## Protocol Section
### Identification Module
**NCT ID:** NCT06422988

**Brief Title:** Do Probiotics Reduce The Risk Of Severe Necrotising Enterocolitis (NEC) In Infants Born Before 32 Weeks Gestation?

**Official Title:** Do Probiotics Reduce The Risk Of Severe Necrotising Enterocolitis (NEC) In Infants Born Before 32 Weeks Gestation? An Observational Study Using Routinely Collected Data.

#### Organization Study ID Info
**ID:** IRAS323099
#### Organization
**Class:** OTHER
**Full Name:** Imperial College London
### Status Module
#### Completion Date
**Date:** 2024-12-30

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-21

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-18

**Overall Status:** ENROLLING_BY_INVITATION

#### Primary Completion Date
**Date:** 2024-07-30

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-30

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-21
**Type:** ACTUAL
**Study First Submit Date:** 2024-04-24
**Study First Submit QC Date:** 2024-05-18
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** University of Nottingham

**Class:** OTHER

**Name:** Newcastle University

**Class:** OTHER

**Name:** Queen Mary University of London

#### Lead Sponsor

**Class:** OTHER

**Name:** Imperial College London

#### Responsible Party

**Investigator Affiliation:** Imperial College London

**Investigator Full Name:** Cheryl Battersby

**Investigator Title:** Clinical Senior Lecturer

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Necrotising enterocolitis (NEC) is one of the leading causes of mortality and morbidity in very preterm infants. This study aims to determine whether NEC rates are different between infants who receive probiotics versus infants who do not receive probiotics. The study has a retrospective cohort design and will utilise routinely collected data from the UK National Neonatal Research Database (NNRD). The cohort will comprise all infants born before 32 weeks gestation and cared for in neonatal units in England and Wales between 2016 and 2022. A propensity score matched approach will be used to conduct two comparisons: i) the risk of necrotising enterocolitis (NEC) between who do and those who do not receive probiotics in the first 14 days of life ii) the risk of NEC between babies who receive the two most common probiotic products used in UK units, (Labinic and Proprems).

### Conditions Module

**Conditions:**

- Enterocolitis, Necrotizing

**Keywords:**

- Probiotics

### Design Module

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** RETROSPECTIVE

#### Enrollment Info

**Count:** 48000

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Receipt of any probiotic in the first 14 days of life. Probiotics to include: Labinic, Proprems probiotic, Acidophillus, Bifidobacterium, Bio-kult, Infloran, LB2.

To address potential recording error, infants whose NNRD records show minimal (one day) of probiotic exposure will only be classed as exposed if they are cared for in a probiotic unit. Probiotic units are defined as:

* units who have confirmed that a guideline was in place to provide probiotics to infants born before 32 weeks gestation and that the guideline was in place at any point in the year that the infant was born OR
* units where more than 50% of the infants eligible to be part of the cohort received probiotics in the six months after the infant was born.

**Intervention Names:**

- Dietary Supplement: Probiotics

**Label:** Exposed to probiotics

#### Arm Group 2

**Description:** Did not receive any probiotic in the first 14 days of life.

**Intervention Names:**

- Dietary Supplement: Probiotics

**Label:** No probiotic exposure

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Exposed to probiotics

- No probiotic exposure

**Description:** Any exposure to probiotics in first 14 days of life

**Name:** Probiotics

**Other Names:**

- Labinic

- Proprems

- Acidophillus

- Bifidobacterium

- Bio-kult

- Infloran

- LB2

**Type:** DIETARY_SUPPLEMENT

### Outcomes Module

#### Primary Outcomes

**Description:** NEC confirmed at surgery or postmortem or listed as a cause of death

**Measure:** Severe necrotising enterocolitis (NEC)

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

#### Secondary Outcomes

**Description:** NEC diagnosed at postmortem or NEC diagnosed during surgery or NEC diagnosed using clinical and radiographic features (where the infant has at least one clinical feature (bilious gastric aspirate or emesis, abdominal distension, occult, gross blood in stool) and at least one radiographic feature (pneumatosis, hepato-biliary gas, pneumoperitoneum)).

**Measure:** Necrotising enterocolitis (NNAP definition)

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Infants who had a recorded diagnosis of necrotising enterocolitis and received at least 5 consecutive days of antibiotics whilst also nil by mouth

**Measure:** Pragmatically defined NEC

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** HQIP NNAP case definition

**Measure:** Late onset sepsis

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Growth of any organisms that appear in the NNAP lists of "Clearly pathogenic organisms" and "Other organisms"

**Measure:** Pragmatically defined late onset sepsis

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Measure:** Survival to discharge home

**Time Frame:** On date of discharge from final neonatal unit, assessed up to 24 months

**Description:** LOS is defined according to the Healthcare Quality Improvement Partnership (HQIP) National Neonatal Audit Programme (NNAP) case definition i.e. blood stream or cerebrospinal fluid confirmed pure growth in culture after first three days of life

**Measure:** Survival without severe NEC or late onset sepsis (LOS)

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** NEC is defined as per the NNAP definition

**Measure:** Survival without any NEC

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Either left or right grade 3 or higher intra-ventricular haemorrhage or cystic periventricular leukomalacia

**Measure:** Brain injury

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Defined as cryotherapy, laser therapy or injection of anti-vascular endothelial growth factor therapy for ROP in either or both eyes

**Measure:** Treated retinopathy of prematurity

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Measure:** Stage of retinopathy of prematurity

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Defined as any respiratory or ventilatory support or supplemental oxygen at 36 weeks postmenstrual age

**Measure:** Bronchopulmonary dysplasia

**Time Frame:** 36 weeks postmenstrual age

**Description:** Defined as ventilation via endotracheal tube or trachestomy, and excluding non-invasive support or CPAP, at 36 weeks postmenstrual age

**Measure:** Severe bronchopulmonary dysplasia

**Time Frame:** 36 weeks postmenstrual age

**Description:** Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants

**Measure:** Length of stay

**Time Frame:** From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

**Description:** Defined as the number of days until an infant is recorded as not requiring any parenteral nutrition or fluid (i.e. no parenteral nutrition or intravenous dextrose)

**Measure:** Time to full feeds

**Time Frame:** Before discharge from final neonatal unit

**Description:** Weight for post-menstrual age standard deviation score

**Measure:** Growth

**Time Frame:** 36 weeks corrected gestational age

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Eligible infants must have been born at less than 32 weeks gestation and be cared for in a English or Welsh unit which contributes data to the National Neonatal Research Database (this includes all NHS neonatal units in England and Wales).
* Infants born in the period January 1st, 2016, to December 31st, 2022 (7 years) will be included.

Exclusion Criteria:

* They have missing data for any of: gestational age at birth, birth weight, year of birth and date of death (for those that died).
* Their NNRD record does not include details of their first admission or begins after Day 3 of life.
* The absolute value of their recorded birthweight for gestational age z score exceeds 4 or is missing.
* They die in the first two postnatal days of life.
* They have a major congenital abnormality

**Maximum Age:** 32 Weeks

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- CHILD

**Study Population:** Infants born very preterm i.e. before 32 weeks gestation

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** London

**Country:** United Kingdom

**Facility:** Imperial College

**Zip:** SW10 9NH

### IPD Sharing Statement Module

**Description:** Study protocol available now. Analysis code will be available after publication of results.

**IPD Sharing:** UNDECIDED

## Document Section

### Large Document Module

#### Large Docs

- Date: 2024-04-12

- Filename: Prot_SAP_000.pdf

- Has ICF: False

- Has Protocol: True

- Has SAP: True

- Label: Study Protocol and Statistical Analysis Plan

- Size: 1459636

- Type Abbrev: Prot_SAP

- Upload Date: 2024-04-23T05:17

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000005759

- Term: Gastroenteritis

- ID: D000005767

- Term: Gastrointestinal Diseases

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000007410

- Term: Intestinal Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M7922

- Name: Enterocolitis

- Relevance: HIGH

- As Found: Enterocolitis

- ID: M22151

- Name: Enterocolitis, Necrotizing

- Relevance: HIGH

- As Found: Enterocolitis, Necrotizing

- ID: M8875

- Name: Gastroenteritis

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10444

- Name: Intestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4055

- Name: Necrotizing Enterocolitis

- Relevance: HIGH

- As Found: Enterocolitis, Necrotizing

### Condition Browse Module - Meshes

- ID: D000004760

- Term: Enterocolitis

- ID: D000020345

- Term: Enterocolitis, Necrotizing

### Intervention Browse Module - Browse Branches

- Abbrev: Ot

- Name: Other Dietary Supplements

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: T367

- Name: Bifidobacterium

- Relevance: HIGH

- As Found: Neonates

### Misc Info Module

- Version Holder: 2024-05-31
