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Trial registered on ANZCTR


Registration number
ACTRN12618000920291
Ethics application status
Approved
Date submitted
29/05/2018
Date registered
31/05/2018
Date last updated
16/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Human Amnion Epithelial Cells for Prevention of Bronchopulmonary Dysplasia in Preterm Infants: A Safety Study
Scientific title
Human Amnion Epithelial Cells for Prevention of Bronchopulmonary Dysplasia: A Phase 1 Dose Escalation Study
Secondary ID [1] 294976 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchopulmonary Dysplasia 307982 0
Extremely preterm birth 307989 0
Condition category
Condition code
Respiratory 307018 307018 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 307024 307024 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Infants born at <29 weeks gestation at high risk of bronchopulmonary dysplasia (BPD) as assessed by respiratory support and oxygen requirements on Day 14 of life will receive intravenously administered allogeneic human amnion epithelial cells (hAECs). The dose of cells will increase between patient cohorts beginning with 2 million hAECs/kg in a single dose reaching 30 million hAECs/kg in 3 divided doses given at 5 day intervals. The dosing schedule is provided below.
Infants 1-3: 2 million hAECs/kg
Infants 4-6: 4 million hAECs/kg
Infants 7-9: 8 million hAECs/kg
Infants 9-12: 10 million hAECs/kg
Infants 13-18: 20 million hAECs/kg in 2 divided doses given at 5 day intervals
infants 19-24: 30 million hAECs/kg in 3 divided doses given at 5 days intervals
hAEC suspension will be prepared by the Amnion cell biology research group at Monash Health Translation Precinct's Cell therapy platform. hAEC suspension will be manufactured in accordance with good manufacturing practice.
Intervention code [1] 301306 0
Treatment: Other
Comparator / control treatment
2 million hAECs/kg administered intravenously
Control group
Dose comparison

Outcomes
Primary outcome [1] 305999 0
The primary outcome is safety of hAEC infusion in infants <29 weeks gestation. Safety will be determined by the occurrence of adverse events.
Adverse events will be defined as;
- Cardiorespiratory Instability and/or Anaphylaxis within 72 hours of hAEC infusion
- Infection within 72 hours of hAEC infusion
- Allogeneic Rejection
- Tumour formation
- Local Site Reaction
Routine care within intensive care and special care nurseries will inform much of the primary outcome. In addition to routine care, screening for potential adverse events will include;
- MRI brain and abdominal ultrasound at 36 weeks PMA, Cranial ultrasound at 6 months corrected age, Chest XRay and abdominal ultrasound at 6, 12 and 24 months corrected age for assessment of tumorgenicity
- Fortnightly blood tests of liver and renal function for duration of hospital admission to assess for evidence of allogeneic rejection

Timepoint [1] 305999 0
Continuous monitoring of cardiovascular and respiratory status during hAEC infusion and for 24 hours post infusion
72 hours post hAEC infusion
7 days post hAEC infusion
fortnightly post hAEC infusion until hospital discharge
36 weeks PMA
6 month, 12 months, 18 months and 24 months corrected age
Secondary outcome [1] 347262 0
Severity of bronchopulmonary dysplasia as assessed by respiratory support requirements as documented in infants medical records and a physiological assessment (modified Walsh air reduction test)
Timepoint [1] 347262 0
36 weeks PMA
Secondary outcome [2] 347264 0
Selected cytokine levels will be assessed from blood samples using a PerkinElmer AlphaLISA system.
Timepoint [2] 347264 0
For each hAEC infusion an infants receives blood will be collected pre, 24 hours post and 5 days post the infusion.
Secondary outcome [3] 347265 0
Death before hospital discharge post 36 weeks PMA
Timepoint [3] 347265 0
Death or hospital discharge
Secondary outcome [4] 347267 0
Incidence of necrotising enterocolitis, modified Bell's Stage greater than or equal to 2 as documented in medical records.
Timepoint [4] 347267 0
Death or hospital discharge
Secondary outcome [5] 347268 0
Incidence of treatment for a patent ductus arteriosus as documented in infants' medical records.
Timepoint [5] 347268 0
Death or hospital discharge
Secondary outcome [6] 347269 0
Incidence of grade III or IV intraventricular haemorrhage or periventricular leukomalacia as documented in infants' medical records.
Timepoint [6] 347269 0
Death or hospital discharge
Secondary outcome [7] 347270 0
Incidence of retinopathy of prematurity, greater than or equal to stage 2 as documented in infants' medical records.
Timepoint [7] 347270 0
Death or hospital discharge
Secondary outcome [8] 347271 0
Incidence of late onset sepsis, culture proven as documented in infants' medical records.
Timepoint [8] 347271 0
Death or hospital discharge
Secondary outcome [9] 347272 0
Length of hospital admission as documented in infants' medical records.
Timepoint [9] 347272 0
Death or hospital admission
Secondary outcome [10] 347273 0
Growth at discharge as documented in infants' medical records.
Timepoint [10] 347273 0
Death or hospital discharge
Secondary outcome [11] 347274 0
Neurodevelopmental outcome as assessed by Bayley Scales of Infant and Toddler Development at 2 years corrected as documented in infants' medical records.
Timepoint [11] 347274 0
2 years corrected age
Secondary outcome [12] 347493 0
Pulmonary hypertension as assessed by echocardiogram
Timepoint [12] 347493 0
36 weeks PMA
Secondary outcome [13] 347495 0
Use of postnatal corticosteroids as documented in infants' medical records.
Timepoint [13] 347495 0
Death or hospital discharge

Eligibility
Key inclusion criteria
Born <29 weeks gestation
Ventilated via an endotracheal tube requiring greater than or equal to 25% oxygen or receiving non-invasive respiratory support requiring greater than or equal to 35% oxygen on day 14 of life to maintain oxygen saturations in range 90-94%.
Minimum age
14 Days
Maximum age
18 Days
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
clinical team consider death imminent or full intensive care is not being offered
significant congenital abnormality, including but not limited to
o severe congenital heart disease
o congenital airway malformation
o severe neurological abnormality
lead treating physician deems that it is inappropriate for the infant to receive hAECs

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)
Not appplicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is a dose escalation study. 3-6 infants will be recruited per dose cohort. The dose will increase in increments from 2 million cells/kg to 30million cells/kg.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Statistics will be descriptive.
The number of infants was based on the number of participants recruited to similar dose escalation trials of stem cell therapies.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10975 0
Monash Children’s Hospital - Clayton
Recruitment hospital [2] 10976 0
The Royal Women's Hospital - Parkville
Recruitment postcode(s) [1] 22764 0
3168 - Clayton
Recruitment postcode(s) [2] 22765 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 299566 0
Government body
Name [1] 299566 0
National Health and Medical Research Council Program Grant
Address [1] 299566 0
GPO Box 1421
Canberra ACT 2601
Country [1] 299566 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
246 Clayton Road
Clayton
VIc 3168
Country
Australia
Secondary sponsor category [1] 298873 0
None
Name [1] 298873 0
Address [1] 298873 0
Country [1] 298873 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300463 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 300463 0
Level 2, I Block
Monash Medical Centre
Clayton VIC
3168
Ethics committee country [1] 300463 0
Australia
Date submitted for ethics approval [1] 300463 0
21/03/2018
Approval date [1] 300463 0
12/06/2018
Ethics approval number [1] 300463 0

Summary
Brief summary
Owing to advances in neonatal care, survival of preterm infants, particularly those born at less than or equal to 28 weeks, is increasing. Survival brings with it the risk of morbidity. Bronchopulmonary dysplasia (BPD), lung disease unique to preterm infants, is an important morbidity associated with long term impairments of lung function and neurodevelopment. Despite advances in the care of preterm infants, rates of BPD in survivors have not changed over recent decades. In fact, pulmonary outcomes in recent cohorts of preterm infants appear worse.
With developments in neonatal medicine over the last few decades the phenotype of BPD has changed. Today, infants at greatest risk of BPD are born in the canalicular phase of lung development, a time when alveolar and distal capillary development commences. Preterm delivery and the interventions compromising neonatal intensive care create a proinflammatory environment disrupting the architecture of vulnerable developing lungs. Targeting inflammation with new generation therapies may provide new therapeutic options for BPD. Preclinical models have demonstrated human amnion epithelial cells (hAECs) can prevent and repair lung injury by modifying the inflammatory response, helping to restore normal lung architecture. hAECs have potential to reduce the incidence and/or severity of BPD.
A small phase 1 study completed at Monash Health in Melbourne, Australia gave 1 million hAECs/kg to infants with established BPD. This was a first-in-human study and appropriately gave a conservative dose of hAECs to assess safety. Prior to larger trials to study the efficacy of hAECs as a preventive therapy for BPD, tolerance to higher doses of hAECs, which are more likely to be efficacious based on preclinical studies, must be established in a younger, less mature population of preterm infants.
Accordingly, we propose a multicentre dose escalation trial to assess the safety of intravenously administered hAECs in preterm infants at high risk of developing BPD. Infants will be assessed as being at high risk of BPD if delivered at less than 29 weeks gestational age and on Day 14 of life require either mechanical ventilation with an FiO2 greater than or equal to 0.25 or non-invasive respiratory support with an FiO2 greater than or equal to 0.35.
24 infants will be recruited and given intravenous hAECs during the third and fourth week of life at doses increasing from 2 million hAECs/kg to 30 million hAECs/kg. The first 12 infants will receive a single infusion to a maximum dose of 10 million hAECs/kg. Larger total doses will be achieved in the final 12 patients by repeat infusions at 5 day intervals.
Safety is the primary outcome and will be defined by the occurrence of adverse events during the 2 year follow-up period. Secondary outcomes include cytokine profiling and neonatal morbidities, in particular the incidence and severity of BPD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83742 0
Dr Elizabeth Baker
Address 83742 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052
Country 83742 0
Australia
Phone 83742 0
+61 3 8345 3763
Fax 83742 0
+61 3 8345 3789
Email 83742 0
elizabeth.baker2@thewomens.org.au
Contact person for public queries
Name 83743 0
Dr Elizabeth Baker
Address 83743 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052
Country 83743 0
Australia
Phone 83743 0
+61 3 8345 3763
Fax 83743 0
+61 3 8345 3789
Email 83743 0
elizabeth.baker2@thewomens.org.au
Contact person for scientific queries
Name 83744 0
Dr Elizabeth Baker
Address 83744 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052
Country 83744 0
Australia
Phone 83744 0
+61 3 8345 3763
Fax 83744 0
+61 3 8345 3789
Email 83744 0
elizabeth.baker2@thewomens.org.au

No data has been provided for results reporting
Summary results
Not applicable