Clinical trial NCT01585935: Preventing Cholestasis Using SMOFLipid®
Official title: Preventing Cholestasis in Premature Infants Using SMOFLipid®
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cholestasis
Psychomotor Disorders, Developmental
Keywords: Infant, Extremely Low Birth Weight
Parenteral Nutrition
Fish Oils
Cholestasis
Psychomotor Disorders, Developmental
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2012-04-26
Enrollment: 230
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Preterm infants of extreme low birth weight (ELBW, \< 1000 gram birth weight) cannot immediately be nourished with mother´s or formula milk and are typically dependent on parenteral nutrition (PN) for a prolonged period of time. This puts them at risk for liver complications of PN, namely parenteral nutrition associated cholestasis (PNAC).

Intravenous lipid emulsions (ILE) based on soy bean oil are standard of care for provision of energy and essential fatty acids in preterm infants. However, they might be implicated in the pathogenesis of PNAC.

ILEs based on pure fish oil are proposed for therapy of PNAC. Recently a lipid emulsion containing 15 % fish oil together with soy bean, olive and MCT oil has become available in Europe (SMOFLIPID®). Such a balanced lipid emulsion might be more favourable than the standard soy bean oil emulsion (Intralipid®) concerning the development of PNAC. Furthermore ILEs containing fish oil might exert a positive effect on neurodevelopment. However, there are no data so far.

The study aims to evaluate the fish oil containing ILE "SMOFlipid®" for its protective effect against PNAC in ELBW infants compared to standard treatment with the soy bean based ILE "Intralipid®". Furthermore neurodevelopment at 12 and 24 months of corrected gestational age will be investigated.

Detailed description: BACKGROUND: Extreme low birth weight infants (ELBW, \< 1000 gram birth weight) are typically dependent on parenteral nutrition (PN) for a prolonged period of time. This puts them at risk for development of liver complications of PN, namely parenteral nutrition associated cholestasis (PNAC).

Intravenous lipid emulsion (ILE) based on soy bean oil are standard of care in preterm infants, but might be implicated in the pathogenesis of PNAC. Fish oil is rich in omega-3 long chain polyunsaturated fatty acids (LC-PUFA) that particularly accumulate in liver and brain of the fetus during the last trimester of pregnancy. In pediatric patients, ILEs based on pure fish oil are proposed as a rescue therapy of PNAC.

Recently a mixed lipid emulsion containing 15 % fish oil together with soy bean , olive and MCT oil has become available for PN in Europe. Such a balanced lipid emulsion might be more favourable than the standard soy bean oil emulsion (Intralipid®) concerning the development of PNAC. Furthermore ILEs containing fish oil might exert a positive effect on neurodevelopment. However there are no data so far.

AIM: To evaluate a fish oil containing ILE (SMOFlipid®) for its prophylactic effect on PNAC in ELBW infants compared to a soy bean based ILE (Intralipid®).

STUDY DESIGN: Double blind prospective randomized trial.

* Primary Outcome: PNAC defined as two conjugated bilirubin \> 1.5 mg/dl measurements on two consecutive occasions.
* Secondary Outcome: The most important secondary outcome is neurodevelopment at 12 and 24 months of corrected age.
* Exploratory Outcomes: Brain maturation measured by amplitude integrated EEG (aEEG) and flashed visual evoked potentials as available from clinical routine examinations

HYPOTHESIS: The use of a mixed lipid emulsion containing fish oil (SMOFLIPID®) will reduce the incidence of PNAC compared to a standard soy bean oil based lipid emulsion.

Eligibility criteria: Inclusion Criteria:

* Birth weight ≤ 1000 Gram
* Admission to the neonatal ward in the first 24 hours of life
* Informed consent and randomization in the first 5 days of life

Exclusion Criteria:

* Triplets or higher
* Conjugated bilirubin \> 1.5 mg/dl before inclusion to the study
* Conditions associated with cholestasis independent of parenteral nutrition, i.e. inborn errors of metabolism, viral infections (cytomegaly virus, HIV, Hep B, Hep C), immune mediated hemolytic disease (Rhesus incompatibility), cystic fibrosis and any other primary cholestatic disease
* Congenital neurological malformations for secondary outcome

Primary outcomes:
measure: Incidence of parenteral nutrition associated cholestasis (PNAC)
timeFrame: Participants will be followed for the duration of hospital stay (expected average 14 weeks)
Secondary outcomes:
measure: Bailey Scales of Infant Development III
timeFrame: At 12 and 24 months corrected gestational age
Other outcomes:
measure: Brain maturational scores assessed by amplitude integrated EEG (aEEG)
timeFrame: Participants will be followed for the duration of hospital stay (expected average 14 weeks)
measure: Visual Evoked Potentials (VEP)
timeFrame: Participants will be followed for the duration of hospital stay (expected average 14 weeks)
Locations:
city: Vienna
country: Austria
facility: Medical University Vienna
Study officials:
affiliation: Medical University Vienna
name: Andreas Repa, MD
role: STUDY_DIRECTOR
affiliation: Medical University Vienna
name: Nadja Haiden, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thanhaeuser M, Fuiko R, Oberleitner-Leeb C, Brandstaetter S, Binder C, Thajer A, Huber-Dangl M, Haiden N, Pablik E, Berger A, Repa A. A Randomized Trial of Parenteral Nutrition Using a Mixed Lipid Emulsion Containing Fish Oil in Infants of Extremely Low Birth Weight: Neurodevelopmental Outcome at 12 and 24 Months Corrected Age, A Secondary Outcome Analysis. J Pediatr. 2020 Nov;226:142-148.e5. doi: 10.1016/j.jpeds.2020.06.056. Epub 2020 Jun 23.
citation: Binder C, Giordano V, Thanhaeuser M, Kreissl A, Huber-Dangl M, Longford N, Haiden N, Berger A, Repa A, Klebermass-Schrehof K. A Mixed Lipid Emulsion Containing Fish Oil and Its Effect on Electrophysiological Brain Maturation in Infants of Extremely Low Birth Weight: A Secondary Analysis of a Randomized Clinical Trial. J Pediatr. 2019 Aug;211:46-53.e2. doi: 10.1016/j.jpeds.2019.03.039. Epub 2019 Apr 25.
citation: Repa A, Binder C, Thanhaeuser M, Kreissl A, Pablik E, Huber-Dangl M, Berger A, Haiden N. A Mixed Lipid Emulsion for Prevention of Parenteral Nutrition Associated Cholestasis in Extremely Low Birth Weight Infants: A Randomized Clinical Trial. J Pediatr. 2018 Mar;194:87-93.e1. doi: 10.1016/j.jpeds.2017.11.012. Epub 2017 Dec 18.