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Human-derived Human Milk Fortifiers (H2MF), Gut Microbiota and Oxidative Stress in Premature Infants

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ClinicalTrials.gov Identifier: NCT03214822
Recruitment Status : Completed
First Posted : July 12, 2017
Last Update Posted : September 30, 2019
Sponsor:
Collaborators:
Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION)
Prolacta Bioscience
Children's Hospital Foundation
Information provided by (Responsible Party):
Meghan Azad, University of Manitoba

Brief Summary:
This is a randomized controlled trial of a human-derived human milk fortifier (H2MF) vs standard bovine-derived human milk fortifier (HMF) evaluating fecal microbiota and fecal and urinary biomarkers of oxidative stress in premature infants.

Condition or disease Intervention/treatment Phase
Very Low Birth Weight Baby Premature Birth Microbial Colonization Oxidative Stress Dietary Supplement: H2MF Not Applicable

Detailed Description:

While breast milk provides complete nutrition for full term infants, supplementation with human milk fortifiers (HMF) is required to achieve optimal weight gain in very low birthweight (VLBW) preterm neonates. Traditionally, HMF have been derived from bovine milk. Bovine-based infant formula has been shown to cause dysbiosis of the infant gut microbiome (Azad et al 2013) and increased oxidative stress in preterm neonates (Friel et al 2011). Microbiome dysbiosis and oxidative stress have been implicated in numerous inflammatory conditions, including both acute (eg. necrotizing enterocolitis, NEC) and long-term (eg. asthma, metabolic syndrome) sequela of preterm birth (Torrazza et al 2013, Goulet et al 2015, Flora et al 2007, Perrone et al 2014). Recent studies show that new human-derived HMF (H2MF) are superior to standard bovine HMF for nourishing VLBW preterm infants and preventing NEC (Sullivan et al 2010, Cristofalo et al 2013). However, the biological basis for these clinical benefits is unknown, which limits our ability to inform and improve feeding strategies for VLBW preterm infants. This will be the first study to evaluate the impact of H2MF on gut microbiota and oxidative stress in preterm infants.

Specific Objectives:

  1. To evaluate the effect of H2MF vs. HMF on gut microbiota composition in premature infants born <1250 gr between 26 and 30 weeks of gestational age.
  2. To evaluate the effect of H2MF vs. HMF on fecal and urinary biomarkers of oxidative stress in premature infants born <1250 gr between 26 and 30 weeks of gestational age.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Using a randomized, controlled, un-blinded parallel design we will enroll 30 VLBW premature neonates (birth weight < 1250 grams, gestational age 26+0 to 30+0 weeks) from the NICU at the Health Sciences Centre Children's Hospital in Winnipeg, MB, Canada. Currently, H2MF is not routinely used in this population at this centre.
Masking: Double (Investigator, Outcomes Assessor)
Masking Description: Masking of care providers is not feasible since the procedures of preparation for HMF and H2MF are different. Outcome assessors (personnel analyzing microbiome profiles and oxidative stress biomarkers) will be masked.
Primary Purpose: Basic Science
Official Title: The Impact of Human-derived Human Milk Fortifiers (H2MF) on Gut Microbiota Development and Oxidative Stress in Premature Infants
Actual Study Start Date : August 1, 2017
Actual Primary Completion Date : July 30, 2019
Actual Study Completion Date : July 30, 2019

Arm Intervention/treatment
No Intervention: HMF (standard of care)
The HMF "Control Group" will receive the current standard feeding protocol of human milk fortified with bovine (cow) human milk fortifier (HMF)
Experimental: H2MF
The H2MF "Intervention Group" will receive identical treatment with human-derived human milk fortifier (H2MF) replacing standard bovine HMF until the baby reaches an adjusted gestation age of 33 weeks; followed by a 5 day ween to standard HMF according to the manufacturer's recommendation.
Dietary Supplement: H2MF
As described in the Experimental Arm description.




Primary Outcome Measures :
  1. Fecal microbiome composition at end of intervention [ Time Frame: 33+0 weeks adjusted gestational age (end of intervention) ]
    Relative abundance of operational taxonomic units (OTUs) determined by 16S rRNA Illumina sequencing

  2. Fecal microbiome diversity at end of intervention [ Time Frame: 33+0 weeks adjusted gestational age (end of intervention) ]
    Shannon diversity index of microbiota, determined by 16S rRNA Illumina sequencing

  3. Fecal microbiome community structure at end of intervention [ Time Frame: 33+0 weeks adjusted gestational age (end of intervention) ]
    Principal coordinate analysis using UniFrac distance matrices based on 16S rRNA Illumina sequencing


Secondary Outcome Measures :
  1. Fecal microbiome at 1 week after intervention begins [ Time Frame: Study day 7 (1 week after intervention begins) ]
    Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.

  2. Fecal microbiome at 2 weeks after intervention ends [ Time Frame: 35+0 weeks adjusted gestational age (2 weeks after intervention ends) ]
    Fecal microbiome composition, diversity and community structure from 16S rRNA Illumina Sequencing.

  3. Oxidative stress (urinary biomarkers) at end of intervention [ Time Frame: 33+0 weeks adjusted gestational age (end of intervention) ]
    F2-isoprostanes, 8-hydroxy deoxyguanine, and visfatin measured in urine.

  4. Oxidative stress (fecal calprotectin) at end of intervention [ Time Frame: 33+0 weeks adjusted gestational age (end of intervention) ]
    Calprotectin measured in feces

  5. Oxidative stress at 1 week after intervention begins [ Time Frame: Study day 7 (1 week after intervention begins) ]
    Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).

  6. Oxidative stress at 2 weeks after intervention ends [ Time Frame: 35+0 weeks adjusted gestational age (2 weeks after intervention ends) ]
    Fecal and urinary biomarkers of oxidative stress (fecal calprotectin, urinary F2-isoprostanes, urinary 8-hydroxy deoxyguanine, urinary visfatin).



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 7 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female infant with birth weight <1250 grams
  • Gestational age between 26+0 to 30+0 weeks at birth
  • Able to adhere to feeding protocol
  • Parenteral nutrition must be started by day of life 2
  • Enteral feeding >80 ml/kg/d should be reached by day of life 14
  • Subject's parent(s)/legal guardian(s) has provided signed and dated informed consent and authorization to use protected health information, as required by national and local regulations.
  • In the investigator's opinion, the subject's parent(s)/legal guardian(s) understands and is able to comply with protocol requirements, instructions, and protocol-stated restrictions, and is likely to complete the study as planned.

Exclusion Criteria:

  • Gestational age > 30+0 weeks at birth (to guarantee a minimum of 3 weeks H2MF treatment, since fortification ends at 33+0 AGA)
  • Gestational age < 26+0 weeks at birth (to minimize baseline heterogeneity, since gestational age influences gut microbiota)
  • Received antibiotics on the first day of specimen collection (to minimize baseline heterogeneity, since antibiotics influence gut microbiota) Note: all infants are expected to receive up to 48 hr antibiotic prophylaxis at birth according to standard NICU protocol; this criterion will exclude infants receiving extended courses of antibiotics.
  • Received probiotics at any time (to minimize baseline heterogeneity, since probiotics influence gut microbiota)
  • Unlikely to survive the study period
  • Presence of clinically significant congenital heart disease or other major congenital malformation
  • Presence prior to enrollment of intestinal perforation or stage 2 necrotizing enterocolitis (NEC) prior to tolerating fortified feeds

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03214822


Locations
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Canada, Manitoba
Health Sciences Centre
Winnipeg, Manitoba, Canada
Sponsors and Collaborators
University of Manitoba
Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION)
Prolacta Bioscience
Children's Hospital Foundation
Investigators
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Principal Investigator: Meghan Azad, PhD University of Manitoba
Study Director: Geert T'Jong University of Manitoba
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Meghan Azad, Prinicpal Investigator, University of Manitoba
ClinicalTrials.gov Identifier: NCT03214822    
Other Study ID Numbers: H2MF Study
First Posted: July 12, 2017    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: At this time we plan to share IPD within our research team only. We will consider sharing with other researchers in the future.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Meghan Azad, University of Manitoba:
Microbiome
Additional relevant MeSH terms:
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Communicable Diseases
Infections
Premature Birth
Birth Weight
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Body Weight
Disease Attributes
Pathologic Processes