Feeding; Difficult, NewbornPhase 2PROPELNCT01603368
Prophylactic Probiotics to Extremely Low Birth Weight Prematures
A Phase 2 study testing Lactobacillus reuteri in people with Feeding; Difficult, Newborn and Growth Failure, run by Ostergotland County Council, Sweden at 2 sites in Sweden.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 day to 3 daysHealthy volunteers can take part
- Conditions the study is for
- Feeding; Difficult, Newborn, Growth Failure, Necrotizing Enterocolitis
- What is being tested?
- Lactobacillus reuteri
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 134 participants
- Where
- 2 sitesSweden
- Study dates
- Jun 2012to Dec 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 3 days
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Birth weight < 1000 g
- Gestational age: v23+0-V27 +6.
- Age < 72 hours at inclusion.
- Signed informed consent by parents.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
Sweden2 sites
Vrinnevi Hospital in Norrköping
Norrköping, 60379
Karolinska
Stockholm, SE-171 76
About this study
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.
Read the 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.
- Being tested
- Lactobacillus reuteri, Placebo
- Keywords
- Probiotics, Lactobacillus reuteri, Prematures, Enteral feeding, Motility, Necrotizing enterocolitis, Sepsis, Weight
- Medical subject headings
- Failure to Thrive, Enterocolitis, Necrotizing, Sepsis, Body Weight
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lactobacillus reuteriDietary supplement
Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day
PlaceboDietary supplement
Oil drops without Lactobacillus reuteri
| Study group | Role | What they receive |
|---|---|---|
| Lactobacillus reuteri | Active comparator | Lactobacillus reuteri DSM 17938, 125 million bacteria/day Receives: Dietary Supplement: Lactobacillus reuteri |
| Placebo | Placebo comparator | The same oil drops as the active study product but without Lactobacillus reuteri Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Birth to gestational week 36+0
Secondary outcomes (18)
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.
Measured: Birth to gestational week 36
Number of Stools
Measured: 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.
Measured: 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.
Measured: At 14th day of life
Mortality
Measured: Birth to gw 36+0
Necrotizing Enterocolitis
Bell´s criteria II-III
Measured: Birth to gw 36+0
Sepsis
Blood culture positive sepsis
Measured: Birth to gw 36+0
Bronchopulmonary Dysplasia
Need of oxygen or CPAP/ventilator at gw 36+0
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: At gestational week 36+0
Neurological Development
Bayleys´s test by psychologist
Measured: 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
Measured: At 2 years corrected age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2012 (estimated)
- Study startJun 2012
- Primary completionDec 2015
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Feeding; Difficult, NewbornStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 134 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ostergotland County Council, Sweden
- Sponsor type
- University, hospital or other
- Collaborators
- BioGaia AB, Ekhaga Foundation, Sweden, Medical Research Council of Southeast Sweden, University Hospital, Linkoeping, The Swedish Research Council, The Swedish Society of Medicine
- Responsible party
- Principal investigator, Thomas Abrahamsson, MD, PhD, Ostergotland County Council, Sweden
- Investigators
- Thomas Abrahamsson, MD, PhD, Principal investigator, Linköping University Hospital; County Council of Östergötland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01603368
- Sponsor's protocol ID
- Dnr 2012/28-31
- Acronym
- PROPEL
- Status last verified
- Jul 2024
- First submitted
- 18 May 2012
- Last updated
- 13 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 33923278Marti 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.
PubMed 33763652
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prophylactic Probiotics to Extremely Low Birth Weight Prematures
- ClinicalTrials.gov ID
- NCT01603368
- Acronym / sponsor ID
- PROPEL / Dnr 2012/28-31
- Keywords
- Probiotics, Lactobacillus reuteri, Prematures, Enteral feeding, Motility, Necrotizing enterocolitis, Sepsis, Weight
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 134 participants (actual)
- Lead sponsor
- Ostergotland County Council, SwedenUniversity, hospital or other
- Collaborators
- BioGaia AB, Ekhaga Foundation, Sweden, Medical Research Council of Southeast Sweden, University Hospital, Linkoeping, The Swedish Research Council, The Swedish Society of Medicine
- Study start
- Jun 2012 (actual)
- Primary completion
- Dec 2015 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 22 May 2012 (estimated)
- Results
- Posted 27 Apr 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lactobacillus reuteri | Active comparator | Dietary Supplement: Lactobacillus reuteriLactobacillus reuteri DSM 17938, 125 million bacteria/day |
| Placebo | Placebo comparator | Dietary Supplement: PlaceboThe same oil drops as the active study product but without Lactobacillus reuteri |
Who may qualify
- Ages
- 1 day to 3 days
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Birth weight < 1000 g
- Gestational age: v23+0-V27 +6.
- Age < 72 hours at inclusion.
- Signed informed consent by parents.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lactobacillus reuteriOil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day | Dietary supplement | Lactobacillus reuteri |
| PlaceboOil drops without Lactobacillus reuteri | Dietary supplement | Placebo |
Primary outcome
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.
18 secondary outcomes
Days With Halted Feeding Due to Food Intolerance
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.
Time frame: Birth to gw 36+0
Weight Gain (SD)
Time frame: At 14th day of life
Mortality
Time frame: Birth to gw 36+0
Necrotizing Enterocolitis
Time frame: Birth to gw 36+0
Sepsis
Time frame: Birth to gw 36+0
Bronchopulmonary Dysplasia
Time frame: Gw 36+0
Weight Gain (SD)
Time frame: At 28th day of life
Weight Gain (SD)
Time frame: At gestational week 36+0
Length Gain (SD)
Time frame: At 14th day of life
Length Gain (SD)
Time frame: At 28th day of life
Length Gain (SD)
Time frame: At gestational week 36+0
Head Circumference Growth (SD)
Time frame: At 14th day of life
Head Circumference Growth (SD)
Time frame: At 28th day of life
Head Circumference Growth (SD)
Time frame: At gestational week 36+0
Neurological Development
Time frame: At 2 years corrected age
Neurological Development Impairment
Time frame: At 2 years corrected age
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33923278Spreckels 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.
- Derived from this study: PubMed 33763652Marti 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Abrahamsson, MD, PhD principal investigator
Linköping University Hospital; County Council of Östergötland
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lactobacillus reuteri in people with Feeding; Difficult, Newborn and Growth Failure, run by Ostergotland County Council, Sweden at 2 sites in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Apr 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Establish Full Enteral Feeds (time frame: Birth to gestational week 36+0). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01603368, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2024; AzTrials last refreshed its copy on 31 Oct 2026.