ANZCTR - Registration

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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]

Nil Known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Bronchopulmonary Dysplasia

Extremely preterm birth

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Reproductive Health and Childbirth

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]

Treatment: Other

Comparator / control treatment

2 million hAECs/kg administered intravenously

Control group

Dose comparison

Outcomes

Primary outcome [1]

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]

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]

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]

36 weeks PMA

Secondary outcome [2]

Selected cytokine levels will be assessed from blood samples using a PerkinElmer AlphaLISA system.

Timepoint [2]

For each hAEC infusion an infants receives blood will be collected pre, 24 hours post and 5 days post the infusion.

Secondary outcome [3]

Death before hospital discharge post 36 weeks PMA

Timepoint [3]

Death or hospital discharge

Secondary outcome [4]

Incidence of necrotising enterocolitis, modified Bell's Stage greater than or equal to 2 as documented in medical records.

Timepoint [4]

Death or hospital discharge

Secondary outcome [5]

Incidence of treatment for a patent ductus arteriosus as documented in infants' medical records.

Timepoint [5]

Death or hospital discharge

Secondary outcome [6]

Incidence of grade III or IV intraventricular haemorrhage or periventricular leukomalacia as documented in infants' medical records.

Timepoint [6]

Death or hospital discharge

Secondary outcome [7]

Incidence of retinopathy of prematurity, greater than or equal to stage 2 as documented in infants' medical records.

Timepoint [7]

Death or hospital discharge

Secondary outcome [8]

Incidence of late onset sepsis, culture proven as documented in infants' medical records.

Timepoint [8]

Death or hospital discharge

Secondary outcome [9]

Length of hospital admission as documented in infants' medical records.

Timepoint [9]

Death or hospital admission

Secondary outcome [10]

Growth at discharge as documented in infants' medical records.

Timepoint [10]

Death or hospital discharge

Secondary outcome [11]

Neurodevelopmental outcome as assessed by Bayley Scales of Infant and Toddler Development at 2 years corrected as documented in infants' medical records.

Timepoint [11]

2 years corrected age

Secondary outcome [12]

Pulmonary hypertension as assessed by echocardiogram

Timepoint [12]

36 weeks PMA

Secondary outcome [13]

Use of postnatal corticosteroids as documented in infants' medical records.

Timepoint [13]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/08/2018

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]

Monash Children’s Hospital - Clayton

Recruitment hospital [2]

The Royal Women's Hospital - Parkville

Recruitment postcode(s) [1]

3168 - Clayton

Recruitment postcode(s) [2]

3052 - Parkville

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council Program Grant

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Hospital

Name

Monash Health

Address

246 Clayton Road
Clayton
VIc 3168

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health Human Research Ethics Committee

Ethics committee address [1]

Level 2, I Block 
Monash Medical Centre 
Clayton VIC 
3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/03/2018

Approval date [1]

12/06/2018

Ethics approval number [1]

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

Attachments [1]

/AnzctrAttachments/375171-HREC Review Only Final Approval letter clean. 18-0000-180A.doc New.1 (002).pdf (Ethics approval)

Contacts

Principal investigator

Name

Dr Elizabeth Baker

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+61 3 8345 3789

elizabeth.baker2@thewomens.org.au

Contact person for public queries

Name

Elizabeth Baker

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+61 3 8345 3789

elizabeth.baker2@thewomens.org.au

Contact person for scientific queries

Name

Elizabeth Baker

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+61 3 8345 3789

elizabeth.baker2@thewomens.org.au

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Embase	Cell Therapy with the Cell or without the Cell for Premature Infants? Time Will Tell.	2021	https://dx.doi.org/10.1164/rccm.202109-2070ED
Dimensions AI	Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells	2021	https://doi.org/10.3389/fphys.2021.724186

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically