ANZCTR - Registration

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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 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]

Nil

Universal Trial Number (UTN)

U1111-1151-8685

Trial acronym

Linked study record

Health condition

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

Bronchopulmonary dysplasia

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

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]

Treatment: Other

Comparator / control treatment

Nil. We will measure pre- and post-treatment outcomes

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Possible local skin reactions including extravasation, erythema, oedema as assessed by physical examination.

Timepoint [1]

On day of treatment for first 24 hours.

Primary outcome [2]

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]

These will be assessed as part of routine intensive neonatal care.

Primary outcome [3]

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]

From day of treatment until discharge.

Secondary outcome [1]

Respiratory function – changes in FiO2, ventilator pressure requirements, Oxygenation index (OI), Respiratory Severity Score (RSS)

Timepoint [1]

From time of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.

Secondary outcome [2]

BPD or death (due to respiratory failure) before discharge

Timepoint [2]

From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.

Secondary outcome [3]

Length of hospital stay

Timepoint [3]

From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.

Secondary outcome [4]

Length of oxygen use

Timepoint [4]

From day of treatment until discharge. Daily checks will be performed as part of routine intensive neonatal care.

Secondary outcome [5]

Period reliant on oxygen support

Timepoint [5]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Funding & Sponsors

Funding source category [1]

University

Name [1]

Monash University

Address [1]

Department of Obstetrics & Gynaecology
Level 5, 246 Clayton Rd
Clayton Vic 3168

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

Level 4, 246 Clayton Rd
Clayton Vic 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

18/11/2013

Approval date [1]

06/02/2014

Ethics approval number [1]

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

Dr Rebecca Lim

Address

The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168

Country

Australia

Phone

+61 3 99024775

Fax

[email protected]

Contact person for public queries

Name

Rebecca Lim

Address

The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168

Country

Australia

Phone

+61 3 99024775

Fax

[email protected]

Contact person for scientific queries

Name

Rebecca Lim

Address

The Ritchie Centre
Monash Institute of Medical Research
27-31 Wright Street
Clayton
VIC 3168

Country

Australia

Phone

+61 3 99024775

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
10500	Study protocol			[email protected]

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
Dimensions AI	Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies	2016	https://doi.org/10.1159/000444918
Dimensions AI	Human amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury	2017	https://doi.org/10.1186/s13287-017-0496-3
Embase	First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study.	2018	https://dx.doi.org/10.1002/sctm.18-0079
Embase	Mesenchymal Stromal Cell Therapy for Respiratory Complications of Extreme Prematurity.	2018	https://dx.doi.org/10.1055/s-0038-1639371
Embase	Two-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia.	2020	https://dx.doi.org/10.1002/sctm.19-0251
Embase	A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia.	2021	https://dx.doi.org/10.3389/fped.2021.615508
Embase	Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells.	2021	https://dx.doi.org/10.3389/fphys.2021.724186
Embase	Amniotic fluid characteristics and its application in stem cell therapy: A review.	2022	https://dx.doi.org/10.18502/ijrm.v20i8.11752

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

Trial Review

Documents added manually

Documents added automatically