An observational study in Very Preterm Infants (<32 Weeks of Gestation), sponsored by Instituto de Investigacion Sanitaria La Fe. Recruiting at 1 site in Spain. Open to participants aged 0 Days to 14 Days. Per ClinicalTrials.gov, last updated 2026-02-11.
Sponsored by Instituto de Investigacion Sanitaria La Fe · Observational
The AdVEMPrem study is exploring whether tiny particles called extracellular vesicles (EVs), which are naturally found in human milk, can help protect very premature babies from serious gut problems such as necrotizing enterocolitis (NEC). NEC is a dangerous condition that affects the intestines of preterm infants and can lead to long-term health issues.
Human milk is the best nutrition for babies, but when a mother's own milk is not available, donor human milk (DHM) is used. EVs in milk carry proteins, fats, and genetic material that may support gut development, immunity, and brain growth. While laboratory studies suggest EVs are beneficial, their effects in premature babies have not yet been proven.
In this study, 20 very preterm infants (\<32 weeks of gestation) will be enrolled during their stay in the Neonatal Intensive Care Unit (NICU). All babies in the study will receive oral supplementation with EVs isolated from donor human milk. Researchers will monitor feeding tolerance, growth, intestinal health, and early development. Blood and urine samples will also be collected to study how EVs affect metabolism and stress markers.
The main goal is to see if EV supplementation is safe and well tolerated. Longer-term follow-up will explore whether EVs improve growth and neurodevelopment as the babies grow. This research could lead to new nutritional strategies to reduce NEC and improve outcomes for premature infants and their families.
Human milk is the optimal source of nutrition for infants, providing essential nutrients and bioactive components that promote growth and development. Very preterm infants (\<32 weeks gestation) are particularly vulnerable to feeding intolerance, impaired growth, and severe complications such as necrotizing enterocolitis (NEC). When a mother's own milk is insufficient or unavailable, pasteurized donor human milk (DHM) is the recommended alternative.
Extracellular vesicles (EVs) are nanosized particles naturally present in human milk that carry proteins, lipids, and nucleic acids involved in cell signaling, intestinal maturation, immune regulation, and neurodevelopment. Preclinical studies suggest that milk-derived EVs may reduce inflammation and support gut and brain development, but their role in clinical outcomes for very preterm infants has not yet been established.
The AdVEMPrem study (PI23/00202, ISCIII) is a prospective, single-arm pilot trial designed to evaluate the tolerance and safety of DHM-derived EV supplementation in very preterm infants. All enrolled infants will receive oral EV supplementation during hospitalization in the Neonatal Intensive Care Unit. Protocols for isolation and quality control of DHM-EVs will be established to ensure reproducible yields. The biochemical composition of milk and EVs will be characterized for product characterization and exploratory analyses, with emphasis on lipid profiles and functional properties. These analyses are not participant-level outcome measures. Clinical, nutritional, and developmental parameters will be monitored during the neonatal period, alongside biomarkers of redox balance and oxidative/nitrosative stress. Long-term follow-up will assess sustained effects on growth and neurodevelopmental trajectories.
Findings from this pilot study will provide foundational evidence for the potential of milk-derived EVs as a safe nutritional strategy to prevent NEC and improve outcomes in preterm infants. Results will inform the design of larger multicenter trials and may contribute to the development of standardized EV-based supplements or analogues from alternative sources, thereby addressing variability in donor milk composition. Ultimately, access to an efficient and safe nutritional supplement could reduce the incidence of NEC, improve infant and family outcomes, and deliver socio-economic and ecological benefits.
2,550 studies on the registry are indexed under Premature Birth; 500 are open to participants now.
This study's planned enrollment of 20 is below the median of 120 across 806 observational studies indexed under Premature Birth.
Browse Premature Birth studies →Instituto de Investigacion Sanitaria La Fe is the lead sponsor of 59 studies on the registry; 14 are open to participants now.
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Preterm infants at risk of developing necrotizing enterocolitis (NEC), recruited between 14 and 28 days of life during their stay in the Neonatal Intensive Care Unit (NICU). A total of 20 infants will be enrolled to receive oral administration of extracellular vesicles (EVs) isolated from donor human milk (DHM) as a dietary supplement.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Infants born before 32 weeks of gestation will receive own mother's milk supplemented with extracellular vesicles isolated from donor human milk.
Dietary Supplement: Donor human milk extracellular vesicles (DHM-EVs)
Infants born before 32 weeks of gestation will receive supplementation with extracellular vesicles isolated from donor human milk, in addition to standard nutritional care.
Number of participants with treatment-related serious adverse events
Safety will be evaluated by the number of participants experiencing one or more treatment-related serious adverse events, defined as any of the following: (i) necrotizing enterocolitis (Bell stage ≥ II); (ii) metabolic or renal complications requiring medical intervention, (iii) cholestasis, or (iv) culture-proven sepsis. Participants experiencing multiple events will be counted once.
Time frame: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)
Tolerance of donor human milk EV supplementation
Feeding tolerance is evaluated by the number of participants without clinical signs of gastrointestinal symptoms and successful progression of enteral feeding.
Time frame: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)
Infant weight
Measurements of weight (grams)
Time frame: From enrollment until term-equivalent age (weekly) and at 3, 6, 12, 18, and 24 months of corrected age
Infant length
Measurements of length (cm)
Time frame: From enrollment until term-equivalent age (weekly) and at 3, 6, 12, 18, and 24 months of corrected age
Infant head circumference
Measurement of head circumference (cm)
Time frame: From enrollment until term-equivalent age (weekly) and at 3, 6, 12, 18, and 24 months of corrected age
Analysis of redox status biomarkers
Evaluation of the ratio reduced/oxidized glutathione
Time frame: 21 days of life
Concentration of TFN alpha (inflammatory biomarker)
Evaluation of TFN alpha in plasma employing an Enzyme-Linked Immunosorbent Assay (ELISA) kit (nM)
Time frame: 21 days of life
Concentration of IL-6 (inflammatory biomarker)
Evaluation of IL-6 in plasma employing an ELISA kit (nM)
Time frame: 21 days of life
Concentration of calprotectin (inflammation biomarker)
Evaluation of calprotectin in plasma employing an ELISA kit (nM)
Time frame: 21 days of life
Ratio of meta-tyrosine/phenylalanine
Evaluation of the ratio of meta-tyrosine/phenylalanine in urine samples by Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS) as an indicator of oxidative damage to proteins
Time frame: 14, 21, and 28 days of life
Ratio of ortho-tyrosine/phenylalanine
Evaluation of the ratio of ortho-tyrosine/phenylalanine in urine samples by LC-MS/MS as an indicator of oxidative damage to proteins
Time frame: 14, 21, and 28 days of life
Ratio of 8-hydroxy-2'-deoxyguanosine/2'-deoxyguanosine
Evaluation of the ratio of 8-hydroxy-2'-deoxyguanosine/2'-deoxyguanosine in urine samples by LC-MS/MS as an indicator of oxidative damage to DNA
Time frame: 14, 21, and 28 days of life
Concentrations of 2,3-dinor-iPF2α-III
Evaluation of 2,3-dinor-iPF2α-III in urine samples by LC-MS/MS as an indicator of oxidative damage to lipids (n mol/g creatinine)
Time frame: 14, 21, and 28 days of life
Concentrations of 5-iPF2α-VI
Evaluation of 5-iPF2α-VI in urine samples by LC-MS/MS as an indicator of oxidative damage to lipids (n mol/g creatinine)
Time frame: 14, 21, and 28 days of life
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) - Motor Composite Score
Motor development will be assessed using the Motor Composite Score of the Bayley-IV. Higher scores indicate better motor development.
Time frame: 6 and 24 months corrected age
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) Language Composite Score
Language development will be assessed using the Language Composite Score of the Bayley-IV. Higher scores indicate better language development.
Time frame: 6 and 24 months corrected age
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) - Cognitive Composite Score
Neurodevelopment will be assessed using the Cognitive Composite Score of the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV). Higher scores indicate better cognitive development.
Time frame: 6 and 24 months of corrected age
Ages and Stages Questionnaire, Third Edition (ASQ-3) Total Score
Developmental screening will be assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3). The ASQ-3 is a parent-completed developmental screening tool consisting of five domains (communication, gross motor, fine motor, problem solving, and personal-social skills). Higher scores indicating better overall development.
Time frame: 6 and 24 months of corrected age
Plan to share: Undecided
Started Feb 2026 (actual). Primary completion is estimated for Dec 2027, 22 months after the start.
Of 372 non-industry observational studies under Premature Birth, half reached primary completion within 35 months of starting (the median), counting those still running; a quarter within 18 and three quarters within 63. This study's planned 22 months is below that.
Counting every sponsor, half of 387 studies reached it within 35 months; a quarter within 18 and three quarters within 61.
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Instituto de Investigacion Sanitaria La Fe