Safety Study of Sibling Cord Blood Cell Infusion to Children With Cerebral Palsy
Phase: PHASE1
Conditions: Cerebral Palsy
Sponsor: Murdoch Childrens Research Institute

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Study identifier: 
Safety of sib CB for CP  
 
 
 
 
Full study title: 
Safety study of sibling cord blood cell infusion to children with cerebral palsy 
 
 
Lay study title: 
Stem Cells in Umbilical Blood Infusion for CP (SCUBI-CP) 
HREC/14/RCHM/38  
RCH HREC ID: 34210 
Version 10, 6th March 2017 
 
 
CONFIDENTIAL 
This document is confidential and the property of the Murdoch Children’s Research Institute and the 
Stem Cell Umbilical Blood Infusion for Cerebral Palsy (SCUBI-CP) Research Group (being The 
Royal Children’s Hospital Melbourne, Cerebral Palsy Alliance, Cell Care Australia, Monash Health, 
MIMR-PHI Institute of Medical Research, The Children’s Hospital at Westmead, Lady Cilento 
Children’s Hospital Brisbane, Children's Health Queensland Hospital and Health Service, and The 
University of Queensland).            
No part of it may be transmitted, reproduced, published, or used without prior written authorisation 
from the institution. 
 
STATEMENT OF COMPLIANCE 
 
This document is a protocol for a clinical trial. The study will be conducted in compliance with all 
stipulations of this protocol, the conditions of ethics committee approval, the NHMRC National 
Statement on Ethical Conduct in Human Research (2007) and the Note for Guidance on Good Clinical 
Practice (CPMP/ICH-135/95). 
 
 

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CONTENTS 
1. 
INVESTIGATORS AND FACILITIES ..................................................................................................... 6 
1.1. 
Study locations ............................................................................................................................... 6 
1.2. 
Study management ........................................................................................................................ 6 
Principal Investigators ........................................................................................................................... 6 
Associate Investigators .......................................................................................................................... 7 
Statistician ............................................................................................................................................. 9 
1.3. 
Internal trial committees ................................................................................................................. 9 
Trial Steering Committee ....................................................................................................................... 9 
Safety and Data Monitoring Committee ................................................................................................. 9 
Scientific Committee .............................................................................................................................. 9 
1.4. 
Funding and resources ................................................................................................................... 9 
2. 
INTRODUCTION AND BACKGROUND .............................................................................................. 10 
2.1. 
Background information ................................................................................................................ 10 
2.2. 
Rationale for current study............................................................................................................ 13 
3. 
STUDY OBJECTIVES ......................................................................................................................... 14 
Primary objective .................................................................................................................................... 14 
Secondary objectives .............................................................................................................................. 14 
4. 
STUDY DESIGN ................................................................................................................................. 14 
4.1. 
Number of participants ................................................................................................................. 17 
4.2. 
Expected duration of study ........................................................................................................... 17 
4.3. 
Primary and secondary outcome measures .................................................................................. 17 
4.4. 
Eligibility Criteria ........................................................................................................................... 18 
4.5. 
Participant withdrawal ................................................................................................................... 20 
5. 
STUDY PROCEDURES ...................................................................................................................... 20 
5.1. 
Recruitment .................................................................................................................................. 20 
5.2. 
Enrolment (visit 1) ........................................................................................................................ 21 
5.3. 
Group allocation ........................................................................................................................... 22 
5.4. 
Baseline (visit 2) ........................................................................................................................... 22 
5.5. 
Infusion (visit 3) ............................................................................................................................ 23 
5.6. 
Rehabilitation therapy ................................................................................................................... 25 
6. 
STUDY VISITS AND PROCEDURES SCHEDULE ............................................................................. 26 
7. 
CLINICAL AND LABORATORY ASSESSMENTS – METHODOLOGY ............................................... 27 
7.1. 
Safety measures .......................................................................................................................... 27 
Medical History ....................................................................................................................................... 27 
Physical examination .............................................................................................................................. 27 
Medical assessment................................................................................................................................ 27 
Observation ............................................................................................................................................ 27 
Assessment of CBU ................................................................................................................................ 27 
Analysis of blood – pre-transplant work up .............................................................................................. 28 

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Analysis of blood – immunology screen .................................................................................................. 28 
Analysis of blood – studying infusion safety and mechanism .................................................................. 28 
7.2. 
Descriptive measure (CP assessment) ......................................................................................... 28 
7.3. 
Evaluative measures .................................................................................................................... 29 
Motor assessment (baseline and at visits 7 and 9) .................................................................................. 29 
Quality of life assessment (baseline and at visits 7 and 9) ...................................................................... 29 
Cognitive assessment (baseline and at visit 9) ........................................................................................ 29 
8. 
REPORTING ADVERSE EVENTS ...................................................................................................... 30 
9. 
STATISTICAL METHODS ................................................................................................................... 31 
10. 
Data management and Administrative Aspects ................................................................................ 32 
Biobank ................................................................................................................................................... 32 
Participant reimbursement ...................................................................................................................... 33 
Financial disclosure and conflicts of interest ........................................................................................... 33 
Use of data and publications policy ......................................................................................................... 33 
11. 
REFERENCES ................................................................................................................................ 33 
Appendix 1: 
Information to go into CP register newsletters ................................................................ 38 
Appendix 2: 
Script for first contact phone conversation (families contacting research team) .............. 39 
Appendix 3: 
Record of verbal consent ................................................................................................ 42 
Appendix 4: 
Letter following verbal consent ....................................................................................... 43 
Appendix 5: 
Template to ask CBB to locate CBU records .................................................................. 44 
Appendix 6: 
Script for phone conversation after CBU record search .................................................. 45 
Appendix 7: 
Script for phone conversation to arrange Visit 1 ............................................................. 47 
Appendix 8: 
Letter to family to request confirmation of diagnosis ....................................................... 49 
Form requesting confirmation of diagnosis .............................................................................................. 50 
Appendix 9: 
Letter to child’s doctor requesting information ................................................................ 51 
Appendix 10: 
Screening questions to establish immune status for medical history ............................... 52 
Appendix 11: 
Post-infusion handout ..................................................................................................... 54 
Appendix 12: 
Serious adverse event report form ................................................................................. 55 
Appendix 13: 
Categorising severity of AEs related to study treatments: NCI Common Terminology 
Criteria for AEs (CTCAE) ........................................................................................................................ 56 
 
 
 

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PROTOCOL SYNOPSIS 
Title 
Safety study of sibling cord blood cell infusion to children with cerebral palsy 
Objectives 
The primary objective of this study is to gain preliminary information on the safety of 
12/12 HLA matched umbilical cord blood cell (UCBC) infusion in children with 
cerebral palsy (CP). 
The secondary objectives of this study are: 
 
A) to gain preliminary information on the treatment effect of 12/12 HLA matched 
UCBC infusion  
B) to better understand the length of time that infused matched sibling UCBCs 
remain within recipients 
C) to gather information and samples for future studies into mechanistic activity 
of UCBCs 
Trial sites 
The Royal Children’s Hospital Melbourne 
Lady Cilento Children’s Hospital Brisbane 
The Children’s Hospital at Westmead (recruitment) 
Monash Health (recruitment) 
Participants 
Number to be enrolled for screening: 48 
Number to continue through trial: 12; Age: 1 - 16 years old 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
ABBREVIATION TERM 
AusCord 
Australian National Network of Umbilical Cord Blood Banks and Cord Blood 
Collection Centres 
ABMDR 
Australian Bone Marrow Donor Registry 
ABMTRR 
Australasian Bone Marrow Transplant Recipient Registry 
AE 
Adverse event 
BMDI CBB 
BMDI Cord Blood Bank 
BMI 
Body mass index 
CBB 
Cord blood bank 
CBU 
Cord blood unit 
CHW 
The Children’s Hospital at Westmead 
CIBMTR 
Center for International Blood & Marrow Transplant Research 
CP 
Cerebral palsy 
DMSO 
Dimethyl sulfoxide 
EPO 
Erythropoietin 
GMFCS 
Gross motor function classification system 
GvHD 
Graft-versus-host disease 
HLA 
Human leucocyte antigen 
LCCH 
Lady Cilento Children’s Hospital Brisbane 
MCRI 
Murdoch Children’s Research Institute 
MNC 
Mononuclear cells 
MRI 
Magnetic resonance imaging 
NSW CPR 
New South Wales Cerebral Palsy Register 
OT 
Occupational therapy 
PT 
Physiotherapy 
PVC 
Peripheral venous catheter 
QCPR 
Queensland Cerebral Palsy Register 
RCH, Melbourne 
The Royal Children’s Hospital Melbourne 
RCT 
Randomised controlled trial 
SAE 
Serious adverse event 
SCBB 
Sydney Cord Blood Bank 
SOP 
Standard operating procedure 
TNC 
Total nucleated cells 
TRECs 
T-cell receptor excision circles 
UCB 
Umbilical cord blood 
UCBCs 
Umbilical cord blood cells 
VCPR 
Victorian Cerebral Palsy Register 

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1. INVESTIGATORS AND FACILITIES 
1.1. 
Study locations 
Infusion sites: 
State 
Site 
Victoria 
The Royal Children’s Hospital Melbourne 
Queensland 
Lady Cilento Children’s Hospital Brisbane* 
* Optional 
Other study procedures: 
State 
Site 
Victoria 
The Royal Children’s Hospital Melbourne 
Monash Health 
New South Wales 
The Children’s Hospital at Westmead 
Queensland 
Lady Cilento Children’s Hospital Brisbane 
All states 
Locally as required 
1.2. 
Study management 
The study will be managed by a research team consisting of principal investigators, associate investigators 
and clinical trial coordinators who will manage the daily operations such as recruitment, follow up 
assessments and study documentation. This is a multisite clinical trial, and each site will be managed by a 
different Principal Investigator. Across the sites, there will be a number of teams for different aspects of the 
trial, each with a designated team leader (please see below). 
This trial is investigator-initiated by a collaborative research group. This trial does not have a sponsor. 
Principal Investigators  
Principal Investigators at each site will coordinate the supporting departments within the hospital. They will 
undertake site meetings and have access to a clinical trial coordinator working in each state. 
The Royal Children’s Hospital Melbourne (test site, lead HREC) 
Prof Dinah Reddihough is group leader of Developmental Disability and Rehabilitation Research in the 
Clinical Sciences theme at MCRI, paediatrician in Developmental Medicine at The Royal Children’s 
Hospital Melbourne and affiliated with the Department of Paediatrics, University of Melbourne. 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: dinah.reddihough@rch.org.au 
Phone: +613 9345 5898 
 
Brisbane site 
 
Dr Priya Edwards is a Paediatric Rehabilitation Specialist in the Queensland Paediatric 
Rehabilitation Service, Children’s Health Queensland Hospital and Health Service. 
Lady Cilento Children’s Hospital 
501 Stanley St South Brisbane Qld 4101 
Email: Priya.Edwards@health.qld.gov.au 
Phone: +617 3636 5400 
 
Monash Medical Centre 
A/Prof Michael Fahey is head of Paediatric Neurology at Monash Children’s Hospital. 

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Monash Health 
246 Clayton Rd, Clayton Vic 3168 
Email: michael.fahey@monash.edu 
Phone: +613 9594 3499 
The Children’s Hospital at Westmead 
Prof Nadia Badawi leads the CP Alliance Research Institute, is a neonatologist at The Children’s 
Hospital at Westmead and affiliated with the University of Notre Dame Australia and the University 
of Sydney 
The Children's Hospital at Westmead 
Locked Bag 4001, Westmead NSW 2145 
Email: nadia.badawi@health.nsw.gov.au 
Phone: +612 9845 2715 
 
Associate Investigators 
Associate investigators will be responsible for coordinating the team in their area of expertise or advising 
according to their expertise. 
Prof Iona Novak, Head of Research at the Research Foundation of the CP Alliance; affiliated with 
Notre Dame University Australia 
187 Allambie Rd 
Allambie Heights, NSW 2100 
Email: INovak@cerebralpalsy.org.au 
Phone: 0409 078 917 
Prof Mark Kirkland, haematologist, medical director of Cell Care Australia; affiliated with Deakin 
University 
42 Corporate Dr 
Heatherton, Vic 3202 
Email: mark.kirkland@cellcare.com.au 
Phone: +613 8551 0221 
Dr Francoise Mechinaud, paediatric transplant specialist. Cancer group leader in the Cell Biology, 
Development and Disease theme of MCRI; Director of the Children’s Cancer Centre at the RCH, 
Melbourne 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: francoise.mechinaud@rch.org.au 
Phone: +613 9345 4893 
Prof Euan Wallace, obstetrician, Monash Medical Centre; Director of the Ritchie Centre, Monash 
University 
Monash Health 
246 Clayton Rd, Clayton Vic 3168 
Email: Euan.Wallace@monash.edu 
Phone: +613 9594 5145 
Dr Katherine Lee, Associate Director of Biostatistics, Melbourne Children’s Trial Centre, and senior 
biostatistician in the Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research 
Institute 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: katherine.lee@mcri.edu.au 
Phone: +613 9345 6549 
Prof Paul Colditz, is Director of the Perinatal Research Centre; at the University of Queensland Centre 
for Clinical Research and neonatologist at the Royal Brisbane and Women’s Hospital. 
UQCCR, Royal Brisbane and Women’s Hospital  
Herston Qld 4029 
Email: p.colditz@uq.edu.au 
Phone: +617 3346 6014 
Dr Ngaire Elwood, cord blood researcher. BMDI Cord Blood Bank; group leader of cord blood bank 
research at Murdoch Children’s Research Institute; The Royal Children’s Hospital Melbourne; The 
University of Melbourne 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: ngaire.elwood@mcri.edu.au 
Phone: +613 9345 6398 

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Dr Chris Fraser, paediatric transplant specialist at Lady Cilento Children’s Hospital Brisbane 
Lady Cilento Children’s Hospital 
501 Stanley St South Brisbane Qld 4101 
Email: chris.fraser@health.qld.gov.au 
Phone: +617 3068 1111 
Dr Helen Savoia, transfusion haematologist. The Royal Children’s Hospital Melbourne; The University 
of Melbourne 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: helen.savoia@rch.org.au 
Phone: +613 9345 5916 
Dr Kylie Crompton, CP researcher. Developmental Disability and Rehabilitation Research in the 
Clinical Sciences theme at MCRI 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: kylie.crompton@mcri.edu.au 
Phone: +613 9936 6756 
Dr Pamela Clark, cord blood researcher. Outgoing director of the Sydney Cord Blood Bank 
Sydney Children’s Hospital 
Level 3, Clinical Sciences Building 
Email: pamela.clark@health.nsw.gov.au 
Phone: +612 9382 0371 
Ms Janet Hough, senior physiotherapist. Monash Health; Victorian Paediatric Rehabilitation Service 
Monash Health 
246 Clayton Rd, Clayton Vic 3168 
Email: janet.hough@monashhealth.org 
Phone: +613 9594 6666 
A/Prof Peter Anderson, psychologist, Group leader, Victorian Infant Brain Study, Clinical Sciences 
theme at Murdoch Children’s Research Institute  
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: peter.anderson@mcri.edu.au 
Phone: +613 9936 6704 
Dr Simon Paget, paediatrician in Kids Rehab at The Children’s Hospital at Westmead, and Lecturer at 
The University of Sydney 
The Children's Hospital at Westmead 
Locked Bag 4001, Westmead NSW 2145 
Email: simon.paget@health.nsw.gov.au 
Phone: +612 9845 2819 
 
Dr Kuang-Chih Hsiao, immunology fellow, Epworth HealthCare; honorary fellow, Murdoch Children’s 
Research Institute; and Clinical Lecturer at The University of Melbourne 
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: kuangchih.hsiao@mcri.edu.au 
 
Dr Karin Tiedemann, transplant specialist (retired); Medical Director, BMDI Cord Blood Bank; Director, 
National Stem Cell Foundation of Australia  
The Royal Children’s Hospital 
50 Flemington Rd, Parkville Vic 3052 
Email: karin.tiedemann@rch.org.au 
 
 
Infusion 
The infusion team will be headed by Dr Francoise Mechinaud, paediatric transplant physician at the RCH 
Melbourne. Dr Chris Fraser, LCCH Brisbane and by Dr Helen Savoia, paediatric transfusion medicine 
specialist, RCH Melbourne. Once the trial is underway, the steering committee will consider expanding the 
trial to include a third infusion site hospital, in NSW, to further demonstrate the feasibility of this trial as a 
multi-site project. 

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Therapy 
All participants will receive their regular rehabilitation therapy.  
Assessment 
Safety assessment will primarily be conducted by both the infusion team (described above).Therapists and 
a psychologist independent of the therapy team providing rehabilitation, and laboratory staff, will complete 
other components of the safety assessment as well as assessments relative to secondary aims of the 
study. The team will undertake structured training in assessment tools prior to trial commencement. 
Statistician 
Dr Katherine Lee, located in the Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research 
Institute. 
 
1.3. 
Internal trial committees 
Trial Steering Committee 
Prof Dinah Reddihough (PI, Melbourne), paediatrician; Committee Chair 
A/Prof Iona Novak (AI), occupational therapist 
Prof Euan Wallace (AI), obstetrician at Monash Medical Centre 
A/Prof Michael Fahey (PI, Monash), neurologist 
Prof Nadia Badawi (PI, Sydney), neonatologist 
Dr Katherine Lee (AI), biostatistician 
Prof Mark Kirkland (AI), cord blood researcher 
Dr Francoise Mechinaud (AI), paediatric transplant specialist 
Dr Priya Edwards (PI, Brisbane), rehabilitation paediatrician 
Prof Paul Colditz (AI), neonatologist 
Dr Kylie Crompton (AI), scientist; Committee Secretary 
Safety and Data Monitoring Committee 
This committee will meet every three months, including after the first three participants have reached one 
month post-infusion for review prior to further participant infusions. 
Prof Ross Pinkerton, paediatric oncologist (Chair) 
Prof Rory Wolfe, statistician 
A/Prof Adam Scheinberg, paediatric rehabilitation specialist 
Dr Richard Mitchell, paediatric transplant specialist 
Dr Catherine Marraffa, developmental paediatrician 
Scientific Committee 
Prof Euan Wallace, obstetrician 
A/Prof Michael Fahey, neurologist 
A/Prof Mark Kirkland, haematologist 
Prof Paul Colditz, neonatologist 
Dr Suzanne Miller, neuropathologist (The Ritchie Centre, MIMR-PHI, Monash University) 
Prof Stephen Holdsworth, immunologist (Monash Health, Monash University) 
Dr Ngaire Elwood, cord blood researcher 
1.4. 
Funding and resources 
Source 
Funding / Resource 
Research Foundation of the Cerebral Palsy Alliance 
In kind; Cash 

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Cell Care Australia 
In kind; Cash 
All other participating institutions 
In kind 
2. INTRODUCTION AND BACKGROUND 
2.1. 
Background information 
Cerebral palsy (CP) describes a group of permanent non-progressive motor and postural disorders arising 
from damage to the developing brain while in utero, during birth or in the first years of life [1, 2], and affects 
around 2 per 1000 live births across the world. The main types of CP include spasticity (stiffness of 
muscles accounting for around 80% of all diagnoses), dyskinesia (abnormal involuntary movements) and 
ataxia (unsteadiness) which result from lack of normal nervous control of muscles. Depending on the 
location and severity of brain damage, different regions of the body may be affected. This is described as 
hemiplegia (one side of the body), diplegia (legs greater than arms) or quadriplegia (all limbs). The degree 
of motor impairment is often described using the Gross Motor Function Classification System (GMFCS), 
with GMFCS I indicating an otherwise normal child who may have impaired speed, balance or coordination, 
increasing in severity to GMFCS V indicating limited motor function, wheelchair use with limited head 
control. CP is often associated with epilepsy, difficulties in speech, sight, hearing, sensation, perception, 
behaviour or cognition. There is currently no cure for CP. 
Scientific rationale 
Recent interest in stem cell therapy for intractable neurological disorders has led to a large number of 
preclinical studies of brain injuries related to CP that show evidence of therapeutic potential. In particular, a 
greater understanding of the varied stem cells to be found in human umbilical cord blood (UCB), which is 
less ethically complicated than many other sources of stem cells, has led to a focus on UCB stem cell 
therapy. The stem cells in UCB do not form cancers and present a lower risk of graft-versus-host disease 
(GvHD) than bone marrow stem cells [3]. Transplantation of UCB cells in acute animal models of CP such 
as excitotoxic white matter injury [4] and neonatal hypoxia-ischaemia [5-10] have shown significant 
neurofunctional improvement, as have models of adult stroke [11-16], spinal cord injury [17-21] and 
traumatic brain injury [22]. On the other hand, preclinical studies showing no benefit from UCB cell (UCBC) 
treatment of acute brain injury have also emerged [23-25]. While some studies involve transplanting 
UCBCs directly to the injured area of the brain, there is strong evidence that the minimally invasive 
intravenous infusion to the periphery is equally as effective [4, 26]. Investigations into the mechanism of 
UCBC transplantation action reveal anti-inflammatory properties, protection of neural cells from secondary 
cell death, promotion of host cell proliferation and migration, and angiogenesis. It does not appear that 
human (xenogeneic) stem cells engraft to replace lost brain cells in immune-supressed animal models. 
Thus the stem cell treatment is not considered a transplant but can be thought of as a transfusion. 
The transfusion mechanisms described above are appropriate for the acute phase of brain injury, which 
involves inflammation, primary and secondary cell death and chemical signalling. Preclinical work has 
almost entirely focussed on acute brain injury, and it is unknown if these mechanisms will operate in the 
same way in the chronic phase of disease. This area has been well reviewed in the literature [27-31]. CP is 
a heterogeneous condition with varied brain pathology, so it is possible that stem cell infusion may act 
through different mechanisms for different children. For example, some children have large brain lesions 
that might benefit from increasing the number of available neurons, whereas there is evidence that some 
infants born preterm may have reduced number of neural connections rather than reduced number of 
neurons [32].  Improvement in functioning for children with the former pathology may be due to recruitment 
of endogenous stem cells caused by UCBC infusion [33]. The latter pathology may potentially be linked to 
increasing synapses and dendritic arborisation rather than generating new neurons from either infused or 
endogenous stem cells [34]. Recruiting endogenous stem cells would take time to replicate, differentiate, 
migrate and integrate new cells, while generating new synapses from existing neurons in situ could occur 
sooner. 
Safety discussion 

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Autologous blood transfusions are safe from the immunological point of view, and using cord blood rather 
than peripheral blood does not change the risk profile. There is an increase in risk when a cryopreserved 
rather than fresh blood product is used due to possible toxicity by residual dimethyl sulfoxide (DMSO) 
which can be reduced by ‘washing’ the cord blood unit prior to infusion. There is also a risk associated with 
any intravenous blood cell infusion that flooding the body with cells may temporarily block capillaries in the 
lungs. Both of these adverse events are temporary and treatable. 
Infusing cells from anyone other than oneself introduces the risk of immune response. The first use of 
allogeneic UCBC infusion was a transplant in 1989 for a child with Fanconi anaemia [35] and 25 years later 
over 30,000 UCBC transplants have been conducted worldwide for children and adults with a range of 
haematological, immunologic and metabolic disorders. UCBC infusions conducted under coverage of 
immune-depleting conditioning regimen improves the likelihood of donor haemopoietic stem cells in the 
cord blood to persist and engraft in the recipient's bone marrow. After optimising the technique for 25 years, 
there is still a risk of mortality from GvHD, whereby the donor cells attack the immune-supressed recipient. 
This risk is reduced with improved HLA matching, and at its lowest using full matched related donors [3]. 
The preclinical data behind stem cell therapy as a possible treatment for CP demonstrates that donor 
UCBCs may not need to persist or engraft to mediate functional benefit. Given the risks and side effects, 
and little expected benefit, this protocol does not use a conditioning regimen or immune-suppressant. 
Without immune suppression, the recipient’s immune system is expected to easily reject infused cells, 
further reducing the risk of GvHD. To minimise the risk of engraftment of UCBCs in participants with 
undiagnosed severe combined immune deficiency, clinical and laboratory screening of participants to 
exclude severe combined immune deficiency will be carried out. 
The risk profile of the proposed UCBC infusion can perhaps be compared with a standard blood 
transfusion. There have been instances of transfusion-associated GvHD (TA-GvHD) from related donors, 
but in all cases these were shown to be in the specific case where the recipient was heterozygous for a 
haplotype that the donor was homozygous for (was haploidentical) [36, 37] – for example if the recipient’s 
haplotype was MN, and the donor was MM, the donor cells recognise the host as foreign but the host does 
not recognise donor cells as foreign. This occurs more frequently in cultures with lower genetic variation 
such as Japan [38] and has led to the irradiation or leucodepletion of blood products from related donors 
[39]. Due to tissue typing and matching, this will not occur in this protocol and reduces the risk of GvHD 
relative to TA-GvHD. 
A fraction of cells may remain in the body long term (microchimerism) as may happen after blood 
transfusion or pregnancy [37]. In studies of microchimerism after feto-maternal blood transfer, an 
association with auto-immune symptoms was found [40-42] which may possibly have relevance here. In a 
small study of long term microchimerism specifically looking for chronic TA-GvHD symptoms, no 
association was found although the level of evidence was low. When comparing cord blood with peripheral 
blood used in a transfusion, the cord blood has immature immune cells less likely to provoke a response 
than peripheral blood immune cells, but cord blood contains a larger proportion of stem cells compared with 
a peripheral blood transfusion which may have an impact on the degree of long term chimerism. Because 
there is no direct evidence of the longevity of matched sibling cord blood cells after infusion to an immune-
competent recipient, we will use new, more sensitive, genetic analysis methods to follow the long term fate 
of cells to track risk of GvHD for individual participants, conducted by the Cytomolecular Diagnostics 
Laboratory, MCRI. This data, along with other safety assessments, will be monitored by the site transplant 
specialist. 
The few relevant clinical studies of UCB stem cell therapy in patients with CP are described below. Clinical 
studies of CP must inevitably be in the chronic phase of disease and may not compare to acute preclinical 
studies. No efficacy studies using UCBCs in children with CP have yet been published internationally. The 
few studies available of UCB stem cell therapy in CP patients demonstrate safety and imply potential 
efficacy of this intervention, and are outlined below. 
Case study – autologous cord blood 

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A case study of two toddlers in Thailand transfused with autologous (their own) UCB along with 
subcutaneous injections of granulocyte colony stimulating factor showed no side effects. The children 
improved as measured by the GMFCS [43]. 
Pilot trials – autologous cord blood 
In a pilot study at Hanyang University Medical Centre, Republic of Korea, 20 children aged 2-10 years, with 
a range of CP types and born either preterm or term, were treated with infusion of their entire donated cord 
blood (rather than the nucleated fraction of cells as used in other studies). Cell numbers ranged from (0.6-
15.65)x107/kg. Neurodevelopmental outcomes were monitored at 4, 8, 12 and 24 weeks and a range of 
neuroimaging studies were conducted at 24 weeks compared with a baseline measures prior to infusion. 
Functional improvements were seen in a range of activities in 25% of patients all of whom had hemiplegia 
or diplegia. No patients with quadriplegia showed definite improvements. There was some possible 
correlation between functional improvements and improvements on brain imaging; however the study was 
underpowered due to low number of patients [44]. Five patients (25%) experienced minor side effects, 
probably due in part to the inclusion of red blood cells in the infusion, which resolved with antihistamine and 
hydration. Despite its limitations, the study demonstrated practicality, safety and possible benefit of UCBC 
therapy [44]. 
Over the period 2004-2009, autologous UCBC infusions (>3x107 nucleated cells/kg infused) were 
performed at Duke University (Duke Blood and Marrow Transplant Program), USA, in children up to 8 years 
old with acquired neurological disorders, including 76% with CP [45]. No neuro-functional data was 
collected, but the infusions were shown to be safe and feasible, with only three adverse reactions across all 
184 participants. These reactions were considered most likely to be due to residual dimethyl sulfoxide, 
DMSO, used in cryopreservation. 
Randomised controlled trials – autologous cord blood 
Subsequent to these studies which established the safety and feasibility of autologous UCBC infusion, 
randomised, placebo-controlled cross-over trials of autologous UCBCs commenced in children with CP. In 
2010, Duke University (NCT01147653 [46]) and Georgia Regents University (NCT01072370 [47]), both in 
the USA, began trials involving 120 and 40 children and due to finish in 2016 and 2014, respectively. In 
addition, the University of Texas Health Science Center has recently started a comparative trial that aims to 
randomise 30 children with CP to a placebo arm and two treatment arms, comprising infusion of either 
autologous UCBCs or autologous bone marrow mononuclear cells (NCT01988584 [48]). 
Randomised controlled trials – allogeneic unrelated donor cord blood 
Bundang CHA Hospital, Republic of Korea recently published a trial of allogeneic (unrelated) cord blood 
combined with erythropoietin (EPO, a neuroactive potentiator), cyclosporine (a neuroactive 
immunosuppressant) and intensive rehabilitation therapy [49]. The trial used two control groups, the first 
received placebo blood, placebo EPO and immunosuppressant, the second received placebo blood and 
immunosuppressant but active EPO, with around 31 participants in each group (a total of 96 completed the 
trial). The cord blood treatment group was the only group to show benefit at 6 months after infusion 
compared with baseline, scoring higher on mental and motor assessment scales, which correlated with 
changes in diffusion tensor imaging (DTI). Sub-group analysis revealed that the younger children, and 
those with better-matched human leucocyte antigen (HLA) blood types, did the best with this treatment. 
There were no differences in serious adverse events between groups [49]. 
The Korean group is now examining allogeneic cord blood infusion combined only with immunosuppressant 
(NCT01528436, listed as complete in July 2012 [50] but unpublished, and NCT01639404 [51]). Two further 
trials have recently been listed on Clinicaltrials.gov, (NCT01991145 [52] and one which is focussed on 
analysing cytokine production, NCT02025972 [53]).  
A recently listed randomised comparative trial is being conducted at the General Hospital of Chinese 
Armed Police Forces, China.  Intrathecal infusion of mesenchymal stem cells derived from allogeneic cord 
blood will be compared with either one year of rehabilitation therapy or with normal clinical care, including 
300 children aged 1-14 years randomised between the three arms (NCT01929434, [54]).  

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The accumulating preclinical evidence of the therapeutic value of UCB stem cell therapy, together with 
evidence from clinical trials for the safety of UCBCs from a range of sources, has led to increasing media 
coverage and has created hope and expectations in the CP community [55]. Yet the literature evidence 
regarding efficacy is mixed and clinical data are scarce. Trials to establish the efficacy of UCBCs in CP are 
complicated by the fact that, although autologous UCBCs are the safest type of stem cells, they are not 
available for most children with CP. On the other hand, unrelated donor UCBCs are readily available but 
pose a higher risk of graft-versus-host disease (GvHD). An alternative is matched sibling UCBCs which 
have the same level of major HLA match as autologous cells and have a decreased, although persistent, 
risk of GvHD relative to unrelated donor UCBCs. These are used clinically for children with haematological 
indications but, to our knowledge, have not been used for children with CP.  
2.2. 
Rationale for current study  
Despite the lack of conclusive evidence, UCBC infusion for CP is already in use in some parts of the world. 
Moreover, Australian children with CP are travelling to China, India, Germany and elsewhere to undergo 
UCBC therapy in an unregulated environment and at great cost. Therefore a well-designed and properly 
administrated trial evaluating the safety and efficacy of UCBCs in CP is necessary to guide clinicians and to 
inform patients and their families; and if successful, to develop treatment streams in Australia. Evidence 
from the previous studies outlined above suggests that autologous UCBCs may be ideal, and full matched 
sibling UCBCs the next best option.  We have previously investigated the number of potential participants 
with autologous cord blood in storage. Although it may have been possible to conduct a trial with this group, 
numbers are small as children with CP are often born pre-term or with traumatic births that preclude cord 
blood collection. Sibling cord blood is more readily available as parents often store sibling blood following 
the diagnosis of a child with CP, and our partner Cell Care Australia is offering to cover the expense of 
prospectively collecting cord blood from siblings of children with CP to enable their eligibility to participate in 
this trial or future trials. Furthermore, during our feasibility assessments we met with representatives of the 
Australian Bone Marrow Donor Registry (ABMDR) which governs Australian public cord blood banks. 
ABMDR would not contemplate involvement in this research without demonstration of capability, and 
presentation of preliminary safety data ethically collected using a safer form of UCBC than unrelated donor 
UCBCs. Our long-term aim is to conduct a randomised trial to assess the efficacy of UCBCs from any 
donor in improving functional abilities of CP, to develop a treatment available to all children with CP. 
UCBCs will be infused intravenously as the least invasive delivery route. In order to give the brain the best 
chance of developing new pathways, rehabilitation therapy will also be used. 
We hypothesise that the infusion of matched cord blood cells to a child with CP will induce a period of 
neuroplasticity that will be safe and may lead to functional benefit. 
In the current study we plan to collect initial safety data. The results from this study will also provide a 
proof-of-concept in order to prepare and demonstrate capability for a number of possible future trials. This 
safety study will be investigate matched sibling UCBCs in children aged 1 to 12 years. In the future we 
would aim to conduct randomised trials to 1) assess efficacy of 12/12 HLA matched UCBCs for children 
with established CP compared with placebo; 2) assess the safety and efficacy of unrelated donor UCBCs 
for children with established CP with placebo and 3) assess the safety and efficacy of prospectively 
collecting CB at the birth of at risk children and re-infusing a) immediately if diagnosed with neonatal 
encephalopathy or b) within one year if signs of developing CP emerge compared with placebo. Future 
trials may focus on younger children since the limited evidence available indicates that younger children 
have the best chance of benefitting from UCBCs, however this age range has not yet been defined. We 
plan to use a wider age range of children for feasibility reasons and to help establish the best cut-point for 
future trials. 

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3. STUDY OBJECTIVES 
Primary objective 
The primary objective of this study is to gain preliminary information on the safety of 12/12 HLA matched 
sibling UCBC infusion in children with CP. 
Secondary objectives 
The secondary objectives of this study are: 
A) to gain preliminary information on the treatment effect of 12/12 HLA matched UCBC infusion 
relative to baseline  
B) to better understand the length of time that infused matched sibling UCBCs remain within recipients 
C) to gather information and samples for future studies into mechanistic activity of UCBCs 
4. STUDY DESIGN 
This is a multi-site safety study. 
Sibling donor UCBCs require careful DNA testing to ensure matching with the recipient (participant). Only 
about 25% of siblings have full-matched blood, the 75% that are not full-matched will be excluded. No 
immunosuppression will be used, as the infused cells do not need to survive for long periods within the 
recipient and immunosuppression increases the safety risk. The first six enrolled participants to receive 
infusions will be GMFCS IV or V; participants with mild or moderate CP (GMFCS I, II or II) will be waitlisted. 
This is because the safety profile of matched sibling UCBC infusion for children with CP is unknown, we 
feel it is more ethical to initially trial in the participants with severe CP and gather information for interim 
Data Safety Monitoring Committee (DSMC) review, before continuing the trial with less impaired 
participants. The DSMC will review safety data from the first three participants after three months post-
infusion and decide whether the trial can progress to the next three participants. After these initial six 
participant infusions, the DSMC will decide whether the trial can progress to infusions of participants with 
mild CP or not. The DSMC will provide a report to the Trial Steering Committee, who will provide the report 
directly to the RCH HREC for review. The HREC will make a final decision about whether the trial can 
expand to include children with mild or moderate CP at this point, or whether the trial will remain restricted 
to children with severe CP only. 
. 
 

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Figure 1: Participant timelines for the study  
 
 
 
 
Figure 2: Recruitment decision making process (next page) 
 
Enrolment 
Infusion 
Safety 
-3wks 
t=0 
1d 
1wk 
1 mo 
3 mo 
Safety 
Baseline 
assessments 
12 mo 
Safety, 
Motor assessment 
/ / 
Depending on lab analysis 
time and scheduling (at 
least 5wks) 
Participant exclusion if required 
Make first contact by phone 
Receive CBB template letter in mail, 
fill in and send to research team 
Receive study Information Statement 
in mail. Family considers study. 
Make call to arrange next steps, 
enrolment appointment 
Receive call to provide information 
Receive call from study coordinator 
with confirmation of CBU storage 
Receive doctor template in mail, 
fill in and send to research team 
Enrolment 
Total time estimated to be at least 8 weeks 
Safety, Motor 
and Cognitive 
Safety 
Safety 
 
6 mo 

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Families contact researchers 
Does the child have CP? 
Yes 
Does the child have an immune system disorder or immune deficiency?  
No 
Did the family collect sibling CB? 
Yes 
  
  
Exclude 
No 
No 
Search CBB records for sibling CBU 
Is sibling CB available? 
Physical examination,  
CP and baseline assessments, 
Blood test for pre-infusion work up, 
and immunology screen 
Exclude 
Blood test for HLA typing; CBU testing 
Is CBU full-matched and usable? 
Exclude 
Delay infusion 
or Exclude 
Physical examination 
UCBC infusion 
n=3 participants of GMFCS IV, V 
n=3 participants of GMFCS IV, V 
 
n=6 participants of all GMFCS 
Participant cleared for infusion 
CBU cleared for release 
Yes 
No 
Yes 
Visit 2 
- 3 wks 
Visit 1 
> - 8 wks 
Visit 3 
Time = 0 
Excess participants excluded 
Safety screen fail 
No letter, consent or 
reasonable explanation 
Ask families for letter from doctor/ 
permission to contact 
Yes 
No 
Alternative 
diagnosis 
Invited to face-to-face Informed Consent 
Consent to trial? 
Does the child have a CP diagnosis from a doctor?  
Letter or consent 
Pre-screening 
Yes 
No 
* May require further 
investigation after consent 
Exclude 
Reasonable explanation* 
Trial publicised through community organisation, registers and private cord blood banks 
Further examination 
Exclude 
Exclude 
Exclude 
CP diagnosis unclear* 
DSMC review
DSMC review
HREC review

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4.1. 
Number of participants 
This trial will initially enrol up to 48 participants who fit initial eligibility criteria of having CP, no immune 
deficiency, and records of a CBU from the participating child or the child’s siblings. This group will undergo 
detailed screening at visits 1 and 2 to determine further participation. Screening at visit 1 involves first line 
immunology screening (see section 7.1), tissue typing and cord blood unit examination of all participants to 
determine eligibility for trial groups. Screening at visit 2 involves general health screens. Enrolment will be 
staggered to allow sequential screening assessment and group allocation. Up to 12 of the 48 enrolled 
participants will continue with the trial after visit 2. 
 
Trial treatment and analysis will involve 12 participants with CP.  
We have previously assessed the potential participant population by linking CP registers and cord blood 
banks (Victorian Cerebral Palsy Register, VCPR, with BMDI Cord Blood Bank, RCH HREC 32183; VCPR 
with Cell Care Australia, RCH HREC 32220; NSW CPR with Sydney Cord Blood Bank, ABMDR HREC 
2012/06 and CP Alliance HREC 2012-12-04). We estimate that in early 2013 there were between 10 and 
24 children over 2 years old with CP who had their own stored UCBCs across Australia. We do not expect 
that sufficient numbers would enrol in a trial of autologous cord blood infusion. Cord blood storage from 
siblings of children with CP increases every year, however we are unable to easily assess the number of 
children in Australia who have CP and sibling cord blood available. We have kept a register of families 
interested in this research that have a child with CP and sibling cord blood in storage and we predict that 15 
(25%) of a predicted 60 suitable families across Australia are likely to be eligible for treatment. We believe 
sufficient numbers will prove to be eligible and will choose to enrol in the trial. The 12 treatment places will 
be filled chronologically from date of enrolment as participants proceed through screening. Once the 12 
treatment places are full, excess participants will be excluded. To minimise this, potential participants will 
be told the approximate likelihood of continuing through the trial given the available number of places at the 
time of arranging a visit for informed consent. Potential participants will also be encouraged to continue any 
required medical programs irrespective of trial exclusion criteria, to prevent children delaying surgery or 
treatment with Botulinum toxin A while awaiting enrolment and then notification that they will either continue 
with the trial or be excluded. Trial infusion schedules will be staggered over six months to accommodate lab 
and space availability. Therefore, children who have received surgery or Botulinum toxin A treatments 
within the exclusion period can have their trial visits and trial treatments delayed to wait out the exclusion 
period if needed. 
The remaining 75% of children who have CP and sibling cord blood available but do not have matching 
blood will be excluded from this trial. All excluded participants will be notified of the level of match or 
mismatch of their stored cord blood when they are notified of their exclusion.  
Once all 12 participant places across sites have been filled, enrolment will cease. 
4.2. 
Expected duration of study 
The study is expected to take 2 years until final follow up and data analysis. This allows recruitment and 
screening over three months, then sequential treatment in groups of three. Each group of three is expected 
to be treated within one month, then followed until three months post-infusion for Data Safety Monitoring 
Committee (DSMC) review and approval to continue. After the first two groups of three, the final six 
participants will be infused. The final 12 month follow up assessment for each participant will occur 13 
months after baseline measurements for each individual. 
4.3. 
Primary and secondary outcome measures 
The primary objective of this study is to collect initial safety data during and after infusion of sibling UCBCs. 
The following outcomes will be collected to assess this objective which will be assessed at three time 
points:  
 
1) During the infusion and up to 36 hours after 
- Clinical assessment, including vital signs and pulse oximetry 
- Laboratory assessment looking for markers of infection 

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- Occurrence of AEs and SAEs 
2) Within the three months after infusion 
- Clinical assessment 
- Laboratory assessment looking for markers of immune reaction 
- Deterioration of motor function as assessed by Gross Motor Function Measure 
- Occurrence of AEs and SAEs 
3) Within the 12 months after infusion  
- Clinical assessment 
- Deterioration of motor or cognitive function as assessed by the appropriate tool (see section 7.3) 
- Occurrence of AEs and SAEs 
 
The secondary outcomes include: 
 
Efficacy of the intervention at 3 months measured by therapists on a suite of standardised 
psychometrically sound measures of movement, cognition and quality of life. This will be assessed 
in an exploratory fashion only. The areas for assessment were selected to focus on motor outcomes 
because CP is a primarily motor disorder; on cognitive outcomes that have shown change in an 
international trial [49] and anecdotally from private stem cell clinics (changes in wakefulness, 
attentiveness and alertness have been described); and how these might affect the participant’s life;  
The motor and quality of life outcomes will also be measured at 3 months. Cognition will be 
measured at 12 months after infusion and used to calculate change from baseline. Again, the 
analysis of the 12 month data will be exploratory in nature. 
 
Understanding the longevity of infused cells. This will be achieved using chimerism studies 
(engraftment analysis), looking for infused cells circulating in a sibling recipient’s blood. We will 
study chimerism by extracting circulating cell free DNA from plasma and using a new quantitative 
PCR method detecting differences in copy number deletions between the recipient and donor. It will 
be reported as the fraction of donor DNA in the sample at each time point for each individual, and 
constitutes both a safety and mechanistic study. 
The final objective of gathering information and samples for future studies into mechanistic activity of 
UCBCs will be achieved by collecting and storing serum, DNA and RNA from peripheral blood provided 
by participants before and after infusion as well as from the CBU. Serum will be used for cytokine 
analysis of participants post-infusion compared to pre-infusion. RNA arrays of neurotrophic and glial 
factors of UCBCs will also be compared with pre-infusion peripheral blood from the participant and with 
standard levels in adult peripheral blood.  
4.4. 
Eligibility Criteria 
Inclusion Criteria 
To be eligible for this study, the following criteria must be fulfilled: 
 
Aged older than 1 year and younger than 16 years at time of enrolment 
 
Diagnosis of any type of CP 
 
CP of any severity 
 
A record of sibling CBU in storage at a TGA accredited private cord blood bank 
 
Ability to travel to one of the trial centres 
 
Ability to participate in assessments  
 
Informed consent by parent/guardian and an indication of willingness/compliance by children 
 
Exclusion Criteria 
Patients will be unable to participate in the trial if they: 
 
Show presence of progressive neurological disease 
 
Have a known genetic disorder 
 
Have a known brain dysplasia 
 
Have ever been diagnosed with an immune system disorder or immune deficiency syndrome 
 
Have infectious disease markers showing up on the virology screen 

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 
The intended cord blood unit shows evidence of contamination, or has fewer than 107 cells per kg body 
mass 
 
Require ventilator support 
 
Are unwell, or if the participant’s medical condition does not allow safe travel 
 
Have previously undertaken any form of cell therapy 
 
Have had, or are scheduled for, treatment with Botulinum toxin A within 3 months before or after 
infusion 
 
Have had, or are scheduled for, surgery within 3 months before or after infusion 
 
Cannot obtain parental or guardian consent 
 
Participants must have CP. During the initial phone call, researchers will ask about a potential participant’s 
CP, and inform families of the inclusion criteria. Nevertheless, as part of baseline assessments participants’ 
CP diagnosis will be evaluated for eligibility. 
CP is highly variable and it is not yet known whether all children with CP will respond to UCBC infusion in 
the same way. We will not exclude children based on the type of their movement disorder, on the area of 
their body that is affected or on the associated impairments that some children have. It is unlikely that 
children with extremely severe CP will gain greatly from this therapy, however, children with severe CP 
have the most to gain from the therapy, and our clinical experience is that these families are the most likely 
to risk travelling overseas for unregulated treatment. We considered that it would be unethical to ask a 
relatively unimpaired child to undertake unknown risk; however we feel that children with mild forms of CP 
have the potential to gain from the treatment as they do from other neuroplastic interventions [56, 57]. 
Therefore, this trial includes all levels of motor severity (GMFCS levels I-V), but groups the participant into 
bands according to severity – mild/moderate (GMFCS I, II and III) and severe (GMFCS IV and V). 
Participants with sibling UCBCs in storage will be scheduled according to severity with severe participants 
receiving infusions first. Safety data will be reviewed by the Data Safety Monitoring Committee after the first 
three (severe) participants, then after all severe participants have received infusions, at which point the 
DSMC report will be provided to the RCH HREC. If the HREC approve, mild/moderate participants will then 
receive infusions. 
All evidence points to younger recipients receiving the most benefit from stem cell therapy, hence this trial 
is restricted to children 16 years or younger. A lower age limit is specified according to common age at 
diagnosis of CP, and development of a child’s immune system; hence this trial is restricted to ages 1-16 
years old. 
At this point, only participants with cord blood units stored in private banks are eligible. If the ABMDR 
HREC and AusCord should approve this protocol, lead HREC approval will be sought to modify the 
protocol to include participants with publicly banked cord blood units. 
It is possible that a participant may fit the exclusion criteria at enrolment or at some point prior to infusion. 
If, in the researcher’s opinion, the participant may be eligible at a later date (e.g. if the participant were 
unwell), they will be referred to the site PI. The site PI will decide whether to remain in contact with the 
family for potential inclusion at a later date. 
In this study we exclude children with known genetic disorders or brain dysplasias (congenital brain 
malformation due to abnormal neural migration during early foetal development) because we do not believe 
they are likely to respond to this therapy. However, we will not be conducting brain imaging or genetic 
testing and recognise the possibility that a child in this study may have an unidentified genetic disorder or 
brain dysplasia. We are excluding children who have previously had cell therapy as the previous therapy 
may continue to have an effect and make data difficult to understand, but as with genetic disorders and 
brain dysplasias, we will rely on self-report and acknowledge the risks of this.  

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4.5. 
Participant withdrawal 
Participants are welcome to withdraw from the study at any time. Researchers will ask the reason for their 
withdrawal, and whether they are withdrawing from study treatments (UCBC infusion if they withdraw 
immediately after screening and baseline assessment) and/or the follow up assessments. If families agree 
to continue with the follow-up, researchers (either site PI or study coordinator) will contact participant 
families at each follow up assessment point by phone to arrange the assessment. Families that have 
previously withdrawn and have asked for no further contact will be excluded from this process. The timing 
and reasons for withdrawal will be documented in all cases. 
Researchers may need to withdraw a participant for the participant’s safety, for example if a serious 
adverse event occurs during infusion that prevents completion of the infusion. Additionally, if the study is 
terminated for any reason, all participants will be withdrawn. If participants require excluded medical 
procedures, such as surgery prior to the UCBC infusion, they will be withdrawn, but if the excluded medical 
procedures are required after the UCBC infusion the protocol violation will be recorded and reported but the 
participant will not be withdrawn from the study.  
Regardless of when or why the participant withdraws, they will be offered medical assistance and follow up 
for the duration of the study to ensure the participant’s safety. 
5. STUDY PROCEDURES 
5.1. 
Recruitment 
In order to distribute information about this study, researchers will provide a description of the trial to CP 
registers and community organisations and to private cord blood banks (Appendix 1: Information to go in 
newsletters). 
 
Researchers will ask CP registers to publish details of this trial in their newsletters and invite 
families to contact researchers. 
 
Researchers will ask community organisations to distribute the information as appropriate. 
 
The private cord blood banks will notify their clients of this trial and invite families to contact 
researchers. 
Recruitment through clinicians and allied health professionals will be welcomed. Our experience is that 
there are many families who are interested in stem cell therapy and have brought this to the attention of 
their clinicians. Researchers will therefore make information available by providing the Australasian 
Academy of Cerebral Palsy and Developmental Medicine (AusACPDM) with information to circulate to 
clinicians and allied health professionals working in the field of CP.  Thus, if families approach their 
clinicians and allied health professionals to discuss the trial, the professionals will have some 
understanding. Making information available for health professionals will also be valuable for later in the 
trial, particularly in areas of Australia far from infusion sites. 
Families that contact the study team will be verbally informed about the trial by the lead site study 
coordinator, will have the opportunity to ask questions and will be informed of eligibility requirements. 
Researchers will ask for verbal consent to record some details about the potential participant in the study 
database (does the child have CP, do they have an immune deficiency, did they store cord blood at birth of 
any child, which child, where, family contact details; see Appendix 2: Script for first contact phone 
conversation, Appendix 3: Record of verbal consent, and Appendix 4: Letter following verbal consent).  
If families believe they donated the potential participant’s sibling UCB, and they would like to find out if the 
CBU is recorded at a CBB, researchers will mail the family a template letter (Appendix 5: Template to ask 
CBB to locate CBU records) which explains the purpose of the requested CBU search, has space for the 
family to fill in required details including the participant’s sibling’s date of birth, hospital of birth, sex and 
mother’s details, and a signature constituting consent for the CBU search and for the CBB to provide 
researchers with results of the CBU search. A second copy of the template letter will be included for 

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families to retain as a record of their consent, and a reply-paid envelope for families to mail the first copy to 
researchers (rather than directly to a CBB, to preserve CBB independence from the trial). Once 
researchers receive this template letter as consent, the trial coordinator will provide the appropriate CBB 
with a copy so that they are able to locate a record of the CBU. Families will be notified of the outcome of 
the record search by phone. The details from those who verbally consented during the initial phone call, 
and signed consent following the record search will be recorded in the study database as part of initial 
recruitment data. 
Once the CBU record search is complete, the lead site study coordinator will phone to provide the results of 
the search, to discuss the next steps with potential participant families (Appendix 6: Script for phone 
conversation after CBU record search, or part of the above phone call if appropriate) and to encourage 
families to discuss the trial with their clinician. An Information Statement without the consent form will be 
mailed to families so that families can continue considering their involvement in the trial. Families will be 
able to contact the lead site study coordinator or researchers to ask questions and discuss the study. If they 
choose to enrol, they must contact the lead site study coordinator or researchers to arrange an initial visit to 
an infusion hospital for the participant and family for informed consent. During this phone contact, the trial 
coordinator will inform families of the current number of places available within the trial and will estimate the 
likelihood that the potential participant will continue through the trial, and will request confirmation of the 
child’s diagnosis (Appendix 7: Script for phone conversation to arrange Visit 1, Appendix 8: Letter to family 
to request confirmation of diagnosis). 
If needed, and if the family consent, a letter and copy of the signed form (Appendix 8:) will be mailed to the 
nominated child’s doctor asking for information (Appendix 9: Letter to child’s doctor requesting information). 
If a family does not provide documentary evidence of CP diagnosis or consent to contact with a diagnosing 
or treating doctor, they may discuss it with the study doctor. If the family do not provide a reasonable 
justification for the lack of CP diagnosis, the child may be excluded. If the family provides reasonable 
justification, the child may require assessment by a paediatrician after Informed Consent, but prior to other 
study procedures. This will be at the discretion of the study doctor. 
A record of all participants that were pre-screened or enrolled by researchers will be sent to and kept by the 
lead site study coordinator, including reasons for ineligibility or non-participation if available, to inform future 
trial design. All participants who do not receive the intervention will also be asked whether they would like 
to be contacted about any appropriate future trials, and they will be informed that future trials may focus on 
younger children. The custodian of this databank will be the lead site study coordinator at the lead site until 
the conclusion of the trial, at which time custodianship will shift to the coordinating principal investigator. 
5.2. 
Enrolment (visit 1) 
At this visit, informed consent will be conducted face-to-face with the parent or legal guardian of the 
intended participant and the legal representative of the cord blood, either in person or by Skype or other 
video conferencing with the trial coordinator or a trial investigator. In most cases, because the intended 
participant and the cord blood donor must be full biological siblings they will have the same parent/guardian 
who is also the legal representative of the privately stored cord blood. Treating clinicians will not be able to 
take informed consent. 
Participants will then give a blood sample for tissue typing to match with CBUs. The samples will be 
collected either by the pathology collection service at the infusion hospital or at a local pathology collection 
service, and then blood for tissue typing will be sent to the transplantation services division of the Australian 
Red Cross Blood Service appropriate to the participant’s location. They will undertake generic HLA-A, HLA-
B and HLA-DR (which are inherited together and called a haplotype; each genome has two haplotypes) 
matching with CBUs to confirm that the identified sibling CBU is a match with the participant. Note that if 
the generic testing of HLA reveals that both haplotypes match, i.e. 6/6, inheritance of HLA alleles as entire 
haplotypes means that 12/12 HLA alleles match but nevertheless we will conduct tissue typing to assess 
12/12 HLA match. Tissue typing data will be received by a transplant physician at each site. If the CBU is a 
match, the transplant physician will order CBU pre-release work up from the CBB. ABO group and rhesus 
type will be checked at this time for participants who will receive sibling UCBCs, but incompatibility will not 

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prevent infusion. Sibling ABO group and rhesus type will be analysed from the CBU if sufficient red blood 
cells are available; otherwise it will be accepted from hospital records if available. If neither of these 
methods reveal the sibling ABO group and rhesus type, the sibling will need to attend the infusion hospital 
and provide a blood sample for testing. 
If the participant has more than one HLA matched sibling CBU available, determining which is selected for 
the trial will rely on ABO Rhesus matching. The presence of multiple sibling CBUs in storage will be 
established prior to enrolment, and extra blood will be collected from the participant during visit 1 to 
determine the participant’s ABO Rhesus group.  
Both the participant and the sibling donor will need to provide saliva samples for genotyping prior to copy 
number deletion chimerism assays. These samples can be collected at the hospital or the trial coordinator 
can provide the family with collection kits which can be returned at visit 2. 
5.3. 
Group allocation 
This study involves only a single group. If an individual participant has multiple eligible cord blood units in 
storage, a full matched sibling unit with matching ABO group will be selected as first preference and full 
matched sibling unit with mismatched ABO group as second preference.  
Around 75% of enrolled participants will be excluded because their sibling UCBCs in storage are not a full 
match. These participants will be notified immediately, but participants with matched CBUs who are 
excluded due to a full treatment group will not be notified immediately because visit 2 involves further 
screening that may require replacement participants. Once all continuing participants have completed visit 
2, excluded participants will be phoned by either the site PI or the trial coordinator to communicate their 
exclusion in the research study. At the conclusion of this study, we will send them a summary of results if 
they would like that. 
Some children may have epilepsy given it is a common association with CP.  Regardless of past history of 
epilepsy, participant families will be required to keep an epilepsy log to record frequency and severity of 
epileptic events to compare with a similar log after infusion (data collection form is attached). 
Families will be referred to counselling services if they feel distressed by learning of their exclusion. 
Families may feel upset to learn that their child will be unable to use the cord blood unit in storage. Families 
may also be upset at the conclusion of the trial if they did not perceive any improvement during the trial. 
5.4. 
Baseline (visit 2) 
Participants will be required to attend a second visit at the infusion hospital prior to infusion to confirm 
eligibility and establish baseline assessments. Participants will meet the trial doctors (both paediatrician 
and transplant specialist) to provide a medical history (including Appendix 10: Immunological screening 
questions) and undergo a physical examination including a photo of the participant’s skin to record 
characteristic colouring and evidence of rash at baseline, the trial therapist who will conduct a CP 
assessment, and the therapist and a psychologist to establish baseline assessments. If clinical 
screening reveals a temporary issue, such as having a current infection, which may affect results of a 
screening immunology test, the participant may need to return to the hospital at an appropriate time in the 
future before continuing further. 
The participant will then provide a blood sample at the hospital pathology collection service which will be 
used for confirmatory HLA typing (blood sent to Red Cross transplantation service for tissue typing of 6 
HLA alleles), virology (blood sent to Red Cross Blood Service for nucleic acid test (NAT) HIV 1 & 2, anti-
HIV 1 & 2 antibodies, Hepatitis B surface antigen, anti-Hepatitis B core antibody, NAT Hepatitis C 
virus,  anti-Hepatitis C virus antibody, anti-Human T-lymphotropic virus 1and 2 antibody and syphilis 
testing) and other pre-infusion screens through the hospital laboratory services to ensure the participant is 
otherwise healthy. The participant’s immune-competence will be screened at this visit, with full blood 
examination, lymphocyte subsets, naïve T cells and immunoglobulins. The results will be interpreted along 
with the participant’s clinical history and responses to the immunology screening questions. Trial doctors 

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will exclude from the study any participants suspected to have an immune deficiency disorder and refer 
them to the local clinical immunology team for further evaluation and management. 
In some cases, it may be necessary to collect blood from the participant’s mother, if Hepatitis B core 
Antibody (HepBcAb) was not tested from her blood at the time of cord blood collection, and depending on 
HepBcAb results from cord plasma sample tests. This allows a full risk assessment of HepB contamination. 
Clinically, HepBcAb positive cord blood that indicates a previous (maternal) exposure to HepB but no 
current infection would be eligible for use, however in this research context we cannot take even this 
minimal risk of contamination.  
This visit must occur a minimum of five weeks after Visit 1, to allow time for HLA typing, the CBU order to 
go to the CBB and three weeks for a private CBB to complete release work up including contamination 
assessment on the CBU and transport of CBU to the cell therapy lab of the infusion hospital. The infusion 
hospital needs a minimum of three weeks between arrival of the CBU and infusion, to finalise release 
assessments. The virology and immunology screen during Visit 2 must occur between 10 and 30 days prior 
to infusion at Visit 3. Visit 2 will be scheduled accordingly. 
5.5. 
Infusion (visit 3) 
Following the confirmation of CP, participants will be invited for a third visit at the infusion hospital where 
they will undergo their infusion. All CBBs in Australia process cord blood to reduce volume, deplete the 
concentration of red blood cells and collect the buffy coat which includes all nucleated cells and a fraction 
of red blood cells (most of which lyse upon cryopreservation). There are minor differences in CBB protocols 
such as the designated minimum volume of cord blood and the minimum of total nucleated cells (TNC) in 
the cord blood eligible for storage. As far as possible, UCBC treatment will be kept uniform among 
participants. If a record search identified a CBU and the participant enrolled in the study, HLA type of the 
CBU will be compared with HLA type of the participant to ensure it is a 12/12 HLA match. AusCord CBUs 
have already been HLA typed and their records will be used; private CBBs will send a pilot sample of the 
CBU to the Red Cross transplantation service for HLA typing. If the CBU is correct, all CBBs will undertake 
a reference thaw if not already completed, to test the quality of the CBU and confirm tissue type. Next, the 
transfusionist will organise CBU transport to the infusion hospital cell therapy lab where it will be stored 
below -180ºC in the vapour phase of liquid nitrogen. On the day of infusion, lab staff will thaw the CBU and 
then wash by diluting in dextrose/albumin and centrifuging to collect cells to minimise the presence of 
DMSO cryopreservant (less than 1% DMSO remains, an undetectable scent). The infusion hospital labs will 
report on post-thaw CBU qualities after release, including TNC, cell viability, CD34+ cell count, aerobic and 
anaerobic contamination and supernatant haemoglobin (see section 7 for details). 
Upon arriving at the infusion hospital day medical facility on the day of the infusion, the participant will 
provide a blood sample to the research nurse. This sample will have DNA, RNA and serum proteins 
extracted to compare with CBU and with post-infusion blood.  
Cannulation 
A peripheral vein catheter (PVC) will be inserted in the foot, hand or antecubital fossa 
after application of a numbing cream.  
 
Age range 
Gauge of PVC  
Infants and toddlers 
24 – 22 
Older children 
22 – 20 
 
Hydration: 
All participants will receive intravenous hydration, starting 2 hours prior to infusion 
and continuing for 4 hours after the conclusion of the infusion. This is to ensure good 
clearance of any residual red blood cells and free haemoglobin following infusion. 
Hydration will continue until urine is clear and there is no indication of hypertension. 
0.9% NaCl (normal saline) 
125 mL/m2/hr for a total of 6 hours 
Ordered by transplant physician or delegate 
Infused by nurse 

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Pre-Medication 
Ordered by transplant physician or delegate 
Administered by nurse 
 
Medication 
Administration Timing 
Reason 
Hydrocortisone 
25-100 mg 
Intravenous 
2 hours prior to infusion To prevent allergic reaction 
Antihistamine* 
Oral or 
intravenous 
1 hour prior to infusion 
To prevent allergic reaction 
Paracetamol 
Oral 
1 hour prior to infusion 
Pain prevention 
Ondansetron 
Oral 
1 hour prior to infusion 
Nausea prevention 
* The antihistamine will be selected according to clinical indication. Promethazine (Phenergan), 
which has sedative properties, may be used for children with saliva and airway control, but if 
there is concern about the airway cetirizine (Zyrtec) or other antihistamines may be used. 
 
Infusion:  
Intravenous (foot, hand or antecubital fossa) 
  
 
Catheter size as above (compromise between smallest being easiest for children,  
 
 
 
whilst remaining large enough to prevent cell damage) 
  
 
Infused over the course of 10-20 mins depending on age of the participant 
  
 
Maximum volume of infusate is 10 mL/kg recipient 
  
 
Ordered by transplant physician or delegate 
  
 
Infused by nurse 
  
 
Additional infusion identity check by study staff 
 
Minimum TNC: 
> 1 x 107 cells/kg body mass (in line with other international trials) 
 
In the case of a Rh+ donor and Rh- recipient, the transfusionist or transplant physician will order anti-
Rhesus D immunoglobulin (Anti-D) from the hospital blood bank, which will be delivered by i.v. or i.m. 
injection 24 hours after infusion (at visit 4) to prevent development of antibodies. The Anti-D administration 
is precautionary, the red blood cell depletion of CBUs and lysing of remaining red blood cells during 
cryopreservation combined with the CBU washing procedure means there should be negligible red blood 
cell antigens (ABO, rhesus, Kell or others) remaining.  
 
All participants will be observed carefully by the nurse following the infusion (see section 7) with a 
transplant physician available if observations fall outside the normal range (see section 8). Blood will be 
collected by the nurse 1 hour after conclusion of infusion to compare with baseline. 
Participants will be released from the hospital if they are haemodynamically stable and do not have 
haemoglobinuria. Participants will return to the hospital the next day for a physical examination and blood 
test. If there is any indication of infection or serious adverse event, the participant may need to remain in 
hospital for observation or medical attention. This is not expected. Participants will be provided with 
emergency phone numbers and instructions (see Appendix 11: Post-infusion handout). 
Further blood samples will be taken at 1 week, 1 month and 3 months, for both research and safety 
reasons (see Table 1). 
Table 1: Details of all proposed blood samples 
Blood 
collection 
Volume 
When is it taken? 
What is it for? 
Where does it go? 
What happens to 
it afterwards? 
1  
9 mL; 
Blood 
spot 
Soon after 
enrolment 
- Low resolution HLA typing 
to match sibling or 
autologous CBU with 
participant 
- Immunology screening 
- Red Cross 
Transplantation 
Services 
- RCH Melbourne 
Immunology Lab* 
Transported, 
destroyed 

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Sibling 
sample 
2.7 mL 
Soon after 
enrolment  
(only if assay 
cannot be 
conducted on 
CBU) 
- To assess blood group and 
rhesus type 
- Infusion hospital 
labs 
Transported, 
destroyed 
Maternal 
sample 
2.7 mL 
3 weeks prior to 
infusion (if not 
previously 
conducted) 
- To assess HepBcAb (to 
assess risk of HepB 
contamination of cord blood) 
- Infusion hospital 
labs 
Transported, 
destroyed 
2 
9 mL 
7 mL 
3 weeks prior to 
infusion 
- Low resolution 
confirmatory HLA typing to 
ensure matching blood is 
used 
- To assess blood group and 
rhesus type  
- To assess health of 
participant 
- Red Cross 
Transplantation 
Services 
- Infusion hospital 
labs 
 
Transported, 
destroyed 
3 
4 mL 
7.2 mL 
2 hours before 
infusion 
- To compare with the blood 
sample taken after 
treatment 
- Cell therapy lab 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
4 
8.2 mL 
4 hours after 
infusion 
- To look for inflammation 
- To compare with blood 
taken at baseline 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
5 
8.2  mL 
24 hours after 
infusion 
- To check for infection 
- To check the cell types in 
the participant’s blood 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
6 
8.2 mL 
1 week after 
- To look for inflammatory 
markers, signs of GvHD  
- To check the cell types in 
the participant’s blood 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
7 
6.4 mL 
1 month after 
- To check the cell types in 
the participant’s blood, 
chimerism assessment 
- To look for inflammatory 
markers, signs of GvHD 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
8 
6.4 mL 
3 months after 
- To check the cell types in 
the participant’s blood, 
chimerism assessment 
- To look for inflammatory 
markers, signs of GvHD 
- Infusion hospital 
labs 
- Cyto-molecular 
diagnostics lab* 
- Research labs* 
Frozen, 
transported and 
stored 
* Centralised testing, involving sample transport to Melbourne. RCH Melbourne Immunology Labs will undertake first 
line immunology screening; MCRI Cyto-molecular Diagnostics Lab will undertake chimerism assays. 
5.6. 
Rehabilitation therapy 
Standard care for children with CP involves the provision of rehabilitation therapies. It has also been 
hypothesised that stem cell-induced neuroplasticity might be optimised under “enriched” conditions, i.e. in 
the presence of activity-dependent plasticity arising from active rehabilitation based on neuroscience 
principles [58]. For both ethical and scientific reasons, all participants enrolled within this study will continue 
to receive their standard rehabilitation treatments. The study will request a monthly home diary of the 
family-determined therapy regimen for the duration of the trial.  

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6. STUDY VISITS AND PROCEDURES SCHEDULE 
Study phase 
Enrolment 
Baseline 
Infusion 
Follow up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Timing 
> 8 wks prior to 
infusion 
21 days prior to 
infusion 
0 
1 day 
1 wk 
1 mo 
3 mo 
6 mo 
12 mo 
Tolerance 
Any time 
> 3 wks since Visit 1 
- Within 10-30 days of clear virology 
screen 
- CBU available 
± 0 days 
±2 days 
± 7 days 
± 2 wks 
± 2 wks 
± 2 wks 
Location 
Hospital 
Hospital 
Hospital 
Hospital 
Hospital, 
home 
Hospital 
Hospital 
Hospital, 
community Hospital 
Informed consent (45 mins) 
X 
 
 
 
 
 
 
 
 
CP assessment (30 mins) 
 
X 
 
 
 
 
 
 
 
Medical history (0.5 hr) 
 
X 
 
 
 
 
 
 
 
Physical examination (0.5 hr) 
 
X 
X 
X 
 
X 
X 
X 
X 
Medical assessment (10 mins) 
 
 
 
X 
X 
weekly 
X 
X 
X 
Assessment of motor function (45 mins) 
 
X 
 
 
 
 
X 
 
X 
Assessment of upper limbs (15 mins) 
 
X 
 
 
 
 
X 
 
X 
Assessment of quality of life (0.5 hr) 
 
X 
 
 
 
 
X 
 
X 
Assessment of cognition (2hr 15) 
 
X 
 
 
 
 
 
 
X 
Infusion of UCB (30 mins) 
 
 
X 
 
 
 
 
 
 
Intravenous fluids, observation (6 hrs) 
 
 
X 
 
 
 
 
 
 
Anti-D administration if required (5 mins) 
 
 
 
X 
 
 
 
 
 
Blood collection 
X 
X 
2X 
X 
X 
X 
X 
 
 
Rehabilitation Therapy 
 
 
 
 
 
 
 
 
 
Length of visit 
1 hr 
6 hrs (may need two visits) 
9 hrs 
1 hr 
1 hr 
1 hr 
2 hrs 
1 hr 
4 hrs 
 

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7. CLINICAL AND LABORATORY ASSESSMENTS – METHODOLOGY 
7.1. 
Safety measures 
Medical History 
A medical history will be taken at visit 2, and permission to access hospital medical records is requested. 
A questionnaire will be used to gather information on immunological health status. 
Physical examination 
Physical examinations will be conducted by both a paediatrician and a transplant specialist prior to infusion. 
They will examine the participant to confirm eligibility by confirming the CP diagnosis during visit 2, and to 
ensure they are healthy. Participant weight and height will be measured and BMI calculated, the doctor will 
listen to the heart and lungs, feel the abdomen, take pulse and respiratory rates and confirm the 
neurological signs including assessing muscle tone and reflexes.   
After infusion, a transplant specialist will physically examine each participant at visits 4, 6,7 and 8 (1 day, 1, 
3 and 12 months post-infusion) as part of the medical assessment, to look for subtle signs of GvHD that 
may not be picked up by participant carers. 
Medical assessment 
Medical assessment will be conducted at 1 day, weekly until 1, 3 and 12 months after infusion, and at any 
time that the participant or their family feel concerned. All medical assessments will be conducted by a 
transplant specialist. It comprises a short list of questions of participant safety over the phone from the trial 
doctor, focused on signs of infection and inflammation. Should the participant show any indication of 
needing more detailed examination, they will be asked to return to the infusion hospital as soon as 
possible. If necessary, they may of course attend their nearest medical service and the trial doctor will 
follow this up. 
At visit 6 (6 months post infusion), a paediatrician either at a trial site hospital or in the local community will 
conduct a general health assessment of the participant. 
Observation 
Vital signs will be monitored by the nurse prior to UCBC infusion, during the infusion, every 15 minutes for 1 
hour, then every 30 minutes for 2 hours. The monitoring will include temperature measurement (in ºC), 
blood pressure (in mmHg), pulse oximetry (in % oxygen saturation) and checks for nausea and discomfort.  
Participants will also be monitored for symptoms of toxicity, including nausea, fever, chills, and for 
symptoms of anaphylaxis including wheezing and urticaria. 
 
A transplant physician will be available and called if vital signs fall outside the normal range (see section 8) 
or if there are signs of an adverse event. 
Assessment of CBU 
Cord blood is assessed initially upon donation prior to cryopreservation, including a maternal health follow 
up. While preparing to release a CBU, the CBB will undertake a reference thaw of a pilot sample to predict 
post-thaw characteristics, and a pilot sample will also be sent to the Red Cross Transplantation Service for 
HLA typing. If the CBU meets quality and release criteria of the CBB and fits eligibility requirements at this 
point, it will be transported to the cell therapy lab at the infusion hospital. 
The cell therapy lab of each infusion hospital will examine the CBU for release. If the CBU passes 
inspection again, the infusion date will be confirmed. On the day of infusion, the CBU will be thawed and 
washed and samples taken to assess for TNC, CD34+ cell count and viability, aerobic and anaerobic 
sterility, and supernatant haemoglobin although results from these assays are not available until a day or 
more after infusion. This follows standard operating procedure in preparation for haemopoietic stem cell 

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(HSC) transplant and hence focuses on HSCs. This is useful information and will form part of the study 
report; however UCBC therapy for CP has quite different aims to a HSC transplant. 
Therefore, the private cord blood bank labs will also conduct assessments of UCBCs with a focus on other 
cell types and potential modes of activity. Immunophenotyping will examine the range of cells present; and 
monocyte activity will be examined. 
Analysis of blood – pre-transplant work up 
Blood samples taken within 3 weeks of infusion will be used to assess general health and eligibility for 
infusion. A full blood examination, blood group and antibody testing, urea, electrolyte and liver function 
tests, C-reactive protein assay and virology screen will be undertaken. 
Analysis of blood – immunology screen 
The immunology screen involves full blood examination, immunoglobulin levels, lymphocyte subsets and 
naïve T-cells (or the local laboratory's equivalent test) performed at the local hospital's diagnostic 
laboratory. Local diagnostic laboratories' reference ranges will be used to interpret results in conjunction 
with the participant’s clinical history and responses to the immunology health screening questionnaire. 
Analysis of blood – studying infusion safety and mechanism 
Blood samples taken immediately before, 4 hours, 24 hours, 1 week, 1 month and 3 months after infusion 
will be used to collect serum, DNA and RNA.  
The sample taken prior to infusion will be used as both a baseline for any changes after infusion, as well as 
a control sample to compare with each participant’s CBU. 
The samples taken up until 1 week post infusion will have a full blood examination, urea, electrolyte and 
liver function tests, C-reactive protein assay and lymphocyte subsets assay. Chimerism will be assessed 
using a new digital PCR method to detect copy number deletions (CNDs) which is more sensitive and 
accurate than current standard chimerism assays (sensitivity to 50 genome equivalents/mL). This assay will 
be centralised to MCRI Cyto-molecular Diagnostics Lab as it is not generally available, and therefore 
requires sample transport. These assays are for safety, and to examine longevity of infused sibling cells in 
the circulation.  
This study will also gather information on the activity of infused cells. The focus will be on 
immunophenotyping, to look at populations of classically (M1) or alternatively (M2) activated macrophages, 
Treg cells and other immune cells, since this is one of the primary modes of UCBC action. 
The samples taken at 1 and 3 months after infusion will be used for C-reactive protein assay and 
lymphocyte subsets assay. These are to examine longevity of infused cells, and for safety studies to 
determine whether infused cells have engrafted, whether chimerism can be detected from participants 
receiving matched sibling UCBCs, and include assays for inflammatory markers. These tests will monitor 
and determine the risk of GvHD for the participants. If chimerism is still detected at 3 months, further testing 
may be needed. 
A portion of the samples will be stored at -80ºC for future studies. This is important, as we expect a far 
greater understanding of the activity of UCBCs in cerebral palsy to emerge over the coming years which 
would guide future research. 
7.2. 
Descriptive measure (CP assessment) 
The participant’s CP will be described during visit 2, using the Australian Spasticity Assessment Scale 
(ASAS), Manual Assessment Classification System (MACS) and the Gross Motor Function Classification 
System (GMFCS) and the Communication Function Classification System (CFCS). In addition, the 
presence of active epilepsy, controlled epilepsy or no epilepsy will be recorded. Other eligibility criteria will 
be addressed during the physical examination. 

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7.3. 
Evaluative measures 
Evaluative measures will be taken at baseline prior to infusion (visit 2) and after intervention at follow-ups 
visits defined below. A copy of the assessment results at baseline and final assessment will be available for 
families if they would like them. 
Motor assessment (baseline and at visits 7 and 9) 
 
The gold standard gross motor measure for CP, the Gross Motor Function Measure 
(GMFM-66) will be used. The GMFM-66 has good validity and reliability, and is the only 
gross motor measure responsive to change for children [59]. The assessment can be 
scored from videotape if needed. 
45 mins to 
complete 
(participant) 
An upper limb assessment will also be used, the Quality of Upper Extremity Skills Test 
(QUEST). This tool is validated for use with children aged 18 months to 8 years and has 
been used in the older range needed for this study [60]. Results will be reported for each 
limb separately. This tool is reliable and sensitive to change, but has the disadvantage that 
it measures impairment reduction rather than functional improvement. The QUEST can be 
scored from videotape if needed. 
15 mins to 
administer 
(participant) 
Quality of life assessment (baseline and at visits 7 and 9) 
Assessors will use the Cerebral Palsy Quality of Life Questionnaire (CP-QOL) for validated 
for adolescents 13-18 years old, or for children less than 12 years the CP QOL-Child. This 
measures social wellbeing and acceptance, feelings about functioning, participation and 
physical health, emotional wellbeing and self-esteem, access to services, pain and impact 
of disability and family health. Some of these items are not expected to change over the 
course of this study. It is completed by the participant’s caregiver, and also by the 
participant for 9-18 year old [61, 62]. 
 
15-25 mins 
to complete 
(parent and 
participant) 
Cognitive assessment (baseline and at visit 9) 
No specific cognitive training programs have been validated for use with children with CP, 
however the limited evidence available indicates there may be some spontaneous 
improvement in cognition. Therefore, cognition will be assessed by a psychologist in an 
age appropriate manner (see Table 2 below), ensuring that an individual is tested using the 
same tool before and after the intervention. There is a possible learning effect with 
cognitive assessment tools, in that using them too often leads to familiarity with the tool 
which confounds data on actual change in cognition, therefore most tools are 
recommended for use only every 12 months. Therefore, we will avoid assessing cognition 
at the 3 and 6 month assessment visits but will assess at baseline (-1 month) and 12 
months. Note that this assessment may not be possible for children with extremely severe 
CP. 
 
1 hour to 
administer 
(participant) 

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Table 2: Cognitive assessment tools for each age range. 
Age Range (at baseline) 
Assessment tool 
1-2.5 years 
(validated 3-42 months) 
Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III)  
>2.5-6 years  
(validated 2.5–7 years) 
Wechsler Preschool Primary Scale of Intelligence (WPPSI–IV) 
>6 years  
(validated 6-16 years) 
Wechsler Intelligence Scale for Children  
(WISC-IV, or WISC-V if released prior to trial commencement) 
The Vineland Adaptive Behaviour Scales (Vineland-II) assesses personal and social skills 
needed for everyday living and is validated for use across the lifespan (birth-90 years). 
This assessment will be used in the parent/caregiver reporting format for all participants, to 
allow use for children with severe CP who would not be able to complete the assessment 
on their own behalf. 
30 mins to 
administer 
(parent) 
The Behaviour Rating Inventory of Executive Function (BRIEF) will be used to provide 
information on how problems such as attention difficulties, poor working memory, 
disinhibition and planning/organisational impairments impact everyday behaviour. The 
BRIEF is used for 5-18 year olds, the preschool version BRIEF-P is used for 2-5 year olds. 
It is a parent questionnaire of 86 items. 
15 mins to 
administer 
(parent) 
The Strengths and Difficulties Questionnaire (SDQ) is a brief series of 25 questions for 
parents which, although broad, correlate well with more detailed assessment tools. A set of 
Australian norms are available. This tool can be used for 2-16 year olds (parents of 2-4 
year olds receive a slightly modified version). 
5 mins to 
administer 
(parent) 
The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) is a 
virtually motor-free assessment for children. 
15mins to 
administer 
(participant) 
8. REPORTING ADVERSE EVENTS 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a patient enrolled in this study, 
whether due to study treatment or not. All AEs will be recorded and evaluated by study doctors, and their 
relationship to the treatment will be assessed. AEs are limited to those that initiate or worsen during the 
course of the trial. AEs will be categorised by severity according to Appendix 13: Categorising severity of 
AEs related to study treatments: NCI Common Terminology Criteria for AEs (CTCAE). 
A serious adverse event (SAE) is an AE that is life threatening; may require immediate hospitalisation or 
transfer to intensive care unit; results in persistent or significant incapacity or even death. It also includes 
any AE that requires immediate medical intervention to prevent any of these listed consequences. Severity 
grades 4 and 5 will automatically be designated as a SAE, some discretion by the study doctor may be 
required for grade 3. 
A suspected unexpected serious adverse reaction (SUSAR) is any unexpected SAE that is suspected to be 
related to the study treatment. For example, infusion-associated graft-versus-host disease (GvHD) and 
anaphylaxis are potential risks that may be classified as SUSARs. 
Eliciting Adverse Event information 
Adverse events will be recorded from the time of infusion until the last visit (12 months post infusion). 
During the UCBC infusion patients will be monitored at 5 minute intervals, then during hydration every 30 
minutes. On leaving the hospital, the patients and their families will be provided with contact details and 

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asked to contact the study team if any unusual health change should occur. They will also be provided with 
a card to provide to a treating doctor should the participant require an unscheduled visit, particularly other 
than at the study site hospital. The card provides details for either the family or the admitting doctor to notify 
study doctors of potential SAEs to ensure information is elicited, and reported, as early as possible. 
The transplant physician will conduct a medical assessment on the day after infusion to assess late 
reactions to infusion (eg. fever, signs of renal insufficiency), and each week (to detect signs of GvHD) until 
the 1 month follow up physical examination. At each study visit patients will be asked how they feel and 
how they have felt in the period since the last visit. They will also be asked if they have had any accidents, 
illnesses, been hospitalised or changed medication. AEs will also be documented from findings of physical 
examination. 
Assessment and Documentation of Adverse Events 
AEs will be reported to the investigator by the infusion team, family or assessing paediatrician or therapist. 
The investigator is then responsible for recording all AEs, regardless of their association with the study.  
The documentation of each AE will include a description of the AE and its severity, timeline, action or 
treatment required and the outcome. After discussion with the study team, the likelihood that the AE was 
the result of the study intervention will be assessed as unrelated, possible, probable or definite. 
All AEs will be followed until resolved, and changes in the AE or repeated episodes will be documented for 
retention and publication. 
Serious Adverse Event Reporting 
Should an AE be categorised as serious, the local HREC will be notified within 72 hours of its occurrence 
using Appendix 12: Serious adverse event report form. The HREC safety reporting form will be completed, 
signed and submitted by the coordinating principal investigator with the trial coordinator. 
Should there be a SUSAR, HREC will be notified within 72 hours as with a SAE. All SUSARs occurring in a 
study participant will be reported to the Therapeutic Goods Administration (TGA) within 2 weeks of first 
occurrence. The report will be completed, signed and submitted by the coordinating principal investigator 
with the trial coordinator.  
Graft-versus-Host Disease (GvHD) of Grade II or above (as defined in Appendix 13:) will stop the trial. The 
DSMC may advise stopping the trial if other SAEs occur, based on clinical discussion of the SAE and its 
potential relationship to the study treatment.  
9. STATISTICAL METHODS 
As the primary aim of this study is to assess safety, the sample size of 12 participants was selected to allow 
sequential groups of three participants, followed by another three participants, followed by the final six 
participants. Although we do not expect the cell content of cord blood units to affect safety, and hence a 
dose escalation safety structure is not required, cell content may relate to the efficacy of the infusion and 
will be analysed at the conclusion of the study. 
While we do not expect the participants to be representative of the general population with CP, we will 
compare group characteristics with population data from the Australian Cerebral Palsy Register to assess 
the generalisability of the results obtained. Given the pilot nature of this trial the results from this study will 
be presented descriptively only. Safety data will be summarised as the proportion of participants who have 
an SAE and an AE within either of the three safety time periods: within 36 hours, within three months or 
within the 12 month study period. The change in lab results at each time point will be presented relative to 
baseline. We will summarise the feasibility data through a summary of the number and proportion of 
patients recruited of those who were contacted the study team, and a breakdown of the reasons for non-
participation. The number of withdrawals and reasons for withdrawal and the number of protocol violations 
and deviations will also be presented. Change in motor and cognitive function will be presented relative to 
baseline. Donor cell longevity data will only be presented for the participants receiving sibling UCBC 
infusions, and categorised as ‘immediate rejection’ to indicate return to baseline fraction of foreign cell-free 

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DNA within 24 hours; ‘rejection’ to indicate return to baseline fraction of foreign cell-free DNA by 1 month; 
‘slow rejection’ to indicate the presence of between 200 donor genome equivalent/ml and engraftment at 3 
months, and ‘engraftment’.  
10. DATA MANAGEMENT AND ADMINISTRATIVE ASPECTS 
Data collected as part of this trial will be entered into case report forms and a study-specific database, 
using the internet-based Research Electronic Data Capture (REDCap) database designed specifically for 
this study which will be accessible only to study staff. While data entry at each site includes participant 
identification, access for data viewing and analysis will be restricted to re-identifiable format (users will be 
assigned to groups to restrict access to identification records from other sites). However, all PIs, the trial 
coordinator and HREC/governance auditors will have access to all records.  
To best fulfil regulatory requirements, consent from participant families will be requested in order to report a 
specific data set to a transplant registry (the Australasian Bone Marrow Transplant Recipient Registry, 
ABMTRR, and/or the Center for International Blood and Marrow Transplant Research, CIBMTR). The data 
includes CBU quality information such as TNC and CD34+ count, whether it was washed, how it was 
administered, and details of any other complication or adverse reaction. After initial data collection, relevant 
data is followed up at 3 months. This data will be collected as part of the study, but requires specific 
Optional Consent from the participant family before forwarding to a registry. 
While all procedures in this protocol are for research purposes rather than routine clinical care, most 
procedures will nevertheless be recorded in a participant’s medical record. This includes blood type; 
information about the infusion including observations before and after, and any reaction to the infusion. 
Information collected as part of this study that will not be recorded in a participant’s medical record include 
CP assessment, study assessments and some blood test results, which will be recorded directly into data 
collection sheets (case report forms, CRFs). Any medically relevant information or adverse event data 
collected during these examinations or at other times however will be recorded in the medical record if 
appropriate. Each participant will be allocated a unique study identification number. 
Study samples fall into three categories: 1) samples sent to Red Cross Transplantation Service, will remain 
fully identifiable and un-coded. 2) Samples collected at infusion hospitals that stay within the hospital and 
will remain identifiable as well as coded and will be destroyed after use. 3) Samples collected for purely 
scientific purposes before and after UCBC infusion will be coded and re-identifiable for processing, analysis 
and storage. As a consequence, many pathology samples will remain identifiable because of the absolute 
importance that a participant is provided with the correct CBU for infusion and that pathology safety assays 
are reported and acted upon immediately. Staff will be checking and rechecking identifying details to match 
with pathology reports. 
Video images will be digitised and stored with other electronic records in a password protected folder at 
each site. 
All paper and electronic records will be securely stored until the youngest participant turns 25 years of age. 
Records of biobanked samples and their consent conditions may be retained longer. 
Biobank 
Samples from each participant, at each time-point, will be stored for future research into the effect of cord 
blood cells or stem cells on children with neurological disorders. This is important because so much 
research is being conducted in the area at present that we expect specific research questions to arise in 
coming years as understanding increases. 
Due to its importance, extended consent for storage of samples will not be optional, but will be included in 
consent for the research study. However, participants and their families will be able to withdraw the 
participant’s samples and information at any time. If this occurs, any remaining samples will be destroyed 

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and information will no longer be available for future study, however information already included in 
analysis will not be removed from analysis, just de-identified. 
The custodians for this biobank will be the coordinating principal investigator Dinah Reddihough and 
Associate Investigator Ngaire Elwood in consultation with the trial Steering Committee. 
Samples will be collected from all sites and sent to MCRI Biobanking for storage. They may therefore be 
transported interstate. Samples will at no time leave Australia; any future research will need to be 
conducted within Australia. 
Participant reimbursement 
Participants will be reimbursed incurred costs related to this trial. This includes reasonable travel, 
accommodation and meals expenses, and parking costs. All trial treatments are provided free of charge. 
Financial disclosure and conflicts of interest 
Cell Care Australia is a private cord blood bank that stands to benefit from a successful outcome of this 
trial. However, they do not stand to benefit any more than other private cord blood banks that are not 
associated with this trial, rather, the entire industry should benefit equally. 
Cell Care may benefit from publicity associated with the trial. This is affected by the size and scope of the 
trial, which is decided by the steering committee of which AI Mark Kirkland is a member. There is therefore 
a potential conflict of interest which has been declared to steering committee and is well recognised. 
Use of data and publications policy 
Only de-identified data will be reported in any publications or conference presentations. No participant will 
be identifiable from data reported. 
Investigators will submit results for publication regardless of the outcome. Authorship will be determined 
according to NHMRC guidelines. The decision of what to publish and when, along with authorship, will be 
made by steering committee. Data will only be published from all sites combined rather than individually, 
and only at the conclusion of the trial.  
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Appendices 
Appendix 1:  Information to go into CP register newsletters 
Australia’s first clinical trial of stem cell infusion as a treatment for cerebral palsy is commencing in XXX. 
The trial is small and aims to find out whether cord blood stem cell infusion is safe for children with cerebral 
palsy. Unfortunately the trial will not be able to tell us whether stem cell therapy improves function for 
children with cerebral palsy or not, but it will tell us what the next step should be in this important area in the 
future. 
The clinical trial team are looking for children with cerebral palsy aged 1-16 years who have a brother or 
sister who has cord blood in storage from their birth. Only around a quarter of brothers and sisters have 
blood that matches, so the doctors in the trial will test the children’s blood to look for a match. Those that 
are a good match may be able to receive the cord blood cells, but those that do not have a good match 
cannot as it would not be safe. Involvement in the trial will be demanding with many hospital visits over a 14 
month period. 
We are looking for about 12 children to be in the trial, across Australia. 
If you would like more information about this trial please contact XXX. 
If you would like more information about stem cell therapy for cerebral palsy generally, have a look at these 
websites: 
http://www.closerlookatstemcells.org/ 
http://www.stemcellsaustralia.edu.au/ 
  
 

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Appendix 2:  Script for first contact phone conversation (families contacting research team) 
Hi, my name is [insert researcher name]. Have you heard about the clinical trial of umbilical cord blood cell 
therapy? Would you like me to tell you a little about the trial, or do you have any questions already? 
[pause to answer questions, describe the study including but not limited to the below] 
This trial is using the stem cells, from a brother or sister’s cord blood but only if they match, and the chance 
of matching is about 25%. Therefore, this trial can only include children with CP who have a siblings’ cord 
blood in storage somewhere. Since only 25%, a quarter, of siblings have matching cord blood, the trial will 
involve testing sibling cord blood to see if it matches and can be used, or if it can’t be used. Three quarters 
won’t match. We expect that only a small group will be eligible for this trial.  
Altogether, we hope to find 12 children from across Australia, who are 1-16 years old, who can participate 
in this trial. It doesn’t matter where the families live in Australia, but families that don’t live in Brisbane or 
Melbourne would have to cope with quite a lot of travel. The trial may be able to provide some help to cover 
the costs of the travel.  
We don’t know whether or not there are 12 children in Australia who are eligible to participate, whose 
families will choose to enrol them in this trial, and who we find have matching cord blood when we test it. 
There may not be 12 children like this in Australia, or there may be lots of children like this. Even if there 
are more than 12 children like this in Australia, we can only have 12 participate.  
There is a list of other things that make the children eligible. Some of them are fairly clear: 
 
Being at least 1 year old at the time of enrolment (so they don’t have to be 1 year old just yet) 
 
Being less than 17 years old at the time of enrolment 
 
Having cerebral palsy, not any other disorder 
 
Not having an immune system disorder or immune deficiency 
 
Not needing ventilator support 
 
Being able to travel to the hospital 
 
Not having any other cell therapy 
 
Some of the things are a little less clear, because they may change, for example if a child is unwell they 
won’t be able to have the infusion, but if it is a virus the doctor may say that your child will get better in time 
to participate. Also, if a child has a genetic disorder or brain dysplasia the cord blood infusion probably 
won’t help at all, but only some people have had genetic testing or MRI done. [Do not mention exclusion 
periods for Botulinum toxin A or surgery at this point]. 
 
Would you mind if I ask a couple of questions to find out if your child might be eligible for this trial?  
 
Does your child have CP? 
 
Who diagnosed your child’s CP? For example, was it a doctor? 
 
[if child is clearly ineligible] 
It sounds like your child would not be able to participate in this trial, because this trial only includes children 
who have CP.  
 
Do you happen to remember if you donated or stored cord blood at the births of any of your 
children? 
 
[if they didn’t] 

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Well, unfortunately that rules this trial out I’m afraid. I don’t know what will happen in the future, some 
researchers are looking at whether cord blood cells from an unrelated donor could be helpful for children 
with cerebral palsy. It’s possible that after this small pilot trial there may be an Australian trial of unrelated 
donor cord blood, but it is a long way off. Keep listening out over the next few years, any clinical trials will 
be publicised in the same ways that this one is. 
[if they did] 
Oh fantastic. Was that for your child who has CP, or their brother or sister? 
Do you know if it was a donation to a public (AusCord) cord blood bank in case someone with leukaemia or 
other problems needed it, or did you pay for the storage with a private service? 
[if through AusCord] 
We can’t include cord blood units that are stored in the public banks at the moment. We hope that this will 
change, and if you would like I can take your details and contact you if it does change.  
The three public banks keep the donations separate, but they all work together as AusCord. The cord blood 
that is donated to AusCord gets used all over the world to help people who are sick with blood and marrow 
disorders and metabolic disorders. Sometimes it also gets used for research. The cord blood you donated 
might still be stored here, or it may have been used. If the trial is allowed to include cord blood stored in 
public banks, we will ask you some questions to find out which hospital and state you gave birth in, but I 
can contact you then. 
[if through a private bank] 
Ok, that should be easy to find then. 
We can find out the status of your cord blood unit by giving the cord blood bank some details to do a 
search. Would you like to do that? They need to know your child’s date of birth, hospital of birth, sex and 
mother’s details. I will post you a template letter for you to fill out with your information, sign, and send back 
to me if you are happy for us to find out and for the cord blood bank to tell us that they have your cord blood 
on record. This doesn’t sign your child up for the clinical trial; it is only for finding out about the cord blood. It 
is important to know that there may be other reasons why your child cannot participate in the trial, from the 
eligibility criteria we discussed earlier. 
Also, please remember that sibling cord blood might match or it might not. Only around a quarter of siblings 
match, so that means that three quarters of children with sibling cord blood available will not be able to use 
the sibling cells. Also, I need to ask: Does your child have an immune system disorder, or an immune 
deficiency? If your child has an immune system disorder or an immune deficiency, having someone else’s 
cells in your child’s body is less safe. 
 
[if the child might have an immune system disorder or immune deficiency] 
It sounds like your child would not be able to participate in this trial, because if your child has an immune 
system disorder or an immune deficiency, infusing someone else's cells into your child's body using this 
study's protocol is less safe 
[all] 
I’ve jotted down some details as we’ve talked. May I include the details you have been telling me in our 
database? I will send you a letter with a list of what we’ve talked about so that you know what we have 
recorded and how to contact us to change anything, ask for your information to be removed or to ask 
questions. Could I please get your postal address so that I can mail it to you (along with the template letter 
for the cord blood banks)? 
Now, if we find that your cord blood donation is still in storage, or if you know it is in a private bank, and if 
you are still interested in the trial, I will also send you a full Information Statement about the whole trial. The 

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Information Statement gives information about reasons your child might not be able to participate in the 
trial, which is important because we do not want to infuse any child when it isn’t safe. The Information 
Statement also has all the details and risks written down in it for you to think about. You can talk about it 
with your child’s doctor.  
Look out for a letter in the mail from us in the next few days, it will list what we talked about today, and also 
includes the template letter for you to fill in and send back to us with a reply-paid envelope that will be 
included [and/or] an Information Statement for you to think about. Our phone number will be on the letter 
and please call back anytime with more questions or to talk about it more. There are lots of things to think 
about with this trial and it is a very personal decision for each family. 
Thanks for your time; I look forward to talking again soon. 
 
 

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Appendix 3:  Record of verbal consent 
 
RECORD OF VERBAL CONSENT 
 
HREC Project Number: 
HREC/14/RCHM/38     RCH HREC ID: 34210 
 
Research Project Title: 
Safety study of sibling cord blood cell infusion to children 
with cerebral palsy 
Participant Name: 
 
Parent Name: 
Mailing Address: 
Phone Number:   
 
Date that family contacted research team:  
Date of actual phone conversation: 
Spoke to (name of parent/participant): 
 
 Yes 
 No 
Do you give your consent for me to ask some questions about your 
child? I would like to find out if they are suitable for this research project. 
 Yes 
 No 
Do you give your consent to store the information you gave me in the 
study database? 
 
Name of person obtaining consent: 
Signature of Person Obtaining Consent: 
 
Date: 
Time: 

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Appendix 4:  Letter following verbal consent 
<Date> 
 
<Address block> 
<Address block> 
<Address block> 
 
Dear <parent name>, 
I would like to thank you and your child for your interest in research into umbilical cord blood cells 
for treatment of children with cerebral palsy. 
I have recorded that you gave verbal consent for us to store the information you gave us over the 
phone in the study database. 
We recorded x pieces of information. They are: 
1. 
That your child has cerebral palsy 
2. 
Whether you stored cord blood for any of your children at their births 
3. 
If so, which cord blood bank you stored it with 
4. 
Your contact details 
 
You are welcome to change your mind at any time without giving a reason, and withdraw your 
consent for storing this information. If you do, we will not store or use the above information in the 
future. If you have questions, want to find out more about the information you gave us, or to 
change or update the information, please contact XXX on <phone number>. 
You will also find in this envelope [either] a template letter for filling in and signing along with a 
prepaid envelope for sending it back to us if you want us to investigate your cord blood unit(s) 
[and/or] the Study Information Statement. 
Thanks so much for your time and for supporting research into cerebral palsy. 
With kind regards, 
 
 
 
Clinical Trial Coordinator 
Contact details 
 
 
 

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Appendix 5:  Template to ask CBB to locate CBU records 
 
 
Does my child/do my children have their cord blood in storage? 
 
Using the information below, could you please ask the cord blood banks to locate the records 
of my child / children’s cord blood unit? These are details from the children who may have 
stored or donated cord blood. 
 
 
Child 1 
Child 2 
Child’s name at birth 
 
 
Child’s Date of birth 
 
 
Hospital where child was born 
 
 
Mother’s name when the child was born 
 
 
Which cord blood bank did you use?  
 
 
 
Mother’s date of birth: 
 
 
I would like to know the results of the record search.  
I give permission for the cord blood bank to release information to the research team and for the 
research team to release information to me. 
 
 
Name of child with cerebral palsy: 
 
Parent/Guardian name:  
 
Parent/Guardian signature: 
 
Date: 
 
 
 

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Appendix 6: Script for phone conversation after CBU record search 
 
Hello, this is [lead site study coordinator’s name], is this a good time to call or would you prefer me to call 
back later? 
The cord blood bank has looked through their records for the cord blood that you remember having 
collected when your child was born. 
[Either] 
They found that the cord blood is not in storage anymore, it was used to help someone who was sick / was 
used for research to improve cord blood banking and cord blood use / was contaminated / they have no 
record of it. This means that your child will not be able to participate in this trial. Would you like to be 
contacted if a future clinical trial might be appropriate for your child? We don’t know if this will happen, but 
we are keeping a list of families interested in this research. 
[if family requested a record search in a public bank] 
We can’t include cord blood units that are stored in the public banks at the moment. We hope that this will 
change, and if you would like I can take your details and contact you if it does change.  
Even if we are allowed to include cord blood units stored in the public banks in the future, getting access to 
your child’s cord blood is difficult because your child’s cord blood may be useful for someone sick. The cord 
blood bank may be able to release it if you apply for it. It will take some time or the bank to process your 
application. They would like to support this research, but the bank’s first priority is people who will definitely 
benefit from the cord blood cells – and in this trial we do not know if your child will receive any benefit at all. 
[or] 
They found that the cord blood is in storage. 
[for all] 
If you are interested in finding out more about this research study, I can mail you a copy of the Information 
Statement for you to have, so that you can think about it. It would be a great idea to talk to your child’s 
doctor about it, talk within your family and spend some time thinking about it. You may decide that this 
study isn’t something you want your child involved in, which is fine, or that your child might not be eligible to 
participate for other reasons listed in the Information Statement. We could discuss this now if it would help 
too? [Explain eligibility criteria if appropriate, see previous script]. 
Now that you know that there is a cord blood unit in storage from one of your children, something to think 
about when you read the Information Statement is that this trial may use the cord blood up. The cord blood 
would not be there in case any of your family happened to get sick and need the cord blood. I truly hope 
that wouldn’t happen, but it is something your whole family need to think about. 
[Do not raise issue of trial possibly being oversubscribed at this point, unless family ask]. 
You already know this phone number, so please call anytime with questions. Also, contact details for the 
study team are on the Information Statement. 
Please take a few weeks to think about it and talk it through with others, and if you think you would like your 
child to participate in this research study, and that your child fits the other eligibility criteria, particularly that 
your child does not have an immune disorder [explain criteria again if appropriate], we can arrange a time 
for you to come to a study hospital and talk with the coordinator there (it might be me), or with a study 
doctor. 
Also, if you are thinking of enrolling your child in the study, before you come in we would like to know a little 
bit more about your child’s cerebral palsy. We could look at a letter from your child’s doctor, or some other 

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documentation, that has your child’s diagnosis in it. Of if you don’t have something like that, we would ask 
your permission to contact your child’s doctor. But don’t worry too much about that yet, spend some time 
thinking about this study first.   
I will call you again in a few weeks if we haven’t heard from you, just to find out if the Information Statement 
makes sense and if you have any questions. But we don’t expect you to have thought about everything by 
that point, or made any decisions don’t worry. 
Thank you for your time. 
 
 

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Appendix 7: Script for phone conversation to arrange Visit 1 
 
Hello, this is [lead site study coordinator’s name], how can I help you, do you have any questions about the 
research study? 
Oh, hi [parent name], you are interested in coming in to talk about the study and possibly enroll [child’s 
name]? Ok. First, would you mind if I just run through the list of eligibility criteria one more time, like a 
checklist? 
1) How old is your child? 
2) Has your child got cerebral palsy? Has your child ever had genetic testing done either to try to 
explain the cerebral palsy or for any other reason? 
3) Has your child ever had a brain scan called a MRI? Do you happen to know what it showed? 
4) Has your child’s neurological condition or motor functioning gotten progressively worse over time? 
5) Has your child ever had cell therapy before? 
6) We need to know if your child has ever been diagnosed with an immune system disorder or with an 
immune deficiency? If you are not sure don’t worry, we will test for it anyway because we don’t want 
to give an infusion if it is more risky than normal. 
7) Is your child on a ventilator? 
8) Will your child and you or another parent or guardian able to travel to a study hospital? 
9) Is your child likely to need Botulinum toxin A (Botox) treatment in the next year or so? When would 
you expect it to happen? 
10) Is your child likely to need any sort of surgery in the next year or so? Any idea what sort of surgery, 
or when it would be? 
 
[Either] 
From your answers, your child will not be able to participate in this study. It would not be safe for your child 
/ this study isn’t appropriate but perhaps a future study might be. 
[Or] 
From your answers, I don’t know if your child will be able to participate or not. It may be something that you 
need to talk about with the study doctor. Would you prefer to speak to the study doctor over the phone, or 
to come to the hospital and talk in person? It is really important that we don’t make mistakes about this. 
Let’s try to find a time for you to come to the hospital. We can’t arrange a meeting for [xxx] weeks because 
we don’t want you to go to the trouble of coming to the hospital if the trial is full, and we don’t know if it is 
full right this minute because we are waiting on results from children that enrolled recently. 
When you and your child come to the hospital, you will meet the trial coordinator (which might be me), and 
maybe the study doctor. We can help answer any more questions and discuss the risks and how much 
effort participating in the study might involve for your family. 
Then, if you choose, you can enroll your child by signing a Consent Form, but you may choose not to enroll 
on this day, or at all. 
If you do choose to enroll your child, your child will then go to the hospital pathology collection service to 
give a blood sample. This sample would be sent to the Australian Red Cross Blood Service Transplant 
Service to be tested for tissue type. If the blood bank does not know the tissue type of the cord blood unit in 
storage, a small amount of cord blood will be sent as well to find out whether it matches. A cord blood 
transplant specialist will receive the results but will not tell us or your family what the results are unless the 
study has already got enough participants. Because children enroll before the transplant specialist knows 
whether their cord blood can be used or not, it is difficult to tell you whether the trial will be full or not. 

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In the meantime, we would like to know a little bit more about your child’s cerebral palsy, to make sure your 
child is eligible before you go to the effort of coming to the hospital. Do you have a copy of a letter from 
your child’s doctor, or some other documentation, that has your child’s diagnosis in it? Do you think it would 
be possible to mail us a copy, I will send out a letter to you describing what is needed with a reply-paid 
envelope for you to mail the document back to us. If you can’t find a letter from your child’s doctor, don’t 
worry, we would ask your permission to contact your child’s doctor instead. 
 
Please call any time to talk about any part of the study, and look out in the mail for our letter. Thank you for 
your time. 
 

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Appendix 8: Letter to family to request confirmation of diagnosis 
 
<Date> 
 
<Address block> 
<Address block> 
<Address block> 
 
Dear <parent name>, 
I would like to thank you and your child for your interest in research into umbilical cord blood cells 
for treatment of children with cerebral palsy. 
Before you visit a study hospital, we would like to know more about your child’s cerebral palsy. 
Please fill in the attached form. If you have a letter from your child’s doctor that says your child’s 
diagnosis, or some other document with your child’s diagnosis, please send a copy with the form 
to the study team using the reply-paid envelope included. 
If you don’t have a letter or document available, the study doctor could contact your child’s doctor 
with your permission. The study doctor would send a copy of the attached form to show your 
child’s doctor that you give permission to discuss your child’s cerebral palsy. The study doctor 
would tell your child’s doctor about the research study, that you have not enrolled your child at this 
time, and why we would like the information. 
If you would like to talk about this, or ask any other questions, please call anytime. 
Thank you, 
 
 
 
Clinical Trial Coordinator 
Contact details 
 

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Form requesting confirmation of diagnosis 
 
 
 
 
 
Name of child:                                         
 
Name of child’s doctor: 
 
Contact details for child’s doctor: 
 
 
 
 
Address:  
 
 
 
 
 
 
 
 
 
Phone: 
 
 
 
 
 
 I have 
 I have not 
attached a letter from my child’s doctor that 
includes my child’s diagnosis. 
 
 I do 
 I do not 
give my permission for the study team to 
contact my doctor to get confirmation of my 
child’s diagnosis 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
Name of Parent / Guardian: 
 
 
Signature of Parent / Guardian: 

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Appendix 9: Letter to child’s doctor requesting information 
 
<Date> 
 
<Address block> 
<Address block> 
<Address block> 
 
 
Dear <doctor’s name>, 
 
Regarding: <child’s name>. 
We are seeking evidence of cerebral palsy diagnosis for <child’s name>, and have permission from 
<parent/guardian name> to contact you for this information. Please see attached written consent. 
The information will be used to consider one aspect of eligibility of <child’s name> for enrolment in a 
clinical trial of single dose intravenous cord blood cell infusion, combined with intensive rehabilitation 
therapy, as a possible treatment for cerebral palsy, called ‘ 
Safety study of sibling cord blood cell infusion to children with cerebral palsy’. 
The trial is a safety study, conducted by an Australian collaborative research group at The Royal 
Children’s Hospital Melbourne and the Lady Cilento Children’s Hospital, Brisbane (Coordinating Principal 
Investigator Dr Dinah Reddihough). This project has received ethics approval from The Royal Children’s 
Hospital Human Research Ethics Committee (Project number HREC/14/RCHM/38; RCH HREC ID: 
34210). 
Before we can consider further including <child’s name> in the study, we need to be sure that he / she 
does in fact have cerebral palsy.  We would very much appreciate a brief note confirming this.   
If you would like to discuss this with the study doctor at <likely infusion hospital>, please call <study 
doctor name and contact>.  
If you would like more information about the clinical trial, please call <study coordinator’s name and 
contact>.  
If you would like more information about the ethics approval for this study, please contact <Director, 
Research Ethics and Governance, contact, of which site> 
Thank you for your time, 
 
Study doctor 
Contact details 

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Appendix 10: Screening questions to establish immune status for medical history 
 
 
If answer Yes to (3), (4), (5), (7), should undergo immune blood tests before deciding if need to be excluded. 
 
If participant needs to have immune blood tests AND answers Yes to (1) and/or (8), consider deferring blood test 
until free from illness for 7 days / free from blood products for 3 months. 
 
If participant needs to have immune blood tests, please record all relevant history (i.e. to which question did 
they answer Yes) in the clinical background section of the pathology request slip. 
 
 
 Y / N 
1)  
Has your child had an infection or a febrile (high temperature) illness 
within the last seven (7) days? 
 
 
 
 
 
If Yes, and if sibling CBU in storage, consider deferring visit 2 blood test until free 
from illness for 7 days 
  
 
 
 
2) 
Has your child ever been diagnosed with an immune system disorder or 
immune deficiency syndrome? 
 
  
If yes(Y), please specify: 
  
If Yes, exclude from participation 
  
 
 
 
3) 
Has your child needed to be admitted to hospital for intravenous (I.V.) 
antibiotics to clear an infection on more than two (2) occasions in their 
life? 
  
  
  
  
 
If Yes, consult with immunologist regarding blood test results before deciding to 
exclude 
 
 
 
 
4) 
Has your child ever needed two (2) or more months of oral antibiotics to 
clear an infection? 
  
  
  
  
 
If Yes, consult with immunologist regarding blood test results before deciding to 
exclude 
 
 
 
 
5) 
Has any Doctor or Maternal Child Health Nurse ever been concerned about 
your child being underweight? 
  
  
  
  
 
If Yes, consult with immunologist regarding blood test results before deciding to 
exclude 
 
 
 
 
6) 
Has your child ever been diagnosed with a genetic disorder such as Down 
syndrome, Di George syndrome etc? 
 
  
If yes(Y), please specify: 
  
  
If Yes, exclude from participation 
 
 
 
 
 
 
 

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7) 
Has any family member or relative of your child ever been diagnosed with 
an immune system disorder or immune deficiency syndrome? 
  
 
If yes(Y), please specify: 
 
 
 
 
 
If Yes, consult with immunologist regarding blood test results before deciding to 
exclude 
 
 
 
 
8) 
Has your child received any blood products such as packed red blood 
cells, platelets, albumin or immunoglobulin in the last three (3) months? 
  
 
If yes(Y), please specify: 
 
  
If Yes, and if sibling CBU in storage, consider deferring visit 2 blood test until free 
from blood products for 3 months 
  
 
 
 
9) 
Was your child born prematurely, before 36 weeks’ gestation? 
  
  
  
  
 
 
 

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Appendix 11: 
Post-infusion handout 
 
Title 
Safety study of sibling cord blood cell infusion to children with cerebral 
palsy 
Short Title 
Stem Cells in Umbilical Blood Infusion for Cerebral Palsy (SCUBI-CP) 
HREC Number 
HREC/14/RCHM/38  
Principal Investigator 
Site PI 
Location  
Site 
 
Post-infusion handout 
Your child will not be released from the hospital unless he/she is healthy enough to leave. In particular, the 
nurse will check 
 
your child’s blood pressure 
 
whether your child is urinating freely 
 
whether there is haemoglobin in your child’s urine. 
We would like to check your child again tomorrow. The doctor will look for signs that your child is having a 
delayed reaction to the infusion. 
The following list of symptoms might be linked to the cord blood cell infusion: 
Possible symptoms 
What it may mean 
When it might happen 
Your child’s urine is purple 
There may be haemoglobin in 
your child’s urine.  
This is most likely within 
36 hours of infusion. 
Nausea or diarrhoea 
Your child may be reacting to 
the infused cells 
This is most likely between 
1 week and 3 months after 
infusion 
Jaundice (yellowing of your 
child’s skin) 
Your child may be reacting to 
the infused cells 
This is most likely between 
1 week and 3 months after 
infusion 
Fever 
Your child may have an 
infection 
This is most likely within 
36 hours of infusion 
Rash 
Your child may be reacting to 
the infused cells 
This is most likely between 
1 week and 3 months after 
infusion 
If you notice that your child has any of these symptoms, please call the 24 hour phone line to talk to a 
transplant doctor:  
Call: (local 24 hour contact number) 
Ask for: BMT transplant doctor 
 
Tell the doctor: Your child has cerebral palsy and is in the trial 
 
 
If you feel your child has serious health problems of any type, please bring them to the Emergency 
Department at site, or dial 000. 

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Appendix 12: 
Serious adverse event report form 
SAE REPORT FORM 
(Individual Reports)  
Internal* SAEs (occurring to RCH participants) must be reported to the RCH HREC within 24-72 hours 
of occurrence and must be accompanied by a detailed report of the event. 
External SAEs (occurring to participants from other sites) must be reported in a prompt manner if 
the information impacts the continued ethical acceptability of the trial or requires documentation 
to be updated (i.e. protocol or PIS). 
*An Internal SAE is one occurring in a participant that RCH researchers are responsible for, this is 
independent of where the event occurs. 
HREC Reference # 
 
Project title 
 
Principal Investigator 
 
 
Date that SAE occurred : 
 
Date Investigator became aware of 
SAE : 
 
Participant ID : 
 
Internal or External (see above 
definition): 
 
Event description and management : 
 
Event outcome (synopsis): 
 
Expectedness of the SAE (PI 
Opinion): 
 Expected    
 Unexpected  
Relationship to the study drug 
  Unrelated 
  Possibly related 
  Probably Related  
 Definitely Related 
 
Other Comments 
Does the protocol require amending as a result of these SAEs? 
(If Yes, please submit a modification request with the amended 
protocol) 
 Yes   
 No 
Do the information statements require amending as a result of 
these SAEs? 
(If Yes, please submit a modification request with the amended forms)   
 Yes   
 No 
 
 
 
 
Signature 
Date 
Please submit 1 hard copy with signature OR an electronic copy signed (or emailed) by the PI to rch.ethics@rch.org.au 

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Appendix 13: Categorising severity of AEs related to study treatments: NCI Common Terminology Criteria for AEs (CTCAE) 
Note that AEs not considered to be related to study treatments are not included here. Additionally, note that definitions including self-care and activities of 
daily living (ADL) must be considered relative to the child’s previous level of functional impairment. 
Adverse Event 
 
Grade 
When it may occur 
1 
2 
3 
4 
5 
Blood disorders 
Haemolysis 
Definition: A disorder 
characterized by laboratory test 
results that indicate widespread 
erythrocyte cell membrane 
destruction. 
 Within 24 hours after 
infusion 
 2-14 days after infusion 
Laboratory evidence of 
haemolysis only (e.g., 
direct antiglobulin test; 
DAT; Coombs; 
schistocytes; decreased 
haptoglobin) 
Evidence of 
haemolysis and >=2 
gm decrease in 
haemoglobin. 
Transfusion or medical 
intervention indicated 
(e.g., steroids) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
 
Thrombotic thrombocytopenic 
Purpura 
Definition: A disorder 
characterized by the presence 
of microangiopathic haemolytic 
anaemia, thrombocytopenic 
purpura, fever, renal 
abnormalities and neurological 
abnormalities such as seizures, 
hemiplegia, and visual 
disturbances. It is an acute or 
subacute condition. 
 5-12 days after infusion 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical 
consequences 
- 
Laboratory findings with 
clinical consequences 
(e.g., renal 
insufficiency, 
petechiae) 
Life-threatening 
consequences, (e.g., 
CNS haemorrhage 
or 
thrombosis/embolism 
or renal failure) 
Death 
Cardiac disorders 
Heart failure 
Definition: A disorder 
characterized by the inability of 
the heart to pump blood at an 
adequate volume to meet 
tissue metabolic requirements, 
or, the ability to do so only at 
an elevation in the filling 
pressure. 
  
Asymptomatic with 
laboratory (e.g., BNP 
[B-Natriuretic Peptide]) 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion Severe 
with symptoms at 
rest or 
Severe with symptoms 
at rest or with minimal 
activity or exertion; 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
haemodynamic 
support) 
Death 
Sinus bradycardia 
Definition: A disorder 
characterized by a dysrhythmia 
with a heart rate less than 60 
beats per minute that originates 
in the sinus node. 
 During or immediately 
after infusion 
Asymptomatic, 
intervention not 
indicated 
Symptomatic, 
medical intervention 
indicated 
Severe, medically 
significant, medical 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated  
Death 

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Sinus tachycardia 
A disorder characterized by a 
dysrhythmia with a heart rate 
greater than 100 beats per 
minute that originates in the 
sinus node. 
 During or immediately 
after infusion 
Asymptomatic, 
intervention not 
indicated 
Symptomatic; non-
urgent medical 
intervention indicated 
Urgent medical 
intervention indicated 
- 
- 
Supraventricular tachycardia 
Definition: A disorder 
characterized by a dysrhythmia 
with a heart rate greater than 
100 beats per minute that 
originates above the ventricles. 
 During or immediately 
after infusion 
Asymptomatic, 
intervention not 
indicated 
 
Non-urgent medical 
intervention indicated 
Medical intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Ventricular arrhythmia 
Definition: A disorder 
characterized by a dysrhythmia 
that originates in the ventricles. 
 During or immediately 
after infusion 
Asymptomatic, 
intervention not 
indicated 
Non-urgent medical 
intervention 
indicated 
Medical intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic 
compromise; urgent 
intervention 
indicated 
Death 
Ventricular tachycardia 
Definition: A disorder 
characterized by a dysrhythmia 
with a heart rate greater than 
100 beats per minute that 
originates distal to the bundle 
of His. 
 During or immediately 
after infusion 
 
- 
Non-urgent medical 
intervention indicated 
Medical intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic 
compromise; urgent 
intervention 
indicated 
Death 
Gastrointestinal disorders 
Diarrhoea  
 
 Diarrhoea includes 
diarrhoea of small bowel 
or colonic origin, and/or 
ostomy diarrhoea. 
Increase of <4 stools 
per day over baseline; 
mild increase in ostomy 
output compared to 
baseline 
Increase of 4 – 6 
stools per day over 
baseline; IV fluids 
indicated <24hrs; 
moderate increase in 
ostomy output 
compared to 
baseline; not 
interfering with ADL 
Increase of ≥7 stools 
per day over baseline; 
incontinence; IV fluids ≥
24 hrs; hospitalization; 
severe increase in 
ostomy output 
compared to baseline; 
interfering with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic 
collapse) 
Death 
Mucositis / stomatitis 
 Mucositis/stomatitis 
(functional/symptomatic) 
may be used for 
identifying GvHD. 
Erythema of the 
mucosa 
Patchy ulcerations or 
pseudo-membranes 
Confluent ulcerations or 
pseudo-membranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant 
spontaneous 
bleeding; life-
threatening 
consequences 
Death 

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Nausea 
Definition: A disorder 
characterized by a queasy 
sensation and/or the urge to 
vomit. 
 During or immediately 
after infusion 
 May be early indication 
of allergic reaction or 
anaphylaxis 
Loss of appetite without 
alteration in eating 
habits 
Oral intake 
decreased without 
significant weight 
loss, dehydration or 
malnutrition 
Inadequate oral caloric 
or fluid intake; tube 
feeding, TPN, or 
hospitalization indicated 
- 
- 
Vomiting 
Definition: A disorder 
characterized by the reflexive 
act of ejecting the contents of 
the stomach through the 
mouth. 
 During or immediately 
after infusion 
 May be early indication 
of allergic reaction or 
anaphylaxis 
1 - 2 episodes 
(separated by 5 
minutes) in 24 hrs 
3 - 5 episodes 
(separated by 5 
minutes) in 24 hrs 
≥6 episodes (separated 
by 5 minutes) in 24 hrs; 
tube feeding, TPN or 
hospitalization indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
General disorders and administration site conditions 
Chills 
Definition: A disorder 
characterized by a sensation of 
cold that often marks a 
physiologic response to 
sweating after a fever. 
 During or immediately 
after infusion 
 Within 36 hours of 
infusion 
Mild sensation of cold; 
shivering; chattering of 
teeth 
Moderate tremor of 
the entire body; 
narcotics indicated 
Severe or prolonged, 
not responsive to 
narcotics 
- 
- 
Fever 
Definition: A disorder 
characterized by elevation of 
the body's temperature above 
the upper limit of normal. 
 During or immediately 
after infusion 
 Within 36 hours of 
infusion 
38.0 - 39.0 ºC 
>39.0 - 40.0 ºC 
>40.0 ºC 
>40.0 ºC for >24 hrs 
Death 
Headache 
Definition: A disorder 
characterized by a sensation of 
marked discomfort in various 
parts of the head, not confined 
to the area of distribution of any 
nerve. 
 During or immediately 
after infusion 
 Up to 36 hours after 
infusion 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Infusion related reaction 
Definition: A disorder 
characterized by adverse 
reaction to the infusion of 
pharmacological or biological 
substances. 
 
 During or immediately 
after infusion 
Mild transient reaction; 
infusion interruption not 
indicated; intervention 
not indicated 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 

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Infusion site extravasation 
Definition: A disorder 
characterized by leakage of a 
pharmacologic or a biologic 
substance from the infusion site 
into the surrounding tissue. 
Signs and symptoms include 
induration, erythema, swelling, 
burning sensation and marked 
discomfort at the infusion site. 
 During or immediately 
after infusion 
- 
Erythema with 
associated symptoms 
(e.g., edema, pain, 
induration, phlebitis) 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
 
Injection site reaction 
Definition: A disorder 
characterized by an intense 
adverse reaction (usually 
immunologic) developing at the 
site of an injection. 
 During or immediately 
after infusion 
Tenderness with or 
without associated 
symptoms (e.g., 
warmth, erythema, 
itching) 
Pain; lipodystrophy; 
oedema; phlebitis 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Irritability 
Definition: A disorder 
characterized by an abnormal 
responsiveness to stimuli or 
physiological arousal; may be 
in response to pain, fright, a 
drug, an emotional situation or 
a medical condition.  
  
Mild; easily consolable 
Moderate; limiting 
instrumental ADL; 
increased attention 
indicated 
Severe abnormal or 
excessive 
response; limiting self-
care ADL; 
inconsolable 
- 
- 
Localized oedema 
Definition: A disorder 
characterized by swelling due 
to excessive fluid accumulation 
at a specific anatomic site. 
 Within 24 hours of 
infusion 
 Pulmonary oedema may 
be indication of 
transfusion-associated 
circulatory overload 
(TACO) 
Localized to dependent 
areas, no increased 
disability or functional 
impairment 
Moderate localized 
oedema and 
intervention 
indicated; limiting 
instrumental ADL 
Severe localized 
oedema and 
intervention indicated; 
limiting self-care ADL 
- 
- 
Non-cardiac chest pain 
Definition: A disorder 
characterized by discomfort in 
the chest unrelated to a heart 
disorder. 
 
 During or immediately 
after infusion 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Pain 
Definition: A disorder 
characterized by the sensation 
of marked discomfort, distress 
or agony. 
 During or immediately 
after infusion 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self-care ADL 
- 
- 
Immune system 

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Allergic reaction  
Definition: A disorder 
characterized by an adverse 
local or general response from 
exposure to an allergen. 
 During or immediately 
after infusion 
Transient flushing or 
rash, drug fever <38ºC; 
intervention not 
indicated 
Intervention or 
infusion interruption 
indicated; responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics); 
prophylactic 
medications 
indicated for ≤24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
 
Anaphylaxis  
Definition: A disorder 
characterized by an acute 
inflammatory reaction resulting 
from the release of histamine 
and histamine-like substances 
from mast cells, causing a 
hypersensitivity immune 
response. Clinically, it presents 
with breathing difficulty, 
dizziness, hypotension, 
cyanosis and loss of 
consciousness and may lead to 
death. 
 During or immediately 
after infusion 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-
related 
oedema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
 
Cytokine release syndrome 
Definition: A disorder 
characterized by nausea, 
headache, tachycardia, 
hypotension, rash, and 
shortness of breath; it is 
caused by the release of 
cytokines from the cells. 
  
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
pressor or ventilatory 
support indicated 
Death 
Infection 
Catheter related infection 
Definition: A disorder 
characterized by an infectious 
 Within 24 hours of 
infusion 
- 
Localized; local 
intervention 
indicated; oral 
IV antibiotic, antifungal, 
or antiviral intervention 
indicated; radiologic or 
Life-threatening 
consequences; 
Death 

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process that arises secondary 
to catheter use. 
intervention indicated 
(e.g., antibiotic, 
antifungal, antiviral) 
operative intervention 
indicated 
urgent intervention 
indicated 
Respiratory infection 
Definition: A disorder 
characterized by an infectious 
process involving the 
respiratory tract. 
 Throughout study 
- 
Moderate symptoms; 
oral intervention 
indicated (e.g., 
antibiotic, antifungal, 
antiviral) 
IV antibiotic, antifungal, 
or antiviral intervention 
indicated; radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Procedural complications 
Bruising 
Definition: A finding of injury of 
the soft tissues or bone 
characterized by leakage of 
blood into surrounding tissues. 
 During or immediately 
after needle 
Localized or in a 
dependent area 
Generalized 
- 
- 
- 
Venous injury  
Definition: A finding of damage 
to a vein. 
 During or immediately 
after needle 
Asymptomatic 
diagnostic finding; 
intervention not 
indicated 
Symptomatic (e.g., 
claudication); repair 
or revision not 
indicated 
Severe symptoms; 
limiting self-care ADL; 
repair or revision 
indicated; disabling 
Life-threatening 
consequences; 
evidence of end 
organ damage; 
urgent operative 
intervention 
indicated 
Death 
Psychiatric disorders 
Agitation 
Definition: A disorder 
characterized by a state of 
restlessness associated with 
unpleasant feelings of irritability 
and tension. 
 During or immediately 
after infusion May be 
early indication of 
anaphylaxis 
Mild mood alteration 
Moderate mood 
alteration 
Severe agitation; 
hospitalization not 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Anxiety 
Definition: A disorder 
characterized by apprehension 
of danger and dread 
accompanied by restlessness, 
tension, tachycardia, and 
dyspnea unattached to a 
clearly identifiable stimulus. 
 Throughout study 
Mild symptoms; 
intervention not 
indicated 
Moderate symptoms; 
limiting instrumental 
ADL 
Severe symptoms; 
limiting self-care ADL; 
hospitalization not 
Indicated 
Life-threatening; 
hospitalization 
indicated 
Death 
Confusion 
Definition: A disorder 
characterized by a lack of clear 
and orderly thought and 
behaviour. 
 
  
Mild disorientation 
Moderate 
disorientation; limiting 
instrumental ADL 
Severe disorientation; 
limiting self-care ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 

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Depression 
Definition: A disorder 
characterized by melancholic 
feelings of grief or 
unhappiness. 
 Throughout study 
Mild depressive 
symptoms 
Moderate depressive 
symptoms; limiting 
instrumental ADL 
Severe depressive 
symptoms; limiting self-
care ADL; 
hospitalization not 
indicated 
Life-threatening 
consequences, 
threats of harm to 
self or others; 
hospitalization 
indicated 
Death 
Restlessness 
Definition: A disorder 
characterized by an inability to 
rest, relax or be still. 
 During or immediately 
after infusion May be 
early indication of 
anaphylaxis 
Mild symptoms; 
intervention not 
indicated 
Moderate symptoms; 
limiting instrumental 
ADL 
Severe symptoms; 
limiting self-care ADL 
- 
- 
Renal and urinary disorders 
Haemoglobinuria 
Definition: A disorder 
characterized by laboratory test 
results that indicate the 
presence of free haemoglobin 
in the urine. 
 During or immediately 
after infusion 
 Within 36 hours of 
infusion 
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated 
- 
- 
- 
- 
Respiratory, thoracic and mediastinal disorders 
Bronchospasm 
Definition: A disorder 
characterized by a sudden 
contraction of the smooth 
muscles of the bronchial wall. 
 During or immediately 
after infusion 
Mild symptoms; 
intervention not 
indicated 
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL 
Limiting self-care ADL; 
oxygen saturation 
decreased 
Life-threatening 
respiratory or 
hemodynamic 
compromise; 
intubation or urgent 
intervention 
indicated 
Death 
Dyspnea 
Definition: A disorder 
characterized by an 
uncomfortable sensation of 
difficulty breathing. 
 
 During or immediately 
after infusion 
Shortness of breath 
with moderate exertion 
Shortness of breath 
with minimal exertion; 
limiting instrumental 
ADL 
Shortness of breath at 
rest; limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Hypoxia 
Definition: A disorder 
characterized by a decrease in 
the level of oxygen in the body. 
 During or immediately 
after infusion 
- 
Decreased oxygen 
saturation with 
exercise (e.g., pulse 
oximeter <88%); 
intermittent 
supplemental oxygen 
Decreased oxygen 
saturation at rest (e.g., 
pulse oximeter <88% or 
PaO2 ≤55 mm Hg) 
Life-threatening 
airway compromise; 
urgent intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death 
Respiratory failure 
Definition: A disorder 
characterized by impaired gas 
exchange by the respiratory 
system resulting in hypoxemia 
and a decrease in oxygenation 
 During or immediately 
after infusion 
- 
- 
- 
Life-threatening 
consequences; 
urgent intervention, 
intubation, or 
ventilatory support 
indicated 
Death 

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of the tissues that may be 
associated with an increase in 
arterial levels of carbon dioxide. 
Stridor 
Definition: A disorder 
characterized by a high pitched 
breathing sound due to 
laryngeal or upper airway 
obstruction. 
 During or immediately 
after infusion 
- 
- 
Respiratory distress 
limiting self-care ADL; 
medical intervention 
indicated 
Life-threatening 
airway compromise; 
urgent intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death 
Wheezing 
Definition: A disorder 
characterized by a high-
pitched, whistling sound during 
breathing. It results from the 
narrowing or obstruction of the 
respiratory airways. 
 During or immediately 
after infusion 
Detectable airway noise 
with minimal symptoms 
Moderate symptoms; 
medical intervention 
indicated; limiting 
instrumental ADL 
Severe respiratory 
symptoms limiting self-
care ADL; oxygen 
therapy or 
hospitalization indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Skin and subcutaneous tissue disorders 
Rash/desquamation 
 Rash/desquamation 
may be used for 
identifying GvHD 
Macular or popular 
eruption or erythema 
without associated 
symptoms 
Macular or popular 
eruption or erythema 
with pruritus or other 
associated 
symptoms; localized 
desquamation or 
other lesions 
covering <50% of 
body surface area 
(BSA) 
Severe, generalized 
erythroderma or 
macular, papular or 
vesicular eruption; 
desquamation covering 
≥50% BSA 
Generalized 
exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
Urticaria 
Definition: A disorder 
characterized by an itchy skin 
eruption characterized by 
wheals with pale interiors and 
well-defined red margins. 
 During or immediately 
after infusion 
 May be early indication 
of allergic reaction or 
anaphylaxis 
Urticarial lesions 
covering <10% BSA; 
topical intervention 
indicated 
Urticarial lesions 
covering 10-30% 
BSA; oral 
intervention indicated 
Urticarial lesions 
covering >30% BSA; IV 
intervention indicated 
- 
- 
Vascular disorders 
Hypertension 
Definition: A disorder 
characterized by a pathological 
increase in blood pressure; a 
repeatedly elevation in the 
blood pressure exceeding 140 
over 90 mm Hg. 
 During or immediately 
after infusion 
 Within 36 hours of 
infusion 
Prehypertension 
(systolic BP 120 - 139 
mm Hg or diastolic BP 
80 - 89 mm Hg) 
Stage 1 hypertension 
BP >ULN medical 
intervention 
indicated; recurrent 
or persistent (≥24hrs) 
Stage 2 hypertension 
(systolic BP >=160 mm 
Hg or diastolic BP ≥100 
mm Hg); medical 
intervention indicated; 
more than one drug or 
more intensive therapy 
Life-threatening 
consequences (e.g., 
malignant 
hypertension, 
transient or 
permanent 
neurologic deficit,  
hypertensive crisis); 
Death 

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than previously used 
indicated 
urgent intervention 
indicated 
Hypotension 
Definition: A disorder 
characterized by a blood 
pressure that is below the 
normal expected for an 
individual in a given 
environment. 
 During or immediately 
after infusion 
 Within 36 hours of 
infusion 
Asymptomatic, 
intervention not 
indicated 
Non-urgent medical 
intervention indicated 
Medical intervention or 
hospitalization indicated 
Life-threatening and 
urgent intervention 
indicated 
Death 
 
 
Graft versus Host Disease [63] 
 
 
 
Stage 
Skin 
Liver (bilirubin) 
Gut (stool output per day) 
0 
No GVHD rash 
< 2mg/dl 
Child: < 10 ml/kg/day or persistent nausea 
1 
Maculopapular rash 25% BSA 
2–3 mg/dl 
Child: 10–19.9 ml/kg/day or persistent nausea, vomiting or anorexia, with a positive 
upper GI biopsy 
2 
Maculopapular rash 25–50% BSA 
3.1–6 mg/dl 
Child: 20–30 ml/kg/day 
3 
Maculopapular rash > 50% BSA 
6.1–15mg/dl 
Child: > 30 ml/kg/day 
4 
Generalized erythroderma plus bullous formation 
> 15mg/dl 
Severe abdominal pain with or without ileus 
Grade 
 
 
 
I 
Stages 1–2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
— 
Stages 2–3 or 
Stages 2–4 
IV 
Stage 4 or 
Stage 4 
—