Clinical trial NCT02475434: Use of Human Milk Cream to Decrease Length of Stay in Extremely Premature Infants
Official title: Post-Discharge Evaluation of Human Milk Cream Study Infants at 18 to 24 Month CGA: A Randomized Trial of the Use of Human Milk Cream to Decrease Length of Stay in Extremely Premature Infants
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Bronchopulmonary Dysplasia
Keywords: Human Milk
Prematurity
Nutrition
Human Milk Cream
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Prolacta Bioscience
name: Medical University Innsbruck
name: The University of Texas Health Science Center, Houston
name: Michigan State University
name: Akron Children's Hospital
name: Timpanogos Regional Hospital
name: Orlando Health, Inc.
name: St. Louis Children's Hospital
name: Baylor Scott and White Health
name: Westchester Medical Center
name: Unity Health Toronto
name: St. John Hospital & Medical Center
name: Texas Tech University Health Sciences Center, El Paso
name: Cook Children's Medical Center
name: University of Oklahoma
First posted: 2015-06-18
Enrollment: 210
Sex: ALL
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: At present, widespread use of the human milk-based caloric supplement (cream) has not occurred, particularly in infants with bronchopulmonary dysplasia (BPD), and further data are needed to support its adoption as a standard care practice.

The investigators hypothesize that infants who receive an exclusive human milk (HM)-based diet with the addition of a HM-derived cream caloric supplement (Cream group) will have a shorter length of initial hospital stay compared to infants receiving the standard regimen of an exclusive HM-based diet (Control group). The investigators hypothesize that the effects of the cream caloric supplement will be greater in the subgroup of infants who develop BPD so the relationship will be evaluated between Cream Supplement study group and postmenstrual age (PMA) at discharge and the incidence of BPD. Investigators will also evaluate the post-hospital discharge growth, body composition, and neurodevelopmental outcomes at 18 to 24 months CGA of the infants 500-1250 grams BW who received an exclusive human milk diet including cream supplement or control in the NICU.

Detailed description: The primary hypothesis of the study is that infants who receive an exclusive HM-based diet with the addition of a HM-derived cream caloric (Cream group) will have a shorter length of initial hospital stay compared to infants receiving the standard regimen of an exclusive HM-based diet (Control group).

The study design is a randomized controlled trial in preterm infants (birth weight 500-1250g) comparing the use of a human milk cream supplement added to an exclusive HM-based diet (Cream group) to an exclusive HM-based diet without the use of a cream supplement (Control group). Each study group will use mother's own milk, donor HM if needed (donor HM should be obtained from a Human Milk Banking Association of North America (HMBANA) or Prolacta milk bank that uses Holder method pasteurization and does not homogenize the milk) and a donor human milk-derived fortifier (Prolact+ H2MF®) according to the study feeding protocol. Feeding will be done by protocol in which fortification will begin when the baby is receiving 60 mL/kg/day of enteral nutrition. The randomization will be performed in blocks (block size to remain blinded) without the use of stratification variables except for study site. While blinding of study groups is always desirable in randomized studies, because of the nature of the interventions and the varying methods by which the nutrition is prepared and delivered in different units, this will not be possible for this study.

Sample Size:

The number of infants to be included in this study is based on the primary endpoint of a reduction in the length of hospital stay in days by 12.1 days with a standard deviation of 31 days. With a two-tailed 5% significance level and 80% power, a sample size of 210 (n=105 per group) is needed to demonstrate a difference of this magnitude between the 2 study groups.

Study Duration:

All study infants will be followed until discharge or transfer from the medical institution or death (hospital stay is an expected average of 10 weeks). Infants will be transitioned completely off an exclusive HM-based diet no earlier than 34 weeks PMA, however, infants will be followed until hospital discharge (total of an estimated average of 10 weeks) to collect anthropometric and study outcome data.

Study Population:

Each study subject must meet all of the indicated inclusion criteria and none of the exclusion criteria.

Study Procedure:

After eligibility of the infant is determined and informed consent is obtained from the parent or legal guardian, infants will be randomized using a stratified (by study site) block scheme noted above into either the group that will receive human milk cream (Cream Supplement) or not (Control). All study infants will follow the study feeding protocol. The use of fortifier, both the timing of initiation and advancing of feeds will be per study protocol as tolerated. Study infants are to receive only an exclusive HM-based diet and they are not to deviate from the protocol (receiving formula, medium chain triglyceride (MCT) oil, liquid protein supplement, bovine fortifier, etc). Once breast milk (either mother's or donor) fortification is initiated and infants reach feeds of at least 100 mL/kg/day, for infants randomized to the cream group, they will start receiving the cream supplement per protocol. HM cream supplement will be added to feeds to provide an additional 2 kcal/oz of energy (amount of cream to add equals amount of unfortified milk x 0.04 rounded to the nearest full mL). For example, 4 mL of cream would be added to 96 mL of unfortified milk and then the fortifier is added to the milk-cream mixture. The Control group will not receive cream and will be fed per Table 1. Infants will be followed and studied until discharge, transfer to a non-study institution, removal from the study or death. Starting no sooner than 34 weeks PMA, infants will be transitioned over 5 days to either mother's milk with bovine fortifier or transitional formula according to investigative site's standard of care. All infants will have a brain MRI at "term equivalent" age (if this is routine practice at the study site). Infants will also have body composition determined by dual energy x-ray absorptiometry (DXA) scan (if available at the study site). One outpatient study visit will occur at 18 to 24 months post discharge to obtain anthropometric data, interim medical history, demographic and socioeconomic information, and nutrition history of the child since discharge (formula, human milk, vitamins, and medications). A neurodevelopmental evaluation (The Bayley Scales of Infant Development III) will also be performed by a certified tester during this visit. In addition, data from NICU hospitalizations will be collected during this visit. Data collection will include: demographics (gestational age, birth weight, gender, and race), APGAR scores, nutrition and feeding related issues (parental nutrition and constituents, feeding regimen, feeding intolerance), growth parameters (weight, length, and head circumference), medications (caffeine, furosemide, chlorothiazide, hydrocortisone, dexamethasone, insulin, and dopamine), nutrition related labs, and morbidities (intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, spontaneous intestinal perforation, episodes of sepsis, chronic lung disease).

Anthropometric Measurements:

At each study site, designated study personnel (preferably no more than 3 consistent trained personnel), will be responsible for weekly anthropometric measurements. The personnel will be trained or will demonstrate proficiency in obtaining anthropometric measurements using proper equipment. They will take weekly weights, lengths using only a study length board to be provided, and head circumference measurements. Each measurement will be taken twice and the average of the two will be recorded (for the weekly measurement).

Human Milk Samples:

Three times a week (on 3 separate days), samples of the human milk (either mother's own or donor) per study infant will be obtained (4 mL in a syringe) and will be stored for future macronutrient analysis after study completion. The samples should be stored at -20 degrees C. The sample should be from a batch of unfortified human milk and should represent the milk to be used to prepare 24 hours of feedings. Stored samples will be sent to the coordinating study center for post-study analysis.

Microbiome Samples:

For all enrolled infants, tracheal aspirates (if intubated in the first 24 hours of life) and stool for post-study evaluation of infants' airway and gastrointestinal microbiome will be collected as feasible. A recent study by Lohmann et al showed that reduced diversity of the microbiome may be an important factor in the development of BPD. In addition, studies have shown that human milk positively affects the microbiome of premature infants. Tracheal aspirates will be obtained per study protocol if infants are intubated at birth to 24 hours of age, 48-72 hours of age, 7 days of age, and 28 days of age or at time of extubation if sooner. Any tracheal aspirate obtained within this time frame is acceptable (samples are of convenience with routine suctioning and care). Stool samples will be obtained per study protocol at the 1st, 2nd, 3rd, and 4th weeks of life. The infants' first stool (meconium) should be obtained. Samples will be collected and frozen at -80 degrees C and will be sent to the coordinating study center for post-study microbiome analysis.

Eligibility criteria: Inclusion Criteria:

* Birth weight 500-1250g.
* Must be likely to be able to adhere to a feeding protocol involving mother's own milk/donor milk that will include fortification using HM-based product (Prolact+H2MF®) and, potentially, human milk-based cream supplement.
* Enteral feeding must begin before day 14 of life and parenteral nutrition must be started by day 2 of life.
* Informed consent obtained from parent or legal guardian prior to reaching 100 ml/kg/day of fortified feeds. Consent should be obtained as soon as possible for eligible infants to collect tracheal aspirates (if intubated) and meconium stool. However, consent must be obtained prior to reaching 100 ml/kg/day of fortified feeds because this is when randomization will occur.

Exclusion Criteria:

* Unlikely to survive the study period.
* Enrolled in another clinical study affecting nutritional management during the study period.
* Decision to not start minimum enteral feed before day 14 of life or parenteral nutrition before day 2 of life.
* Presence of clinically significant congenital heart disease or other major congenital malformation.
* Presence prior to enrollment of intestinal perforation or Stage 2 Necrotizing enterocolitis prior to tolerating fortified feeds.
* Reasonable likelihood of early transfer to a non-study institution.
* Unable to participate for any reason based on the decision of the study investigator.

Primary outcomes:
measure: Length of Stay
timeFrame: From birth to death or discharge from the Neonatal ICU, assessed up to 5 months
Secondary outcomes:
measure: Incidence of Bronchopulmonary dysplasia and relationship to postmenstrual age at discharge in infants who received cream supplement
timeFrame: From birth to death or discharge from the Neonatal ICU, assessed up to 5 months
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Orlando Health, Inc. - Winnie Palmer Hospital for Women and Babies
state: Florida
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Boardman
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine / Texas Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Orem
country: United States
facility: Wasatch Neonatal
state: Utah
city: Innsbruck
country: Austria
facility: University Hospital
Study officials:
affiliation: Texas Children's Hospital, Baylor College of Medicine
name: Amy B Hair, MD
role: PRINCIPAL_INVESTIGATOR
References:
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