Human Milk Fortification in Extremely Preterm Infants

Sepsis Clinical Trial

— N-forte  

Official title:

Nordic Study on Human Milk Fortification in Extremely Preterm Infants: a Randomized Controlled Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03797157
• Other study ID #: RegionOstergotland
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: February 1, 2019
• Est. completion date: December 31, 2027

Study information

• Verified date: December 2022
• Source: Ostergotland County Council, Sweden
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 229
• Est. completion date: December 31, 2027
• Est. primary completion date: September 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Enterocolitis
• Enterocolitis, Necrotizing
• Mortality
• Necrotizing Enterocolitis
• Sepsis

Intervention

Dietary Supplement:
• H2MF
H2MF is a human milk-based breastmilk fortifier for preterm infants
• Bovine milk-based fortifier
Bovine milk-based fortifier is the standard breast milk fortifier in Sweden

Locations

Country	Name	City	State
Sweden	Queen Silvia Children´s Hospital	Göteborg
Sweden	Crown Princess Victoria Children´s Hospital	Linköping
Sweden	Karolinska Hospital	Stockholm
Sweden	Norrlands Universitetssjukhus	Umeå
Sweden	Akademiska Barnsjukhuset	Uppsala

Sponsors (6)

Lead Sponsor	Collaborator
Thomas Abrahamsson, MD, PhD	Prolacta Bioscience, Region Stockholm, Region Uppsala, Sahlgrenska University Hospital, Sweden, Vasterbottens lans landsting

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	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	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	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	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	Time to reach full enteral feeds	The day of life the infant has received at least 150 mL/kg enteral feeds	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	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	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	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	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	Number of large gastric aspirates per day	=100% pre-feed volume (2 hours feeding volume if continuous feeding). Lower limit=2 ml/kg.	From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	Stool frequency		From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	Time to regain birth weight		From birth until discharge from hospital (but not longer than gestational week 44+0)
Secondary	Change in head circumference in centimeters		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).
Secondary	Change in weight in gram		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).
Secondary	Change in length in centimeters		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).
Secondary	The mortality incidence		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of necrotising enterocolitis: Bell´s stage II-III		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence spontaneous intestinal perforation		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of abdominal surgery		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence culture-proven sepsis		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of suspected sepsis, not culture-proven		From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of pneumonia	Pathological X-ray confirmed by an independent radiologist, need of increased respiratory support/oxygen and laboratory inflammatory response	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of bronchopulmonary dysplasia	Need of extra oxygen, continuous positive air pressure (CPAP) or ventilator at gestational week 36+0	At gestational week 36+0
Secondary	The incidence of retinopathy of the prematurity	Classified into stage I-V. The diagnosis is set after gestational week 42+0	From birth until gestational week 42+0
Secondary	The incidence of intraventricular haemorrhage	Classified into grade I-IV according to Papile	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	The incidence of periventricular leukomalacia	Criteria according to de Vries	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	Number of days with intensive care	Need of respirator or CPAP until discharge (not later than gestational week 44+0).	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	Length of stay at the hospital	Gestational week and day at discharge (not later than gestational week 44+0).	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	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)	From birth until discharge from hospital (but not loner than gestational week 44+0)
Secondary	Neurocognitive development at 2 years	Bayleys III, PARCA-R (Parental Report of Children´s Abilities-Revised) and ASQ-3 (Ages and stages questionnaire)	At 2 years of age
Secondary	Prevalence of cerebral palsy at 2 years		At 2 years of age
Secondary	Prevalence of epilepsy at 2 years		At 2 years of age
Secondary	Prevalence of squint and/or impaired vision at 2 years		At 2 years of age
Secondary	Prevalence of impaired hearing at 2 years		At 2 years of age
Secondary	The number of infants needing extra oxygen and/or ventilatory support after discharge from the hospital at the neonatal period		From gestational week 44 until 2 years of age
Secondary	The incidence of wheeze and/or asthma		From birth until 2 years of life
Secondary	The incidence of severe infections after discharge from the neonatal unit		From gestational week 44 until 2 years of age
Secondary	The number of infants needing feeding tube after discharge from the hospital at the neonatal period		From gestational week 44 until 2 years of age
Secondary	The number of infants needing extra nutritional support after discharge from the hospital at the neonatal period		From gestational week 44 until 2 years of age
Secondary	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.	At 5.5 years of age
Secondary	The prevalence of cerebral palsy at 5.5 years		At 5.5 years of age
Secondary	The prevalence of epilepsy at 5.5 years of age		At 5.5 years of age
Secondary	The prevalence of squint and/or impaired vision at 5.5 years of age		At 5.5 years of age
Secondary	The prevalence of children with impaired hearing at 5.5 years of age		At 5.5 years of age
Secondary	The prevalence of wheeze and/or asthma at 5.5 years of age		At 5.5 years of age
Secondary	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	At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Secondary	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	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	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).	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	Levels of growth factors in plasma samples	The levels of growth factors such as IGF-1 and the associated IGFBP-3 will be analysed.	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	Levels of lipids in plasma samples	Fatty acids in plasma	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	Levels of neurotransmitters in plasma samples	Neurotransmitters such as GABA and serotonin in plasma	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	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).	At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Secondary	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	At 1, 2 and 4 weeks of age and gestational week 36+0
Secondary	Levels of proteins in breast milk samples	Protein composition will be measured with multiplex methods	At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Secondary	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.	At 1, 2, 3 and 4 weeks of age and gestational week 36+0
Secondary	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	From birth until discharge from hospital (but not loner than gestational week 44+0)