Condition category
Digestive System
Date applied
09/03/2018
Date assigned
13/04/2018
Last edited
15/07/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Recent medical discoveries have found that intestinal levels of Bifidobacterium infantis (B. infantis) help to develop a healthy gut in infants and protects against harmful bacteria. Data from around the world point to B. infantis as universally associated with newborn babies, and that this bacteria is naturally introduced to babies who are born vaginally and breastfed. The growth of protective Bifidobacterium strains within the intestine of the breastfed infant is supported by components in breast milk called human milk oligosaccharides (HMO). These HMO feed the bifidobacteria that in turn protect and guide the intestinal health of the developing infant. However, the ever-growing number of deliveries by Caesarean section is resulting in babies with very low levels of intestinal B. infantis. Our goal is to investigate whether short term daily probiotic supplementation (B. infantis) in breastfed babies delivered by Caesarean section promotes a healthy infant faecal microbiome profile that can be maintained by breastfeeding until weaning at 6 months.

Who can participate?
Pregnant women over the age of 18 who are planning to have a Caesarean section birth in addition to breastfeeding their baby for at least 6 months.

What does the study involve?
Approximately 70 women will be recruited to provide vaginal and rectal swabs for baseline assessment of the maternal microbiome before Caesarean section. At postnatal Day 7-9, infants that are eligible to continue in the study (i.e. breastfed and not exposed to antibiotics for > 3 days) will be randomly allocated to receive either a daily supplement of B. infantis or a dummy treatment of lactose in breast milk for 28 days. All women will be contacted regularly by a research midwife trained in lactation support. Infant faecal samples/swabs and mother's breast milk will be collected at regular intervals during the study until 6 months of age. There will be up to three follow-up visits until 2 years of age. The infant gut microbiome, and other indicators of gut health, will be analysed along with components of the mother’s breast milk.
Mothers will complete questionnaires and infant health logs throughout the course of the study.

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).

What are the possible benefits and risks of participating?
There are no known side-effects to the supplement or placebo. Filling surveys and collecting samples may be time consuming for new mothers. All women will receive regular extra support (e.g. by telephone and hospital or home visit) from a breastfeeding specialist midwife to help establish breastfeeding.

Added 01/08/2019: There are risks associated with infant heel sticks and drawing blood from a vein, which include bruising and short-term pain or soreness, although these are generally considered to be mild and/or rare.

Where is the study run from?
The PROMESA study is taking place at St. Thomas' Hospital.

When is the study starting and how long is it expected to run for?
February 2017 to June 2022 (updated 01/08/2019, previously: October 2020)

Who is funding the study?
Evolve BioSystems, Inc. (US)

Who is the main contact?
1. Dr. Rachel Tribe
Reader in Women and Children's Health at King's College London
rachel.tribe@kcl.ac.uk
2. Robin Flannery
Director, Clinical Development and Operations at Evolve BioSystems, Inc.
rflannery@evolvebiosystems.com

Trial website

Contact information

Type

Public

Primary contact

Dr Annette Briley

ORCID ID

Contact details

Department of Women and Children's Health
King's College
London
Women's Health Academic Centre KHP
10th Floor North Wing
St Thomas' Hospital
LONDON
SE1 7EH
United Kingdom

Type

Scientific

Additional contact

Dr Rachel Tribe

ORCID ID

Contact details

Department of Women and Children's Health
King's College
London
Women's Health Academic Centre KHP
10th Floor North Wing
St Thomas' Hospital
LONDON
SE1 7EH
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

IRAS# 221152

Study information

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?

Acronym

PROMESA

Study hypothesis

The principal question is whether short term daily probiotic supplementation in breastfed infants delivered by Caesarean section promotes a healthy infant faecal microbiome profile that can be maintained by breastfeeding until weaning at 6 months.

Added 15/07/2020:
The principal question for the extension study is whether promoting a healthy gut by supplementing breastfed infants delivered by Caesarean section with B. infantis for 3 months will improve the development of the infant immune system and prevent a proinflammatory phenotype at 3 months of age.

Ethics approval

London - Camberwell St Giles Research Ethics Committee,10/01/2018, ref:17/LO/0641

Added 15/07/2020:
Extension approved 09/06/2020

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

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Other

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Infant gut microbiome

Intervention

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 extension study of approximately 52 additional recruits to evaluate the development and function of the immune system in infant participants. The extension study will not be randomized or placebo-controlled. Patients at a ‘probiotic’ site (St. Thomas’ Hospital) will receive a daily supplement of B. infantis in breast milk for approximately 90 days and patients at a ‘control’ site (Chelsea and Westminster Hospital) will receive no probiotic nor placebo. Participants who agree to take part in the extension study will provide an additional infant blood sample at 1 month (Day 28-34) of life. Participants will collect infant stool samples at only three timepoints (Baseline, Month 1 and Month 3). Infants will not be followed for 2 years, their study involvement will end at the time of the 3 month blood draw. The study will not be randomized, the control group will not receive a placebo and will be enrolled at a hospital separate to the probiotic cohort.

Intervention type

Supplement

Phase

Drug names

Primary outcome measure

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 measures

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

Overall trial start date

01/02/2017

Overall trial end date

01/06/2022

Reason abandoned (if study stopped)

Eligibility

Participant 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)

Participant type

Healthy volunteer

Age group

Mixed

Gender

Both

Target number of participants

105

Participant 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
4. Mothers who experienced medical complications that would preclude them from breastfeeding
5. Infants who had exposure to maternal vaginal microbiome via oral swab

Recruitment start date

09/02/2018

Recruitment end date

06/01/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

King's College London/Guy's and St. Thomas' NHS Foundation Trust
London
SE1 7EH
United Kingdom

Sponsor information

Organisation

Evolve BioSystems, Inc.

Sponsor details

2121 2nd Street
Suite B107
Davis
CA
95618
United States of America

Sponsor type

Industry

Website

Funders

Funder type

Not defined

Funder name

Evolve BioSystems, Inc.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

planned publication in a high-impact peer reviewed journal

Intention to publish date

30/01/2020

Participant level data

Not expected to be available

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

15/07/2020: The following changes were made to the trial record to describe an extension to the study: 1. The study hypothesis was updated. 2. The ethics approval was added. 3. The study design was updated. 4. The interventions were updated. 5. The primary outcome measure was updated. 6. The secondary outcome measures were updated. 7. The inclusion criteria were updated. 01/08/2019: The following changes were made to the trial record: 1. The protocol has been uploaded as an additional file (ISRCTN11690200_PROTOCOL_16Jan2019) 2. The overall end date was changed from 01/12/2021 to 01/06/2022. 3. The interventions were changed. 4. The recruitment end date was changed from 01/10/2019 to 06/01/2020. 5. The primary outcome measure was changed. 6. The secondary outcome measures were changed. 7. The target number of participants was changed from 70 to 105. 8. The participant exclusion criteria were changed. 9. The plain English summary was updated to reflect these changes. 30/07/2019: Internal review. 29/11/2018: The following changes were made: 1. The recruitment end date was changed from 1/10/2018 to 01/10/2019. 2. The overall trial end date was changed from 01/10/2020 to 01/12/2021.