ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616000405415

Ethics application status

Approved

Date submitted

24/03/2016

Date registered

30/03/2016

Date last updated

6/07/2022

Date data sharing statement initially provided

13/05/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Intravenous pentoxifylline as adjunct therapy to improve long-term disability in preterm infants

Scientific title

Can Pentoxifylline improve long-term outcomes in preterm infants with late-onset sepsis or necrotising enterocolitis? A pragmatic, randomised, placebo-controlled trial

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

PROTECT

Linked study record

Health condition

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

Preterm infants

Late-onset sepsis (LOS)

Necrotising enterocolitis (NEC)

Long-term disability

Condition category

Condition code

Reproductive Health and Childbirth

Complications of newborn

Inflammatory and Immune System

Other inflammatory or immune system disorders

Neurological

Studies of the normal brain and nervous system

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Ideally within 6 hours (no later than 12 hours) of onset of suspected LOS or NEC patient will receive Pentoxifylline intravenous infusion 1ml/kg/h for 12h/day (60mg/kg/day) for 2 days. If the diagnosis of NEC or sepsis diagnosis is confirmed, this will be followed by 1ml/kg/h for 6hr/day (30mg/kg/day) on days 3-6. If the diagnosis of NEC or LOS is not confirmed the intervention will be discontinued at that time.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Within 6hr of onset of suspected LOS or NEC patient will receive normal saline (NaCl 0.9%) intravenous infusion 1ml/kg/h for 12h/day for 2 days. If the diagnosis of NEC or sepsis diagnosis is confirmed, this will be followed by 1ml/kg/h for 6hr/day (30mg/kg/day) on days 3-6. If the diagnosis of NEC or LOS is not confirmed the intervention will be discontinued at that time

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome is survival without any disability at 24 months (corrected for gestation) in infants treated with intravenous Pentoxifylline or placebo for LOS or NEC.

Presence/absence of disability at 24 months (+/- 6months) corrected for gestation will be assessed by way of a clinical follow-up visit, including administration of Bayley Scales of Infant Development, 3rd edition (BSID III).

Disability is defined as:
A) mild (-1SD to -2SD), ambulant Cerebral Palsy (GMFCS I+II) or unilateral deafness
B) moderate (-2SD to -3SD), ambulant (with aids) Cerebral Palsy (GMFCS III), or has bilateral hearing impairment
C) severe (<-3SD), non-ambulant Cerebral Palsy (GMFCS IV+V), or blindness where vision is <6/60.
Scores on the BSID III will be assessed relative to a standardized mean (+/-SD) of 100+/-15, with higher scores indicating better performance for composite and individual components of cognitive, motor and language.

Timepoint [1]

At 24 months (+/- 6months) corrected for gestation.

Secondary outcome [1]

Survival until discharge home and at 24 months (+/- 6 months). This outcome will be assessed by hospital record review and regular phone/letter contact (every 6 months) with the family until the child reaches 24 months of age.

Timepoint [1]

Until 24 months (+/- 6 months).

Secondary outcome [2]

Any disability at 24 months (+/- 6 months). Any disability will be assessed by the following assessments: A) BSID III and/or B) Ages and Stages Questionnaire III and/or C) Modified Short Health Status Questionnaire documenting either major developmental delay (including language or speech problems) or D) Cerebral Palsy with inability to walk unassisted or E) Severe visual loss (cannot fixate/legally blind or corrected acuity <6/60 in both eyes) or F) Deafness (requiring a hearing aid or cochlear implants).

Timepoint [2]

At 24 months (+/- 6months) corrected for gestation.

Secondary outcome [3]

Disability by different grades and types will be assessed based on the BSID III and/or ASQ score and/or short health questionnaire administered to access cerebral palsy, deafness and blindness. All available information will be used to determine the absence/presence of disability.

Timepoint [3]

At 24 months (+/- 6months) corrected for gestation

Secondary outcome [4]

Composite secondary outcome looking at i) surgery for proven NEC and ii) progression of NEC Stage II to Stage IIIA/B as per Modified Bell's Staging Criteria for NEC.

Timepoint [4]

Until discharged home.

Secondary outcome [5]

Duration of parenteral nutrition defined as the period of time (hours) during which any nutritional requirements are provided by parenteral nutrition (lipid emulsion and amino acid solutions). Information will be extracted from medical records reveiw.

Timepoint [5]

Until discharged home.

Secondary outcome [6]

Brain injury is defined as grade 3 and 4 intraventricular haemorrhage (IVH; on either side of the head) seen during ultrasound according to the system of grading defined by the Australian and New Zealand Neonatal Network (ANZNN) guidelines, or the presence by ultrasound any of the following: periventricular leukomalacia (PVL), porencephalic cysts or hydrocephalus requiring neurosurgical intervention.

Timepoint [6]

Until discharge home

Secondary outcome [7]

Duration of mechanical ventilation in days. Mechanical ventilation is defined as respiratory support provided either by endotracheal tube ventilation, continuous positive airway pressure or humidified high-flow oxygen. Information will be extracted from medical records reveiw.

Timepoint [7]

Until discharged home.

Secondary outcome [8]

Chronic lung disease (also known as bronchopulmonary dysplasia) is defined as receiving supplemental oxygen or any form respiratory support (mechanical ventilation, continuous positive airway pressure, humidified high flow oxygen). Information will be extracted from medical records reveiw.

Timepoint [8]

36 weeks corrected gestational age.

Secondary outcome [9]

Severe retinopathy of prematurity (ROP) is defined as warranting treatment with laser surgery, cryotherapy or monoclonal antibody therapy (according to local site guidelines). Information will be extracted from medical records reveiw.

Timepoint [9]

Until discharged home.

Secondary outcome [10]

Length of hospital stay is defined as the number of days from the Neonatal Intensive Care Unit admission to final discharge home. Information will be extracted from medical records reveiw.

Timepoint [10]

Until discharged home.

Secondary outcome [11]

Plasma cytokine levels, before study treatment commencement and during treatment, will be measured by multiplex assay platform. Plasma cytokine levels will only be measured in a subset of infants enrolled at the Perth, Western Australia, site.

Timepoint [11]

Small blood samples will be taken at 1) time of blood draw for screening for LOS and/or NEC, and 2) 48 hours after commencment of study treatment.

Secondary outcome [12]

Magnetic Resonance Image (MRI) will be used to define white matter injury. White matter injury, white matter integrity and development will be defined using the following methods: i) standardized qualitative scoring and diffusion measures of white matter integrity, which is define the extent of injury to white and gray matter and the cerebellum, these will be scored using a standard system and will be performed by two blinded assessors; ii) diffusion weighted images will be acquired by measuring apparent diffusion coefficient and anisotropy in eight template-based cerebral regions and in the corticospinal tract, corpus callosum, anterior limb of the internal capsule and optic radiation, and iii) tract-based spatial statistics will be applied to the diffusion data to identify regions of difference between randomised groups at term. MRI will only be measured in a subset of infants enrolled at the Perth, Western Australia, site.

Timepoint [12]

At 38-42 weeks corrected gestational age.

Secondary outcome [13]

Time to full enteral feeds, the time in days required for infant to achieve an enteral intake of 120ml/kg/day or more, for three consecutive days. Information will be extracted from medical records review.

Timepoint [13]

Until discharge home

Eligibility

Key inclusion criteria

Gestation <29 weeks at birth.
< 6 hours (no later than 12 hours) from blood culture taken for suspected late-onset sepsis or NEC.
Informed parental consent.

Minimum age

72 Hours

Maximum age

6 Months

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Congenital malformations, chromosomal abnormalities or any other condition considered incompatible with disability-free survival at 24 months of age.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Upon consent, infants will be randomised using a web-based randomisation system.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Treatment allocation will be balanced using minimisation for the following characteristics: study site, gender and birth gestation (<26 weeks gestation or >/= 26 weeks gestation. Multiple birth infants will be randomised individually.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Primary analysis population: 900 infants (approximately 50% of all infants randomised) are expected to show evidence of LOS or NEC within 48 hours of randomisation, yielding 80% power to detect a 25% reduction in risk of death or disability at 24 months (+/- 6 months) from 40%-30%, with two-tailed alpha of 0.05. Analysis allows for 5% loss to follow-up and 5% non-compliance.

Secondary analysis population: Full cohort of approximately 1,800 randomised babies will provide 80% power to detect a difference between event rates of 30% (control) versus 24% (intervention) at the two-sided 5% level of significance.

Sub-group analysis population (Perth, Western Australia only): For cytokine analysis the expected sample size of 80 infants will achieve at least 90% power at 2p=0.05 to detect a difference of 0.75 standard deviation between the mean cytokine concentrations of PTX and placebo groups. MRI o f80 infants will allow detection of a similar difference in MRI score between PTX and placebo groups with >90% power.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/08/2016

Actual

21/11/2016

Date of last participant enrolment

Anticipated

4/08/2024

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

1800

Accrual to date

799

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

King Edward Memorial Hospital - Subiaco

Recruitment hospital [2]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [3]

Nepean Hospital - Kingswood

Recruitment hospital [4]

Royal North Shore Hospital - St Leonards

Recruitment hospital [5]

Mater Mother's Hospital - South Brisbane

Recruitment hospital [6]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [7]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [8]

The Royal Childrens Hospital - Parkville

Recruitment hospital [9]

The Canberra Hospital - Garran

Recruitment hospital [10]

The Royal Women's Hospital - Parkville

Recruitment hospital [11]

John Hunter Children's Hospital - New Lambton

Recruitment hospital [12]

Royal Hospital for Women - Randwick

Recruitment hospital [13]

Flinders Medical Centre - Bedford Park

Recruitment hospital [14]

Liverpool Hospital - Liverpool

Recruitment hospital [15]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [16]

Royal Hobart Hospital - Hobart

Recruitment postcode(s) [1]

6008 - Subiaco

Recruitment postcode(s) [2]

2050 - Camperdown

Recruitment postcode(s) [3]

2747 - Kingswood

Recruitment postcode(s) [4]

2065 - St Leonards

Recruitment postcode(s) [5]

4101 - South Brisbane

Recruitment postcode(s) [6]

4029 - Royal Brisbane Hospital

Recruitment postcode(s) [7]

3084 - Heidelberg

Recruitment postcode(s) [8]

3168 - Clayton

Recruitment postcode(s) [9]

3052 - Parkville

Recruitment postcode(s) [10]

2605 - Garran

Recruitment postcode(s) [11]

3052 - Melbourne University

Recruitment postcode(s) [12]

2305 - New Lambton Heights

Recruitment postcode(s) [13]

2031 - Randwick

Recruitment postcode(s) [14]

5042 - Bedford Park

Recruitment postcode(s) [15]

2170 - Liverpool

Recruitment postcode(s) [16]

2145 - Westmead

Recruitment postcode(s) [17]

7000 - Hobart

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington

Country [2]

New Zealand

State/province [2]

Auckland

Country [3]

New Zealand

State/province [3]

Christchurch

Country [4]

Singapore

State/province [4]

Country [5]

Canada

State/province [5]

Alberta

Country [6]

Canada

State/province [6]

Quebec

Country [7]

Taiwan, Province Of China

State/province [7]

Taichung

Country [8]

New Zealand

State/province [8]

Waikato

Country [9]

Ireland

State/province [9]

Dublin

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC) project grant

Address [1]

GPO Box 1421
Canberra, ACT, 2601

Country [1]

Australia

Primary sponsor type

University

Name

University of Sydney

Address

c/o Dr Alpana Ghadge
Locked Bag 77
Camperdown, NSW 1450

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

The University of Western Australia

Address [1]

35 Stirling Highway,
Perth, Western Australia, 6009

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Human Research Ethics Committee

Ethics committee address [1]

Hunter New England Local Health District
Locked Bag 1
New Lambton, NSW, 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

31/03/2016

Approval date [1]

27/05/2016

Ethics approval number [1]

16/04/20/3.04

Ethics committee name [2]

Northern A Health and Disability Ethics Committee

Ethics committee address [2]

PO Box 5013
Wellington 6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

08/02/2017

Approval date [2]

09/05/2017

Ethics approval number [2]

17/NTA/33

Ethics committee name [3]

SingHealth Centralised Institutional Review Board E

Ethics committee address [3]

Singapore Health Services Pte Ltd
31 Third Hospital Avenue
#03-03 Bowyer Block C
Singapore
168753

Ethics committee country [3]

Singapore

Date submitted for ethics approval [3]

29/04/2017

Approval date [3]

04/08/2017

Ethics approval number [3]

2017/2382

Ethics committee name [4]

Research Ethics Committee China Medical University and Hosptial

Ethics committee address [4]

2 Yude Road, Taichung, 40447

Ethics committee country [4]

Taiwan, Province Of China

Date submitted for ethics approval [4]

15/11/2017

Approval date [4]

18/12/2017

Ethics approval number [4]

DMR-106115/CMUH106-REC2 127

Ethics committee name [5]

Research Ethics Committee, The National Maternity Hospital

Ethics committee address [5]

Holles Street,
Dublin 2.
DO2 YH21

Ethics committee country [5]

Ireland

Date submitted for ethics approval [5]

08/01/2021

Approval date [5]

12/01/2021

Ethics approval number [5]

EC.34/2019

Ethics committee name [6]

Health Research Ethics Board, University of Alberta

Ethics committee address [6]

308 Campus Tower, University of Alberta, Edmonton, AB T6G 1K8

Ethics committee country [6]

Canada

Date submitted for ethics approval [6]

06/06/2018

Approval date [6]

09/11/2018

Ethics approval number [6]

Pro00079690

Summary

Brief summary

Preterm infants are highly susceptible to bacterial late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), both are major causes of systemic inflammation and contribute to brain injury and long-term disability in premature infants. Treating LOS and NEC are essential for survival, but suppressing systemic inflammation can also help reduce mortality, hospital stay and disability due to brain injury. The current treatments for NEC and LOS are limited to antibiotics, supportive care and surgery in some NEC cases, all of which do not aid in reducing systemic inflammation, therefore there is a need to reduce systemic inflammation. Pentoxifylline is a safe, low-cost, non-steroidal drug with potent immune-modulating activity with the potential of suppressing systemic inflammation induced by LOS or NEC. A recent Cochrane Review of 6 randomised controlled trials (RCT) suggests that PTX, given with antibiotics in neonatal sepsis, reduces mortality and length of hospital stay.

We are conducting an international multicentre trial that will enrol and consent approximately 1,800 preterm infants (born <29 weeks gestational age). The primary aim is to evaluate the effect of treatment with intravenous Pentoxifylline versus placebo, starting within 6 hours from blood culture taken for suspected LOS or NEC. After 48 hours treatment will cease if diagnosis is refuted or will continue for 4 days if diagnosis is proven. The primary outcome to measure effectiveness is survival without disability at 18-24 months of age (corrected for gestation).

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Tobias Strunk

Address

Neonatal Clinical Care Unit
A Block, First Floor
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008

Country

Australia

Phone

+61893401260

Fax

[email protected]

Contact person for public queries

Name

Dr Alpana Ghadge

Address

NHMRC Clinical Trials Centre
c/o Dr Alpana Ghadge
Locked Bag 77
Camperdown NSW 1450

Country

Australia

Phone

+61295625341

Fax

[email protected]

Contact person for scientific queries

Name

A/Prof Tobias Strunk

Address

Neonatal Clinical Care Unit
A Block, First Floor
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008

Country

Australia

Phone

+61893401260

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

To maintain confidentiality of participants, individual data will be coded and only grouped data, which does not identify individual participants, will be published.

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	"How can a drug to treat claudication in adults save preterm newborns?".	2020	https://dx.doi.org/10.1007/s00431-020-03631-6
Embase	Stratified Management for Bacterial Infections in Late Preterm and Term Neonates: Current Strategies and Future Opportunities Toward Precision Medicine.	2021	https://dx.doi.org/10.3389/fped.2021.590969
Dimensions AI	Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial)	2021	https://doi.org/10.1186/s12887-021-02975-8
Dimensions AI	Pentoxifylline alone or in combination with gentamicin or vancomycin inhibits live microbe-induced pro-inflammatory cytokine production in human cord blood and cord blood monocytes in vitro	2018	https://doi.org/10.1128/aac.01462-18

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

Trial Review

Documents added manually

Documents added automatically