Prephage - Faecal Bacteriophage Transfer for Enhanced Gastrointestinal Tract Maturation in Preterm Infants - Donor Study

• ClinicalTrials.gov Identifier: NCT05272566
• Recruitment Status: Active, not recruiting
• First Posted: March 9, 2022
• Last Update Posted: October 19, 2023
• Sponsor: Rigshospitalet, Denmark
• Collaborator: Lise Aunsholt, Neonatologist, Clinical Professor
• Information provided by (Responsible Party): Gustav Riemer Jakobsen, Rigshospitalet, Denmark

Tracking Information

• First Submitted Date: February 15, 2022
• First Posted Date: March 9, 2022
• Last Update Posted Date: October 19, 2023
• Actual Study Start Date: April 1, 2022
• Estimated Primary Completion Date: March 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2022)

Gut microbiome [ Time Frame: 1 year ]

Total genomic DNA will be subjected to deep metagenome sequencing and related to the study outcomes. When extracting faecal DNA as well as viral DNA/RNA, physical fractionation or selective lysis will be employed to ensure host DNA is kept to a minimum. Remaining host DNA material will be removed during bioinformatics filtering and mapping of the shotgun metagenomics data.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 28, 2022)

• Clinical development [ Time Frame: 1 year ]
  Clinical evaluation by pediatric doctor, outcome is dichotomous in terms of following normal development or not according to clinical evaluation
• Weight [ Time Frame: 1 year ]
  weight in kilograms
• Length [ Time Frame: 1 year ]
  Length in centimeters
• Time to establish breastfeeding [ Time Frame: 2 weeks ]
  Days from birth till sufficiently breastfeeding
• Length of hospital stay after birth [ Time Frame: 1 month ]
  Length of hospital stay after birth
• Days to regain birthweight [ Time Frame: 1 month ]
  Time after birth to regain birthweight
• Stool characteristics - Amount [ Time Frame: 1 year ]
  Score from 1-4 using Amsterdam Stool Scale
• Stool characteristics - Consistency [ Time Frame: 1 year ]
  Score from 1-6 using Diapered Infant Stool Scale
• Stool characteristics - Color [ Time Frame: 1 year ]
  Score from 1-6 using Amsterdam Stool Scale
• Defacation frequency [ Time Frame: 1 year ]
  Amount af defacations per week
• Full solid food [ Time Frame: 1 year ]
  Age at which infant is no longer breastfed
• Frequency of infections [ Time Frame: 1 year ]
  Infections per year

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prephage - Faecal Bacteriophage Transfer for Enhanced Gastrointestinal Tract Maturation in Preterm Infants - Donor Study
• Official Title: Prephage - Faecal Bacteriophage Transfer for Enhanced Gastrointestinal Tract Maturation in Preterm Infants - Donor Study

Brief Summary

PrePhage - Fecal bacteriophage transfer for enhanced gastrointestinal tract maturation in preterm infants

This pilot triol has the primary goal of demonstrating the safety of transferring viruses and proteins from healthy term infants to preterm infants born between gestational age (GA) 26 + 0 and 30+6. The long-term goal is to develop a safe and effective treatment to prevent the severe gut disease called necrotizing enterocolitis (NEC).

NEC is a common disease in neonatal intensive care units affecting 5-10% of all admitted patients. 15-30% of the affected children die from the disease, and many of the survivors suffer from the effects of extensive gut surgery.

While the disease is caused by many different factors, recent research has shown the gut microbiome to be a central factor in the development of NEC. Furthermore, in the recent years special viruses called bacteriophages have shown potential in the treatment of various diseases.

By collecting feces from healthy, term infants and filtering it thoroughly, the investigators can provide a treatment that contains practically only viruses, proteins and nutrients. It is our belief that giving the preterm infants a mix of viruses including bacteriophages will prevent NEC.

To do this, the investigators will go through 3 stages:

Recruiting and following healthy donor infants to study the microbiota and use feces from them to donate in stage 2 and 3 Examining the safety of the treatment as well as how it works in preterm piglets

STAGE 3 will be performed only if stage 2 shows no serious risks for the infants

Testing the treatment in preterm infants. 10 preterm infants will receive the treatment and 10 preterm infants will receive placebo. The investigators expect to see no serious side effects to the treatment. The investigators hope, but do not expect to be able to see a beneficial effect of the treatment.

If this pilot trial shows promising results, it will be followed be a larger clinical trial.

Detailed Description

Detailed Description:

PrePhage - Fecal bacteriophage transfer for enhanced gastrointestinal tract maturation in preterm infants

This pilot trial aims to investigate if fecal filtrate transfers (FFT) to preterm infants is safe and tolerable. To investigate this, the investigators will recruit 20 donor infants and their mothers from time of delivery, and both will be subjected to a novel screening program including blood, urine, breastmilk, fecal screening and standard clinical investigation. Donor fecal samples will be collected from time of birth and with varying intervals for consecutive 3 years for 3 purposes: 1) to conduct safety studies in preterm piglets before transfer to preterm recipient infants, 2) to conduct FFT to preterm infants, and 3) to map normal microbiota development in healthy infants. The feces used for donation will be collected between 2-4 weeks after birth. After 1 year, donated feces will be released for FFT to preterm, but only if the donor infant at this time has been healthy and normally developed. Donors are followed up for consecutive 3 years after birth. Maternal fecal samples will be compared to infant samples, to investigate maternal to infant transfer of microbiota, as well as changes in infant microbiota in response to environment.

20 preterm infants with gestational age between 26 +0 - 30+6 weeks + days, are block randomized to either FFT or saline placebo within 24 hours after birth and the following 3 days, in total 4 donations. The recipients are clinically and biochemically closely monitored by attending staff and the group of investigators according to best clinical practice and predefined clinical observation. The recipients are followed up for consecutive 3 years to evaluate potential late side-effects and to monitor change in fecal microbiome after transplant or placebo.

The primary endpoint is to assess safety of FFT to preterm infants with expected no increase in necrotizing enterocolitis (NEC), sepsis and death in the intervention group. The secondary endpoint is to assess if, FFT treatment will reduce incidence of feeding tolerance and improve healthy gut development in recipient preterm infants. The investigators expect to find FFT safe and with fewer cases of NEC and sepsis. The investigators do not expect to prove the effect of the intervention in this study. However, the investigators aim to follow up with a double-blinded multicenter randomized control trial - powered to document our hypothesis - that when colonizing with a healthy microbiome, it is possible decrease incidence of NEC in premature infants.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Fecal Samples from both mothers and infants, only non-human DNA/RNA analyzed

• Sampling Method: Non-Probability Sample
• Study Population: Families are recruited from out-patients clinics at the secondary level in Copenhagen

Condition

• Feeding Patterns
• Microbial Colonization

• Intervention: Not Provided

Study Groups/Cohorts

• Infants

  30 healthy, term infants are recruited for 2 purposes:

  1. To study the development of gut bacteria and viruses over time
  2. To use as donors in a separate trial
• Mothers

  30 healthy pregnant women are recruited along with their infants

  1. To compare gut bacteria and viruses with those of their children
  2. To screen for disease transferrable by breastfeeding

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 18, 2023): 38
• Original Estimated Enrollment (submitted: February 28, 2022): 60
• Estimated Study Completion Date: May 1, 2024
• Estimated Primary Completion Date: March 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria for infants

• The donor must be of term (>37+0 weeks GA, < 41+0 weeks GA),
• Be born vaginally with no maternal pre-birth infection,
• Be exclusively breastfed un till fulfilled donation at 4 weeks of age,
• Have no known predisposition for disease.

Exclusion criteria for infants

• Antibiotic exposure before collection of faecal material for donation,
• Disease between time of birth and collection of feces for donation,
• Major congenital anomalies or birth defects, perinatal asphyxia, need for mechanical ventilation or cardiovascular support before time of inclusion.
• Positive stool sample for C. difficile toxin, parasites or other pathogens
• Positive HIV, HBV, or HCV or CMV
• Parents who do not want to know the HIV, HBV or HCV status of the child

Inclusion criteria for mothers

• Women aged 18-45 and currently healthy
• No continuous medical consumption with effects on microbiome
• Non-smoking
• Ability to give informed consent

Exclusion criteria for mothers

• Known or high risk of infectious disease such as HIV, HBV, or HCV
• Positive CMV IgM during pregnancy
• Positive stool sample for C. difficile toxin, parasites or other pathogens
• Systemic antibiotic treatment < 1 months prior to study
• New tattoo < 1 month prior to study
• Risky sexual behavior
• Gestational diabetes
• Family history of inflammatory bowel disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT05272566
• Other Study ID Numbers: PrePhage, Donor
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: Truly anonymizing data with infants recently born in a small society such as Denmark is challening. The data may be released at a later date.

• Current Responsible Party: Gustav Riemer Jakobsen, Rigshospitalet, Denmark
• Original Responsible Party: Same as current
• Current Study Sponsor: Rigshospitalet, Denmark
• Original Study Sponsor: Same as current
• Collaborators: Lise Aunsholt, Neonatologist, Clinical Professor

Investigators

• Principal Investigator: Lise Aunsholt, md, phd; Rigshospitalet, Denmark

• PRS Account: Rigshospitalet, Denmark
• Verification Date: October 2023