Trial Outcomes & Findings for Intestinal Permeability in Preterm Infants (NCT NCT01756040)

NCT ID: NCT01756040

Last Updated: 2023-11-18

Results Overview

Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 211 participants
• Primary outcome timeframe: 7-10 days postnatal
• Results posted on: 2023-11-18

Participant Flow

Infants born 24-32 weeks gestation were enrolled at a level IV Neonatal Intensive Care Unit at the University of Maryland Medical Center in the intestinal permeability study during 2 enrollment periods [Cohort 1(April 15, 2013-October 15, 2014) (N=44)] and [Cohort 2 (October 15, 2018-June 11, 2021) (N=167)].

Parental consent was obtained for 214 infants, but parents of three infants withdrew consent prior to receipt of the sugar probe (lactulose/rhamnose) dose. Two infants died after consent, but before receiving the sugar probe dose. Seven infants were not dosed due to feeding intolerance (N=4), spontaneous intestinal perforation (N=2), transfer/discharge prior to dosing day (N=1). The remaining 201 enrolled infants received at least 1 dose of the sugar probe.

Participant milestones

Measure	Lactulose - Rhamnose Solution Preterm Infants age 24-32 weeks gestation Lactulose -rhamnose solution: Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
IP in Preterm Infants: Cohort 1 STARTED	44
IP in Preterm Infants: Cohort 1 COMPLETED	43
IP in Preterm Infants: Cohort 1 NOT COMPLETED	1
IP in Preterm Infants: Cohort 2 STARTED	167
IP in Preterm Infants: Cohort 2 COMPLETED	158
IP in Preterm Infants: Cohort 2 NOT COMPLETED	9

Reasons for withdrawal

Measure	Lactulose - Rhamnose Solution Preterm Infants age 24-32 weeks gestation Lactulose -rhamnose solution: Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
IP in Preterm Infants: Cohort 1 Death	1
IP in Preterm Infants: Cohort 2 Death	1
IP in Preterm Infants: Cohort 2 did not receive sugar probe dose	8

Baseline Characteristics

Intestinal Permeability in Preterm Infants

Baseline characteristics by cohort

Measure	Lactulose - Rhamnose Solution n=211 Participants Preterm Infants age 24-32 weeks gestation Lactulose -rhamnose solution: Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
Age, Categorical <=18 years	211 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=93 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants
Age, Continuous	1.93 days STANDARD_DEVIATION 1.08 • n=93 Participants
Age, Customized Gestational age · Gestational age 24wk 0d-28wk6d	63 Participants n=93 Participants
Age, Customized Gestational age · Gestational age 29wk 0 d- 32 wk 6d	148 Participants n=93 Participants
Sex: Female, Male Female	100 Participants n=93 Participants
Sex: Female, Male Male	111 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	204 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	9 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	123 Participants n=93 Participants
Race (NIH/OMB) White	72 Participants n=93 Participants
Race (NIH/OMB) More than one race	2 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=93 Participants
Region of Enrollment United States	211 participants n=93 Participants
Birthweight <1000 gm BW	53 Participants n=93 Participants
Birthweight ≥1000 gm BW	158 Participants n=93 Participants

PRIMARY outcome

Timeframe: 7-10 days postnatal

Population: Study participants who had lactulose/rhamnose sugar solution administered between 7-10 days postnatal age and urine collected over 4 hours that was measured for lactulose/rhamnose concentration by HPLC.

Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)

Outcome measures

Measure	Gestational Age <29 wk n=55 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=134 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Intestinal Permeability	0.0731 ratio Standard Deviation 0.0076	0.0720 ratio Standard Deviation 0.0078

SECONDARY outcome

Timeframe: 7-10 days postnatal

Population: Infants at 7-10 days of age in the first cohort who had stool collected on the same day as urinary IP measurement that was assayed by ELISA for A1AT concentration.

Stool alpha-1 antitrypsin concentrations

Outcome measures

Measure	Gestational Age <29 wk n=6 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=7 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Stool Alpha-1 Antitrypsin	359.5 µg/ml Standard Deviation 137.0	1285.3 µg/ml Standard Deviation 802.3

SECONDARY outcome

Timeframe: 7-10 days postnatal

Population: Infants who had both urinary La/Rh ratio and stool Clostridiales abundance determined

Relative abundance (%) Clostridiales species

Outcome measures

Measure	Gestational Age <29 wk n=43 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=36 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Stool Microbiota Relative Abundance	6.52 percentage of Clostridiales in stool Interval 0.108 to 15.68	0.07 percentage of Clostridiales in stool Interval 0.003 to 0.605

SECONDARY outcome

Timeframe: 7-10 days postnatal

Number of days breast milk feeding prior to La/Rh measurement between d7-10 days of age.

Outcome measures

Measure	Gestational Age <29 wk n=76 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=50 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Breastmilk Feeding Duration Prior to La/Rh Measurement	7.02 days Standard Deviation 1.38	6.1 days Standard Deviation 1.96

OTHER_PRE_SPECIFIED outcome

Timeframe: 0-28 days postnatal

Population: Infants who had urinary La/Rh measured between 7-10 days of age (total N=189)

Frequency of ≥ Stage 2 Necrotizing enterocolitis

Outcome measures

Measure	Gestational Age <29 wk n=105 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=84 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Occurrence of Necrotizing Enterocolitis	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 7-10 days postnatal

Population: Study participants who had urinary La/Rh ratio measured on postnatal day 7-10.

Percent of participants with antibiotic exposure prior to La/Rh measurement

Outcome measures

Measure	Gestational Age <29 wk n=105 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=84 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Percent Participants Exposed to Antibiotics Prior to La/Rh Measurement	79 Participants	67 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 0-100 days postnatal

Population: Study participants who had urinary La/Rh ratio measured between 7-10 days of age.

Postnatal age when all nutrition is provided by enteral feeds

Outcome measures

Measure	Gestational Age <29 wk n=105 Participants Preterm Infants age 24wk 0 d-28 wk 6 d gestation	Gestational Age ≥29 Weeks n=84 Participants Participants with gestational age at birth 29 wk 0 d to 32 wk 6 d
Postnatal Age Full Feeds Reached	11.46 days Standard Deviation 5.04	22.02 days Standard Deviation 45.5

Adverse Events

Lactulose - Rhamnose Solution

Serious events: 22 serious events

Other events: 32 other events

Deaths: 2 deaths

Serious adverse events

Measure	Lactulose - Rhamnose Solution n=211 participants at risk Preterm Infants age 24-32 weeks gestation Lactulose -rhamnose solution: Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
Nervous system disorders Progressive hydrocephalus	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Nervous system disorders Intraventricular hemorrhage, Grade IV	0.95% 2/211 • Number of events 2 • Birth- 28 days of life. Adverse events were collected daily for participants.
Nervous system disorders Intraventricular hemorrhage, Grade III	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Respiratory, thoracic and mediastinal disorders pneumothorax	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Respiratory, thoracic and mediastinal disorders pulmonary interstitial emphysema	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Respiratory, thoracic and mediastinal disorders Worsening respiratory status	1.4% 3/211 • Number of events 3 • Birth- 28 days of life. Adverse events were collected daily for participants.
Cardiac disorders patent ductus arteriosus	1.9% 4/211 • Number of events 4 • Birth- 28 days of life. Adverse events were collected daily for participants.
Gastrointestinal disorders Spontaneous intestinal perforation	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Hepatobiliary disorders direct hyperbilirubinemia	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Infections and infestations sepsis	1.9% 4/211 • Number of events 4 • Birth- 28 days of life. Adverse events were collected daily for participants.
Infections and infestations Urinary tract infection	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Blood and lymphatic system disorders pleocytosis	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Blood and lymphatic system disorders neutropenia	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Metabolism and nutrition disorders Hypercalcemia	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.
Metabolism and nutrition disorders Hyperkalemia	0.95% 2/211 • Number of events 2 • Birth- 28 days of life. Adverse events were collected daily for participants.
Metabolism and nutrition disorders metabolic acidosis	0.95% 2/211 • Number of events 2 • Birth- 28 days of life. Adverse events were collected daily for participants.
Respiratory, thoracic and mediastinal disorders Pulmonary hemorrhage	0.47% 1/211 • Number of events 1 • Birth- 28 days of life. Adverse events were collected daily for participants.

Other adverse events

Measure	Lactulose - Rhamnose Solution n=211 participants at risk Preterm Infants age 24-32 weeks gestation Lactulose -rhamnose solution: Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue
Gastrointestinal disorders Vomiting	4.7% 10/211 • Number of events 10 • Birth- 28 days of life. Adverse events were collected daily for participants.
Blood and lymphatic system disorders low serum bicarbonate	10.9% 23/211 • Number of events 23 • Birth- 28 days of life. Adverse events were collected daily for participants.
Metabolism and nutrition disorders hyperkalemia	6.6% 14/211 • Number of events 14 • Birth- 28 days of life. Adverse events were collected daily for participants.
Metabolism and nutrition disorders Elevated BUN	5.2% 11/211 • Number of events 11 • Birth- 28 days of life. Adverse events were collected daily for participants.
Blood and lymphatic system disorders anemia	5.2% 11/211 • Number of events 11 • Birth- 28 days of life. Adverse events were collected daily for participants.

Additional Information

Rose Marie Viscardi, M.D.

University of Maryland Baltimore

Phone: 410-328-6003

Email: rviscard@som.umaryland.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place