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Trial registered on ANZCTR


Registration number
ACTRN12623001352695
Ethics application status
Approved
Date submitted
21/11/2023
Date registered
21/12/2023
Date last updated
21/12/2023
Date data sharing statement initially provided
21/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Feasibility of Allogeneic Cord Blood-Derived Cell Therapy in Preterm Infants with Severe Brain Injury (ALLO Trial)
Scientific title
Safety and Feasibility of Allogeneic Cord Blood-Derived Cell Therapy in Preterm Infants with Severe Brain Injury (ALLO Trial)
Secondary ID [1] 310985 0
None
Universal Trial Number (UTN)
Trial acronym
ALLO trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Brain Injury 332085 0
Severe Intraventricular Haemorrhage 332086 0
Diffuse Cystic Periventricular Leucomalacia 332087 0
Condition category
Condition code
Neurological 328809 328809 0 0
Other neurological disorders
Reproductive Health and Childbirth 328810 328810 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Summary of intervention: One intravenous infusion of 4/6 or higher Human leucocyte antigen (HLA)-matched allogeneic Umbilical Cord Blood Cells (UCBCs) obtained from Bone Marrow Donor Institute (BMDI) Cord Blood Bank at an approximate dose of 50 million cells per kilogram (as available).


20 preterm infants, with 10 each in each stratum (<28 weeks, ALLO-1 trial and 28 to 36+6 weeks, ALLO-2 trial), will be enrolled.

1. HLA matching: Allogeneic UCBCs will be obtained from BMDI Cord Blood Bank with an HLA matching of at least 4/6 HLA. The donor UCBCs must match a minimum of 4 out of 6 HLA markers in the recipient. As HLA matching and processing UCBCs may be time-consuming, the eligibility (cranial ultrasound) will be reconfirmed before administering the allogeneic UCBCs after successful HLA matching.

2. Age of administration: Allogeneic UCBCs will be administered via IV infusion anytime from birth until three months of life, generally within 2-3 weeks of diagnosis of severe preterm brain injury.

3. Cell infusion: Only one allogeneic UCBC infusion will be administered intravenously by the nurse in the neonatal intensive care unit under the supervision of the doctor. The doctor will monitor the baby for any adverse events during the infusion and ensure the infusion is provided and completed as per the protocol and standard operating procedures.

4. UCBC dose: At least 50 million total nucleated cells (TNCs) per kilogram of body weight will be administered. This therapeutic dose is based on preclinical and clinical studies of UCBCs for different types of perinatal brain injury.

5. Route: The UCBCs will be administered intravenously via a peripheral intravenous cannula over 1-hour duration.
Intervention code [1] 327426 0
Treatment: Other
Comparator / control treatment
There is no concurrent control arm, However, an exploratory analysis will be conducted by comparing the babies who received the therapy to a contemporary cohort of babies with severe preterm brain injury during the study period who have not received the therapy (declined to receive experimental therapy, or babies who did not receive the therapy as there was no matched cord blood available).
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336613 0
Feasibility of availability of allogeneic umbilical cord blood cells in surviving preterm infants with severe brain injury.
Timepoint [1] 336613 0
At conclusion of the study
Primary outcome [2] 336614 0
Safety of allogeneic umbilical cord blood cells in surviving preterm infants with severe brain injury.
Timepoint [2] 336614 0
Serious adverse events will be monitored during and for 48 hours post-infusion.
Graft versus host disease monitoring will take place during the first three months after cell infusion (before and 24 hours, 7 days, 1 month, 2 months and 3 months after infusion) for the safety endpoint. However, clinical assessments will continue until 2 years of age (6, 9, 12, 18 and 24 months post-infusion).
Secondary outcome [1] 428967 0
Death
Timepoint [1] 428967 0
24 months of corrected age
Secondary outcome [2] 428968 0
Moderate to severe bronchopulmonary dysplasia
Timepoint [2] 428968 0
36 weeks of postmenstrual age
Secondary outcome [3] 428969 0
Severe retinopathy of prematurity
Timepoint [3] 428969 0
Before neonatal discharge
Secondary outcome [4] 428970 0
Necrotising enterocolitis
Timepoint [4] 428970 0
Anytime occurring before neonatal discharge
Secondary outcome [5] 428971 0
Culture-proven sepsis
Timepoint [5] 428971 0
Before neonatal discharge
Secondary outcome [6] 428972 0
Early adverse neurological outcomes, such as developmental delay, cerebral palsy or high risk of cerebral palsy
Timepoint [6] 428972 0
3-4 months corrected age
Secondary outcome [7] 428973 0
Late neurological adverse outcomes, such as cognitive delay, motor delay, language delay, and their severity
Timepoint [7] 428973 0
24 to 36 months of corrected age
Secondary outcome [8] 428974 0
Cerebral Palsy and its severity
Timepoint [8] 428974 0
24 to 36 months of corrected age
Secondary outcome [9] 428975 0
Blindness
Timepoint [9] 428975 0
24 to 36 months of corrected age
Secondary outcome [10] 428976 0
Deafness
Timepoint [10] 428976 0
24 to 36 months of corrected age
Secondary outcome [11] 428977 0
Cytokine analysis
Timepoint [11] 428977 0
Before and after (24 hours and 7 days) the therapy
Secondary outcome [12] 428991 0
Graft versus Host disease
Timepoint [12] 428991 0
Before the therapy
After the therapy (24 h, 7 days, 1, 2, 3, 6, 9, 12, 18 and 24 months)
Secondary outcome [13] 428992 0
Brain injury and its severity
Timepoint [13] 428992 0
Term-equivalent age

Eligibility
Key inclusion criteria
1. Preterm infants born before 28 completed weeks of gestation (up to 27+6 weeks, ALLO-1 trial) OR born between 28 and 36+6 weeks of gestation (ALLO-2 trial) AND
2. Severe brain injury detected on neonatal neuroimaging any time after birth. A severe brain injury will be considered as grade 3 (intraventricular haemorrhage with ventricular distension) or 4 (parenchymal haemorrhagic infarct) IVH and diffuse cystic (grade 3) periventricular leucomalacia.
Minimum age
22 Weeks
Maximum age
36 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Infants with known major congenital anomalies
2. Infants whose care is being redirected to comfort care.

Cell therapy will only be administered when preterm infants are clinically stable, which is deemed by the treating physician. Also, infants should not be receiving antimicrobial therapy for confirmed or presumed late-onset neonatal sepsis at the time of cell infusion as their course may be unpredictable and may confound adverse events falsely attributing to the cell therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A preliminary statistical plan is as follows: Descriptive statistics will be used to report demographics and outcomes. The categorical variables will be described as frequency and percentage and continuous variables as median (interquartile range) and mean (standard deviation), depending on the normality of the data, which will be determined by the Shapiro-Wilk test. The data will be analysed using STATA Version 17.0 (StataCorp LLC, College Station, Tx, USA). Paired t-tests or Wilcoxon signed-rank tests will be performed to compare the laboratory parameters before and after infusion.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2024
Actual
Date of last participant enrolment
Anticipated
1/04/2028
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 25865 0
Monash Children’s Hospital - Clayton
Recruitment postcode(s) [1] 41698 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 315246 0
Government body
Name [1] 315246 0
National Health and Medical Research Council
Country [1] 315246 0
Australia
Funding source category [2] 315250 0
Charities/Societies/Foundations
Name [2] 315250 0
Lion's Cord Blood Foundation
Country [2] 315250 0
Australia
Funding source category [3] 315251 0
Hospital
Name [3] 315251 0
Monash Children's Hospital
Country [3] 315251 0
Australia
Primary sponsor type
Hospital
Name
Monash Children's Hospital
Address
246 Clayton Rd, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 317276 0
None
Name [1] 317276 0
Address [1] 317276 0
Country [1] 317276 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314166 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 314166 0
246 Clayton Road Clayton Victoria 3168
Ethics committee country [1] 314166 0
Australia
Date submitted for ethics approval [1] 314166 0
21/05/2023
Approval date [1] 314166 0
23/11/2023
Ethics approval number [1] 314166 0
HREC/98055/MonH-2023-375621(v1)

Summary
Brief summary
This trial aims to assess the safety and feasibility of using allogeneic UCBCs in preterm infants with severe brain injury. The primary objectives include evaluating the availability of at least 4/6 HLA-matched allogeneic UCBCs for more than 60% of eligible infants and assessing the safety of UCBCs administration by monitoring adverse events and the absence of graft versus host disease (GVHD).

Secondary objectives involve evaluating the impact of UCBC administration on short and long-term clinical outcomes, such as death, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, sepsis, developmental delay, cerebral palsy, blindness, and deafness. Additionally, the trial aims to assess the effect of UCBCs on immune responses by measuring cytokine levels.

The study will enroll 20 preterm infants with severe brain injury, divided into two strata based on gestational age. The infants will receive one intravenous infusion of 4/6 or higher HLA-matched allogeneic UCBCs obtained from the BMDI Cord Blood Bank at a dose of 50 million cells per kg. The trial will span 3-5 years, including a 24-month post-intervention follow-up period. The recruitment will be limited to Monash Children's Hospital.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130650 0
A/Prof Atul Malhotra
Address 130650 0
246 Clayton Rd, Monash Children's Hospital, Clayton VIC 3168
Country 130650 0
Australia
Phone 130650 0
+61 3 8572 3650
Fax 130650 0
Email 130650 0
[email protected]
Contact person for public queries
Name 130651 0
Atul Malhotra
Address 130651 0
246 Clayton Rd, Monash Children's Hospital, Clayton VIC 3168
Country 130651 0
Australia
Phone 130651 0
+61 3 8572 3650
Fax 130651 0
Email 130651 0
[email protected]
Contact person for scientific queries
Name 130652 0
Atul Malhotra
Address 130652 0
246 Clayton Rd, Monash Children's Hospital, Clayton VIC 3168
Country 130652 0
Australia
Phone 130652 0
+61 3 8572 3650
Fax 130652 0
Email 130652 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.