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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
13/05/2019
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] 288845 0
None
Universal Trial Number (UTN)
Trial acronym
PROTECT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm infants 298131 0
Late-onset sepsis (LOS) 298132 0
Necrotising enterocolitis (NEC) 298133 0
Long-term disability 298134 0
Condition category
Condition code
Reproductive Health and Childbirth 298298 298298 0 0
Complications of newborn
Inflammatory and Immune System 298299 298299 0 0
Other inflammatory or immune system disorders
Neurological 298300 298300 0 0
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] 294303 0
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] 297779 0
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] 297779 0
At 24 months (+/- 6months) corrected for gestation.
Secondary outcome [1] 322194 0
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] 322194 0
Until 24 months (+/- 6 months).
Secondary outcome [2] 322195 0
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] 322195 0
At 24 months (+/- 6months) corrected for gestation.
Secondary outcome [3] 322196 0
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] 322196 0
At 24 months (+/- 6months) corrected for gestation
Secondary outcome [4] 322197 0
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] 322197 0
Until discharged home.
Secondary outcome [5] 322198 0
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] 322198 0
Until discharged home.
Secondary outcome [6] 322199 0
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] 322199 0
Until discharge home
Secondary outcome [7] 322200 0
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] 322200 0
Until discharged home.
Secondary outcome [8] 322201 0
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] 322201 0
36 weeks corrected gestational age.
Secondary outcome [9] 322202 0
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] 322202 0
Until discharged home.
Secondary outcome [10] 322203 0
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] 322203 0
Until discharged home.
Secondary outcome [11] 322204 0
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] 322204 0
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] 322205 0
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] 322205 0
At 38-42 weeks corrected gestational age.
Secondary outcome [13] 325464 0
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] 325464 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
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)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 5486 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [2] 5487 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 5488 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 5489 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 5491 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [6] 5492 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 5493 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [8] 5494 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [9] 5495 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [10] 5496 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [11] 5498 0
The Canberra Hospital - Garran
Recruitment hospital [12] 5499 0
The Royal Women's Hospital - Parkville
Recruitment hospital [13] 6127 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [14] 6128 0
Royal Hospital for Women - Randwick
Recruitment hospital [15] 8684 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [16] 13730 0
Liverpool Hospital - Liverpool
Recruitment hospital [17] 13731 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 12970 0
6008 - Subiaco
Recruitment postcode(s) [2] 12971 0
2050 - Camperdown
Recruitment postcode(s) [3] 12972 0
2747 - Kingswood
Recruitment postcode(s) [4] 12973 0
2065 - St Leonards
Recruitment postcode(s) [5] 12975 0
4101 - South Brisbane
Recruitment postcode(s) [6] 12976 0
4029 - Royal Brisbane Hospital
Recruitment postcode(s) [7] 12977 0
5006 - North Adelaide
Recruitment postcode(s) [8] 12978 0
3084 - Heidelberg
Recruitment postcode(s) [9] 12979 0
3168 - Clayton
Recruitment postcode(s) [10] 12980 0
3052 - Parkville
Recruitment postcode(s) [11] 12982 0
2605 - Garran
Recruitment postcode(s) [12] 12983 0
3052 - Melbourne University
Recruitment postcode(s) [13] 13569 0
2305 - New Lambton Heights
Recruitment postcode(s) [14] 13570 0
2031 - Randwick
Recruitment postcode(s) [15] 16795 0
5042 - Bedford Park
Recruitment postcode(s) [16] 26476 0
2170 - Liverpool
Recruitment postcode(s) [17] 26477 0
2145 - Westmead
Recruitment outside Australia
Country [1] 7735 0
New Zealand
State/province [1] 7735 0
Wellington
Country [2] 7736 0
New Zealand
State/province [2] 7736 0
Auckland
Country [3] 7737 0
New Zealand
State/province [3] 7737 0
Christchurch
Country [4] 7738 0
Singapore
State/province [4] 7738 0
Country [5] 7739 0
Canada
State/province [5] 7739 0
British Columbia
Country [6] 7740 0
Canada
State/province [6] 7740 0
Alberta
Country [7] 7741 0
Canada
State/province [7] 7741 0
Manitoba
Country [8] 7742 0
Canada
State/province [8] 7742 0
Saskatchewan
Country [9] 7743 0
Canada
State/province [9] 7743 0
Ontario
Country [10] 7744 0
Canada
State/province [10] 7744 0
Quebec
Country [11] 7745 0
Canada
State/province [11] 7745 0
Nova Scotia
Country [12] 7746 0
Switzerland
State/province [12] 7746 0
Country [13] 7747 0
China
State/province [13] 7747 0
Shenzhen, Guangdong Province
Country [14] 7748 0
Taiwan, Province Of China
State/province [14] 7748 0
Taichung

Funding & Sponsors
Funding source category [1] 293205 0
Government body
Name [1] 293205 0
National Health and Medical Research Council (NHMRC) project grant
Address [1] 293205 0
GPO Box 1421
Canberra, ACT, 2601
Country [1] 293205 0
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] 292007 0
None
Name [1] 292007 0
Address [1] 292007 0
Country [1] 292007 0
Other collaborator category [1] 278919 0
University
Name [1] 278919 0
The University of Western Australia
Address [1] 278919 0
35 Stirling Highway,
Perth, Western Australia, 6009
Country [1] 278919 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294688 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 294688 0
Hunter New England Local Health District
Locked Bag 1
New Lambton, NSW, 2305
Ethics committee country [1] 294688 0
Australia
Date submitted for ethics approval [1] 294688 0
31/03/2016
Approval date [1] 294688 0
27/05/2016
Ethics approval number [1] 294688 0
16/04/20/3.04
Ethics committee name [2] 298331 0
Northern A Health and Disability Ethics Committee
Ethics committee address [2] 298331 0
PO Box 5013
Wellington 6011
Ethics committee country [2] 298331 0
New Zealand
Date submitted for ethics approval [2] 298331 0
08/02/2017
Approval date [2] 298331 0
09/05/2017
Ethics approval number [2] 298331 0
17/NTA/33
Ethics committee name [3] 303355 0
SingHealth Centralised Institutional Review Board E
Ethics committee address [3] 303355 0
Singapore Health Services Pte Ltd
31 Third Hospital Avenue
#03-03 Bowyer Block C
Singapore
168753
Ethics committee country [3] 303355 0
Singapore
Date submitted for ethics approval [3] 303355 0
29/04/2017
Approval date [3] 303355 0
04/08/2017
Ethics approval number [3] 303355 0
2017/2382
Ethics committee name [4] 303356 0
Research Ethics Committee China Medical University and Hosptial
Ethics committee address [4] 303356 0
2 Yude Road, Taichung, 40447
Ethics committee country [4] 303356 0
Taiwan, Province Of China
Date submitted for ethics approval [4] 303356 0
15/11/2017
Approval date [4] 303356 0
18/12/2017
Ethics approval number [4] 303356 0
DMR-106115/CMUH106-REC2 127

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 64674 0
Prof Karen Simmer AO
Address 64674 0
Neonatal Clinical Care Unit
A Block, First Floor
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country 64674 0
Australia
Phone 64674 0
+61893401260
Fax 64674 0
Email 64674 0
karen.simmer@health.wa.gov.au
Contact person for public queries
Name 64675 0
Dr Alpana Ghadge
Address 64675 0
NHMRC Clinical Trials Centre
c/o Dr Alpana Ghadge
Locked Bag 77
Camperdown NSW 1450
Country 64675 0
Australia
Phone 64675 0
+61295625341
Fax 64675 0
Email 64675 0
protect@ctc.usyd.edu.au
Contact person for scientific queries
Name 64676 0
A/Prof Tobias Strunk
Address 64676 0
Neonatal Clinical Care Unit
A Block, First Floor
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country 64676 0
Australia
Phone 64676 0
+61893401260
Fax 64676 0
Email 64676 0
tobias.strunk@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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 other documents available
Summary results
No Results