PrePhage - Faecal Bacteriophage Transfer for Enhanced Gastrointestinal Tract Maturation in Preterm Infants

PrePhage - Faecal Bacteriophage Transfer for Enhanced Gastrointestinal Tract Maturation in Preterm Infants - Clinical Trial

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:

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

Study Overview

• Status: Recruiting
• Conditions: Necrotizing Enterocolitis; Microbial Substitution
• Intervention / Treatment: Other: Fecal Filtrate Transfer; Other: Placebo

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: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Gustav R Jakobsen, md; Phone Number: +4550569536; Email: gustav.riemer.jakobsen@regionh.dk
• Study Contact Backup: Name: Lise Aunsholt, md, phd; Phone Number: +4561991137; Email: lise.aunsholt@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Gustav R Jakobsen, Medical doctor; Phone Number: +4550569536; Email: gustav.riemer.jakobsen@regionh.dk
    • Contact: Lise Aunsholt, MD, ph.d., professor; Phone Number: +4561991137; Email: lise.aunsholt@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria for participant preterm infants

• Preterm infants born between GA 26+0 and 30+6
• Delivery at RH or transferred to RH NICU within 24 hours of delivery
• Children administered prophylactic antibiotics due to maternal risk factors, specifically: premature rupture of membranes, groub b streptococcus positive, feber during labour
• Signed parental consent

Exclusion criteria for participant preterm infants

• Major congenital anomalies or birth defects
• Antibiotics for more than 72 hours after birthExtremely SGA infant (weight SD score < -3 SD)
• Need for mechanical ventilation or cardiovascular support before first FFT treatment

Inclusion criteria for mothers of participants

• Women aged 18-45
• Ability to give informed consent

Exclusion criteria for participant mothers

● Mothers who have severe infection, defined by need for other treatment to support infection-related comorbidities, besides from antibiotics (e.g. inotropic treatment, iv fluid resuscitation)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FFT treatment; Treatment with fecal filtrate transfer in saline solution administered by nasogastric tube	Other: Fecal Filtrate Transfer; Treatment with donated fecal samples filtered to contain practically no bacteria and mainly viruses, including bacteriophages
Placebo Comparator: Placebo Treatment; Treatment with saline solution administered by nasogastric tube	Other: Placebo; Saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
No serious adverse events	No increased incidence of sepsis, NEC and death in the treatment group	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feeding tolerance	Using a standardized clinical scoring system, nurses at our NICU will evaluate any negative reactions to enteral feeding. It includes evaluation of aspirate, feces, amount of enteral nutrition administered, objective evaluation of the abdomen, and signs of obstipation	1 month
Microbiota Composition	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.	1 month
Time to full enteral feeding		1 month
Blood pressure	Blood pressure in mmHg	1 month
Temperature	Rectal temperature in degrees celsius	1 month
Pulse	Pulse measured using samsung monitoring equipment according to standard at our NICU	1 month
Length	Length in cm	1 month
Weight	Weight in kilograms	1 month
Stool characteristics - Amount	Score from 1-4 using Amsterdam stool scale	1 month
Stool characteristics - Consistency	Score from 1-6 using diapered infant stool scale	1 month
Stool characteristics - Color	Score from 1-6 using Amsterdam Stool Scale	1 month
Days of hospitalization		1 month

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Lise Aunsholt, Neonatologist, Clinical Professor
• Investigators: Principal Investigator: Lise Aunsholt, md, phd, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 15, 2022
• First Submitted That Met QC Criteria: February 28, 2022
• First Posted (Actual): March 9, 2022

Study Record Updates

• Last Update Posted (Actual): November 15, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Enterocolitis; Enterocolitis, Necrotizing
• Other Study ID Numbers: Rigshospitalet - PrePhage

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: An anonomized version of the data will be published along with the main report from the intervention study
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No