A Phase 2/3 interventional study of H2MF and Bovine milk-based fortifier in Necrotizing Enterocolitis, Sepsis and Mortality, sponsored by Thomas Abrahamsson, MD, PhD. Active, not recruiting at 5 sites in Sweden. Per ClinicalTrials.gov, last updated 2024-07-23.
Sponsored by Thomas Abrahamsson, MD, PhD · Phase 2/3, Interventional, and Prevention
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.
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.
228 studies on the registry are indexed under Enterocolitis, Necrotizing; 44 are open to participants now.
This study's enrollment of 229 is above the median of 103 across 127 interventional studies indexed under Enterocolitis, Necrotizing.
Browse Enterocolitis, Necrotizing studies →This is the only study on the registry with Thomas Abrahamsson, MD, PhD as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Human milk-based breast milk fortifier
Dietary Supplement: H2MF
Standard care: bovine milk-based breast milk fortifier
Dietary Supplement: Bovine milk-based fortifier
H2MF is a human milk-based breastmilk fortifier for preterm infants
Bovine milk-based fortifier is the standard breast milk fortifier in Sweden
The incidence of the composite of necrotizing enterocolitis, culture-proven sepsis and mortality
An infant should have had any of these diagnoses to fulfil the criterion
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
The incidence of the composite of necrotizing enterocolitis and culture-proven sepsis
An infant should have had any of these diagnoses to fulfil the criterion
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
The incidence of the composite of necrotizing enterocolitis culture-proven sepsis, bronchopulmonary dysplasia, retinopathy of prematurity and mortality (Mortality and morbidity index)
An infant should have had any of these diagnoses to fulfil the criterion
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Time to reach full enteral feeds
The day of life the infant has received at least 150 mL/kg enteral feeds
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Number of feeding interruptions
Number of days feedings held for ≥12 hours or feeds reduced by \>50% (ml/kg/d) not due to a clinical procedure or transitioning to the breast
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Numbers of days with parenteral nutrition
Number of days of parental amino acid and/or lipid infusion. Only days when the enteral feed \<150mL/kg/day should be included
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Number of large gastric aspirates per day
≥100% pre-feed volume (2 hours feeding volume if continuous feeding). Lower limit=2 ml/kg.
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Stool frequency
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Time to regain birth weight
Time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
Change in head circumference in centimeters
Time frame: 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).
Change in weight in gram
Time frame: 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).
Change in length in centimeters
Time frame: 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).
The mortality incidence
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of necrotising enterocolitis: Bell´s stage II-III
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence spontaneous intestinal perforation
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of abdominal surgery
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence culture-proven sepsis
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of suspected sepsis, not culture-proven
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of pneumonia
Pathological X-ray confirmed by an independent radiologist, need of increased respiratory support/oxygen and laboratory inflammatory response
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of bronchopulmonary dysplasia
Need of extra oxygen, continuous positive air pressure (CPAP) or ventilator at gestational week 36+0
Time frame: At gestational week 36+0
The incidence of retinopathy of the prematurity
Classified into stage I-V. The diagnosis is set after gestational week 42+0
Time frame: From birth until gestational week 42+0
The incidence of intraventricular haemorrhage
Classified into grade I-IV according to Papile
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
The incidence of periventricular leukomalacia
Criteria according to de Vries
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
Number of days with intensive care
Need of respirator or CPAP until discharge (not later than gestational week 44+0).
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
Length of stay at the hospital
Gestational week and day at discharge (not later than gestational week 44+0).
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
Length of need of feeding tube
Gestational week and day when the infant does not need it anymore (not later than gestational week 44+0)
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
Neurocognitive development at 2 years
Bayleys III, PARCA-R (Parental Report of Children´s Abilities-Revised) and ASQ-3 (Ages and stages questionnaire)
Time frame: At 2 years of age
Prevalence of cerebral palsy at 2 years
Time frame: At 2 years of age
Prevalence of epilepsy at 2 years
Time frame: At 2 years of age
Prevalence of squint and/or impaired vision at 2 years
Time frame: At 2 years of age
Prevalence of impaired hearing at 2 years
Time frame: At 2 years of age
The number of infants needing extra oxygen and/or ventilatory support after discharge from the hospital at the neonatal period
Time frame: From gestational week 44 until 2 years of age
The incidence of wheeze and/or asthma
Time frame: From birth until 2 years of life
The incidence of severe infections after discharge from the neonatal unit
Time frame: From gestational week 44 until 2 years of age
The number of infants needing feeding tube after discharge from the hospital at the neonatal period
Time frame: From gestational week 44 until 2 years of age
The number of infants needing extra nutritional support after discharge from the hospital at the neonatal period
Time frame: From gestational week 44 until 2 years of age
The prevalence of neurocognitive development at 5.5 years
Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV TM) and Movement ABC-2: the total scale points as well as the points of sub scales (motor, cognitive, language) will be presented. The prevalence of infants with a realist below 2 standard deviations will be defined to have mental retardation.
Time frame: At 5.5 years of age
The prevalence of cerebral palsy at 5.5 years
Time frame: At 5.5 years of age
The prevalence of epilepsy at 5.5 years of age
Time frame: At 5.5 years of age
The prevalence of squint and/or impaired vision at 5.5 years of age
Time frame: At 5.5 years of age
The prevalence of children with impaired hearing at 5.5 years of age
Time frame: At 5.5 years of age
The prevalence of wheeze and/or asthma at 5.5 years of age
Time frame: At 5.5 years of age
Microbiome composition in stool samples
The relative abundance and diversity of microbial taxa will be analyses with next generation sequencing and be related till the study intervention
Time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Levels of subclasses of T and B cells and granulocytes in blood samples
T helper subsets (TH1, Th2, TH17, Treg), T cells subsets associated with the intestinal mucosa (gamma/delta-T cells, MAIT cells) and neutrophils will be assessed using masscytometry
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of immune markers in plasma
Pre planned analyses are anti-inflammatory (e.g. IL-10) and proinflammatory (e.g. TNF) cytokines and chemokines (e.g. CXCL11, CCL18).
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of growth factors in plasma samples
The levels of growth factors such as IGF-1 and the associated IGFBP-3 will be analysed.
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of lipids in plasma samples
Fatty acids in plasma
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of neurotransmitters in plasma samples
Neurotransmitters such as GABA and serotonin in plasma
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of metabolic peptides in urine samples
Metabolic peptide will be measured with proton nuclear magnetic resonance spectroscopy (NMR), liquid chromatography (LC) and mass spectroscopy couple to gas chromatography (GC-MC).
Time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Levels of markers of central nervous system (CNS) damage in plasma samples
Markers of CNS damage such as neurofilament light protein will be measured in plasma
Time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
Levels of proteins in breast milk samples
Protein composition will be measured with multiplex methods
Time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Levels of human milk oligosaccharides in breast milk samples
The levels of human milk oligosaccharides will be measured with high-performance anion-exchange chromatography with pulsed amperometric detection.
Time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Health care costs
The number of days at each level of care will be recorded until discharge from the hospital (not longer than gestational week 44+0). The cost will be calculated by multiplying the number of days at each level of care by the average cost
Time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
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