A Phase 2 interventional study of Lactobacillus reuteri and Placebo in Feeding; Difficult, Newborn, Growth Failure and Necrotizing Enterocolitis, sponsored by Ostergotland County Council, Sweden. Completed at 2 sites in Sweden. Open to participants aged 1 Day to 3 Days, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-08-13.
Sponsored by Ostergotland County Council, Sweden · Phase 2, Interventional, and Prevention
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.
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.
84 studies on the registry are indexed under Failure to Thrive; 12 are open to participants now.
This study's enrollment of 134 is above the median of 100 across 56 interventional studies indexed under Failure to Thrive.
Browse Failure to Thrive studies →Ostergotland County Council, Sweden is the lead sponsor of 18 studies on the registry; 4 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Lactobacillus reuteri DSM 17938, 125 million bacteria/day
Dietary Supplement: Lactobacillus reuteri
The same oil drops as the active study product but without Lactobacillus reuteri
Dietary Supplement: Placebo
Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day
Oil drops without Lactobacillus reuteri
Time to Establish Full Enteral Feeds
The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time.
Time frame: Birth to gestational week 36+0
Days With Halted Feeding Due to Food Intolerance
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.
Time frame: Birth to gestational week 36
Number of Stools
Time frame: Recorded over the first four weeks
Time Until Birth Weight is Regained. Specifies the Number of Full Days the Child Has Lived.
Specifies the number of full days the child has lived.
Time frame: Birth to gw 36+0
Weight Gain (SD)
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.
Time frame: At 14th day of life
Mortality
Time frame: Birth to gw 36+0
Necrotizing Enterocolitis
Bell´s criteria II-III
Time frame: Birth to gw 36+0
Sepsis
Blood culture positive sepsis
Time frame: Birth to gw 36+0
Bronchopulmonary Dysplasia
Need of oxygen or CPAP/ventilator at gw 36+0
Time frame: Gw 36+0
Weight Gain (SD)
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.
Time frame: At 28th day of life
Weight Gain (SD)
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.
Time frame: At gestational week 36+0
Length Gain (SD)
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.
Time frame: At 14th day of life
Length Gain (SD)
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.
Time frame: At 28th day of life
Length Gain (SD)
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.
Time frame: At gestational week 36+0
Head Circumference Growth (SD)
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.
Time frame: At 14th day of life
Head Circumference Growth (SD)
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.
Time frame: At 28th day of life
Head Circumference Growth (SD)
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.
Time frame: At gestational week 36+0
Neurological Development
Bayleys´s test by psychologist
Time frame: At 2 years corrected age
Neurological Development Impairment
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
Time frame: At 2 years corrected age
Extremely preterm infants with a birth weight \<1000 g were recruited within 72 hours after birth in two level 3 NICUs .
| Milestone | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Started | 68 | 66 |
| Completed | 68 | 66 |
| Not completed | 0 | 0 |
The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time.
| days | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Time to Establish Full Enteral Feeds | 15 (11 to 23) | 15 (10 to 20) |
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.
| days | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Days With Halted Feeding Due to Food Intolerance | 5.5 (3 to 9.5) | 6 (4 to 10) |
| number of stools | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Number of Stools | 69.6 (64.1 to 75.1) | 69.9 (63.8 to 75.9) |
Specifies the number of full days the child has lived.
Results for this outcome have not been posted.
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Weight Gain (SD) | -0.88 ± 0.81 | -0.88 ± 0.81 |
| participants | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Mortality | 5 | 5 |
Bell´s criteria II-III
| participants | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Necrotizing Enterocolitis | 7 | 8 |
Blood culture positive sepsis
| participants | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Sepsis | 25 | 23 |
Need of oxygen or CPAP/ventilator at gw 36+0
| participants | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Bronchopulmonary Dysplasia | 40 | 39 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Weight Gain (SD) | -1.14 ± 1.07 | -1.25 ± 0.95 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Weight Gain (SD) | -0.40 ± 1.30 | -0.24 ± 1.10 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Length Gain (SD) | -1.02 ± 1.00 | -1.20 ± 1.01 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Length Gain (SD) | -1.67 ± 1.47 | -1.96 ± 1.28 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Length Gain (SD) | -1.44 ± 1.65 | -1.34 ± 1.52 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Head Circumference Growth (SD) | -0.92 ± 0.56 | -1.11 ± 0.82 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Head Circumference Growth (SD) | -1.21 ± 0.85 | -1.73 ± 0.91 |
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.
| change in standard deviations | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Head Circumference Growth (SD) | -0.57 ± 1.29 | -0.79 ± 1.24 |
Bayleys´s test by psychologist
Results for this outcome have not been posted.
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
Results for this outcome have not been posted.
Collected over From birth until 36+0 weeks corrected postmenstrual age. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Lactobacillus Reuteri | 5/68 (7.4%) | 55/68 (80.9%) | 0/68 (0%) |
| Placebo | 5/66 (7.6%) | 52/66 (78.8%) | 0/66 (0%) |
| Event | Lactobacillus Reuteri | Placebo |
|---|---|---|
| Severe morbidity or deathGeneral disorders | 55/68 | 52/66 |
| Infection by the probiotic bacteriumInfections and infestations | 0/68 | 0/66 |
| Age, Continuous(age in postmenstrual weeks at birth) | Probiotic | Placebo | Total |
|---|---|---|---|
| Mean | 25.5 ± 1.2 | 25.5 ± 1.3 | 25.5 ± 1.2 |
| Sex: Female, Male(Participants) | Probiotic | Placebo | Total |
|---|---|---|---|
| Female | 36 | 24 | 60 |
| Male | 32 | 42 | 74 |
| Birth weight(gram) | Probiotic | Placebo | Total |
|---|---|---|---|
| Mean | 731 ± 129 | 740 ± 148 | 735 ± 138 |
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Studies of the drug tested here: Lactobacillus reuteri
Ostergotland County Council, Sweden