Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000219987
Ethics application status
Approved
Date submitted
30/03/2010
Date registered
28/02/2011
Date last updated
19/01/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the effect on heart function of direct myocardial injection of autologous bone marrow for treatment of patients with "end-stage" ischaemic heart failure.
Scientific title
A study of the effect of direct endomyocardial injection of autologous bone marrow cells on left ventricular ejection function in patients with "end-stage" ischaemic heart failure.
Secondary ID [1] 1562 0
HKCTR-763 Hong Kong Clinical Trials Register
Universal Trial Number (UTN)
Trial acronym
END-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart failure 257066 0
Coronary artery disease 257067 0
Condition category
Condition code
Cardiovascular 257221 257221 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Device - Myostar injection catheter.

On the day of the endomyocardial injection procedure, bone marrow cells will be obtained from the iliac crest under local anaesthesia in a sterile environment. A total of 80 ml of marrow blood will be aspirated, placed in heparinised phosphate buffered saline, and transported immediately to a culture laboratory dedicated to cell manipulation for bone marrow transplantation. Mononuclear cells will be isolated by Ficoll density gradient centrifugation, washed twice in phosphate buffered saline, re-suspended in phosphate buffered saline enriched with 10% autologous plasma at a concentration of 10 to the 7th power cells per ml, and returned directly to Cardiac Catheterisation Laboratory (CCL) for use. The composition of the final cell suspension will be determined by flow cytometry.

Standard bone marrow examinations (smear and trephine biopsy) will be performed, as well as microbiological examination and culture, to exclude any abnormalities.

Following bone marrow aspiration, participants will be transported to the CCL where an initial diagnostic left ventriculography and coronary angiography will be performed to visualise the target region for implantation procedure and the corresponding coronary anatomy.

An electromechanical mapping system (NOGA XP, Biosense) will be employed to identify the target ischaemic area/s for injection and to pinpoint any scarred or infarcted areas of myocardium. The system uses a location pad with coils generating ultralow magnetic field energy, a stationary reference catheter with a miniature magnetic field sensor located on the body surface, a navigation sensor mapping catheter and electrodes providing endocardial signals, and a workstation for information processing and 3-dimensional left ventricular reconstruction.

Once the mapping procedure is complete, percutaneous myocardial injection of autologous bone marrow cells (10 to 12 injections of 0.1 ml of bone marrow of concentration of 10 7th power cells per mL at each pre-determined target site) will occur on the same day in the CCL.

Once all results of the six month follow-up investigations is known, the treatment arm allocation of participants will be "unblinded". Participants in the control group will be given the option to crossover to the treatment group, that is, to receive autologous bone marrow endomyocardial injection.
Intervention code [1] 256233 0
Treatment: Devices
Intervention code [2] 256234 0
Treatment: Other
Comparator / control treatment
Blinded placebo percutaneous endomyocardial injection.

The placebo will be formulated using the same process as the true interventional treatment (phosphate buffered saline enriched with 10% autologous plasma). As the interventionalist will be blinded to the contents of the prepared injection, all procedures outlined in the interventional description will be performed. Once the mapping procedure is complete, percutaneous endomyocardial injection of placebo (10 to 12 injections of 0.1 ml) will occur on the same day in the CCL.
Control group
Placebo

Outcomes
Primary outcome [1] 258112 0
Left ventricular ejection fraction (LVEF) as determined by cardiac magnetic resonance imaging (cMRI).
Timepoint [1] 258112 0
Baseline, 6 months post-procedure.
Secondary outcome [1] 263734 0
Incidence of all adverse events, defined as any undesirable clinical occurrence in a subject whether or not it is
considered to be procedural related. Specifically, the incidence of hospitalisation for heart failure, myocardial
infarction and death from cardiovascular causes.

The achievement of the research objectives will be evaluated by comparison of baseline data and follow up data
The occurrence of such adverse events will be determined by data linkage to medical records to detect hospital presentations for the above conditions, and/or upon post procedural clinical assessment. Validation of diagnosis and the outcomes of each event will be assessed by the use of standard diagnostic tools, such as serum laboratory tests, Holter monitoring, echocardiography, electrocardiogram (ECG), physical examination and patient history.
Timepoint [1] 263734 0
Baseline to 6 months post-procedure.
Secondary outcome [2] 263735 0
Effect of treatment on patients' clinical status. This will be assessed by recording the patient's symptoms according to the New York Heart Association (NYHA) classification and Canadian Cardiovascular Society (CCS) classification, as well as recording the use of medication and additional nitroglycerine used to cover anginal attacks. Six-minute hall walk and physical examination will also be performed.
Timepoint [2] 263735 0
Baseline, 3 months, 6 months post-procedure.
Secondary outcome [3] 263736 0
Effect of treatment on patients' exercise capacity. Changes in exercise duration and cardiopulmonary efficiency will be determined by performing standardised treadmill testing (modified Bruce protocol) and mixed venous oxygen (MVO2) measurement.
Timepoint [3] 263736 0
Baseline, 3 months and 6 months post-procedure.
Secondary outcome [4] 263737 0
Effect of treatment on the myocardium (infarct and peri-infarct region) function and perfusion will be assessed by myocardial perfusion imaging using the single photon emission computed tomography (SPECT) technique.

A 9-segment model will be used for analysis in which the short-axis slices will be selected for interpretation, representing basilar, midventricular, and apical levels of the LV. The mid and basilar short-axis slices will be subdivided into 4 segments representing the anterior, anteroseptal, inferoposterior, and lateral regions. A qualitative assessment for these 9 segments (normal, reversible defect, fixed defect) will be performed and perfusion score calculated.
Timepoint [4] 263737 0
Baseline, 6 months post-procedure.
Secondary outcome [5] 263738 0
The safety of the endomyocardial injection technique will be determined by the incidence of all adverse events, defined as any undesirable clinical occurrence in a subject whether or not it is considered to be procedural related.

All adverse events will be reported and classified as mild, moderate or severe according to EN14155 definition. The Principal Investigator will determine the causal relationship of individual adverse events to the study procedure/s.
Timepoint [5] 263738 0
Procedure to six months post-procedure.

Eligibility
Key inclusion criteria
Age 18 -80 years.
CCS classification II-IV angina and/or NYHA classification II-III heart failure symptoms.
Received stable and “best” cardiac medical therapy including diuretics, long-acting nitrates, beta-blocker, and angiotensin-converting enzyme inhibitors without control of symptoms.
Not suitable for conventional revascularization (due to diffuse disease, chronic total occlusion, lack of graftable vessels or any combination thereof).
LVEF <40% by echocardiography.
Recent coronary angiogram (within the last 6 months) to document the coronary anatomy and insure the presence of Coronary Artery Disease (CAD) that is not amenable to standard revascularization procedures.
Serum creatinine less than 250mmol/L, normal liver function, and normal blood count: white blood cell (WBC) count, granulocytes; platelet count, haemolglobin (Hb).
Reversible perfusion defect on SPECT.
Hemodynamically stable.
Subject is willing to comply with specified follow-up evaluations.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Atrial fibrillation.
History of syncope or major ventricular arrhythmias such as sustained ventricular tachycardia or ventricular fibrillation.
Severe valve disease.
Aortic or mitral valve prosthesis.
History of cancer in last 5 years.
Acute or chronic active sepsis, including human immunodeficiency virus (HIV) positive; hepatitis B or C positive.
Left ventricular (LV) wall thickness less than 8 mm in the target territory (by echocardiography or MRI).
LV thrombus and/or spontaneous echo-contrast in the LV detected by echocardiography or LV aneurysm.
Severe aorto-femoral-iliac disease.
Recent heart attack within the last 30 days.
Hypertrophic or restrictive cardiomyopathy.
Severe co-morbidity associated with a reduction in life expectancy of less than 1 year.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation by sequential sealed opaque envelope.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by tabled sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
1/05/2011
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 256734 0
Commercial sector/Industry
Name [1] 256734 0
Johnson and Johnson Medical Pty. Limited
Country [1] 256734 0
Australia
Funding source category [2] 256735 0
Other
Name [2] 256735 0
Hunter Medical Research Institute
Country [2] 256735 0
Australia
Primary sponsor type
Hospital
Name
John Hunter Hospital
Address
Lookout Road, New Lambton Heights, NSW 2305
Country
Australia
Secondary sponsor category [1] 256020 0
None
Name [1] 256020 0
Address [1] 256020 0
Country [1] 256020 0
Other collaborator category [1] 1175 0
Hospital
Name [1] 1175 0
Queen Mary Hospital
Address [1] 1175 0
Department of Medicine, The University of Hong Kong, Rm 1928, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong
Country [1] 1175 0
Hong Kong

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258744 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 258744 0
Locked Bag 1, HRMC, NSW 2310
Ethics committee country [1] 258744 0
Australia
Date submitted for ethics approval [1] 258744 0
Approval date [1] 258744 0
10/11/2009
Ethics approval number [1] 258744 0
09/03/18/3.01
Ethics committee name [2] 260521 0
Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster
Ethics committee address [2] 260521 0
Rm 903, Administration Block, Queen Mary Hospital, Hong Kong
Ethics committee country [2] 260521 0
Hong Kong
Date submitted for ethics approval [2] 260521 0
Approval date [2] 260521 0
16/10/2008
Ethics approval number [2] 260521 0
UW 08-121

Summary
Brief summary
The aim of this study is to evaluate the efficacy and safety of percutaneous catheter-based direct intramyocardial
injection of autologous bone marrow cells, a new therapeutic strategy, in patients with severe CAD experiencing symptoms of angina and chronic ischaemic heart failure, where all conventional medical treatment
options have been exhausted. Our recent randomised, placebo controlled trial (Angiogenesis - Protect CAD)
demonstrated the beneficial effects of bone marrow cell therapy over placebo saline injection on symptoms, functional capacity and LVEF in patients with chronic myocardial ischaemia who failed conventional medical
treatment and revascularisation procedures. However, the clinical implications of this treatment for severe CAD needs
to be demonstrated in a larger population with more definitive primary endpoints.
Positive evidence to support the use of this therapeutic approach may have a profound impact on the health and well
being of chronically ill CAD patients, by providing a catheter-based treatment that is cost-effective and utilises easily
reproducible techniques for the harvesting and injection of bone marrow. Furthermore, the patients's own bone marrow may be considered as a readily available resource which overcomes issues associated with immunological rejection response.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30999 0
Dr Suku Thambar
Address 30999 0
Cardiovascular Department
John Hunter Hospital
Lookout Road
New Lambton Heights NSW 2305
Country 30999 0
Australia
Phone 30999 0
+61-2-4921 4204
Fax 30999 0
Email 30999 0
Suku.Thambar@hnehealth.nsw.gov.au
Contact person for public queries
Name 14246 0
Dr Suku Thambar
Address 14246 0
Cardiovascular Department, John Hunter Hospital, Lookout Road, New Lambton Heights, NSW 2305
Country 14246 0
Australia
Phone 14246 0
+61 2 4921 4216
Fax 14246 0
+61 2 4921 4210
Email 14246 0
Melissa.Chaplin@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 5174 0
Dr Hung Fat Tse
Address 5174 0
Department of Medicine, The University of Hong Kong, Rm 1928, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong
Country 5174 0
Hong Kong
Phone 5174 0
+852 2855 3598
Fax 5174 0
+852 28186304
Email 5174 0
hftse@hkucc.hku.hk

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Results publications and other study-related documents

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