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NCT Number: NCT01603368

Prophylactic Probiotics to Extremely Low Birth Weight Prematures

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.

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Key information

Conditions

Feeding; Difficult, Newborn Body Weight Digestive System Diseases Enterocolitis Enterocolitis, Necrotizing Failure to Thrive Gastroenteritis Gastrointestinal Diseases Growth Failure Infections Inflammation Intestinal Diseases Necrotizing Enterocolitis Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Signs and Symptoms Systemic Inflammatory Response Syndrome

Age range

1 day–3 day

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Vrinnevi Hospital in Norrköping, Norrköping, Sweden

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About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Lactobacillus reuteri

Dietary Supplement

Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day

Placebo

Dietary Supplement

Oil drops without Lactobacillus reuteri

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. Number of Stools

    Time frame: Recorded over the first four weeks

  3. 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.

  4. 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.

  5. Mortality

    Time frame: Birth to gw 36+0

  6. Necrotizing Enterocolitis

    Time frame: Birth to gw 36+0

    Bell´s criteria II-III

  7. Sepsis

    Time frame: Birth to gw 36+0

    Blood culture positive sepsis

  8. Bronchopulmonary Dysplasia

    Time frame: Gw 36+0

    Need of oxygen or CPAP/ventilator at gw 36+0

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Neurological Development

    Time frame: At 2 years corrected age

    Bayleys´s test by psychologist

  18. 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

Sponsors and collaborators

Lead sponsor

Ostergotland County Council, Sweden

Other

Collaborators

  • BioGaia AB
  • Ekhaga Foundation, Sweden
  • Medical Research Council of Southeast Sweden
  • The Swedish Research Council
  • The Swedish Society of Medicine
  • University Hospital, Linkoeping

Registry information

Acronym: PROPEL

Important dates

Study start
2012
Primary completion
2015
Study completion
2015
First posted
May 22, 2012
Registry last updated
Aug 13, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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