Preventing Cholestasis Using SMOFLipid®

Study Overview
=================
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.

Official Title
-----------------
Preventing Cholestasis in Premature Infants Using SMOFLipid®

Conditions
-----------------
Cholestasis, Psychomotor Disorders, Developmental

Intervention / Treatment
-----------------
* Drug: SMOFLIPID
* Drug: INTRALIPID


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 5 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Smoflipid<br>SMOFLIPID will be used for parenteral lipid supply | Drug: SMOFLIPID<br>* target dose: 3g/kg/d<br>* Other names: SMOFLIPID (mixture of soy, fish, MCT and olive oil);|
| Active Comparator: Intralipid<br>INTRALIPID will be used for parenteral lipid supply | Drug: INTRALIPID<br>* target dose: 3g/kg/d<br>* Other names: INTRALIPID (soy bean oil);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of parenteral nutrition associated cholestasis (PNAC) | PNAC definition: Two consecutive conjugated bilirubin measurements > 1.5 mg/dl | Participants will be followed for the duration of hospital stay (expected average 14 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bailey Scales of Infant Development III | Cognitive, Motor and Language Development | At 12 and 24 months corrected gestational age | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infant, Extremely Low Birth Weight, Parenteral Nutrition, Fish Oils, Cholestasis, Psychomotor Disorders, Developmental