Randomized Study of Human-Milk Based Nutrition Versus Formula in Premature Infants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether very low birth weight infants (less than or equal to 1250g or about 2 3/4 pounds) born prematurely fed a diet of only human milk and human milk-derived nutrition have better health outcomes than babies fed at least some formula (made from cow's milk)or formula-derived nutrition.

Detailed Description
-----------------
The goal of this study is to evaluate the short-term effect (up to 90 days of life) of purely human-based nutrition using mother's own milk (when available), donor milk preparations and a human-based fortifier (Prolact+4) as needed when compared with mother's own milk supplemented with pre-term formula and using a bovine-based HMF (as needed for fortification of mother's own milk), i.e. Study Group 1; or, when mother's milk is not available, comparing the use of donor milk (plus human milk based fortification) with pre-term/term formula, i.e. Study Group 2. In both instances the comparison will be based on the primary endpoint of days of TPN, and on parameters such as time to full enteral feeding (approximately 150-160 mL/kg/day), amount of IV fluid support, culture-proven sepsis, NEC, death, growth and short-term development, cultured-proven sepsis and incidence of feeding intolerance in either a 2-arm (human nutrition versus bovine nutrition: Study Group 2) or 3-arm randomized design (human fortifier given when feedings reach 40 mL/kg/day, human fortifier given when feedings reach 100 mL/kg/day, and bovine-based HMF given when feedings reach 100 mL/kg/day [or pre-term formula if mother's milk is not available]: Study Group 1). Statistically, the study will attempt to evaluate a null hypothesis of equivalent results with respect to these parameters between either the three types of fortifications in Study Group 1 or the two types of overall nutrition in Study Group 2, as compared with an alternative of some inequality between the groups, i.e. letting μ be the mean number of days of TPN any of the study arms, then for Study Group 1 the hypotheses may be written as: H0: μ control = μ human 40 = μhuman 100 and HA: At least two of μ control, μ human 40, and μhuman 100 are not equal, where control is the bovine-based HMF group, human 40 is the human fortifier group starting at 40 mL/kg/day (arm 2) and human 100 is the human fortifier group starting at 100 mL/kg/day (arm 1). For Study Group 2, the competing hypotheses are: H0: μ formula = μ human and HA: μ formula ≠ μ human , where formula is the pre-term/term formula group and human is the human-based (donor milk/human-based fortifier) group. In addition, data will be collected on overall survival and length of stay in the NICU. Any baby that does not complete the full study period will be right-censored in this regard for the purposes of data evaluation. For centers that obtain long-term follow up (18-24 months) on their patients, data on developmental outcomes will be evaluated as available.

Official Title
-----------------
A Randomized Study of Human Milk-Based Versus Bovine-based Nutrition for Very Low Birth Weight Pre-Term Infants

Conditions
-----------------
Infant, Very Low Birth Weight

Intervention / Treatment
-----------------
* Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier
* Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier
* Dietary Supplement: Human milk fortifier (bovine-based), pre-term formula
* Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier
* Dietary Supplement: Pre-term/term formula


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Birth weight between 500 and 1250g. Have a reasonable expectation of survival for the maximum 90 day duration of the study. In Study Group 1, must be able to adhere to a feeding protocol involving mother's own milk and that may include donor human milk with fortification using a human-based product (Prolact+4) or fortification with a bovine-based human milk fortifier and the use of a pre-term/term formula; or in Study Group 2 the use of donor human milk with Prolact+4 or a pre-term/term formula from the time that the infant initiates enteral feeding through day 90 of life, until discharge from the study institution, discharge home, death or the initiation of at least 50% total oral nutrition (4 complete feeds in a 24 hour period), whichever comes first. Enteral feeding must begin before the 21st day of life. Total parenteral nutrition (TPN) initiated within 48 hours after birth. Informed consent obtained from parent or legal guardian. Exclusion Criteria: Less than a reasonable expectation of survival for the infant's particular gestational age through the study period (first 90 days of life, discharge to a non-study institution, discharge home, death or initiation of 50% oral nutrition, whichever comes first). On any other clinical study affecting nutritional management during the study period. Decision to not start minimum enteral feed before day 21 of life. Decision to not start TPN within the first 48 hours after birth. Unable to obtain informed consent from parent or legal guardian prior to the initiation of enteral feeding. Presence of clinically significant congenital heart disease. Presence of any major congenital malformations. Reasonable potential for early transfer to a non-study institution. Unable to participate for any reason based on the decision of the study investigator.

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 21 Days

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

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

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

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1, arm 1<br>Human breast milk + Prolact20/Neo20 (as needed) + Prolact+4 (initiated when nutrition volume reaches 100 mL/kg/day, where Prolact20/Neo 20 are donor human milk formulations at 20 cal/oz, Prolact+4 is a human-milk derived human milk fortified designed to add 4 cal/oz to 20 cal/oz human breast milk. | Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier<br>* Human milk fortifier is initiated when nutrition volume reaches 100 mL/kg/day<br>* Other names: Prolact+4;|
| Experimental: Group1, Arm 2<br>Human breast milk + Prolact20/Neo20 (as needed) + Prolact+4 (initiated when nutrition volume reaches 40 mL/kg/day), where Prolact20/Neo 20 are donor human milk formulations at 20 cal/oz, Prolact+4 is a human-milk derived human milk fortified designed to add 4 cal/oz to 20 cal/oz human breast milk. | Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier<br>* Human milk fortifier is initiated when nutrition volume reaches 40 mL/kg/day<br>* Other names: Prolact+4;|
| Active Comparator: Group 1, Arm 3<br>Human breast milk + bovine-based human milk fortifier (initiated when nutrition volume reaches 100 mL/kg/day) + pre-term formula (as needed) | Dietary Supplement: Human milk fortifier (bovine-based), pre-term formula<br>* Bovine-based human milk fortifier is initiated when nutrition volume reaches 100 mL/kg/day<br>|
| Experimental: Group 2, Arm 1<br>Prolact20/Neo20 + Prolact+4 (initiated when nutrition volume reaches 100 mL/kg/day), where Prolact20/Neo 20 are donor human milk formulations at 20 cal/oz, Prolact+4 is a human-milk derived human milk fortified designed to add 4 cal/oz to 20 cal/oz human breast milk. | Dietary Supplement: Pasteurized human milk and pasteurized human milk fortifier<br>* Human milk fortifier initiated when nutrition volume reaches 100 mL/kg/day<br>* Other names: Prolact+4;|
| Active Comparator: Group 2, Arm 2<br>Pre-term/term formula (minimum 20 cal/oz) | Dietary Supplement: Pre-term/term formula<br>* Bovine milk-derived nutrition formulated for very low birth weight infants<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary measure of efficacy for the study is the number of days of TPN (total parenteral nutrition) |  | The first 90 days of life, discharge from the study institution or initiation of 50% oral nutrition (50% of the feeding volume in a given 24 hour period provided PO, or 4 complete PO feeds in a given 24 hour period), whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight gain and other measures of growth including length and head circumference |  | The first 90 days of life, transfer to non-study institution, or initiation of 50% oral feeding, whichever comes first | 
| Daily amount of all nutrition |  | The first 90 days of life, transfer to non-study institution, or initiation of 50% oral feeding, whichever comes first | 
| Time to discharge from the NICU and hospital |  | The first 90 days of life, transfer to non-study institution, or initiation of 50% oral feeding, whichever comes first | 
| Frequency of occurrence of late-onset sepsis and necrotizing enterocolitis |  | The first 90 days of life, transfer to non-study institution, or initiation of 50% oral feeding, whichever comes first | 
| Frequency of feeding intolerance |  | The first 90 days of life, transfer to non-study institution, or initiation of 50% oral feeding, whichever comes first | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Human milk nutritional intervention, Pre-term, very low birth weight, Fortification of human breast milk