Plain English Summary
Background and study aims
Fortification of human milk is a standard practice in Neonatal Intensive Care Units for feeding very low birth weight infants (VLBWI). However, preterm infants often still experience suboptimal (low) growth and feeding intolerance. New fortification strategies and different commercially available fortifiers have been developed over the years, and are being constantly improved. Commercially available fortifiers are a blend of ingredients from different sources, including plant oils and cow’s milk proteins, and contain different levels of nutrients to human milk. Donkey milk has been recently suggested as a valid alternative for children allergic to cow’s milk due to its similarity to human milk. Donkey milk could therefore be a suitable ingredient for developing a new human milk fortifier for very low birth weight infants and preterm newborns. The aim of the study is to assess feeding tolerance, growth and short- and long-term outcomes in preterm infants fed with a new fortifier and protein supplement made from donkey milk, in comparison to infants fed with a traditional fortifier and protein supplement made from cow’s milk.
Who can participate?
Very low birth weight/preterm infants (gestational age less than 32 weeks, or birthweight less than 1500 g)
What does the study involve?
Newborns are randomly allocated to be fed with a fortifier and protein supplement made from either cow’s milk or donkey milk for a minimum of 21 days (if necessary, fortification is continued after this period using the same type of product). Feeding tolerance, growth and short-term outcomes are assessed at the start of the study and at 7, 14 and 21 days, and long-term outcomes are assessed at 6, 12 and 18 months.
What are the possible benefits and risks of participating?
This is the first study in which a protein concentrate made from donkey milk is given to preterm newborns. This could improve feeding tolerance and growth. Participation in the study will not involve any health risk to infants. Standard clinical practices will be applied. The only difference will be the kind of fortification used.
Where is the study run from?
University of Turin (Italy)
When is the study starting and how long is it expected to run for?
January 2014 to January 2018
Who is funding the study?
1. Compagnia di San Paolo (Italy)
2. Regione Piemonte (Italy)
Who is the main contact?
1. Dr Alessandra Coscia (scientific)
2. Prof. Enrico Bertino (public)
3. Dr Francesco Cresi (scientific)
4. Dr Laura Cavallarin (scientific)
Trial website
Contact information
Type
Scientific
Primary contact
Dr Alessandra Coscia
ORCID ID
Contact details
Via Ventimiglia 3
Turin
10126
Italy
Type
Public
Additional contact
Prof Enrico Bertino
ORCID ID
Contact details
Via Ventimiglia 3
Turin
10126
Italy
Type
Scientific
Additional contact
Dr Francesco Cresi
ORCID ID
http://orcid.org/0000-0002-2139-6855
Contact details
Via Ventimiglia 3
Turin
10126
Italy
Type
Scientific
Additional contact
Dr Laura Cavallarin
ORCID ID
Contact details
Largo Braccini 2
Grugliasco (TO)
10095
Italy
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
P/001-2017
Study information
Scientific title
Randomized controlled clinical trial in single-blind to evaluate the nutritional adequacy of a novel human milk fortifier derived from donkey milk for the nutrition of preterm or low-weight newborns
Acronym
Fortilat-Study
Study hypothesis
Feeding Very Low Birthweight newborns according to ADJ fortification principles, with human milk fortified by a protein supplement and a multi-component supplement (both derived from donkey milk), will improve the nutritional tolerance and the clinical, metabolic, neurological and auxological outcome at short- and long-term.
Ethics approval
Ethics Committee of Città della Salute e della Scienza di Torino Board Affiliation: Città della Salute e della Scienza di Torino, 11/03/2014, ref: 0025847
Study design
Single-center single-blind randomized controlled clinical trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
See additional files (Italian)
Condition
Enteral nutrition in very low birthweight infants
Intervention
Starting from the first fortifier administration, i.e., after reaching an enteral feeding ≥ 80ml/kg/d, newborns included in the trial will be randomized 1:1 by a software-generated list to the following groups:
Group 1: ADJ Fortification with multi-component fortifier (FM85 Nestlè) and protein concentrate (Protifar Nutricia) derived from bovine milk for a minimum of 21 days (if necessary, fortification will be continued after this period using the same type of product)
Group 2: ADJ Fortification with multi-component fortifier and protein concentrate derived from donkey milk (not commercially available, prepared according to cGMP criteria) for a minimum of 21 days (if necessary, fortification will be continued after this period using the same type of product).
The experimental products were produced by ultrafiltration of pasteurized donkey milk in a pilot stainless steel plant by using polyacrylonitrile membrane. Retentate from the ultrafiltration processes were then pasteurized and aseptically lyophylized and packed, and underwent to the required analyses to ensure compliance to the Regione Piemonte legislation. The products are stored at -80°C until used.
A nutrition protocol following the criteria of ADJ fortification has been established to ensure that fortification advancement is consistent for all study participants. Since the protein concentration and energy content of the bovine milk based products differ from the donkey milk based products, the amounts of powder required to obtain the same level of fortification are different depending on the product in use. Advancing of enteral feeds is strictly regulated according to the feeding protocol adopted in the NICU, based on the evaluation of signs of feeding intolerance. The criteria for hospital discharge are uniform, i.e., satisfactory weight gain while receiving full oral feeding, maintenance of adequate thermal stability and resolution of acute medical conditions.
Sample size
The sample size has been determined based on the occurrence of primary endpoint (at least one episode of interruption of enteral feeding longer than 8 hours). Based on the data available in the NICU from the population of VLBWI or preterm infants, about 45% of infants present at least one interruption of enteral feeding longer than 8 hours. In the hypothesis that the use of a better tolerated fortifier causes a 25% reduction in the frequency of the primary endpoint, and setting the risk of type I errors and the power at the usual 5 and 80%, 62 newborns per group have been considered as required.
Statistical analysis
At the end of the recruitment, the occurrence of the primary endpoint will be evaluated on the intention-to-treat population (all randomized infants). The comparison between the two study groups will be performed with the exact Fisher test. For secondary endpoints, the comparison will be made using appropriate generalized linear models. The difference between the treatments concerning the variation of the anthropometric indices, expressed as SDS (standard deviation score) will be performed with a repeated measures model.
Intervention type
Supplement
Phase
Drug names
Primary outcome measure
Occurrence of at least one episode of alimentary intolerance, defined as the necessity to interrupt enteral feeding for more than 8 consecutive hours during the study period from T0 to T3 (day 21)
Secondary outcome measures
1. Short-term outcome measures:
1.1. Number of alimentary intolerance episodes, measured using clinical protocol focused on feeding tolerance every day during observational period (T0-T3)
1.2. Number of feeding interruption episodes (even for periods shorter than 8 hours) , measured using clinical protocol focused on feeding tolerance every day during observational period (T0-T3)
1.3. Total hours of enteral feeding interruption, measured using clinical protocol focused on feeding tolerance every day during observational period (T0-T3)
1.4. Time required to reach full enteral feeding (150 ml/kg/d of enteral feeding), measured using evaluation of clinical records at discharge
1.5. Variation of anthropometric indices (weight, length and cranial circumference), measured using weight, length, cranial circumference scale during the study period and at 40 ± 1 weeks of postmenstrual age
1.6. Hospitalization duration, measured using evaluation of clinical records at discharge
2. Clinical indices, measured using clinical evaluation at discharge:
2.1. Necrotizing enterocolitis (NEC), classified following Bell stages
2.2. Suspected or diagnosed sepsis
2.3. Death
3. Analytical parameters, measured using specific tests conducted in laboratory analysis:
3.1. Calcium, phosphorus, alkaline phosphatase, BUN, creatinine and albumin, measured at T0, T1, T2 and T3
3.2. Amino acid profile in plasma and urine, measured at T0 and T3
3.3. Indices of metabolic acidosis (pH, BE, bicarbonates), measured at T0, T1, T2 and T3
4. Gastic emptying time, assessed using echography at T3 in patients with GERD symptoms
5. Gastroesophageal reflux, assessed using pH-impedance monitoring at T3 in patients with GERD symptoms
6. Urinary metabolomic profile, measured using NMR metabolomics at T0 and T3
7. Faecal analysis (calprotectin), measured using specific tests conducted in laboratory analysis at T0 and T3
8. Occurrence of other pathological events, measured using clinical evaluation during the study period from T0 to T3
9. Long-term outcome measures:
9.1. Auxological outcome (weight, length, cranial circumference), measured using weight, length, cranial circumference scale at 6, 12 and 18 months
9.2. Neuroevolutionary outcome, tested according to Griffiths scale at 18 months
T0: before starting the fortification
T1: day 7 after beginning the fortification (if level 3 of ADJ fortification) or as soon as level 3 is reached
T2: day 14 since beginning of fortification
T3: day 21 since beginning of fortification
Overall trial start date
01/01/2014
Overall trial end date
01/01/2018
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Gestational age < 32 weeks, or birthweight < 1500 grams
2. Feeding with human milk (fresh or donor) > 80% of the total
3. Enteral feeding ≥80ml/kg/d of human milk reached within the first 4 weeks of life
4. Informed consent by a parent
Participant type
Patient
Age group
Neonate
Gender
Both
Target number of participants
Within a population of low-weight or preterm newborns, about 45% of subjects present at least one interruption of enteral feeding longer than 8 hours (priimary endpoint). In the hypothesis that the use of a better tolerated fortifier causes a 25% reduction in the frequence of the primary endpoint, and setting risk of type I errors and potency at the usual 5 and 80%, 62 newborns per group are required
Participant exclusion criteria
1. Severe gastrointestinal pathologies (diagnosed or suspect necrotizing enterocolitis, colostomy, intestinal obstruction, symptoms of peritonitis, presence of blood in the feces)
2. Chromosomal abnormalities or major malformations
3. Hereditary metabolic pathologies
4. Intravascular disseminated coagulation (IDC), shock
5. Patent Ductus Arteriosus (PDA) requiring medical care or surgery
6. Severe renal insufficiency (serum creatinine > 2 mg/dl)
Recruitment start date
27/11/2014
Recruitment end date
22/12/2016
Locations
Countries of recruitment
Italy
Trial participating centre
Neonatology and Neonatal Intensive Care Unit, Città della Salute e della Scienza di Torino, Ospedale S. Anna, Department of Public Health and Pediatrics, University of Turin
Via Ventimiglia, 3
Turin
10126
Italy
Funders
Funder type
Research organisation
Funder name
Compagnia di San Paolo
Alternative name(s)
Fondazione Compagnia di San Paolo, San Paolo Company
Funding Body Type
private sector organisation
Funding Body Subtype
foundation
Location
Italy
Funder name
Regione Piemonte (FORTILAT project - Call "Poli di Innovazione", Por-Fesr 2007-2013 Program)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal.
IPD sharing plan
The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Chiara Peila (chiara.peila@gmail.com).
Intention to publish date
01/01/2019
Participant level data
Available on request
Basic results (scientific)
Publication list
2018 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/29316931