years and a lost-to-follow-up rate of 5%, according to the
registry data (see above).
Applying a group sequential Wang and Tsiatis design with
boundary shape parameter Delta=0.3, we need 334 patients in each treatment arm and have to
include n=668 patients overall to achieve a statistical power of 80% when comparing
treatment arms.
The log-rank test of the final analysis will be performed at a two-sided significance level
=4.34%. This corresponds to a critical bound of the log-rank test statistic of 2.021. A global
significance level of 5% is assured by this procedure.
2
References
1.
Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Holschermann H,
Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher
AM. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N
Engl J Med 2006;355(12):1210-21.
2.
Seeger FH, Rasper T, Fischer A, Muhly-Reinholz M, Hergenreider E, Leistner DM,
Sommer K, Manavski Y, Henschler R, Chavakis E, Assmus B, Zeiher AM, Dimmeler S.
Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrowderived mononuclear cells used for cardiovascular repair. Circ Res 2012;111(7):854-62.
Appendix Table 1
Secondary efficacy endpoints
Comparison between observed and SHFM-predicted mortality in the
repeated treatment group
Comparison between the 2 treatment groups at 2-year and 5-year
follow-up

Cardiac mortality, cardiovascular mortality

Rehospitalization for heart failure

Ischemic cardiac events (STEMI, NSTEMI, ACS)

Coronary revascularisations (PCI / CABG)

Heart transplantation, Assist-device implantation

New resynchronization therapy, ICD implantation

NYHA-Status, NT-proBNP serum levels

Minnesota Living with Heart Failure Questionnaire

Prespecified combined clinical endpoints:
o
Death and rehospitalisation for heart failure
o
Cardiac Death and rehospitalisation for heart failure
o
Cardiac
and
Cardiovascular
Death
and
infarction
and
rehospitalisation for heart failure
o
Death and myocardial infarction
o
Death
and
myocardial
rehospitalisation for heart failure
o
Secondary safety endpoints
Death and any cardiovascular event

All in-hospital events (during hospitalization for cell therapy)

Life-threatening
arrhythmias
(sustained
ventricular
tachycardia; ventricular fibrillation and cardiopulmonary
resuscitation)

Any new malignant disease
3

Bleeding events

Safety of intracoronary application of autologous bone
marrow-derived cells (procedural complications, adverse
events at 30 days, SAEs at 4 months after each cell
application)
Appendix Table 2
Exclusion
criteria
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

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


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

Non-ischemic cardiomyopathy
Foreseeable necessity for revascularization in other vessel than the infarct
vessel at the time of study therapy
Hemodynamic relevant severe valvular disease / indication for operative /
interventional revision
Heart failure with preserved ejection fraction (diastolic heart failure),
LVEF > 45%
Unstable Angina
Severe peripheral artery occlusive disease (≥ Fontaine stadium III)
Active infection (C-reactive protein > 10 mg/dl), any chronic
inflammatory disease,
Neoplastic disease without documented remission in the last 5 years
Stroke ≤ 3 months
Impaired renal function (Serum creatinine > 2,5 mg/dl or eGFR [MDRD]
≤ 30 ml/min) at the time of study inclusion
Relevant liver disease (GOT > 2x upper normal limit, spontaneous INR >
1,5).
Diseases of hematopoetic system, anemia (Hemoglobin < 8.5 mg/dl),
thrombocytopenia < 100.000/µl)
Splenomegaly
Allergy or intolerance of clopidogrel, prasugrel, ticagrelor, heparin,
bivalirudin
History of bleeding disorder
Gastrointestinal bleeding ≤ 3 months
Major surgery or trauma ≤ 3 months
Uncontrolled hypertension
Pregnancy, lactation period
Mental retardation
Previous cardiac cell therapy within last 12 months
Participation in another clinical trial ≤ 30 days
4
REPEAT Flowchart
5