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Trial registered on ANZCTR


Registration number
ACTRN12616000219482
Ethics application status
Approved
Date submitted
12/02/2016
Date registered
18/02/2016
Date last updated
22/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Intravenous pentoxifylline as adjunct therapy in preterm infants with late-onset sepsis or necrotizing enterocolitis
Scientific title
Pharmacokinetics of intravenous pentoxifylline as adjunct therapy in preterm infants with late-onset sepsis or necrotizing enterocolitis
Secondary ID [1] 288525 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm infant 297612 0
Late-onset sepsis 297613 0
Necrotising enterocolitis 297614 0
Pentoxifylline pharmacokinetics 297615 0
Condition category
Condition code
Reproductive Health and Childbirth 297805 297805 0 0
Complications of newborn
Inflammatory and Immune System 297806 297806 0 0
Other inflammatory or immune system disorders
Infection 297828 297828 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Within 6 hours of onset of suspected late-onset sepsis or NEC patients will receive Pentoxifylline intravenous infusion 1ml/kg/h for 12h/day (60mg/kg/day) for 2 days followed by 1ml/kg/h for 6hr/day (30mg/kg/day) for 4 days if NEC or sepsis diagnosis is confirmed.
Intervention code [1] 293897 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297331 0
The primary outcome is to describe the pharmacokinetic profile (absorption, distribution, metabolism, and excretion) of Pentoxifylline in preterm infants with suspected sepsis or NEC. Pentoxifylline plasma levels will be determined by means of liquid chromatography-mass spectrometry.
Timepoint [1] 297331 0
At time of suspected or confirmed sepsis or NEC while an inpatient from birth. Four small (0.2ml each) blood samples will be taken before, at 6-12hr, 12-24h and >24h after the start of the initial PTX dose. If they are diagnosed with confirmed or probably sepsis or NEC (based on blood culture, abdominal X-ray and CRP equal or greater than 20mg/L) after 48hr they will continue on PTX for 4 additional days at 6hr/day (30mg/kg/day) and one additional blood sample will be taken once during this time. We will also utilise any leftover blood samples taken for routine blood tests once these are complete. This will allow us to opportunistically analyse and integrate into our analysis the small remaining blood samples that would normally be discarded. The use of a population pharmacokinetic model allows for this utilisation of unplanned samples, unlike traditional pharmacokinetic studies. PTX levels will be determined and the optimal population pharmacokinetics model (with the inclusion of significant covariates such as weight and gestational age) obtained from which simulations of alternative dose regimens will be performed.
Secondary outcome [1] 320746 0
Safety of Pentoxifylline. All enrolled infants will be closely monitored as per NICU guidelines (continuous cardiorespiratory monitoring) and any possible side effects will be assessed and reported to the local ethics committee without delay.
Timepoint [1] 320746 0
Until discharge from the neonatal unit.
Secondary outcome [2] 320795 0
Mortality. Did the baby survive until discharge from the neonatal unit ?
Timepoint [2] 320795 0
Until discharge from the neonatal unit
Secondary outcome [3] 320866 0
Need for NEC surgery. Any NEC related surgical intervention will be recorded.
Timepoint [3] 320866 0
Until discharge.
Secondary outcome [4] 320868 0
Chronic lung disease.
O2 requirement at 36weeks gestational age will be recorded from the medical records.
Timepoint [4] 320868 0
36 weeks gestational age
Secondary outcome [5] 320869 0
Extent of bowel resection for NEC.
Length of bowel removed during NEC related surgery will be recorded.
Timepoint [5] 320869 0
Until discharge
Secondary outcome [6] 320870 0
Intraventricular haemorrhage. Worst grade haemorrhage will be recorded from routine cranial ultrasound scans.
Timepoint [6] 320870 0
Until discharge
Secondary outcome [7] 320871 0
Periventricular leukomalacia. Presence/Absence of PVL will be recorded from routine cranial ultrasound scans.
Timepoint [7] 320871 0
Until discharge
Secondary outcome [8] 320873 0
Retinopathy of prematurity. Worst degree of ROP will be recorded from routine ROP screening results.
Timepoint [8] 320873 0
Until discharge

Eligibility
Key inclusion criteria
Gestation less than 32 weeks at birth and greater than 72 hours since birth
Less than 6 hours from the onset of symptoms suggestive of 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

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)
Sequence generation is not appropriate
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)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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)
WA
Recruitment hospital [1] 5265 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 12727 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 292874 0
Charities/Societies/Foundations
Name [1] 292874 0
Telethon
Address [1] 292874 0
Women and Infants Research Foundation
King Edward Memorial Hospital
374 Bagot Road, Subiaco, Western Australia, 6008
Country [1] 292874 0
Australia
Primary sponsor type
Individual
Name
Tobias Strunk
Address
Neonatal Clinical Care Unit
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country
Australia
Secondary sponsor category [1] 291618 0
None
Name [1] 291618 0
None
Address [1] 291618 0
NA
Country [1] 291618 0
Other collaborator category [1] 278818 0
University
Name [1] 278818 0
University of Western Australia
Address [1] 278818 0
35 Stirling Highway
Crawley
Western Australia
6009
Country [1] 278818 0
Australia
Other collaborator category [2] 278819 0
University
Name [2] 278819 0
Curtin University
Address [2] 278819 0
Kent St
Bentley
Western Australia
6102
Country [2] 278819 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294377 0
Women and Newborn Health Services Research Ethics Committee
Ethics committee address [1] 294377 0
WNHS HREC
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Ethics committee country [1] 294377 0
Australia
Date submitted for ethics approval [1] 294377 0
06/10/2015
Approval date [1] 294377 0
03/02/2016
Ethics approval number [1] 294377 0
2015218EW

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 will enrol and consent 23 preterm infants (<29 weeks gestational age) and intravenously administer Pentoxifylline, adjunct to standard care, for 48hrs within 6 hours of the onset of symptoms suggestive of sepsis or NEC. After 48 hours treatment will cease if diagnosis is refuted or will continue for 4 days if diagnosis is proven. To measure the pharmacokinetic profile of Pentoxifylline a series of four small blood samples will be taken prior to starting treatment and during treatment. The pharmacokinetic profile will allow us to model the optimal infusion frequency and duration, which will be used as a guideline in larger randomised controlled trials that will assess white matter injury and long-term disability.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63498 0
A/Prof Tobias Strunk
Address 63498 0
Neonatal Clinical Care Unit
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country 63498 0
Australia
Phone 63498 0
+61893401260
Fax 63498 0
Email 63498 0
tobias.strunk@health.wa.gov.au
Contact person for public queries
Name 63499 0
A/Prof Tobias Strunk
Address 63499 0
Neonatal Clinical Care Unit
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country 63499 0
Australia
Phone 63499 0
+61893401260
Fax 63499 0
Email 63499 0
tobias.strunk@health.wa.gov.au
Contact person for scientific queries
Name 63500 0
A/Prof Tobias Strunk
Address 63500 0
Neonatal Clinical Care Unit
King Edward Memorial Hospital
374 Bagot Rd, Subiaco, Western Australia, 6008
Country 63500 0
Australia
Phone 63500 0
+61893401260
Fax 63500 0
Email 63500 0
tobias.strunk@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary