Clinical trial NCT03797157: Human Milk Fortification in Extremely Preterm Infants
Official title: Nordic Study on Human Milk Fortification in Extremely Preterm Infants: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Necrotizing Enterocolitis
Sepsis
Mortality
Lead sponsor: Ostergotland County Council, Sweden
Sponsor class: OTHER
Collaborators: name: Sahlgrenska University Hospital
name: Region Uppsala
name: Vasterbottens lans landsting
name: Prolacta Bioscience
name: Region Stockholm
First posted: 2019-01-09
Enrollment: 229
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a randomised controlled multi-centre trial comparing the effect of diet supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The infants will be randomised to receive either the human breast-milk based H2MF® or the standard bovine protein-based nutrient fortifier when oral feeds have reached \<100 ml/kg/day.

The randomised intervention, stratified by centre, will continue until the target gestational week 34+0. The infant must not be fed with formula during the intervention period. The allocation will be concealed before inclusion, but after randomisation the study is not blinded.

Primary endpoint of the intervention is the composite variable necrotizing enterocolitis (NEC), sepsis and mortality.

The enrolled infants are characterised with clinical data including growth, feeding intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and complications collected daily in a study specific case report form from birth until discharge from the hospital (not longer than gestational week 44+0). A follow up focusing on neurological development, growth and feeding problems will be performed at 2 years of age (corrected) and 5.5 years of age.

Detailed description: This is a randomised controlled multi-centre trial comparing the effect of diet supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The infants will be randomised to receive either the human breast-milk based H2MF® or the standard bovine protein-based nutrient fortifier when oral feeds have reached \<100 ml/kg/day. If fortification with extra enteral lipids is needed during the intervention period, the infants receiving H2MF® will be supplemented with the human milk-based Prolact CR®, while the infants receiving standard bovine protein-based fortification will be supplemented with the standard lipid products used at the unit. The study subject will be enrolled at level III neonatal intensive care unit (NICU)s. Only infants with a home clinic with the logistics to maintain the intervention until gestational week 34+0 will be included.

The randomised intervention, stratified by centre, will continue until the target gestational week 34+0. The infant must not be fed with formula during the intervention period. The allocation will be concealed before inclusion, but after randomisation the study is not blinded. It would not be possible to prescribe the fortifier and prepare of the breast milk in a blinded fashion, since the fortifiers are not exactly equal in nutrient content and also look different. Instead the assessment of several of the outcomes will be made blinded, such as the assessment of X-ray images in NEC cases.

The enrolled infants are characterised with clinical data including growth, feeding intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and complications collected daily in a study specific case report form from birth until discharge from the hospital (not longer than gestational week 44+0). A follow up focusing on neurological development, growth and feeding problems will be performed at 2 years of age (corrected) and 5.5 years.

Since it is often difficult to distinguish between the diagnoses of NEC and sepsis, and their clinical consequences, the investigator's primary endpoint of the intervention is the composite variable NEC, sepsis and mortality. Secondary endpoints are feeding intolerance and other severe complication such as Bronchopulmonary dysplasia (BPD), Retinopathy of prematurity (ROP) and neurological impairment. Stool, urine and blood samples are also collected for microbiology, metabolomic and immunology analysis in order to study underlying mechanisms. Health economic analyses will be made to evaluate the costs and benefits of an introduction of human milk-based fortifier in NICUs in the Nordic countries.

Analyses will be conducted using an intention to treat approach. An evaluation will be performed when 20 infants have been included to evaluate feasibility and make it possible to adjust the protocol for the remaining part of the study. Safety analyses will be performed by an independent data and safety monitoring board (DSMB) when 50, 100 and 150 infants have been included. A sample size re-estimation will be made by an independent statistician when 150 infants have been included. Thus, the definitive sample size might be increased (never decreased) based on this interim analysis. The study can be terminated before 322 infants have been enrolled based on a decision of the sponsor and the DSMB, if the primary outcome is significantly lower (with a significance level \<0.001) in the H2MF® than in the standard fortification group in the interim analysis made after 150 infants have completed the neonatal period. The study subject will be enrolled at level III NICUs in the Nordic Countries. All study subjects will be followed during the neonatal period until discharge (not longer than gestational week 44+0) and also be included in a follow up at 2 and 5.5 years of age based on the national follow up program for extremely preterm infants.

Eligibility criteria: Inclusion Criteria:

* Gestational age at birth 22+0-27+6: based on prenatal ultrasonography.
* Enteral feeds \< 100 mL/kg/day at the day of randomisation.
* Written informed consent from the legal guardians of the infant.
* The home clinic of the infant has the logistics of maintaining the intervention until gestational week 34+0

Exclusion Criteria:

* Lethal or complicated malformation known at the time of inclusion
* Chromosomal anomalies known at the time of inclusion
* No realistic hope for survival at the time of inclusion
* Gastrointestinal malformation known at the time of inclusion
* Abdominal surgery before the time of inclusion
* Participation in another intervention trial aiming at having an effect on growth, nutrition, feeding intolerance or severe complications such as NEC and sepsis
* Infants having nutrient fortifier or formula prior to randomisation

Primary outcomes:
measure: The incidence of the composite of necrotizing enterocolitis, culture-proven sepsis and mortality
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary outcomes:
measure: The incidence of the composite of necrotizing enterocolitis and culture-proven sepsis
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: The incidence of the composite of necrotizing enterocolitis culture-proven sepsis, bronchopulmonary dysplasia, retinopathy of prematurity and mortality (Mortality and morbidity index)
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Time to reach full enteral feeds
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Number of feeding interruptions
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Numbers of days with parenteral nutrition
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Number of large gastric aspirates per day
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Stool frequency
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Time to regain birth weight
timeFrame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Change in head circumference in centimeters
timeFrame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: Change in weight in gram
timeFrame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: Change in length in centimeters
timeFrame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: The mortality incidence
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of necrotising enterocolitis: Bell´s stage II-III
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence spontaneous intestinal perforation
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of abdominal surgery
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence culture-proven sepsis
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of suspected sepsis, not culture-proven
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of pneumonia
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of bronchopulmonary dysplasia
timeFrame: At gestational week 36+0
measure: The incidence of retinopathy of the prematurity
timeFrame: From birth until gestational week 42+0
measure: The incidence of intraventricular haemorrhage
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of periventricular leukomalacia
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: Number of days with intensive care
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: Length of stay at the hospital
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: Length of need of feeding tube
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: Neurocognitive development at 2 years
timeFrame: At 2 years of age
measure: Prevalence of cerebral palsy at 2 years
timeFrame: At 2 years of age
measure: Prevalence of epilepsy at 2 years
timeFrame: At 2 years of age
measure: Prevalence of squint and/or impaired vision at 2 years
timeFrame: At 2 years of age
measure: Prevalence of impaired hearing at 2 years
timeFrame: At 2 years of age
measure: The number of infants needing extra oxygen and/or ventilatory support after discharge from the hospital at the neonatal period
timeFrame: From gestational week 44 until 2 years of age
measure: The incidence of wheeze and/or asthma
timeFrame: From birth until 2 years of life
measure: The incidence of severe infections after discharge from the neonatal unit
timeFrame: From gestational week 44 until 2 years of age
measure: The number of infants needing feeding tube after discharge from the hospital at the neonatal period
timeFrame: From gestational week 44 until 2 years of age
measure: The number of infants needing extra nutritional support after discharge from the hospital at the neonatal period
timeFrame: From gestational week 44 until 2 years of age
measure: The prevalence of neurocognitive development at 5.5 years
timeFrame: At 5.5 years of age
measure: The prevalence of cerebral palsy at 5.5 years
timeFrame: At 5.5 years of age
measure: The prevalence of epilepsy at 5.5 years of age
timeFrame: At 5.5 years of age
measure: The prevalence of squint and/or impaired vision at 5.5 years of age
timeFrame: At 5.5 years of age
measure: The prevalence of children with impaired hearing at 5.5 years of age
timeFrame: At 5.5 years of age
measure: The prevalence of wheeze and/or asthma at 5.5 years of age
timeFrame: At 5.5 years of age
measure: Microbiome composition in stool samples
timeFrame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
measure: Levels of subclasses of T and B cells and granulocytes in blood samples
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of immune markers in plasma
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of growth factors in plasma samples
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of lipids in plasma samples
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of neurotransmitters in plasma samples
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of metabolic peptides in urine samples
timeFrame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
measure: Levels of markers of central nervous system (CNS) damage in plasma samples
timeFrame: At 1, 2 and 4 weeks of age and gestational week 36+0
measure: Levels of proteins in breast milk samples
timeFrame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
measure: Levels of human milk oligosaccharides in breast milk samples
timeFrame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
measure: Health care costs
timeFrame: From birth until discharge from hospital (but not loner than gestational week 44+0)
Other outcomes:
Locations:
city: Göteborg
country: Sweden
facility: Queen Silvia Children´s Hospital
city: Linköping
country: Sweden
facility: Crown Princess Victoria Children´s Hospital
city: Stockholm
country: Sweden
facility: Karolinska Hospital
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Uppsala
country: Sweden
facility: Akademiska Barnsjukhuset
Study officials:
affiliation: Region Östergötland
name: Thomas R Abrahamsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jensen GB, Ahlsson F, Domellof M, Elfvin A, Naver L, Abrahamsson T. Nordic study on human milk fortification in extremely preterm infants: a randomised controlled trial-the N-forte trial. BMJ Open. 2021 Nov 23;11(11):e053400. doi: 10.1136/bmjopen-2021-053400.