Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02479776 |
| Other study ID # |
07CC37 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
June 8, 2015 |
| Last updated |
June 23, 2015 |
| Start date |
May 2008 |
| Est. completion date |
March 2015 |
Study information
| Verified date |
June 2015 |
| Source |
Great Ormond Street Hospital for Children NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United Kingdom: Research Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
The bone marrow mononuclear cell fraction has been used as therapy after myocardial
infarction and in dilated cardiomyopathy in adults. The absence of adult co-morbidities may
enhance the potential effectiveness of pediatric stem cells.This study is a randomized,
crossover, placebo controlled pilot study to primarily determine the safety and feasibility
of stem cell intracoronary therapy in children. Secondary end points are MRI measurements
and NTproBNP.
Ten children (mean age 7.2 years, range 2.2-14.1, 6 male) with dilated cardiomyopathy (NYHA/
Ross Classification 2-4) will be recruited. Bone marrow aspiration MRI and cell injection
are performed under the same anaesthetic. Patients will be crossed over at 6 months.
Description:
This pilot study is of a randomized, crossover, placebo controlled design. The Consolidated
Standards of Reporting Trials (CONSORT) statement was used to guide the development of the
protocol. Ethical Approval was obtained for this project in April 2008.
A CONSORT flow diagram was produced and a project plan for a crossover study designed.
Although the primary end point of the study was safety and feasibility the investigator
aimed to look at functional outcome as a secondary endpoint. Statistical review of the
available literature indicated a 3% change in ejection fraction (EF) as measured by magnetic
resonance imaging (MRI) would represent a meaningful change and calculated 10 patients would
be sufficient to detect this mean change in EF, assuming a SD of difference of 3% with 80%
power and 5% significance. For all calculations it was assumed that the distribution of
differences was Normal. Calculation of a sample size for the crossover study required a
definition of the minimum difference to be detected.
Children aged 1 year to 16 years at review, either attending Heart Failure Clinic at Great
Ormond Street Hospital (GOSH) or referred for admission and management of their heart
failure at GOSH will be invited to participate in the study. The lower age limit was
selected to permit coronary artery catheterisation to be feasibly performed taking into
account the size of the patient.
On recruitment all patients have impaired systolic function as determined by reduced
shortening fraction on echocardiogram (more than 2 SD below normal). The functional status
of the recruited patients was class 2-4 as defined by the NYHA or Ross classification.
Exclusion criteria were the need for high dependency or intensive care and congenital heart
disease, viral infection that would preclude the use of hospital Cell Therapy Laboratory
facilities, active malignancy and unstable cardiac drug therapy.
Potential patients will be identified from case notes, and they and their families
approached either by telephone or following clinic review to evaluate their interest in
participation. Any patients who appeared interested in participating in the study will be
given age and language appropriate written information; and also given a contact telephone
numberso that additional information could be supplied if required. Each family will be
given the opportunity to discuss the study with the research team before consent for
inclusion was obtained.
Protocol:
Ten patients who met the eligibility criteria will be recruited for this study. Each patient
is randomized at entry to the study to determine whether they would receive stem cells at
Period One or Period Two of the protocol. Randomisation was performed using a
computer-generated random number table, Graph pad.
Following recruitment and randomisation, patients have their individual admission time-line
planned. Those patients who are to receive stem cells at their first study admission are
reviewed within the 28 days preceding that date. At this review, screening for infection, as
per our hospital Cell Therapy Laboratory protocol (including HIV and hepatitis B and C) will
be performed, following full written consent.
On the day of the procedure the patient will be admitted to the cardiac day-care facility
for baseline observations and clinical assessment. The study procedure will be performed in
the Cardiac MRI theatre under general anaesthetic. Blood samples will be taken at the time
of anaesthesia for routine investigation (full blood count, urea, electrolytes, liver
function and NTproBNP).
Those patients receiving intracoronary stem cells at this admission have 20mL of bone marrow
aspirated from the posterior iliac crest under aseptic conditions immediately after
induction of anaesthesia.
Bone marrow aspiration technique:
Those patients on anticoagulation therapy are highlighted in advance of all procedures and
admissions, and optimal coagulation management implemented prior to, during and following
the bone marrow aspiration. All bone marrow processing is undertaken at the Great Ormond
Street Hospital cell therapy processing facility.
Following anaesthetic induction and the securing of a stable airway the patient is
positioned to permit bone marrow aspiration. Full aseptic conditions are observed throughout
the procedure. A volume of 20 mL of bone marrow is aspirated from a single needle puncture
site using heparinized 10mL syringes attached to the bone marrow needle following removal of
the central trocar. The aspirated bone marrow is transferred to sterile heparinized
universal specimen bottles. Immediately after aspiration the bone marrow sample is taken to
the cell therapy laboratory for mononuclear cell separation using standard techniques of
gradient centrifugation.
The mononuclear cell separation protocol takes approximately 90 minutes to complete. The
bone marrow sample is processed to provide 1mL for intra-coronary injection and 1mL to be
cryogenically frozen for further phenotypic analysis at a later date. A small aliquot of
stem cell suspension is analysed to obtain total mononuclear cell counts per millilitres.
This cell count represents the total number of mononuclear cells injected via intra-coronary
catheterisation. In addition cell viability was also assessed.
Whilst waiting for the prepared stem cells, the cardiac MRI scan is performed using a breath
hold protocol for image acquisition. Following the MRI scan the patient is transferred by
means of the mechanized sliding table back into the angiography suite.
On return to the angiography suite the patient is maintained under general anaesthesia until
notice is given by the stem cell laboratory that the stem cell processing is nearing
completion. Following contact with the stem cell laboratory an arterial sheath is placed in
the femoral artery of the study patient and advanced until its tip is sited in the left main
coronary artery. Partial occlusion of the coronary artery was observed as demonstrated by ST
segment changes and damping of the pressure trace is routinely monitored during such
procedures. The 1mL volume is slowly injected via the coronary artery catheter into the left
main coronary artery followed by a 1mL 0.9% saline flush over a period of 2 minutes.
Following the intracoronary injection of stem cell suspension the cardiac catheter is
removed and haemostasis at the skin entry site achieved. The patient is then woken and
recovered in a standard manner.
Patients are admitted to the cardiac ward overnight with routine monitoring of the arterial
catheterisation access site and bone marrow aspiration site; cardiac care observations are
continued throughout. Patients are discharged the following day and electively reviewed in
the outpatient's clinic at three months post-procedure or advised to contact the Research
Fellow sooner if any concerns.
Cross-over of interventions occurs at six months with the stem cell group receiving placebo
via the cardiac catheterisation (no bone marrow harvest is required for the placebo arm of
the study) on the second occasion. The same admission, monitoring and follow up will be
arranged as for the stem cell stage of the study. The placebo used for the intracoronary
injection used is 1mL 0.9% saline, consistent with the placebo solution used in adult
studies. The 1mL of placebo is followed with a 1mL 0.9% saline flush for correlation with
the stem cell arm of the study. An interim clinic review is again arranged at three months
post procedure and a follow up cardiac MRI scan at six months. The time scale was chosen
after review of the available adult literature which showed that effects on the left
ventricle were usually seen within 6 months.
Those patients randomly allocated placebo at stage one of the study cross over to receive
stem cells at stage two. Interim and final follow up arrangements are the same for the stem
cell and placebo groups.
Anaesthesia was standardized for all patients and the same anaesthetist used for all
procedures. Bone marrow preparation was also standardized and performed by the same
scientist in each case. Computer data entry will be double-checked. Patient identifiers are
removed from the anonymous images to allow blind analysis later on; in this way unbiased
image analysis is performed. A single researcher using Osirix software performs off-line
analysis of the data. As a second check of these data the researcher's results are
evaluated, again blind to patient identifiers, by a second analyser. The key to the blinding
of the MRI data is devised, applied and stored securely by a clinician not otherwise
involved in the study. Indexed values correct the data for age, sex, height and weight and
permit true comparisons to be made between the series of studies of the same individual and
between different individuals.
Primary outcome measures:
The primary outcome measures were freedom from death and transplantation or any complication
which could be considered related to bone marrow injection or anaesthesia
(infection/malignancy/anaphylaxis/renal deterioration). A safety monitoring committee,
including a cardiologist from Great Ormond Street Hospital not involved in the trial, an
external cardiologist and a lay representative, will be established. Any adverse events will
be reported to the committee which was empowered to halt the trial at any time if concerns
arose.
Secondary outcome measures:
Ejection fraction, left ventricular volumes and mass are derived from cardiac MRI. Blood is
taken for NT proBNP. In addition functional status is assessed by the New York Heart
Association classification or the Ross classification in younger children.
Each patient has a cardiac MRI under general anaesthetic. The anaesthetist and anaesthesia
protocol are the same for all patients.
All images are obtained with a 1.5-T MR scanner (Avanto, Siemens, Erlangen, Germany) using a
12-element phased-array coil for signal reception and the body coil for signal transmission.
A vector ECG system is used for cardiac gating.
Left ventricular (LV) volumes are measured from contiguous short-axis steady state free
precession cine covering both ventricles (7-13 slices, depending on the size of the child).
Each slice is acquired in a single 10- to 15-second breath hold as previously described. All
image processing is performed using in-house plug-ins for the open-source Osirix DICOM
(digital imaging and communications in medicine) software. The LV end-diastolic volume (EDV)
and end-systolic volume (ESV) are measured by manual segmentation of the endocardial borders
in the short-axis data. Careful segmentation of the basal slices in conjunction with
4-chamber and LV long-axis views is performed to overcome problems with delineating the
mitral valve. Ventricular stroke volume (SV) was the difference between the EDV and ESV, and
ventricular ejection fraction (%) was (SV/EDV)×100.
For each of the secondary end points, EDV, ESV and EF, comparisons between treatments are
made on an intention to treat basis. A crossover analysis on post treatment measures is
conducted using an analysis of variance model, considering sequence, period and treatment
effects. Carry-over effect is tested first and where there is no evidence of a significant
effect, the treatment effect is tested. A subsequent generalized estimating equation (GEE)
model was fitted which allowed for an adjustment for baseline measures.
Where the distribution of the data was clearly non-Normal the investigators use a
logarithmic transformation. Stata is used for all statistical analyses and all tests were
two-sided. A P value < 0.05 was considered significant.
