Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| BioGaia AB | INDUSTRY |
| Ekhaga Foundation, Sweden | UNKNOWN |
| Medical Research Council of Southeast Sweden | OTHER_GOV |
| University Hospital, Linkoeping |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lactobacillus reuteri | Active Comparator | Lactobacillus reuteri DSM 17938, 125 million bacteria/day |
|
| Placebo | Placebo Comparator | The same oil drops as the active study product but without Lactobacillus reuteri |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lactobacillus reuteri | Dietary Supplement | Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Birth to gestational week 36+0 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Birth to gestational week 36 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Thomas Abrahamsson, MD, PhD | Linköping University Hospital; County Council of Östergötland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vrinnevi Hospital in Norrköping | Norrköping | 60379 | Sweden | |||
| Karolinska |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33923278 | Derived | 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. | |
| 33763652 | Derived |
Not provided
Not provided
Inclusion should be completed to allow first dose of study product to be administered within 72 hours from birth.
Extremely preterm infants with a birth weight <1000 g were recruited within 72 hours after birth in two level 3 NICUs .
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Lactobacillus Reuteri | Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day |
| FG001 | Placebo | The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Probiotic | Lactobacillus reuteri |
| BG001 | Placebo | |
| BG002 | Total |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Postmenstrual weeks |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Six infants - Four allocated to receive L. reuteri and two allocated to the placebo group died before reaching full enteral feeding and were not included in the analyses. | Posted | Median | Inter-Quartile Range | days | Birth to gestational week 36+0 |
|
From birth until 36+0 weeks corrected postmenstrual age
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lactobacillus Reuteri | Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection by the probiotic bacterium | Infections and infestations | Systematic Assessment | Positive culture with Lactobacillus reuteri from a normally sterile location (typically blood, cerebrospinal fluid). |
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Thomas Abrahamsson, MD PhD | University of Linköping | +46.10.1030000 | thomas.abrahamsson@liu.se |
Not provided
| ID | Term |
|---|---|
| D005183 | Failure to Thrive |
| D020345 | Enterocolitis, Necrotizing |
| D018805 | Sepsis |
| D001835 | Body Weight |
| ID | Term |
|---|---|
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D004760 | Enterocolitis |
| D005759 | Gastroenteritis |
Not provided
Not provided
| OTHER |
| The Swedish Research Council | OTHER_GOV |
| The Swedish Society of Medicine | OTHER |
Not provided
Not provided
Not provided
Not provided
| Placebo | Dietary Supplement | Oil drops without Lactobacillus reuteri |
|
| Number of Stools | 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. | 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. | At 14th day of life |
| Mortality | Birth to gw 36+0 |
| Necrotizing Enterocolitis | Bell´s criteria II-III | Birth to gw 36+0 |
| Sepsis | Blood culture positive sepsis | Birth to gw 36+0 |
| Bronchopulmonary Dysplasia | Need of oxygen or CPAP/ventilator at gw 36+0 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | At gestational week 36+0 |
| Neurological Development | Bayleys´s test by psychologist | 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 | At 2 years corrected age |
| Stockholm |
| SE-171 76 |
| Sweden |
| 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. |
Total of all reporting groups |
| Standard Deviation |
| age in postmenstrual weeks at birth |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Birth weight | Mean | Standard Deviation | gram |
|
|
|
| Secondary | 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. | Posted | Median | Inter-Quartile Range | days | Birth to gestational week 36 |
|
|
|
| Secondary | Number of Stools | Only infants with complete records of stools during the first four weeks are included | Posted | Mean | 95% Confidence Interval | number of stools | Recorded over the first four weeks |
|
|
|
| Secondary | 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. | Not Posted | Birth to gw 36+0 | Participants |
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 14th day of life |
|
|
|
| Secondary | Mortality | Posted | Number | participants | Birth to gw 36+0 |
|
|
|
| Secondary | Necrotizing Enterocolitis | Bell´s criteria II-III | Posted | Number | participants | Birth to gw 36+0 |
|
|
|
| Secondary | Sepsis | Blood culture positive sepsis | Posted | Number | participants | Birth to gw 36+0 |
|
|
|
| Secondary | Bronchopulmonary Dysplasia | Need of oxygen or CPAP/ventilator at gw 36+0 | Only patients surviving to gestational week 36+0 could be assessed for the diagnosis. | Posted | Number | participants | Gw 36+0 |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 28th day of life |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At gestational week 36+0 |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 14th day of life |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 28th day of life |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At gestational week 36+0 |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 14th day of life |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At 28th day of life |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | change in standard deviations | At gestational week 36+0 |
|
|
|
| Secondary | Neurological Development | Bayleys´s test by psychologist | Not Posted | Aug 2024 | At 2 years corrected age | Participants |
| Secondary | 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 | Not Posted | Aug 2024 | At 2 years corrected age | Participants |
| 5 |
| 68 |
| 55 |
| 68 |
| 0 |
| 68 |
| EG001 | Placebo | The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri | 5 | 66 | 52 | 66 | 0 | 66 |
|
| Severe morbidity or death | General disorders | Systematic Assessment | This compound measure reports if any of the following occurred: Necrotizing enterocolitis stage 2 - 3 Culture proven sepsis Bronchopulmonary dysplasia ROP, grade 3-5 IVH, grade 3-4 Periventricular leukomalacia Death |
|
Not provided
Not provided
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |