None listed
Conditions
Brief summary
HYPOTHESIS: Pentoxifylline may be beneficial as a specific secondary prophylaxis for necrotising enterocolitis (NEC) in preterm neonates. AIM: To evaluate the safety and efficacy of pentoxifylline as a secondary prophylaxis for preventing progression of NEC in preterm neonates in a randomised, placebo-controlled pilot trial. BACKGROUND: NEC is the most common neonatal gastrointestinal emergency. NEC related mortality (20-40%) and morbidity including long-term neurodevelopmental impairment and the socioeconomic burden continue to be high. Despite extensive research the pathogenesis of NEC remains poorly understood. No single specific strategy exists for either prevention or treatment of NEC. Pentoxifylline is a non-steroidal anti-inflammatory agent with diverse immunomodulatory properties including inhibition of TNF alpha- an important pro-inflammatory cytokine implicated in the pathogenesis of NEC. It has been shown to significantly reduce the incidence and severity of NEC in an experimental trial. PATIENTS AND METHODS: Eligibility criteria: Preterm neonates (gestation: <32 weeks) with definite (equal to or greater than Stage II) NEC will be eligible for enrolment after the diagnosis of the illness is made and informed parental consent is obtained. Exclusion criteria: (1) Failure to obtain informed parental consent (2) Presence of congenital malformation/s (3) Presence of chromosomal aberrations (4) Presence of hepatic or renal impairment (5) Exposure to pentoxifylline within 1 week prior to enrolment. Randomisation, allocation, blinding: The Coordinating Pharmacist (CP) will supply the medication packs containing either the placebo or pentoxifylline, identified only by a number designating the allocation. Only the supplier and the CP will be aware of the allocation. A software program written for the trial will perform randomisation. The electronic online randomisation will be stratified by neonatal gestational age (up to 27 weeks and at /above 28 weeks) within each participating center to ensure that the smallest and sickest neonates would be equally distributed between pentoxifylline and placebo groups. Pentoxifylline and placebo (normal saline) solutions have identical appearance and will be supplied in identical looking ampoules. The parents and all study personnel including the statisticians will be masked to the allocation status. Drug protocol: Enrolled neonates will be allocated to an IV infusion of either pentoxifylline or an equal volume of placebo at 5mg/kg/hour for 12 hours a day (60mg/kg/day) for 2 consecutive days, followed by infusion for 6 hours a day (30mg/kg/day) for the next 4 consecutive days. Statistical considerations: The estimated sample size for the pilot trial is 80 (Pentoxifylline: 40, Placebo: 40). Pentoxifylline safety will be assessed by analysing the adverse events in the first 30 neonates allocated to the drug. Guidelines for monitoring and analysing adverse events are provided. The results will help in determining the feasibility and sample size of a large definitive trial. Subgroup: A subgroup analyses is planned for neonates with gestational age up to 27 weeks given that the mortality and morbidity including long term neurodevelopmental impairment related to NEC is significantly higher in them. Primary and secondary outcomes: The primary outcome would be the safety and efficacy of pentoxifylline in reducing the progression of NEC from at or greater than Stage II to Stage III and/or death. Adverse events of interest will include systemic hypotension and intraventricular hemorrhage. The secondary outcomes will include the duration of hospital stay and TPN support, and the time to full enteral feeds (150 ml/kg/day) after NEC. OUTCOMES AND SIGNIFICANCE: Our research has the potential for providing a simple strategy for preventing progression of NEC in preterm neonates that is associated with significant mortality and morbidity including long-term neurodevelopmental impairment.
Interventions
Enrolled neonates will be allocated to an intravenous infusion of either pentoxifylline at 5mg/kg/hour for 12 hours a day (60mg/kg/day) for 2 consecutive days. The duration of the infusion would then be reduced to 6 hours a day (30mg/kg/day) for the next 4 consecutive days. The total duration of treatment will thus be 6 da
Enrolled neonates will be allocated to an intravenous infusion of either pentoxifylline at 5mg/kg/hour for 12 hours a day (60mg/kg/day) for 2 consecutive days. The duration of the infusion would then be reduced to 6 hours a day (30mg/kg/day) for the next 4 consecutive days. The total duration of treatment will thus be 6 days or shorter in case of stoppage due to any significant adverse drug reaction/s. The study drug solution (5mg/ml) will be infused at 1ml/kg/hour.
Sponsors
KEM Hospital for Women, Perth
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Prevention
Masking
Blinded (masking used)
Eligibility
Sex/Gender
All
Age
0 to 32 Weeks
Healthy volunteers
No
Inclusion criteria
(1) Preterm neonates with at or greater than Stage II (definite) NEC will be eligible for enrolment as soon as the diagnosis is made and (2) Informed parental consent is obtained and (3) At least one cranial ultrasound has been performed prior to the diagnosis of NEC as routine surveillance for IVH or any other intracranial pathology.
Exclusion criteria
(1) Failure to obtain informed parental consent (2) Presence of major congenital malformation/s (3) Presence of chromosomal aberrations (4) Presence of *hepatic impairment (Elevated serum aminotransaminase, alkaline phosphatase, and/or ammonia levels to >2.5 times the normal in presence of prolonged prothrombin and partial thromboplastin time) (5) Presence of *renal impairment (Blood urea nitrogen > 30 mg/dl, urine output <0.6 ml/kg/hour for at least 6 hours, and creatinine > 0.8 mg/dL) *Normal values (ALT: 3-54 U/L, AST: 10-65 U/L, Alkaline phosphatase: 110-400 U/L, Ammonia: 20-80 ?g/dL) and definitions of hepatic and renal impairment: Ref: Appendix A and D: 732-3 In Manual of Neonatal Care, Fifth Edition 2004, Eds: Cloherty JP, Eichenwald EC, Stark AR.
Outcome results
None listed