Back to resultsStandard Lipid Therapy vs IVFE Minimization for Prevention of PNALD
Primary Purpose
Cholestasis
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Intralipid 20% I.V. Fat Emulsion
Sponsored by
About this trial
This is an interventional prevention trial for Cholestasis
Eligibility Criteria
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
Sites / Locations
- University of Colorado/Children's Hospital Colorado
- University of Florida
- University of Michigan
- Primary Children's Hospital
- Seattle Children's Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Reduced Lipid
Standard Lipid
Arm Description
Subjects will receive a minimized dose (1 g/kg/day) of the soybean-based lipid component of parenteral nutrition.
Subjects will receive the standard dose (up to 3 g/kg/day) of the soybean-based lipid component of parenteral nutrition.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
The Time to Development of PNAC
The time to development was compared between the standard and reduced lipid groups.
The Time to Development of Severe PNAC
The time to development from randomization was compared between the standard and reduced lipid groups.
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.
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.
The Prevalence of Essential Fatty Acid Deficiency (EFAD)
The number of participants who experienced EFAD was compared between the standard and reduced lipid groups.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT02357576
First Posted
February 2, 2015
Last Updated
December 14, 2020
Sponsor
University of Michigan
Collaborators
Seattle Children's Hospital, University of Florida, Primary Children's Hospital, University of Colorado, Denver
1. Study Identification
Unique Protocol Identification Number
NCT02357576
Brief Title
Standard Lipid Therapy vs IVFE Minimization for Prevention of PNALD
Official Title
Phase 3 Study of Standard Lipid Therapy Versus Intravenous Fat Emulsion Minimization for the Prevention of Parenteral Nutrition-Associated Liver Disease
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
May 21, 2016 (Actual)
Primary Completion Date
October 12, 2017 (Actual)
Study Completion Date
November 8, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Michigan
Collaborators
Seattle Children's Hospital, University of Florida, Primary Children's Hospital, University of Colorado, Denver
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cholestasis
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Reduced Lipid
Arm Type
Experimental
Arm Description
Subjects will receive a minimized dose (1 g/kg/day) of the soybean-based lipid component of parenteral nutrition.
Arm Title
Standard Lipid
Arm Type
Active Comparator
Arm Description
Subjects will receive the standard dose (up to 3 g/kg/day) of the soybean-based lipid component of parenteral nutrition.
Intervention Type
Drug
Intervention Name(s)
Intralipid 20% I.V. Fat Emulsion
Primary Outcome Measure Information:
Title
Rate of Rise of Direct Bilirubin as a Function of Time
Description
The rate of rise (change over time) of direct bilirubin was compared between the two groups at different time points.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Prevalence of Parenteral Nutrition-associated Cholestasis (PNAC) (Direct Bilirubin ≥2 mg/dL)
Description
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.
Time Frame
12 weeks
Title
Prevalence of Severe Parenteral Nutrition-associated Cholestasis (PNAC) (Direct Bilirubin ≥4 mg/dL in Subjects on Parenteral Nutrition for at Least 2 Weeks)
Description
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.
Time Frame
12 weeks
Title
The Time to Development of PNAC
Description
The time to development was compared between the standard and reduced lipid groups.
Time Frame
12 weeks
Title
The Time to Development of Severe PNAC
Description
The time to development from randomization was compared between the standard and reduced lipid groups.
Time Frame
12 weeks
Title
Peak Total Bilirubin Level
Description
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.
Time Frame
12 weeks
Title
Peak Direct Bilirubin Level
Description
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.
Time Frame
12 weeks
Title
The Prevalence of Essential Fatty Acid Deficiency (EFAD)
Description
The number of participants who experienced EFAD was compared between the standard and reduced lipid groups.
Time Frame
12 weeks
Title
Adequacy of Growth as Evaluated by Z-scores for Weight
Description
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.
Time Frame
12 weeks
Title
Adequacy of Growth as Evaluated by Z-scores for Height
Description
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.
Time Frame
12 weeks
Title
Adequacy of Growth as Evaluated by Z-scores for Head Circumference
Description
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.
Time Frame
12 weeks
Title
Adverse Events, as Defined by Any Episode of Sepsis and Catheter-related Blood Stream Infections
Description
The number of episodes were compared between the standard and reduced lipid groups of suspected sepsis episodes, NEC, or catheter-related blood stream infections.
Time Frame
12 weeks
Title
Bayley Scales for Infant and Toddler Development (BSID-III) at One Year
Description
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.
Time Frame
1 year
Title
Bayley Scales for Infant and Toddler Development (BSID-III) at Two Years
Description
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.
Time Frame
2 years
Title
MacArthur-Bates Communicative Development Inventories (CDI)
Description
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.
Time Frame
2 years
Title
Brief Infant Toddler Social Emotional Assessment (BITSEA) Part 1 of 2
Description
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.
Time Frame
2 years
Title
Gross Motor Function Classification System (GMFCS)
Description
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.
Time Frame
2 years
Title
Behavioral Assessment System for Children-Third Edition (BASC3) Part 1 of 2
Description
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.
Time Frame
2 years
Title
Behavioral Assessment System for Children-Third Edition (BASC3) Part 2 of 2
Description
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.
Time Frame
2 years
Title
Brief Infant Toddler Social Emotional Assessment (BITSEA) Part 2 of 2
Description
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.
Time Frame
2 years
10. Eligibility
Sex
All
Maximum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Meghan A Arnold, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado/Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32601
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Primary Children's Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Standard Lipid Therapy vs IVFE Minimization for Prevention of PNALD
We'll reach out to this number within 24 hrs