PrematurityPhase 1IPPINCT01756040
Intestinal Permeability in Preterm Infants
A Phase 1 study testing Lactulose -rhamnose solution in people with Prematurity and Intestinal Permeability, run by University of Maryland, Baltimore at 1 site in United States.
Trial summary
Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency characterized by increased intestinal permeability, affects approximately 7 to 10% of infants <1500 g birthweight, and typically occurs within 7 to 14 days of birth. Mortality is as high as 30-50%. Read more about this study
- Who is it for?
- Ages Up to 4 days
- Conditions the study is for
- Prematurity, Intestinal Permeability
- What is being tested?
- Lactulose -rhamnose solution
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 211 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Feb 2013to 31 Aug 2021
- Phase
- Phase 1
- 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 Up to 4 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- <5 days
- Gestational age 24-32 weeks
Who cannot join
- Nonviable or planned withdrawal of care
- Significant GI dysfunction (e.g. heme-positive stools, abdominal distension (girth >2 cm baseline), or bilious emesis/aspirates.
- Triplet or higher order multiple
- Severe asphyxia
- Lethal chromosome abnormalities
- Cyanotic congenital heart disease
Show all 9Show fewer
- Intestinal atresia or perforation
- Abdominal wall defects
- Known galactosemia or other galactose intolerance
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Maryland Medical Center
Baltimore, Maryland, 21201
About this study
Official title: Gut Permeability in Very Low Birth Weight Infants
Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency characterized by increased intestinal permeability, affects approximately 7 to 10% of infants <1500 g birthweight, and typically occurs within 7 to 14 days of birth. Mortality is as high as 30-50%. Prematurity is the greatest risk factor for the development of NEC due to the physiological immaturity of the gastrointestinal tract and altered or abnormal gut microbiota. Several studies have demonstrated that the initiation of an intense systemic and local inflammatory cascade leads to intestinal necrosis. The human intestine is lined by a single layer of cells exquisitely responsive to multiple stimuli and is populated by a complex climax community of microbial partners. Under normal circumstances, these intestinal cells form a tight but selective barrier to "friends and foes": microbes and most environmental substances are held at bay, but nutrients are absorbed efficiently. Epithelial barrier integrity is itself dynamic and matures over time starting soon after birth, though the mechanisms regulating dynamic permeability are poorly understood. Low birth weight, prematurity, and early postnatal age are associated with a leaky gut. Although intestinal permeability is higher at birth in preterm than term infants, there is usually rapid maturation of the intestinal barrier over the first few days of life in both populations. The investigators hypothesize that increased levels of measures of intestinal permeability (urine lactulose/rhamnose (LA/Rh), and fecal alpha1- antitrypsin will identify infants at high risk for NEC and that intestinal probiotic strains will be associated with intestinal barrier maturation. The purpose of the study is to determine whether clinical factors in combination with non-invasive stool test such as antitrypsin (A1AT) and microbiota composition profile are associated with intestinal permeability determined by excretion of non-metabolized sugar probes in urine (LA/Rh ratio). These studies may lead to a non-invasive screening test to identify preterm infants at risk for NEC.
Read the detailed description
The proposed study will evaluate the intestinal permeability measured by the urinary La/Rh ratio at one timepoint between d7-10 of life in 200 preterm infants 24-32 weeks gestation in preparation for a future study of probiotics to improve intestinal permeability in this population.
Primary Objective: To estimate mean and variance in IP measured by urinary Lactulose/Rhamnose ratio at 7-10d of life in neonates born between 24 and 32 weeks of gestational age.
Secondary Objectives
- To assess stool microbiome characteristics in association with intestinal permeability in preterm infants measured by the urinary lactulose/rhamnose ratio.
- Conditions
- Prematurity, Intestinal Permeability
- Being tested
- Lactulose -rhamnose solution
- Keywords
- intestinal permeability, preterm infants, dual sugar test, intestinal microbiota
- Medical subject headings
- Premature Birth
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lactulose -rhamnose solutionDrug
Also called dual sugar solution
Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
| Study group | Role | What they receive |
|---|---|---|
| Lactulose - rhamnose solution | Other | Preterm Infants age 24-32 weeks gestation Receives: Drug: Lactulose -rhamnose solution |
What is being measured
The primary outcome is the main question the study is designed to answer.
Intestinal Permeability
Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)
Measured: 7-10 days postnatal
Secondary outcomes (3)
Stool Alpha-1 Antitrypsin
Stool alpha-1 antitrypsin concentrations
Measured: 7-10 days postnatal
Stool Microbiota Relative Abundance
Relative abundance (%) Clostridiales species
Measured: 7-10 days postnatal
Breastmilk Feeding Duration Prior to La/Rh Measurement
Number of days breast milk feeding prior to La/Rh measurement between d7-10 days of age.
Measured: 7-10 days postnatal
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2012 (estimated)
- Study start1 Feb 2013
- Primary completion31 Aug 2021
- Study completion31 Aug 2021
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 (16)Papers the sponsor has linked to this study.
- Other trials for PrematurityStudies 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 1
- Primary purpose
- Screening
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 211 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rose Viscardi, University of Maryland, Baltimore
- Investigators
- Alessio Fasano, MD, Principal investigator, Massachusetts General HospitalRose M Viscardi, MD, Principal investigator, University of Maryland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01756040
- Sponsor's protocol ID
- HP-00049647
- Acronym
- IPPI
- Status last verified
- Nov 2023
- First submitted
- 19 Dec 2012
- Last updated
- 18 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008 Nov;173(5):1243-52. doi: 10.2353/ajpath.2008.080192. Epub 2008 Oct 2.
PubMed 18832585Bjarnason I. Intestinal permeability. Gut. 1994 Jan;35(1 Suppl):S18-22. doi: 10.1136/gut.35.1_suppl.s18.
PubMed 8125384van Wijck K, Bessems BA, van Eijk HM, Buurman WA, Dejong CH, Lenaerts K. Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose? Clin Exp Gastroenterol. 2012;5:139-50. doi: 10.2147/CEG.S31799. Epub 2012 Jul 19.
PubMed 22888267van Wijck K, Verlinden TJ, van Eijk HM, Dekker J, Buurman WA, Dejong CH, Lenaerts K. Novel multi-sugar assay for site-specific gastrointestinal permeability analysis: a randomized controlled crossover trial. Clin Nutr. 2013 Apr;32(2):245-51. doi: 10.1016/j.clnu.2012.06.014. Epub 2012 Aug 11.
PubMed 22892368Beach RC, Menzies IS, Clayden GS, Scopes JW. Gastrointestinal permeability changes in the preterm neonate. Arch Dis Child. 1982 Feb;57(2):141-5. doi: 10.1136/adc.57.2.141.
PubMed 7065710Piena-Spoel M, Albers MJ, ten Kate J, Tibboel D. Intestinal permeability in newborns with necrotizing enterocolitis and controls: Does the sugar absorption test provide guidelines for the time to (re-)introduce enteral nutrition? J Pediatr Surg. 2001 Apr;36(4):587-92. doi: 10.1053/jpsu.2001.22288.
PubMed 11283883Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blanco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res. 2002 Jan;51(1):64-70. doi: 10.1203/00006450-200201000-00012.
PubMed 11756641Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, Huijmans JG, Tibboel D. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Ann Surg. 2005 Apr;241(4):599-606. doi: 10.1097/01.sla.0000157270.24991.71.
PubMed 15798461Piena M, Albers MJ, Van Haard PM, Gischler S, Tibboel D. Introduction of enteral feeding in neonates on extracorporeal membrane oxygenation after evaluation of intestinal permeability changes. J Pediatr Surg. 1998 Jan;33(1):30-4. doi: 10.1016/s0022-3468(98)90355-4.
PubMed 9473094Malagon I, Onkenhout W, Klok M, van der Poel PF, Bovill JG, Hazekamp MG. Gut permeability in neonates after a stage 1 Norwood procedure. Pediatr Crit Care Med. 2005 Sep;6(5):547-9. doi: 10.1097/01.pcc.0000175990.72753.97.
PubMed 16148815Noone C, Menzies IS, Banatvala JE, Scopes JW. Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Eur J Clin Invest. 1986 Jun;16(3):217-25. doi: 10.1111/j.1365-2362.1986.tb01332.x.
PubMed 3089818van Elburg RM, Fetter WP, Bunkers CM, Heymans HS. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed. 2003 Jan;88(1):F52-5. doi: 10.1136/fn.88.1.f52.
PubMed 12496227Catassi C, Bonucci A, Coppa GV, Carlucci A, Giorgi PL. Intestinal permeability changes during the first month: effect of natural versus artificial feeding. J Pediatr Gastroenterol Nutr. 1995 Nov;21(4):383-6. doi: 10.1097/00005176-199511000-00003.
PubMed 8583288Roskes L, Chamzas A, Ma B, Medina AE, Gopalakrishnan M, Viscardi RM, Sundararajan S. Early human milk feeding: Relationship to intestinal barrier maturation and postnatal growth. Pediatr Res. 2025 May;97(6):2065-2073. doi: 10.1038/s41390-024-03622-5. Epub 2024 Oct 14.
PubMed 39397156Mahdally SM, Izquierdo M, Viscardi RM, Magder LS, Crowley HM, Bafford AC, Drachenberg CB, Farfan MJ, Fasano A, Sztein MB, Salerno-Goncalves R. Secretory-IgA binding to intestinal microbiota attenuates inflammatory reactions as the intestinal barrier of preterm infants matures. Clin Exp Immunol. 2023 Oct 13;213(3):339-356. doi: 10.1093/cei/uxad042.
PubMed 37070830
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Gut Permeability in Very Low Birth Weight Infants
- ClinicalTrials.gov ID
- NCT01756040
- Acronym / sponsor ID
- IPPI / HP-00049647
- Conditions
- Prematurity, Intestinal Permeability
- Keywords
- intestinal permeability, preterm infants, dual sugar test, intestinal microbiota
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 211 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Study start
- 1 Feb 2013 (actual)
- Primary completion
- 31 Aug 2021 (actual)
- Study completion
- 31 Aug 2021 (actual)
- First posted
- 24 Dec 2012 (estimated)
- Results
- Posted 18 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency characterized by increased intestinal permeability, affects approximately 7 to 10% of infants <1500 g birthweight, and typically occurs within 7 to 14 days of birth. Mortality is as high as 30-50%. Prematurity is the greatest risk factor for the development of NEC due to the physiological immaturity of the gastrointestinal tract and altered or abnormal gut microbiota. Several studies have demonstrated that the initiation of an intense systemic and local inflammatory cascade leads to intestinal necrosis. The human intestine is lined by a single layer of cells exquisitely responsive to multiple stimuli and is populated by a complex climax community of microbial partners. Under normal circumstances, these intestinal cells form a tight but selective barrier to "friends and foes": microbes and most environmental substances are held at bay, but nutrients are absorbed efficiently. Epithelial barrier integrity is itself dynamic and matures over time starting soon after birth, though the mechanisms regulating dynamic permeability are poorly understood. Low birth weight, prematurity, and early postnatal age are associated with a leaky gut. Although intestinal permeability is higher at birth in preterm than term infants, there is usually rapid maturation of the intestinal barrier over the first few days of life in both populations. The investigators hypothesize that increased levels of measures of intestinal permeability (urine lactulose/rhamnose (LA/Rh), and fecal alpha1- antitrypsin will identify infants at high risk for NEC and that intestinal probiotic strains will be associated with intestinal barrier maturation. The purpose of the study is to determine whether clinical factors in combination with non-invasive stool test such as antitrypsin (A1AT) and microbiota composition profile are associated with intestinal permeability determined by excretion of non-metabolized sugar probes in urine (LA/Rh ratio). These studies may lead to a non-invasive screening test to identify preterm infants at risk for NEC.
Detailed description
The proposed study will evaluate the intestinal permeability measured by the urinary La/Rh ratio at one timepoint between d7-10 of life in 200 preterm infants 24-32 weeks gestation in preparation for a future study of probiotics to improve intestinal permeability in this population.
Primary Objective: To estimate mean and variance in IP measured by urinary Lactulose/Rhamnose ratio at 7-10d of life in neonates born between 24 and 32 weeks of gestational age.
Secondary Objectives
- To assess stool microbiome characteristics in association with intestinal permeability in preterm infants measured by the urinary lactulose/rhamnose ratio.
Study design
- Primary purpose
- Screening
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Lactulose - rhamnose solution | Other | Drug: Lactulose -rhamnose solutionPreterm Infants age 24-32 weeks gestation |
Who may qualify
- Ages
- Up to 4 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- <5 days
- Gestational age 24-32 weeks
Key exclusion criteria (9 listed)
- Nonviable or planned withdrawal of care
- Significant GI dysfunction (e.g. heme-positive stools, abdominal distension (girth >2 cm baseline), or bilious emesis/aspirates.
- Triplet or higher order multiple
- Severe asphyxia
- Lethal chromosome abnormalities
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 |
|---|---|---|
| Lactulose -rhamnose solutionAlso: dual sugar solutionMeasurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue | Drug | Lactulose - rhamnose solution |
Primary outcome
Intestinal Permeability
Time frame: 7-10 days postnatal
Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)
3 secondary outcomes
Stool Alpha-1 Antitrypsin
Time frame: 7-10 days postnatal
Stool Microbiota Relative Abundance
Time frame: 7-10 days postnatal
Breastmilk Feeding Duration Prior to La/Rh Measurement
Time frame: 7-10 days postnatal
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18832585Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008 Nov;173(5):1243-52. doi: 10.2353/ajpath.2008.080192. Epub 2008 Oct 2.
- Background: PubMed 8125384Bjarnason I. Intestinal permeability. Gut. 1994 Jan;35(1 Suppl):S18-22. doi: 10.1136/gut.35.1_suppl.s18.
- Background: PubMed 22888267van Wijck K, Bessems BA, van Eijk HM, Buurman WA, Dejong CH, Lenaerts K. Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose? Clin Exp Gastroenterol. 2012;5:139-50. doi: 10.2147/CEG.S31799. Epub 2012 Jul 19.
- Background: PubMed 22892368van Wijck K, Verlinden TJ, van Eijk HM, Dekker J, Buurman WA, Dejong CH, Lenaerts K. Novel multi-sugar assay for site-specific gastrointestinal permeability analysis: a randomized controlled crossover trial. Clin Nutr. 2013 Apr;32(2):245-51. doi: 10.1016/j.clnu.2012.06.014. Epub 2012 Aug 11.
- Background: PubMed 7065710Beach RC, Menzies IS, Clayden GS, Scopes JW. Gastrointestinal permeability changes in the preterm neonate. Arch Dis Child. 1982 Feb;57(2):141-5. doi: 10.1136/adc.57.2.141.
- Background: PubMed 11283883Piena-Spoel M, Albers MJ, ten Kate J, Tibboel D. Intestinal permeability in newborns with necrotizing enterocolitis and controls: Does the sugar absorption test provide guidelines for the time to (re-)introduce enteral nutrition? J Pediatr Surg. 2001 Apr;36(4):587-92. doi: 10.1053/jpsu.2001.22288.
- Background: PubMed 11756641Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blanco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res. 2002 Jan;51(1):64-70. doi: 10.1203/00006450-200201000-00012.
- Background: PubMed 15798461Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, Huijmans JG, Tibboel D. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Ann Surg. 2005 Apr;241(4):599-606. doi: 10.1097/01.sla.0000157270.24991.71.
- Background: PubMed 9473094Piena M, Albers MJ, Van Haard PM, Gischler S, Tibboel D. Introduction of enteral feeding in neonates on extracorporeal membrane oxygenation after evaluation of intestinal permeability changes. J Pediatr Surg. 1998 Jan;33(1):30-4. doi: 10.1016/s0022-3468(98)90355-4.
- Background: PubMed 16148815Malagon I, Onkenhout W, Klok M, van der Poel PF, Bovill JG, Hazekamp MG. Gut permeability in neonates after a stage 1 Norwood procedure. Pediatr Crit Care Med. 2005 Sep;6(5):547-9. doi: 10.1097/01.pcc.0000175990.72753.97.
- Background: PubMed 3089818Noone C, Menzies IS, Banatvala JE, Scopes JW. Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Eur J Clin Invest. 1986 Jun;16(3):217-25. doi: 10.1111/j.1365-2362.1986.tb01332.x.
- Background: PubMed 12496227van Elburg RM, Fetter WP, Bunkers CM, Heymans HS. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed. 2003 Jan;88(1):F52-5. doi: 10.1136/fn.88.1.f52.
- Individual participant dataSharing planned: No
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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.
Alessio Fasano, MD principal investigator
Massachusetts General Hospital
Rose M Viscardi, MD principal investigator
University of Maryland
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lactulose -rhamnose solution in people with Prematurity and Intestinal Permeability, run by University of Maryland, Baltimore at 1 site in United States.
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 2 inclusion and 9 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 18 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 18 Nov 2023). 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?
Intestinal Permeability (time frame: 7-10 days postnatal). 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 NCT01756040, which also lists 16 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 18 Nov 2023.