- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01603368
Prophylactic Probiotics to Extremely Low Birth Weight Prematures (PROPEL)
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.
Study Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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-
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Norrköping, Sweden, 60379
- Vrinnevi Hospital in Norrköping
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Stockholm, Sweden, SE-171 76
- Karolinska
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Lactobacillus reuteri
Lactobacillus reuteri DSM 17938, 125 million bacteria/day
|
Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day
|
Placebo Comparator: Placebo
The same oil drops as the active study product but without Lactobacillus reuteri
|
Oil drops without Lactobacillus reuteri
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to Establish Full Enteral Feeds
Time Frame: Birth to gestational week 36+0
|
The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time.
|
Birth to gestational week 36+0
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Days With Halted Feeding Due to Food Intolerance
Time Frame: Birth to gestational week 36
|
Episode with food intolerance.
Retention volume> food volume given the last 2 hours (retention checked routinely every 4 hours) and/or clinical signs consistent with necrotizing enterocolitis (reduced general condition and inflated abdomen).
The number of such events will also be indicated.
|
Birth to gestational week 36
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Number of Stools
Time Frame: Recorded over the first four weeks
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Recorded over the first four weeks
|
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Time Until Birth Weight is Regained. Specifies the Number of Full Days the Child Has Lived.
Time Frame: Birth to gw 36+0
|
Specifies the number of full days the child has lived.
|
Birth to gw 36+0
|
Weight Gain (SD)
Time Frame: At 14th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 14th day of life
|
Mortality
Time Frame: Birth to gw 36+0
|
Birth to gw 36+0
|
|
Necrotizing Enterocolitis
Time Frame: Birth to gw 36+0
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Bell´s criteria II-III
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Birth to gw 36+0
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Sepsis
Time Frame: Birth to gw 36+0
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Blood culture positive sepsis
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Birth to gw 36+0
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Bronchopulmonary Dysplasia
Time Frame: Gw 36+0
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Need of oxygen or CPAP/ventilator at gw 36+0
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Gw 36+0
|
Weight Gain (SD)
Time Frame: At 28th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 28th day of life
|
Weight Gain (SD)
Time Frame: At gestational week 36+0
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At gestational week 36+0
|
Length Gain (SD)
Time Frame: At 14th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 14th day of life
|
Length Gain (SD)
Time Frame: At 28th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 28th day of life
|
Length Gain (SD)
Time Frame: At gestational week 36+0
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At gestational week 36+0
|
Head Circumference Growth (SD)
Time Frame: At 14th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 14th day of life
|
Head Circumference Growth (SD)
Time Frame: At 28th day of life
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At 28th day of life
|
Head Circumference Growth (SD)
Time Frame: At gestational week 36+0
|
In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated.
At gestational week 36+0 also absolute values will be analyzed.
A positive delta z-score indicates faster growth than the growth chart would predict.
|
At gestational week 36+0
|
Neurological Development
Time Frame: At 2 years corrected age
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Bayleys´s test by psychologist
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At 2 years corrected age
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Neurological Development Impairment
Time Frame: At 2 years corrected age
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A composite of several outcomes: impaired cognition at the Bayleys´test, cerebral palsy, blindness and deafness, divided into normal, mild, moderate and severe.
Mild -1SD to -2SD, Moderate <-2D to 3 SD and Severe <3SD
|
At 2 years corrected age
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Thomas Abrahamsson, MD, PhD, Linköping University Hospital; County Council of Östergötland
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Dnr 2012/28-31
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