Promotion of a healthy gut microbiome in elective caesarean section arrivals (PROMESA) by supplementing breastfed newborns with an infant probiotic.

• Register: ISRCTN
• Last refreshed on: 24 October 2022
• Main ID: ISRCTN11690200
• Date of registration: 13/04/2018
• Prospective Registration: No
• Primary sponsor: Evolve BioSystems, Inc.
• Public title: Promotion of a healthy gut microbiome in elective caesarean section arrivals (PROMESA) by supplementing breastfed newborns with an infant probiotic.
• Scientific title: PROMESA: Promotion of a healthy gut microbiome in elective caesarean section arrivals. Can exclusive breastfeeding supplemented with a probiotic promote a sustained healthy gut microbiota in babies born by caesarean section?
• Date of first enrolment: 09/02/2018
• Target sample size: 105
• Recruitment status: Ongoing
• URL: https://www.isrctn.com/ISRCTN11690200
• Study type: Interventional
• Study design: PROMESA is an interventional single-centre randomized double-blinded placebo-controlled trial of a dietary (probiotic) supplement added to breast milk for the enhancement of the normal neonatal gut microbiome in term babies delivered by Caesarean section. Added 15/07/2020: The extension study will be a multi-centre non-randomized study (Other)
• Phase: Not Applicable

Countries of recruitment

England, United Kingdom

Contacts

• Name: Rachel Tribe

• Name: Annette Briley

Key inclusion & exclusion criteria

Inclusion criteria:
Current inclusion criteria as of 17/12/2020:

1. Singleton pregnancies (primip or multi)
2. Pregnant women age 18 and above
3. Elective Caesarean section =37 weeks gestation
4. Maternal pre-pregnancy BMI < 35kg/m²
5. Intention to exclusively breastfeed for at least 35 days, preferably for 6 months
6. Non-smoker (gave up prior to pregnancy)
7. Intention to exclusively breastfeed for at least 3 months
8. Non-smoker (never smoked or gave up prior to enrolment)

_____

Previous inclusion criteria:

1. Singleton pregnancies (primip or multi)
2. Pregnant women age 18 and above
3. Elective Caesarean section =37 weeks gestation
4. Maternal pre-pregnancy BMI < 35kg/m²
5. Resident in UK for 3 years or more
6. Intention to exclusively breastfeed for at least 35 days, preferably for 6 months
7. Non-smoker (gave up prior to pregnancy)

Added 15/07/2020:
8. Willingness to vaccinate infant with BCG vaccine no later than Day 4
9. Intention to exclusively breastfeed for at least 3 months
10. Non-smoker (never smoked or gave up prior to enrolment)

Exclusion criteria:
Current exclusion criteria as of 17/12/2020:

At antenatal screening
1. Multiple pregnancy
2. Vaginal deliveries
3. Fetus has a known medical condition that would preclude breastfeeding or alter gut microbiota
4. Maternal breast surgery or injury within the past 5 years that would reduce the likelihood of successful exclusive breastfeeding (not exclusionary if mother can evidence successful breastfeeding of a previous infant after the surgery or injury)
5. Plan to administer non-study probiotics to infant any time throughout the study
6. Plan to apply maternal vaginal swab to infant’s mouth
7. Maternal infection with HIV or Hepatitis C or experiencing symptoms of COVID-19
8. Maternal smoking (current)
9. Maternal medication use that may alter infant’s gut microbiotia (e.g. daily antibiotics)

At Day 7 postnatal screen, pre-randomization:
1. Infants who have taken antibiotics for more than 3 days
2. Intake of formula within 24 hours of the Postnatal Eligibility Screen
3. Infants born with medical complications such as: respiratory distress syndrome, birth defects, and infection
4. Mothers who experienced medical complications that would preclude them from breastfeeding
5. Infants who had exposure to maternal vaginal microbiome via oral swab
6. Infants who have received the BCG vaccine
7. Infants whose caregivers intend to vaccinate their infant with the BCG vaccine prior to 3 months of life
8. Infants with known exposure to an individual testing positive for, or experiencing symptoms of, COVID-19

_____

Previous exclusion criteria:

At antenatal screening
1. Multiple pregnancy
2. Recent arrival in UK (< 3 years)
3. Vaginal deliveries
4. Mothers with another child < 14 months of age at recruitment
5. Fetus has a known medical condition that would preclude breastfeeding or alter gut microbiota
6. Maternal breast surgery or injury within the past 5 years that would reduce the likelihood of successful exclusive breastfeeding (not exclusionary if mother can evidence successful breastfeeding of a previous infant after the surgery or injury)
7. Plan to administer non-study probiotics to infant any time throughout the study
8. Plan to apply maternal vaginal swab to infant’s mouth
9. Maternal infection with HIV or Hepatitis C
10. Maternal type 1 or type 2 diabetes (gestational diabetes is not exclusionary)
11. Maternal pre-eclampsia
12. Smoking this pregnancy
13. Plan to leave UK in < 6 months (added 01/08/2019)
14. Maternal medication use that may alter infant’s gut microbiotia (e.g. daily antibiotics) (added 01/08/2019)

At Day 7 postnatal screen, pre-randomization:
1. Infants who have taken antibiotics for more than 3 days
2. Intake of formula within 24 hours of the Day 7-9 visit
3. Infants born with medical complications such as: respiratory distress syndrome, birth defects, and infection


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Infant gut microbiome
Digestive System

Intervention(s)

Approximately 70 women will be recruited to provide vaginal and rectal swabs for baseline assessment of the maternal microbiome prior to Caesarean section. Newborn infants will be randomised to receive either a daily probiotic supplement (Bifidobacterium longum subsp. infantis EVC001 - 8x10^9 CFU) or placebo mixed with breast milk for 28 days. Infant faecal samples and mother's breast milk will be collected at regular intervals during the study until 6 months of age. Additional infant stool samples will be collected at 12,18 and 24 months. Randomisation will be carried out online via the MedSciNet web portal (www.medscinet.com) and linked to the participant’s initial Subject ID. Allocation will be stored remotely from the main study database, so that members of the study team remain blinded to probiotic/placebo allocation. Recruitment and trial coordinators will not have access to the randomisation sequence. Subjects will be randomized at a 1:1 ratio of intervention to placebo. Minimisation will be based on parity and maternal pre-pregnancy BMI >30.

Added 01/08/2019:
A protocol amendment was made to include a continuation study of 30-40 additional recruits to evaluate immune and inflammation markers in infant participants. Participants who agree to take part in the continuation study will not provide maternal vaginal, rectal, or breast milk samples, but will instead provide a cord blood sample and 2 infant blood samples, one on Day 0-4 of life and another at 3 months (Day 84-104). Randomisation and minimisation will be conducted in the same manner as the original protocol for the same probiotic/placebo interventions.

Added 15/07/2020:
A protocol amendment was made to include an extensi

Primary Outcome(s)

1.The change in infant faecal microbiota before, during and after probiotic or placebo supplementation by shotgun sequencing or next generation sequencing (NGS, e.g. Illumina MISeq or HiSeq)

Added 01/08/2019:
2. Continuation study: The change in levels of immune cells and markers from baseline (Day 0 – Day 4) to 3 months (Day 84 – Day 104)

Added 15/07/2020:
3. Extension study: The change in infant faecal B. infantis colonization levels from baseline during B. infantis supplementation as measured by quantitative PCR

Secondary Outcome(s)

1.Biochemistry of infant stools by assessing pH levels, HMO and short-chain fatty acids using liquid chromatography-mass spectrometry may be performed on samples collected at Baseline (Day 4-7), 1 month, 3 months, 6 months, 12 months, 18 months and 24 months.
2. Comparison of the composition of the maternal and infant microbiome at baseline using shotgun sequencing or next generation sequencing.
3.Adverse events will be recorded on daily and weekly adverse event logs, as well as infant health surveys, for the duration of the study. Medical records will be reviewed as needed for confirmation.

Added 01/08/2019:
4. Continuation study: The correlation between gut microbiota composition and abundance and levels of immune cells and markers
5. Continuation study: The differences between B. infantis and placebo supplementation on levels of immune cells and markers
6. Continuation study: The differences between B. infantis and placebo supplementation on vaccine response (antibody titres)

Added 15/07/2020:
7. Extension study: The differences between probiotic and control infants with respect to:
7.1. The infant faecal microbiome composition as measured by shotgun metagenomics, and
7.2. Levels of enteric inflammation as measured by inflammatory cytokines in infant stool.
Exploratory Endpoints for the Extension Study Include:
• The differences between treatment and control infants with respect to: Immune and inflammatory responses as measured by calprotectin, lipocalin-2, and soluble faecal IgA and IgG in infant stool
• Immune-sensing of the microbiome as measured by IgA-seq in infant stool
• Stool metabolomics
• The development of immune cell populations in whole blood by mass cytometry
• Plasma proteins by immunoassays
• Transcriptional analysis in whole blood by RNA-Seq
• Plasma metabolomics
• Functional analysis of Peripheral Blood Mononuclear Cells (PBMCs, blood immune cells)
• Transcriptomics of PBMCs and stool

Secondary ID(s)

IRAS# 221152

Source(s) of Monetary Support

Evolve BioSystems, Inc.

Ethics review

Status:
Approval date:
Contact:

London - Camberwell St Giles Research Ethics Committee,10/01/2018, ref:17/LO/0641 Added 15/07/2020: Extension approved 09/06/2020 Added 17/12/2020: Amendment approved 19/11/2020

Results

• Results available: Yes
• Date Completed: 20/12/2022