Clinical trial NCT06048614: Saline Enema Administration in Meconium Obstruction of Prematurity and Impact on the Resolution, Feeds, Microbiome, and Gut-brain Axis.
Official title: The Administration of Saline Enema Versus Glycerin Suppository as a Treatment Intervention for Meconium Obstruction of Prematurity (MOP) and to Study the Impact on the Resolution of MOP, Time to Reach Full Enteral Feeds, Gut Microbiome, and Gut-brain Axis, a Randomised Control Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Meconium Obstruction of Prematurity
Lead sponsor: KK Women's and Children's Hospital
Sponsor class: OTHER_GOV
Collaborators: name: Singapore General Hospital
name: Genome Institute of Singapore
name: Translational Immunology Institute
name: Duke-NUS Graduate Medical School
First posted: 2023-09-21
Enrollment: 95
Sex: ALL
Minimum age (years): 1
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The treatment group will receive SE with normal saline (20-40 ml/kg/per SE) 2 times a day at 48 to 72 hrs of age at the earliest. The infant with medical instability procedure will be deferred until the infant is medically fit and intervention is continued until the infant reaches full feeds, defined as 110 ml/kg/day or yellow stools whichever is earlier. SE will be recommenced if the infant does not open bowel for 2 days before reaching full feeds. In ≤ 750 grams infant, paediatric surgeons would perform the first catheterisation with 6F catheter, insertion length will be limited to 8 cm, and saline is infused with the aid of gravity. Syringe flushing is allowed if gravity force fail to drive saline to the intestine.Two ultrasound abdominal examination will be performed and first scan will coincide with first SE in 500-750 grams infants.Failure to resolve the MOP with SE will be designated as treatment failure and managed with contrast enema or Laparotomy by paediatric surgeons.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to study the effect of twice-daily saline enema (SE) in the treatment obstruction of prematurity (MOP) in infants with the birth weight ≤1.25kg. The main questions, the trial aims to answer are

1. To validate the finding of our pilot study which had shown that twice-daily SE reduces the time to reach full enteral feeds in premature infant as compared to premature infant treated with Glycerine Suppository (GS), in a larger cohort. Infant with MOP fails to pass meconium in the first 48 hours of life and develop symptoms and signs like abdominal distension and feed intolerance.
2. The other aims of this study are to test whether the intervention is

   1. Effective treatment for MOP
   2. Reduce the duration of ICU stay
   3. Reduce the rate of necrotizing enterocolitis, sepsis, Total Parenteral Nutrition (TPN) days and number of intravenous catheter days
3. The study also wants to explore the impact of this intervention on the gut microbiome, gut-brain interaction and immune response of the new-born.

Detailed description: Very low birth weight infants (VLBW ≤ 1.5 kg) constitute more than 60% of bed occupancy in level III neonatal units. They face the risk of 10-50% long-term disability, and their initial healthcare cost ranges from S$50,000 to 1 million, an important healthcare issue.

The incidence of meconium obstruction of prematurity (MOP) is 20-30% in extremely low birth weight (ELBW ≤ 1 kg) infants. The intervention based on the current standard of care increase the risk of laparotomy necrotizing enterocolitis, intestinal perforation, and neurodevelopmental risks posed by general anaesthesia. Our published pilot RCT demonstrated that saline enema (SE) is an effective, feasible, and safe intervention to reduce the time to reach full enteral feeds and is a potentially effective treatment for MOP in ELBW (\< 1 kg) infants.

Our primary hypothesis is that Infants with Twice-daily high-volume SE (20-40 ml/kg/day) intervention will result in reduced time to reach full enteral feeds compared to infants treated with conventional management with Glycerin suppository (GS) in (≤1.25kg) infants with MOP. Our exploratory hypothesis is that SE will have a protective effect on the gut microbiome, inflammatory and immune response in preterm infants.

Ninety-five infants born over three years in KK Hospital (KKH) and Singapore General Hospital (SGH) will be enrolled and randomized at 48 hours or later to receive SE or GS. The standardized protocol will be used for the accreditation and administration of SE. Primary, secondary, and exploratory outcomes data, including treatment failure data, will be recorded. Infants will be followed up to 36 weeks of gestation or discharge, whichever is earlier. Maternal and infant characteristics, inflammatory and immune response, and safety outcome data will be collected.

If the findings of our pilot trial are confirmed, the protocol can become the standard of care in preterm infants with MOP. Additionally, significant healthcare cost savings will be realized alongside an improved understanding of the Microbiome, immune and inflammatory response pertaining to the gut.

Eligibility criteria: Inclusion Criteria:

* Criteria A: For infant presenting with early onset of MOP

  1. Birth weight 500 - 1250 gram
  2. ≥ 23 weeks gestation
  3. No BO for 48 hours
  4. BO present but with a small amount or stain of meconium
  5. Feeds intolerance or abdominal X-ray showing dilated loops of bowel
* Criteria B: For infant presenting with Late onset of MOP

  1. Birth weight 500 - 1250 gram
  2. ≥ 23 weeks gestation
  3. Infants who passed meconium initially and develop evidence of meconium obstruction at a later age (feed intolerance or vomiting and abnormal abdominal X-ray with or without abdominal distension)

Exclusion Criteria:

Infants that:

1. Neuromuscular disorder
2. Moderate or severe asphyxia
3. Inability to start enteral feeding, which continued for 3 consecutive days before 2 weeks of post-natal age for reasons unrelated to meconium inspissation or its complication
4. Without parental consent
5. Aggravated medical instability
6. Single mothers \< 21 years

Primary outcomes:
measure: Time to reach full enteral feeds in days
timeFrame: Before 36 weeks of corrected age of discharge of the infant
Secondary outcomes:
measure: Rate of treatment failure
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Rate of (a) Culture positive sepsis (b) Necrotising enterocolitis.
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Duration in days of (a) ICU stay (b) Total parenteral nutrition (c) PICC days.
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Overall cost of care calculated in SGD at the time of discharge
timeFrame: Before 36 weeks of corrected age of discharge of the infant
Other outcomes:
measure: Identification and quantification of bacteria from meconium/stool samples by DNA sequencing and analysis of top 50 bacteria Genus
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: To measure the serum level of IL 6 in pg/ml
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: To measure the serum level of neurotransmitters noradrenaline in pg/L
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure serum levels of dopamine in arbitrary units (peak area of analyte divided by peak area of an internal standard)
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure serum levels of serotonin in arbitrary units (peak area of analyte divided by peak area of an internal standard)
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure serum levels of GABA in arbitrary units (peak area of analyte divided by peak area of an internal standard)
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure level of Propionate in µM
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure level of Butyrate in µM
timeFrame: Before 36 weeks of corrected age of discharge of the infant
measure: Measure level of Acetate in µM
timeFrame: Before 36 weeks of corrected age of discharge of the infant
Locations:
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children Hospital
Study officials:
affiliation: Singhealth Duke-NUS Medical School, NUS and LKC Medical School
name: Thowfique Ibrahim, FRCPCH, FAMS
role: PRINCIPAL_INVESTIGATOR
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