Restoration of the Gut Microbiome After Cesarean Section (RestoreGut)

"Restoration of the Gut Microbiome After Cesarean Section (RestoreGut)" - A Double-blinded Randomized Controlled Feasibility Trial

This study aims to develop a therapy for restoring the gut microbiome in infants born via CS. We will conduct a randomized, placebo-controlled feasibility trial to assess the ability of microbiome restoration by FMT and FVT in infants born by cesarean section.

Study Overview

• Status: Not yet recruiting
• Conditions: Microbial Colonization
• Intervention / Treatment: Biological: Microbiome restoration - FMT; Biological: Microbiome restoration - FVT; Biological: Placebo; Other: Vaginal birth, untreated control

Detailed Description

When a child is born vaginally, the passage through the birth canal provides the first and very important bacterial colonization. As the child ages, various environmental exposures, such as dietary changes and the presence of older siblings in the home, facilitate a natural maturation of the child's gut microbiome, providing a vast and continuous stimulation of the child's developing immune system. However, factors such as mode of delivery and intrapartum antibiotics can perturb this natural developmental process and cause long-term microbial derangements. The prevalence of cesarean section (CS) birth has increased globally in recent decades, and with it, antibiotic treatment to prevent perinatal infection. Similar patterns have occurred for the prevalence of chronic childhood disease, particularly asthma, with an estimated 300 million asthmatic cases worldwide.

We hypothesize that early intervention with mother-to-infant FMT can restore a CS-perturbed microbiome to a normal microbial trajectory. We also hypothesize that seeding the virome fraction (FVT) will cause the neonate's microbiome to resemble the mother's since the transferred phages are enriched and preserved in the intestinal mucus layer, thereby providing the recipient with selective antimicrobial protection while allowing species resembling the mother's own to establish during subsequent bacterial transmission.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jakob Stokholm, MD, PhD; Phone Number: +45 38677360; Email: stokholm@copsac.com
• Study Contact Backup: Name: Kaare D. Tranæs, Msc; Phone Number: +45 38677360; Email: kaare.tranaes@dbac.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
    • Contact: Hanne Hegaard, Professor; Phone Number: +45 27583632; Email: Hanne.Kristine.Hegaard@regionh.dk
  • Copenhagen
    • Gentofte, Copenhagen, Denmark, 2820
      • Copsac, DBAC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Gestational age < week 38+0 days
• Proficient in spoken/written Danish
• Single pregnancy (no twins or triplets)
• Pre-pregnancy BMI between 18.5 and 35 kg/m2
• No chronic intestinal, endocrine, cardiac, or kidney disorders
• No known gestational complications (gestational diabetes, preeclampsia, gestational hypothyroidism)
• No regular use of prescription medication or any drugs that, in the research team's opinion, may interfere with the study's results.
• Willingness to abstain from giving the child products with probiotics (fermented dairy like yogurt or A38 are allowed).

Exclusion Criteria:

Maternal:

• Use of antibiotics within one month of stool donation
• Acute gastroenteritis within one month of stool donation
• Use of antibiotics within one month of birth
• Time since last travel abroad relative to data of fecal donation according to the requirements for blood donations ("Regler for tappepauser" - blooddonor.dk)
• Positive test results for pathogens during donor material screening.
• Antibiotic treatment at birth (vaginal births only)
• Spontaneous onset of labor or emergency cesarean section before scheduled cesarean section.

Infant:

• Instances of major birth defects or intrauterine growth retardation (IUGR)
• Infants requiring pediatric support at the time of transplant administration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FMT (Fecal microbiota transplantation); Mother-to-infant fecal microbiota transplantation	Biological: Microbiome restoration - FMT; Pathogen-free microbiota from maternal stool sample is transferred from mother to infant.; Other Names: Fecal Microbiota Transplantation
Active Comparator: FVT (Fecal virome transplantation); Mother-to-infant fecal virome transplantation	Biological: Microbiome restoration - FVT; Sterile-filtered and ultracentrifuged FMT, containing only viruses, is transferred from mother to infant.; Other Names: Fecal Virome Transplantation
Placebo Comparator: Placebo; Inactive solution buffer placebo	Biological: Placebo; Inactive solution buffer
Other: Vaginal control group; Non-randomized control group used for secondary outcomes comparisons.	Other: Vaginal birth, untreated control; No intervention. This group is for secondary outcomes comparisons.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbial development trajectory	Compositional differences to placebo-treated infants	During the first year of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbial development trajectory	Compositional resemblance to vaginally-born infants	During the first year of life

Collaborators and Investigators

• Sponsor: Professor Klaus Bønnelykke
• Investigators: Study Chair: Klaus Bønnelykke, MD, PhD, Head of COPSAC

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 12, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases
• Other Study ID Numbers: H-24002284

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual-level personally identifiable clinical data from the children participating in the cohort cannot be made freely available, to protect the privacy of the participants and their families, in accordance with the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR) that prohibit distribution even in pseudo-anonymized form. However, research collaborations are welcome, and data can be made available under a joint research collaboration by contacting the COPSAC Data Protection Officer (DPO), Ulrik Ralfkiaer, PhD (dpo@dbac.dk).
• IPD Sharing Time Frame: Sequences will be deposited in the Sequence Read Archive repository after publication. External research collaborations are welcome after the initial publication.
• IPD Sharing Access Criteria: Sequences will be openly accessible, individual participant data only under research collaborations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No