Clinical trial NCT05272566: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Feeding Patterns
Microbial Colonization
Keywords: Microbiome
Bacteriophage
Feeding Pattern
Stool Pattern
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Lise Aunsholt, Neonatologist, Clinical Professor
First posted: 2022-03-09
Enrollment: 38
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Families are recruited from out-patients clinics at the secondary level in Copenhagen

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.

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

Primary outcomes:
measure: Gut microbiome
timeFrame: 1 year
Secondary outcomes:
measure: Clinical development
timeFrame: 1 year
measure: Weight
timeFrame: 1 year
measure: Length
timeFrame: 1 year
measure: Time to establish breastfeeding
timeFrame: 2 weeks
measure: Length of hospital stay after birth
timeFrame: 1 month
measure: Days to regain birthweight
timeFrame: 1 month
measure: Stool characteristics - Amount
timeFrame: 1 year
measure: Stool characteristics - Consistency
timeFrame: 1 year
measure: Stool characteristics - Color
timeFrame: 1 year
measure: Defacation frequency
timeFrame: 1 year
measure: Full solid food
timeFrame: 1 year
measure: Frequency of infections
timeFrame: 1 year
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Gustav R Jakobsen
Study officials:
affiliation: Rigshospitalet, Denmark
name: Lise Aunsholt, md, phd
role: PRINCIPAL_INVESTIGATOR
References: