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Trial registered on ANZCTR


Registration number
ACTRN12614000174684
Ethics application status
Approved
Date submitted
6/01/2014
Date registered
12/02/2014
Date last updated
8/02/2021
Date data sharing statement initially provided
8/02/2021
Date results information initially provided
8/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Amnion cells for the treatment of bronchopulmonary dysplasia in premature babies
Scientific title
A pilot study evaluating the safety of intravenously administered human amnion epithelial cells for treatment of bronchopulmonary dysplasia (BPD) in premature babies
Secondary ID [1] 283854 0
Nil
Universal Trial Number (UTN)
U1111-1151-8685
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchopulmonary dysplasia 290831 0
Condition category
Condition code
Respiratory 291198 291198 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 291479 291479 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A single dose of allogeneic human amnion epithelial cells (hAECs) resuspended in saline (1 million per kilogram bodyweight) will be administered intravenously. Routine intensive care monitoring will continue post administration of hAECs, however one of the trial principal investigators/ coordinator (Dr Atul Malhotra) would be available 24/7 for any unlikely adverse events over the next 7 days (e.g. anaphylaxis, respiratory failure, seizures).
Intervention code [1] 288534 0
Treatment: Other
Comparator / control treatment
Nil. We will measure pre- and post-treatment outcomes
Control group
Uncontrolled

Outcomes
Primary outcome [1] 291189 0
Possible local skin reactions including extravasation, erythema, oedema as assessed by physical examination.
Timepoint [1] 291189 0
On day of treatment for first 24 hours.
Primary outcome [2] 291204 0
Possible anaphylaxis and rejection, which will be reflected in acute deterioration of respiratory, cardiovascular parameters as detailed below.

a. Respiratory deterioration – increase in FiO2, ventilator requirements, air leaks, pulmonary haemorrhage
b. Cardiovascular compromise – hypotension, hypertension

Features of rejection as evidenced by impairment in hepatic, gastrointestinal or renal parameters.
c. Gastrointestinal – feed intolerance, necrotizing enterocolitis (NEC)
d. Hepatic – new onset jaundice, elevation of hepatic enzymes, coagulation dysfunction – thrombocytopenia, disseminated intravascular coagulation as evidenced by increase in international normalized ratio (INR), prothrombin time (PT), etc.
e. Neurological – abnormal neurological state, seizures
f. Renal – oliguria, anuria, polyuria, and biochemical renal dysfunction (deranged blood urea, serum creatinine)
bradycardia, tachycardia, rhythm abnormalities
Timepoint [2] 291204 0
These will be assessed as part of routine intensive neonatal care.
Primary outcome [3] 291205 0
Possible introduction of infection. These will be assessed by observation of clinical signs, laboratory evidence (increase in white cell counts, bacterial/ viral growth on sterile cultures) or late development of blood borne infections.
Timepoint [3] 291205 0
From day of treatment until discharge.
Secondary outcome [1] 306206 0
Respiratory function – changes in FiO2, ventilator pressure requirements, Oxygenation index (OI), Respiratory Severity Score (RSS)
Timepoint [1] 306206 0
From time of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.
Secondary outcome [2] 306228 0
BPD or death (due to respiratory failure) before discharge
Timepoint [2] 306228 0
From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.
Secondary outcome [3] 306229 0
Length of hospital stay
Timepoint [3] 306229 0
From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.
Secondary outcome [4] 306819 0
Length of oxygen use
Timepoint [4] 306819 0
From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.
Secondary outcome [5] 306820 0
Period reliant on oxygen support
Timepoint [5] 306820 0
From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.

Eligibility
Key inclusion criteria
1. Extreme prematurity (less than or equals to 28 weeks gestation at birth)
2. At least 36 weeks postmenstrual age
3. Ongoing requirement for respiratory support, inclusive of either intubated neonates and non-invasive respiratory support (NIMV/ CPAP) with mean/ end pressure >7 cm H2O
4. Stable, yet dependent on respiratory support in terms of oxygen requirement i.e. FiO2 between 0.3 and 0.5.
Minimum age
36 Weeks
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants who are mechanically ventilated with FiO2 requirement less than 0.3 or more than 0.5.
Infants with active infection (who are on intravenous antibiotics)
Infants with intercurrent viral illness
Infants with severe preterm brain injury (Grade III-IV IVH, cystic PVL)
Infants with active necrotizing enterocolitis (NEC)
Infants receiving medical or surgical therapy for patent ductus arteriosus (PDA) at the time of enrolment

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)
Allocation is not concealed.
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
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The length of hospital stay, reliance on oxygen and ventilatory support post recruitment will be analysed using a repeat measures one-way ANOVA, including the baseline value as a covariate. For the primary analysis the treatment effect will be considered constant over time, secondary analyses will examine the possibility of a trend over time. Plots of mean score over time will be shown for clarification.

Initially, the treatment effect will be assumed to be constant over time, but if time by treatment interaction is shown to be important by including this parameter in the model (the conventional level of p=0.05 will be used here) then further investigation into effects at differing time points will be made by analysing the least-square means as above. Plots of mean score over time will be shown for clarification.

All other continuous measures (clinical measures, etc) will be considered in the same manner as above (adjusting by baseline value if available). Dichotomous outcomes (mortality, etc) will be presented as risk ratios, with a corresponding chi-squared test performed.

Apart from baseline value, no adjustments for covariates will be made in the first instance in any of the investigations. Treatment estimates will only be adjusted when subgroups are explored. Interaction between treatment and subgroup variables will be examined in a similar fashion as above by including the relevant parameters in the model. This will be done in turn for each subgroup variable and adjusted estimates presented.

All tests are 2-sided and results will be presented as a point estimate along with 95% confidence intervals. All analyses will be conducted by the PI and statistician at Monash University.

This study is a proof-of-principle phase 1 trial and as such a power calculation has not been performed to calculate sample size. The purpose of this trial is to determine safety of treatment as well as appropriate outcome measures that can be used to calculate power for a future phase 2 randomised controlled trial for the same intervention.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2014
Actual
7/08/2015
Date of last participant enrolment
Anticipated
Actual
7/08/2017
Date of last data collection
Anticipated
Actual
15/08/2019
Sample size
Target
6
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1896 0
Monash Medical Centre - Clayton campus - Clayton

Funding & Sponsors
Funding source category [1] 288504 0
University
Name [1] 288504 0
Monash University
Country [1] 288504 0
Australia
Primary sponsor type
Hospital
Name
Monash Health Research Directorate
Address
Monash Health
Level 4, 246 Clayton Rd
Clayton Vic 3168
Country
Australia
Secondary sponsor category [1] 287209 0
None
Name [1] 287209 0
Address [1] 287209 0
Country [1] 287209 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290362 0
Monash Health HREC
Ethics committee address [1] 290362 0
Level 4, 246 Clayton Rd
Clayton Vic 3168
Ethics committee country [1] 290362 0
Australia
Date submitted for ethics approval [1] 290362 0
18/11/2013
Approval date [1] 290362 0
06/02/2014
Ethics approval number [1] 290362 0
13324B

Summary
Brief summary
In Australia, about one in twelve babies are born prematurely. Compared to those born at term gestation these babies, particularly those born very or extremely preterm, are at increased risk of life-threatening conditions such as bronchopulmonary dysplasia. This condition represents a major challenge because, not only is it life-threatening, but also there is no specific directed treatment. Current management is essentially limited to supportive care. As such, the mortality and morbidity toll exacted by bronchopulmonary dysplasia remains challenging, to say the least.

We have recently shown that stem-like cells can be isolated from the amniotic membrane. These cells, term human amnion epithelial cells (hAECs), bear many characteristics of traditional stem cells such as pluripotency, ability to self-renew and are able to escape immune surveillance, thus avoiding immune rejection even when administered xenogeneically. In our preclinical studies, we showed that hAECs were able to prevent and rescue lung injury in animal models of adult and neonatal lung disease.

In this clinical trial, we aim to evaluate the safety of hAECs delivered intravenously to preterm babies with established bronchopulmonary dysplasia.

In this trial, we will determine the following:
1. Safety of hAECs administered intravenously to premature babies with established bronchopulmonary dysplasia.
2. Effect of hAECs administration on the infant’s short term respiratory parameters.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45322 0
Dr Rebecca Lim
Address 45322 0
The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168
Country 45322 0
Australia
Phone 45322 0
+61 3 99024775
Fax 45322 0
Email 45322 0
[email protected]
Contact person for public queries
Name 45323 0
Rebecca Lim
Address 45323 0
The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168
Country 45323 0
Australia
Phone 45323 0
+61 3 99024775
Fax 45323 0
Email 45323 0
[email protected]
Contact person for scientific queries
Name 45324 0
Rebecca Lim
Address 45324 0
The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168
Country 45324 0
Australia
Phone 45324 0
+61 3 99024775
Fax 45324 0
Email 45324 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10500Study protocol  [email protected]



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes First-In-Human Administration of Allogeneic Amnion... [More Details] 365566-(Uploaded-08-06-2020-12-38-57)-Journal results publication.pdf

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIVentilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies2016https://doi.org/10.1159/000444918
Dimensions AIHuman amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury2017https://doi.org/10.1186/s13287-017-0496-3
EmbaseFirst-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study.2018https://dx.doi.org/10.1002/sctm.18-0079
EmbaseMesenchymal Stromal Cell Therapy for Respiratory Complications of Extreme Prematurity.2018https://dx.doi.org/10.1055/s-0038-1639371
EmbaseTwo-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia.2020https://dx.doi.org/10.1002/sctm.19-0251
EmbaseA Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia.2021https://dx.doi.org/10.3389/fped.2021.615508
EmbaseCrescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells.2021https://dx.doi.org/10.3389/fphys.2021.724186
EmbaseAmniotic fluid characteristics and its application in stem cell therapy: A review.2022https://dx.doi.org/10.18502/ijrm.v20i8.11752
N.B. These documents automatically identified may not have been verified by the study sponsor.