Standard Lipid Therapy vs IVFE Minimization for Prevention of PNALD

Study Overview
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Brief Summary
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Parenteral nutrition-associated cholestasis (PNAC) and liver disease (PNALD) are associated with significant morbidity and mortality in neonates and is felt to be exacerbated by soybean-based lipid emulsions. Much research is currently being directed at identifying ways to reduce this risk. Reduction of the dose of soybean-based lipid given as a component of parenteral nutrition is one possible strategy. In this study we will compare standard dosing of soybean-based lipid (up to 3/kg/day) with a minimized dose (1 g/kg/day) and evaluate for the development of cholestasis and adequate growth between the two groups. Longterm followup will include an assessment of neurodevelopmental outcomes at 12 and 24 months of age. Funding source - FDA OOPD

Official Title
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Phase 3 Study of Standard Lipid Therapy Versus Intravenous Fat Emulsion Minimization for the Prevention of Parenteral Nutrition-Associated Liver Disease

Conditions
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Cholestasis

Intervention / Treatment
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* Drug: Intralipid 20% I.V. Fat Emulsion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: neonates and infants who are at least 28 weeks corrected gestational age at the time of enrollment who are parenteral nutrition (PN) naive current direct bilirubin <2 mg/dL any of the following conditions: meconium ileus and peritonitis gastroschisis omphalocele >4cm or with liver herniated outside of the abdominal cavity necrotizing enterocolitis requiring surgical intervention volvulus intestinal atresia with >50% bowel loss Exclusion Criteria: weight <1 kg metabolic pathway defect which is associated with liver dysfunction in the neonatal period, including: hereditary fructose intolerance, galactosemia due to transferase deficiency and neonatal tyrosinemia, and/or disorder of lipid metabolism hepatic insufficiency as documented by either a biopsy with cirrhosis and/or marked aberration in synthetic function renal failure primary or secondary liver disease, regardless of liver function (includes hepatitis) use of extracorporeal membrane oxygenation (ECMO) suspected congenital obstruction of the hepatobiliary tree documented active infection which may be communicable, including infections hepatitis or HIV previous receipt of choleretic agents currently receiving phenobarbital or other barbiturates history of PNAC direct bilirubin >=2 mg/dL at time of enrollment congenital or acquired anomaly which will require major cardiovascular surgery major congenital or chromosomal anomaly hypoxic ischemic encephalopathy congenital defect of the brain major seizure disorder

Ages Eligible for Study
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Maximum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced Lipid<br>Subjects will receive a minimized dose (1 g/kg/day) of the soybean-based lipid component of parenteral nutrition. | Drug: Intralipid 20% I.V. Fat Emulsion<br> <br> |
| Active Comparator: Standard Lipid<br>Subjects will receive the standard dose (up to 3 g/kg/day) of the soybean-based lipid component of parenteral nutrition. | Drug: Intralipid 20% I.V. Fat Emulsion<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Rise of Direct Bilirubin as a Function of Time | The rate of rise (change over time) of direct bilirubin was compared between the two groups at different time points. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Parenteral Nutrition-associated Cholestasis (PNAC) (Direct Bilirubin ≥2 mg/dL) | The number of participants who had a direct bilirubin ≥2 mg/dL were compared between the standard and reduced lipid groups. Bilirubin data was collected from baseline until 7 days after PN has been discontinued, but not to exceed a total of 12 weeks. | 12 weeks | 
| Prevalence of Severe Parenteral Nutrition-associated Cholestasis (PNAC) (Direct Bilirubin ≥4 mg/dL in Subjects on Parenteral Nutrition for at Least 2 Weeks) | The number of participants with severe PNAC defined as a direct bilirubin ≥4 mg/dL were compared between the standard and reduced lipid groups. Bilirubin data was collected from baseline until 7 days after PN has been discontinued, but not to exceed a total of 12 weeks. | 12 weeks | 
| The Time to Development of PNAC | The time to development was compared between the standard and reduced lipid groups. | 12 weeks | 
| The Time to Development of Severe PNAC | The time to development from randomization was compared between the standard and reduced lipid groups. | 12 weeks | 
| Peak Total Bilirubin Level | The peak (highest) total bilirubin collected from each subject from after week 1 to end of treatment. This was compared between the standard and reduced lipid groups. | 12 weeks | 
| Peak Direct Bilirubin Level | The peak (highest) direct bilirubin collected from each subject from after week 1 to end of treatment. This was compared between the standard and reduced lipid groups. | 12 weeks | 
| The Prevalence of Essential Fatty Acid Deficiency (EFAD) | The number of participants who experienced EFAD was compared between the standard and reduced lipid groups. | 12 weeks | 
| Adequacy of Growth as Evaluated by Z-scores for Weight | Z-scores were compared between subjects in the two treatment groups by week. Z-scores are the number of standard deviations above (positive value) or below (negative value) the median on the FENTON and WHO growth charts. Fenton scores were used for infants born <37 weeks gestation. WHO scores were used for infants born at ≥37 weeks gestation. | 12 weeks | 
| Adequacy of Growth as Evaluated by Z-scores for Height | Z-scores were compared between subjects in the two treatment groups. Z-scores are the number of standard deviations above (positive value) or below (negative value) the median on the FENTON and WHO growth charts. Fenton scores were used for infants born <37 weeks gestation. WHO scores were used for infants born at ≥37 weeks gestation. | 12 weeks | 
| Adequacy of Growth as Evaluated by Z-scores for Head Circumference | Z-scores were compared between subjects in the two treatment groups. Z-scores are the number of standard deviations above (positive value) or below (negative value) the median on the FENTON and WHO growth charts. Fenton scores were used for infants born <37 weeks gestation. WHO scores were used for infants born at ≥37 weeks gestation. | 12 weeks | 
| Adverse Events, as Defined by Any Episode of Sepsis and Catheter-related Blood Stream Infections | The number of episodes were compared between the standard and reduced lipid groups of suspected sepsis episodes, NEC, or catheter-related blood stream infections. | 12 weeks | 
| Bayley Scales for Infant and Toddler Development (BSID-III) at One Year | The Bayley Scales of Infant and Toddler Development (BSID-III) is designed to assess developmental functioning of infants and toddlers, ages 1 month to 42 months. The instrument includes five distinct scales, of which three scales and associated subscales are utilized for the purposes of this study: cognitive, language (receptive and expressive communication) and motor (fine motor and gross motor). Raw scores are converted to scaled scores using age-standardized norm. The cognitive scaled scores range from 1-19. 1 is a low score and 19 is a high score. The Language scaled scores are calculated by adding the Receptive Communication scores ranging from 1-19 and the Expressive communication scores ranging from 1-19 to give the Language Scaled score of 2-38. The Motor scaled scores are calculated by adding the Fine Motor scores ranging from 1-19 and the Gross Motor scores ranging from 1-19 to give the Motor scaled ranging from 2-38. Higher scores are better than lower scores. | 1 year | 
| Bayley Scales for Infant and Toddler Development (BSID-III) at Two Years | The Bayley Scales of Infant and Toddler Development (BSID-III) is designed to assess developmental functioning of infants and toddlers, ages 1 month to 42 months. The instrument includes five distinct scales, of which three scales and associated subscales are utilized for the purposes of this study: cognitive, language (receptive and expressive communication) and motor (fine motor and gross motor). Raw scores are converted to scaled scores using age-standardized norm. The cognitive scaled scores range from 1-19. 1 is a low score and 19 is a high score. The Language scaled scores are calculated by adding the Receptive Communication scores ranging from 1-19 and the Expressive communication scores ranging from 1-19 to give the Language Scaled score of 2-38. The Motor scaled scores are calculated by adding the Fine Motor scores ranging from 1-19 and the Gross Motor scores ranging from 1-19 to give the Motor scaled ranging from 2-38. Higher scores are better than lower scores. | 2 years | 
| MacArthur-Bates Communicative Development Inventories (CDI) | The MacArthur-Bates Communicative Development Inventories (CDI) are parent report instruments which capture information about children's developing abilities in early language. Scores are reported as percentiles compared to age-standardized norms. Higher scores are better than lower scores. | 2 years | 
| Brief Infant Toddler Social Emotional Assessment (BITSEA) Part 1 of 2 | Dichotomous scores are generated based on cut-off scores, which identify subjects to be at risk. The problem scale measures behaviors of the child that if present, represent a problem. The competence scale measures behaviors of the child that if absent, represent a problem. BITSEA percentile rankings are determined from a table that has a limited range and are adjusted for age and sex. A high problem score leads to a low problem percentile. A high competence score leads to a high competence percentile. Percentile rankings for both problem and competence scores range from 4% or less to 26% or higher. 4 is the lowest percentile score and 26 is the highest percentile score. The 25th percentile is the lower limit of the average range. Higher percentile scores are better than lower percentile scores in both problem and competence categories. | 2 years | 
| Gross Motor Function Classification System (GMFCS) | This classification is based on observation with a scale of 1-5. A lower number classification is better than a higher classification, with 1 being the best. | 2 years | 
| Behavioral Assessment System for Children-Third Edition (BASC3) Part 1 of 2 | The Behavioral Assessment System for Children-Third Edition is a comprehensive set of forms that helps to understand the behaviors and emotions of children. Scores are reported as T-Scores. T-Scores range from 0-120. In a normative population, the mean of standard scores is 50, and standard deviation is 10. For Externalizing Problems T-Score, Internalizing Problems T-Score, Behavioral Symptoms Index T-Score, Clinical Probability Index T-Score, and Functional Impairment Index T-Score lower scores are better than higher scores. For these categories, higher scores are more problematic with scores between 60-70 regarded as at risk and scores 70 and above regarded as clinically significant and requiring further assessment and possible treatment. For Adaptive Skills T-Score, a higher score is better than a lower score. For Adaptive Skills T-Score, lower scores are more problematic with scores between 30-40 regarded as at risk and scores at or below 30 regarded as clinically significant. | 2 years | 
| Behavioral Assessment System for Children-Third Edition (BASC3) Part 2 of 2 | The Behavioral Assessment System for Children-Third Edition is a comprehensive set of forms that helps to understand the behaviors and emotions of children. For Overall Executive Functioning Index, Attentional Control Index, Behavioral Control Index, and Emotional Control Index, scores are Not Elevated or Elevated. Not Elevated is better than Elevated. | 2 years | 
| Brief Infant Toddler Social Emotional Assessment (BITSEA) Part 2 of 2 | Dichotomous scores are generated based on cut-off scores, which identify subjects to be at risk. The problem scale measures behaviors of the child that if present, represent a problem. The competence scale measures behaviors of the child that if absent, represent a problem. | 2 years |