Clinical trial NCT01603368: Prophylactic Probiotics to Extremely Low Birth Weight Prematures
Official title: Prophylactic Probiotics to Extremely Low Birth Weight Prematures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Feeding; Difficult, Newborn
Growth Failure
Necrotizing Enterocolitis
Sepsis
Keywords: Probiotics
Lactobacillus reuteri
Prematures
Enteral feeding
Motility
Necrotizing enterocolitis
Sepsis
Weight
Lead sponsor: Ostergotland County Council, Sweden
Sponsor class: OTHER
Collaborators: name: BioGaia AB
name: Ekhaga Foundation, Sweden
name: Medical Research Council of Southeast Sweden
name: University Hospital, Linkoeping
name: The Swedish Research Council
name: The Swedish Society of Medicine
First posted: 2012-05-22
Enrollment: 134
Sex: ALL
Minimum age (years): 1
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Mortality and incidence of severe complications is still high among extremely premature infants. Common causes of severe complications in this population are poor nutrition, necrotizing enterocolitis, and severe infections. Feeding intolerance is also a common problem resulting in prolonged need for intravenous lines and poor nutrition.

The aim of the study is to evaluate whether supplementation with the probiotic bacterium Lactobacillus reuteri DSM 17938 daily to premature infants with extremely low birth weight increases feeding tolerance to breast milk and thereby improves nutrition, increases growth and reduces serious complications and mortality in this population. Beyond this, possible mechanisms underlying these effects will be analyzed in stool, breast milk and blood samples.

Detailed description: RATIONALE Mortality and incidence of severe complications is still high among extremely premature infants. Common causes of severe complications in this population are poor nutrition, necrotizing enterocolitis (NEC), and severe infections. Feeding intolerance is also a common problem resulting in prolonged need for intravenous lines and poor nutrition. There is scientific evidence that dietary supplements with probiotics may have an effect on these manifestations.

Lactobacillus reuteri is a well studied probiotic bacterium that has been tested in several clinical studies in premature infants and older children, and the results of these studies and animal studies suggest that this bacterium may also have an effect on growth and mortality in extremely premature infants. Lactobacillus reuteri reduces colonization with pathogenic microbes, stimulates gastric and intestinal motility and shortens hospital stay in moderately premature infants. In animal models, L. reuteri also induces anti-inflammatory immune responses, reduces the symptoms of inflammatory bowel disease and the incidence of NEC. Administration of L. reuteri also improves the intestinal barrier both in human studies in children and in animal studies. Dietary supplements of L. reuteri to extremely premature infants may therefore improve feeding tolerance and nutrition and reduce the incidence of severe complications in this population.

HYPOTHESIS Premature infants with extremely low birth weight receiving daily supplements of Lactobacillus reuteri DSM 17938 will reach full enteral feeding faster compared with children receiving placebo.

STUDY DESIGN This study will be conducted as a prospective multi-center double blind placebo-controlled study in neonatal intensive care units in Sweden. In total 134 neonates with extremely low birth weight (\<1000g) and gestational age \<28+0 weeks will be randomized to receive either dietary supplements of Lactobacillus reuteri or placebo. Study product will be identical to the active and placebo group besides the addition of Lactobacillus reuteri (1.25 x 100 million bacteria=0.2 ml oil drops per day) in the active group. The supplementation will commence within 1-3 days after birth and will be given daily until gestational week 36+0. The infants will be followed until gestational week 36+0 and data on feeding tolerance, nutrition, growth, infections, NEC, bronchopulmonary dysplasia, death, and potential confounders will be entered in an individual study protocol. Stool, breast milk, and blood samples will be collected for analyses of possible underlying mechanisms.

A 2-year follow up including examination by pediatrician, growth parameters, questionnaire and psychology testing (Bayley´s test) will be performed.

Eligibility criteria: Inclusion Criteria:

* Birth weight \< 1000 g
* Gestational age: v23+0-V27 +6.
* Age \< 72 hours at inclusion.
* Signed informed consent by parents.

Exclusion Criteria:

* Fatal or complex congenital malformation at inclusion time.
* Chromosomal defect at inclusion time.
* No realistic hope of survival at inclusion time.
* Gastrointestinal malformation at inclusion time.
* Participation in another study which aims to influence nutrition, growth, feeding tolerance or necrotizing enterocolitis.

Primary outcomes:
measure: Time to Establish Full Enteral Feeds
timeFrame: Birth to gestational week 36+0
Secondary outcomes:
measure: Days With Halted Feeding Due to Food Intolerance
timeFrame: Birth to gestational week 36
measure: Number of Stools
timeFrame: Recorded over the first four weeks
measure: Time Until Birth Weight is Regained. Specifies the Number of Full Days the Child Has Lived.
timeFrame: Birth to gw 36+0
measure: Weight Gain (SD)
timeFrame: At 14th day of life
measure: Mortality
timeFrame: Birth to gw 36+0
measure: Necrotizing Enterocolitis
timeFrame: Birth to gw 36+0
measure: Sepsis
timeFrame: Birth to gw 36+0
measure: Bronchopulmonary Dysplasia
timeFrame: Gw 36+0
measure: Weight Gain (SD)
timeFrame: At 28th day of life
measure: Weight Gain (SD)
timeFrame: At gestational week 36+0
measure: Length Gain (SD)
timeFrame: At 14th day of life
measure: Length Gain (SD)
timeFrame: At 28th day of life
measure: Length Gain (SD)
timeFrame: At gestational week 36+0
measure: Head Circumference Growth (SD)
timeFrame: At 14th day of life
measure: Head Circumference Growth (SD)
timeFrame: At 28th day of life
measure: Head Circumference Growth (SD)
timeFrame: At gestational week 36+0
measure: Neurological Development
timeFrame: At 2 years corrected age
measure: Neurological Development Impairment
timeFrame: At 2 years corrected age
Other outcomes:
Locations:
city: Norrköping
country: Sweden
facility: Vrinnevi Hospital in Norrköping
city: Stockholm
country: Sweden
facility: Karolinska
Study officials:
affiliation: Linköping University Hospital; County Council of Östergötland
name: Thomas Abrahamsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Spreckels JE, Wejryd E, Marchini G, Jonsson B, de Vries DH, Jenmalm MC, Landberg E, Sverremark-Ekstrom E, Marti M, Abrahamsson T. Lactobacillus reuteri Colonisation of Extremely Preterm Infants in a Randomised Placebo-Controlled Trial. Microorganisms. 2021 Apr 24;9(5):915. doi: 10.3390/microorganisms9050915.
citation: Marti M, Spreckels JE, Ranasinghe PD, Wejryd E, Marchini G, Sverremark-Ekstrom E, Jenmalm MC, Abrahamsson T. Effects of Lactobacillus reuteri supplementation on the gut microbiota in extremely preterm infants in a randomized placebo-controlled trial. Cell Rep Med. 2021 Feb 22;2(3):100206. doi: 10.1016/j.xcrm.2021.100206. eCollection 2021 Mar 16.