Clinical trial NCT03067714: A Clinical Study to Investigate the Effect of a Partially Hydrolysed Infant Formula With Added Synbiotics on Gut Microbiota Composition and Clinical Effectiveness in Infants at High Risk of Developing Allergy
Official title: A Randomised, Double-blind, Controlled, Parallel-group, Multi-country Study to Investigate the Effect of a Partially Hydrolysed Infant Formula With Added Synbiotics on Gut Microbiota Composition and Clinical Effectiveness in Infants at High Risk of Developing Allergy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immunity
Lead sponsor: Nutricia Research
Sponsor class: INDUSTRY
First posted: 2017-03-01
Enrollment: 855
Sex: ALL
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: With the rising prevalence of allergic diseases and the subsequent risk of developing other immune-related disorders, primary prevention of allergy has become a major priority. It is generally acknowledged that breastfeeding is one of the main pillars in allergy prevention. Infant formulas based on hydrolysed proteins have been developed to be used by infants at increased risk of developing allergy in case a mother is unable or chooses not to breastfeed her infant. It has recently been demonstrated that the gut microbiota composition and microbiota activity of infants receiving an infant formula based on partially hydrolysed proteins, supplemented with oligosaccharides, is more similar to breastfed infants than to infants receiving standard cow's milk formula, demonstrated by increased levels of bifidobacteria. However the interaction between microbial changes impacted by an hypoallergenic concept and its influence on early life immune development should be further explored. The aim of the present study is therefore to investigate the bifidogenic effect of a hypoallergenic formula supplemented with prebiotics and probiotics compared to standard infant formula in infants at increased risk of developing allergic disease. This study will secondary assess the effects of this concept on the development of allergic manifestations up to the age of 12 months, which will be verified in a separate clinical study MAESTRO as primary outcome. Furthermore, the effects on growth and safety will be studied.


Eligibility criteria: Inclusion Criteria:

1. Healthy term infants (gestational age ≥ 37 and ≤ 42 weeks) at high risk of developing allergy based on family history of allergy (\*1).
2. Infants aged ≤ 16 weeks (max. 16 weeks + 0 days), preferably as soon as possible after birth.
3. Infants who start formula feeding within 16 weeks of age (infants of mothers who have chosen not to breastfeed or mothers who completely/partially cease breastfeeding before the subject's age of 16 weeks) (\*2) OR Infants who are exclusively breastfed and whose mothers have the intention to exclusively breastfeed at least until their infant is 16 weeks of age (\*2,3).
4. Written informed consent from one or both parents (according to local laws) and/or legal guardian.

1\* Family history of allergy is defined as at least one first-degree relative (parent or full sibling) with self-reported historically doctor confirmed allergic disease (allergic rhinitis, asthma, food allergy, allergic eczema). In case of a self-reported historically non-doctor confirmed allergic disease, doctor confirmation must be done as part of the screening procedure according to local practice (e.g. skin prick test, IgE measurement).

2\* Subjects whose mother intents to switch to formula feeding before the subject's age of 16 weeks but in the end still exclusively breastfeed, will be included in the breastfed reference group. The other way around, subjects whose mother intents to exclusively breastfeed for at least 16 weeks, but in the end decides to switch to formula earlier, will be included in the randomised groups. All these subjects should meet all other in-/exclusion criteria.

3\* Exclusive breast feeding. WHO definition: only breast milk and no other liquids or solids except for drops or syrups consisting of vitamins, mineral supplements or medicines \[2\]. In addition to the WHO definition, in this study water is allowed as well as formula feeding during the first 72 hours of life.

* Exclusion Criteria:

  1. Consumption of any amount of infant formula based on intact protein before randomisation, except from consumption during the first 72 hours of life.
  2. Consumption of any amount of infant formula with added probiotics and/or probiotic supplement before randomisation.
  3. Existing allergic manifestations (e.g. allergic skin disorders, food allergy) before randomisation according to investigator's clinical assessment.
  4. Established or suspected cows' milk allergy, lactose intolerance, galactosaemia, or in infants on a fibre-free diet.
  5. Severe congenital abnormalities which could influence the subjects' growth (e.g. cystic fibrosis, bronchopulmonary dysplasia, tracheomalacia, tracheoesophageal fistula, major congenital heart disease, or any other condition according to investigator's clinical judgement).
  6. Severe neonatal illnesses (e.g. respiratory distress syndrome, severe sepsis intraventricular hemorrhage, severe neonatal jaundice, necrotizing enterocolitis, persistent pulmonary hypertension of the newborn, or any other condition which required to be treated with intravenous and/or intramuscular antibiotics).
  7. Known underlying disease predisposing to infection (e.g. HIV, viral hepatitis B, and C, auto-immune diabetes, immune deficiency).
  8. Severe renal failure and hepatic failure according to investigator's clinical judgement.
  9. Incapability of the parents to comply with study protocol or investigator's uncertainty about the willingness or ability of the subject to comply with the protocol requirements
  10. Participation in other studies involving investigational or marketed products concomitantly or within two weeks prior to screening visit.

Primary outcomes:
measure: Faecel levels of Bifidobacteria
timeFrame: 17 weeks
Secondary outcomes:
measure: Faecal levels of Bifidobacteria and adult-like bacterial cluster
timeFrame: 52 weeks
measure: IgE-mediated allergic manifestations
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Algemeen Stedelijk Ziekenhuis
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Namur
country: Belgium
facility: Centre Hospitalier Régional de Namur
city: Praha
country: Czechia
facility: MUDr. Daniel Drazan, prakticky lekar pro deti a dorost
city: Praha
country: Czechia
facility: MUDr. Jitka Fabianova
city: Praha
country: Czechia
facility: Prakticky lekar pro deti a dorost
city: Praha
country: Czechia
facility: Ustav pro peci o matku a dite
city: Strakonice
country: Czechia
facility: Nemocnice Strakonice, a.s.
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Balassagyarmat
country: Hungary
facility: Dr. Kenessey Albert Korhaz-Rendelointezet
city: Budapest
country: Hungary
facility: Pestszentimrei Gyermekrendelő / Elitance Duo Kft.
city: Budapest
country: Hungary
facility: Rózsavölgyi Gyermekháziorvosi Rendelő / CEBA Egészségügyi Bt.
city: Debrecen
country: Hungary
facility: Gyermekorvosi Rendelő
city: Miskolc
country: Hungary
facility: Futurenest Kft.
city: Miskolc
country: Hungary
facility: Prehospital Med Kft
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Korhaz
city: Szeged
country: Hungary
facility: Házi Gyermekorvosi Rendelő /Babadoki Kft.
city: Hadera
country: Israel
facility: Hillel Yaffe Medical center
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Petah tikva
country: Israel
facility: Schneider Children's Medical
city: Reẖovot
country: Israel
facility: Kaplan Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Milano
country: Italy
facility: Ospdale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo, Università degli studi di Pavi
city: Roma
country: Italy
facility: UOC Allergologia, Osp. Pediatrico Bambino Gesù, IRCCS;
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
state: Brabant
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Beek
country: Netherlands
facility: PT&R
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Utrecht
country: Netherlands
facility: EB UtrechtResearch BV
city: Singapore
country: Singapore
facility: Kandang Kerbau Women's and Children's Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Dolný Kubín
country: Slovakia
facility: PEGYS s.r.o.
city: Dunajská Streda
country: Slovakia
facility: Juvenalia, s.r.o.
city: Košice
country: Slovakia
facility: GASTREN, spol. s.r.o.
city: Martin
country: Slovakia
facility: PEDMAN s.r.o.
city: Martin
country: Slovakia
facility: Univerzitna nemocnica Martin
city: Nitra
country: Slovakia
facility: Fakultna nemocnica Nitra
city: Prešov
country: Slovakia
facility: GASTOL s.r.o.
city: Trenčín
country: Slovakia
facility: Fakultna nemocnica Trencin
city: Zlaté Moravce
country: Slovakia
facility: Ambulancia vseobecneho lekara pre deti a dorast
city: Granada
country: Spain
facility: Hospital HLA Inmaculada Servicio de Pediatría
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Hospital Materno Infantil La Paz
city: Manresa
country: Spain
facility: Hospital Sant Joan de Deu
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Sevilla
country: Spain
facility: Instituto Hispalense de Pediatría
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taoyuan
country: Taiwan
facility: LinKou Chang Gung Memorial Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: The Newcastle Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
References: