Prophylactic Probiotics to Extremely Low Birth Weight Prematures (PROPEL)

December 12, 2022 updated by: Thomas Abrahamsson, MD, PhD, Ostergotland County Council, Sweden

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

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

Interventional

Enrollment (Actual)

134

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Norrköping, Sweden, 60379
        • Vrinnevi Hospital in Norrköping
      • Stockholm, Sweden, SE-171 76
        • Karolinska

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 day to 3 days (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
Number of Stools
Time Frame: Recorded over the first four weeks
Recorded over the first four weeks
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
Bell´s criteria II-III
Birth to gw 36+0
Sepsis
Time Frame: Birth to gw 36+0
Blood culture positive sepsis
Birth to gw 36+0
Bronchopulmonary Dysplasia
Time Frame: Gw 36+0
Need of oxygen or CPAP/ventilator at gw 36+0
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
Bayleys´s test by psychologist
At 2 years corrected age
Neurological Development Impairment
Time Frame: At 2 years corrected age
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

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Thomas Abrahamsson, MD, PhD, Linköping University Hospital; County Council of Östergötland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2012

Primary Completion (Actual)

December 1, 2015

Study Completion (Actual)

December 1, 2015

Study Registration Dates

First Submitted

May 18, 2012

First Submitted That Met QC Criteria

May 21, 2012

First Posted (Estimate)

May 22, 2012

Study Record Updates

Last Update Posted (Estimate)

January 10, 2023

Last Update Submitted That Met QC Criteria

December 12, 2022

Last Verified

December 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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