Very Preterm Infants (<32 Weeks of Gestation)AdVEMPremNCT07402083
Administration of Extracellular Vesicles From Donor Human Milk in Preterm Infants
An observational study of Very Preterm Infants (<32 Weeks of Gestation), run by Instituto de Investigacion Sanitaria La Fe at 1 site in Spain.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 0 to 14 days
- Conditions the study is for
- Very Preterm Infants (<32 Weeks of Gestation)
- What is being tested?
- Donor human milk extracellular vesicles (DHM-EVs)
- How many people
- 20 participants
- Where
- 1 siteSpain
- Study dates
- 5 Feb 2026to 31 Dec 2029
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 14 days
- All sexes
- No healthy volunteers
- Child
Study population: 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.
Who may be able to join
- Preterm infants born at <32 weeks gestational age
- Age between 0 and 14 days of life at enrollment
- At risk of developing necrotizing enterocolitis (NEC)
- Written informed consent obtained from parent(s) or legal guardian(s)
Who cannot join
- Major congenital anomalies or chromosomal abnormalities
- Severe gastrointestinal malformations (e.g., gastroschisis, intestinal atresia)
- Conditions incompatible with enteral feeding or EV supplementation
- Participation in another interventional clinical trial
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Spain1 site, 1 recruiting
- Recruiting
Hospital Universitario y Politécnico La Fe
Valencia, Valencia, 46026
Julia Kuligowski, PhD, +34961246661, julia.kuligowski@uv.es
Julia Kuligowski, PhD
About this study
Official title: Administration of Extracellular Vesicles Isolated From Donor Human Milk as a Dietary Supplement for the Prevention of Necrotizing Enterocolitis in Preterm Infants
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.
Read more
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.
Read the detailed description
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.
- Being tested
- Donor human milk extracellular vesicles (DHM-EVs)
- Keywords
- Preterm birth (<32 weeks), Donor human milk (DHM), Extracellular vesicles (EVs), Feeding tolerance, Necrotizing enterocolitis (NEC), Neurodevelopment, Donor Human Milk Extracellular Vesicle (DHMEVs)
- Medical subject headings
- Premature Birth, Enterocolitis, Necrotizing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Donor human milk extracellular vesicles (DHM-EVs)Dietary supplement
Infants born before 32 weeks of gestation will receive supplementation with extracellular vesicles isolated from donor human milk, in addition to standard nutritional care.
| Study group | Role | What they receive |
|---|---|---|
| EV supplementation in very preterm infants | Infants born before 32 weeks of gestation will receive own mother's milk supplemented with extracellular vesicles isolated from donor human milk. Receives: Dietary Supplement: Donor human milk extracellular vesicles (DHM-EVs) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)
Secondary outcomes (16)
Infant weight
Measurements of weight (grams)
Measured: 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)
Measured: 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)
Measured: 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
Measured: 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)
Measured: 21 days of life
Concentration of IL-6 (inflammatory biomarker)
Evaluation of IL-6 in plasma employing an ELISA kit (nM)
Measured: 21 days of life
Concentration of calprotectin (inflammation biomarker)
Evaluation of calprotectin in plasma employing an ELISA kit (nM)
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 6 and 24 months of corrected age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Feb 2026
- Study start5 Feb 2026
- Primary completion31 Dec 2027 (estimated)
- Study completion31 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Very Preterm Infants (<32 Weeks of Gestation)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Instituto de Investigacion Sanitaria La Fe
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital Universitario La Fe
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07402083
- Sponsor's protocol ID
- PI23/00202
- Other IDs
- PI23/00202
- Acronym
- AdVEMPrem
- Status last verified
- Feb 2026
- First submitted
- 9 Dec 2025
- Last updated
- 11 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Albiach-Delgado A, Pinilla-Gonzalez A, Cascant-Vilaplana MM, Solaz-Garcia A, Torrejon-Rodriguez L, Lara-Canton I, Parra-Llorca A, Cernada M, Gormaz M, Pertierra A, Tapia C, Iriondo M, Aguar M, Kuligowski J, Vento M. The effect of inhaled nitric oxide treatment on biomarkers of oxidative/nitrosative damage to proteins and DNA/RNA. Free Radic Biol Med. 2025 Feb 16;228:350-359. doi: 10.1016/j.freeradbiomed.2025.01.020. Epub 2025 Jan 14.
PubMed 39818239Ramos-Garcia V, Ten-Doménech I, Moreno-Giménez A, Gormaz M, Parra-Llorca A, Shephard AP, et al. ATR-FTIR spectroscopy for the routine quality control of exosome isolations. Chemometrics and Intelligent Laboratory Systems 2021:104401. https://doi.org/10.1016/j.chemolab.2021.104401.
Buratta S, Urbanelli L, Tognoloni A, Latella R, Cerrotti G, Emiliani C, Chiaradia E. Protein and Lipid Content of Milk Extracellular Vesicles: A Comparative Overview. Life (Basel). 2023 Feb 1;13(2):401. doi: 10.3390/life13020401.
PubMed 36836757Pisano C, Galley J, Elbahrawy M, Wang Y, Farrell A, Brigstock D, Besner GE. Human Breast Milk-Derived Extracellular Vesicles in the Protection Against Experimental Necrotizing Enterocolitis. J Pediatr Surg. 2020 Jan;55(1):54-58. doi: 10.1016/j.jpedsurg.2019.09.052. Epub 2019 Oct 25.
PubMed 31685268Miyake H, Lee C, Chusilp S, Bhalla M, Li B, Pitino M, Seo S, O'Connor DL, Pierro A. Human breast milk exosomes attenuate intestinal damage. Pediatr Surg Int. 2020 Feb;36(2):155-163. doi: 10.1007/s00383-019-04599-7. Epub 2019 Nov 12.
PubMed 31713717Liao Y, Du X, Li J, Lonnerdal B. Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Mol Nutr Food Res. 2017 Nov;61(11). doi: 10.1002/mnfr.201700082. Epub 2017 Aug 15.
PubMed 28688106Galley JD, Besner GE. The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles. Nutrients. 2020 Mar 11;12(3):745. doi: 10.3390/nu12030745.
PubMed 32168961Chutipongtanate S, Morrow AL, Newburg DS. Human Milk Extracellular Vesicles: A Biological System with Clinical Implications. Cells. 2022 Jul 30;11(15):2345. doi: 10.3390/cells11152345.
PubMed 35954189Lonnerdal B. Human Milk MicroRNAs/Exosomes: Composition and Biological Effects. Nestle Nutr Inst Workshop Ser. 2019;90:83-92. doi: 10.1159/000490297. Epub 2019 Mar 13.
PubMed 30865991Chen W, Chen X, Qian Y, Wang X, Zhou Y, Yan X, Yu B, Yao S, Yu Z, Zhu J, Han S. Lipidomic Profiling of Human Milk Derived Exosomes and Their Emerging Roles in the Prevention of Necrotizing Enterocolitis. Mol Nutr Food Res. 2021 May;65(10):e2000845. doi: 10.1002/mnfr.202000845. Epub 2021 Apr 22.
PubMed 33715285Zonneveld MI, Brisson AR, van Herwijnen MJ, Tan S, van de Lest CH, Redegeld FA, Garssen J, Wauben MH, Nolte-'t Hoen EN. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. J Extracell Vesicles. 2014 Aug 14;3. doi: 10.3402/jev.v3.24215. eCollection 2014.
PubMed 25206958Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007 Aug 1;179(3):1969-78. doi: 10.4049/jimmunol.179.3.1969.
PubMed 17641064Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekstrom K, El Andaloussi S, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gartner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Gorgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ 2nd, Kornek M, Kosanovic MM, Kovacs AF, Kramer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lasser C, Laurent LC, Lavieu G, Lazaro-Ibanez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li IT, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Line A, Linnemannstons K, Llorente A, Lombard CA, Lorenowicz MJ, Lorincz AM, Lotvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SL, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG Jr, Meehan KL, Mertens I, Minciacchi VR, Moller A, Moller Jorgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-'t Hoen EN, Noren Hooten N, O'Driscoll L, O'Grady T, O'Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostergaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BC, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IK, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KM, Rughetti A, Russell AE, Saa P, Sahoo S, Salas-Huenuleo E, Sanchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schoyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PR, Silva AM, Skowronek A, Snyder OL 2nd, Soares RP, Sodar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BW, van der Grein SG, Van Deun J, van Herwijnen MJ, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ Jr, Veit TD, Vella LJ, Velot E, Verweij FJ, Vestad B, Vinas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MH, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yanez-Mo M, Yin H, Yuana Y, Zappulli V, Zarubova J, Zekas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018 Nov 23;7(1):1535750. doi: 10.1080/20013078.2018.1535750. eCollection 2018.
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Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Administration of Extracellular Vesicles Isolated From Donor Human Milk as a Dietary Supplement for the Prevention of Necrotizing Enterocolitis in Preterm Infants
- ClinicalTrials.gov ID
- NCT07402083
- Acronym / sponsor ID
- AdVEMPrem / PI23/00202
- Keywords
- Preterm birth (<32 weeks), Donor human milk (DHM), Extracellular vesicles (EVs), Feeding tolerance, Necrotizing enterocolitis (NEC), Neurodevelopment, Donor Human Milk Extracellular Vesicle (DHMEVs)
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Instituto de Investigacion Sanitaria La FeUniversity, hospital or other
- Collaborators
- Hospital Universitario La Fe
- Study start
- 5 Feb 2026 (actual)
- Primary completion
- 31 Dec 2027 (estimated)
- Study completion
- 31 Dec 2029 (estimated)
- First posted
- 11 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| EV supplementation in very preterm infants | – | Dietary Supplement: Donor human milk extracellular vesicles (DHM-EVs)Infants born before 32 weeks of gestation will receive own mother's milk supplemented with extracellular vesicles isolated from donor human milk. |
Who may qualify
- Ages
- 0 to 14 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- Study population
- 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.
Key inclusion criteria (4 listed)
- Preterm infants born at <32 weeks gestational age
- Age between 0 and 14 days of life at enrollment
- At risk of developing necrotizing enterocolitis (NEC)
- Written informed consent obtained from parent(s) or legal guardian(s)
Key exclusion criteria (4 listed)
- Major congenital anomalies or chromosomal abnormalities
- Severe gastrointestinal malformations (e.g., gastroschisis, intestinal atresia)
- Conditions incompatible with enteral feeding or EV supplementation
- Participation in another interventional clinical trial
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Dietary supplement | EV supplementation in very preterm infants |
Primary outcome
Number of participants with treatment-related serious adverse events
Time frame: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)
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.
Tolerance of donor human milk EV supplementation
Time frame: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)
Feeding tolerance is evaluated by the number of participants without clinical signs of gastrointestinal symptoms and successful progression of enteral feeding.
16 secondary outcomes
Infant weight
Time frame: From enrollment until term-equivalent age (weekly) and at 3, 6, 12, 18, and 24 months of corrected age
Infant length
Time frame: From enrollment until term-equivalent age (weekly) and at 3, 6, 12, 18, and 24 months of corrected age
Infant head circumference
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
Time frame: 21 days of life
Concentration of TFN alpha (inflammatory biomarker)
Time frame: 21 days of life
Concentration of IL-6 (inflammatory biomarker)
Time frame: 21 days of life
Concentration of calprotectin (inflammation biomarker)
Time frame: 21 days of life
Ratio of meta-tyrosine/phenylalanine
Time frame: 14, 21, and 28 days of life
Ratio of ortho-tyrosine/phenylalanine
Time frame: 14, 21, and 28 days of life
Ratio of 8-hydroxy-2'-deoxyguanosine/2'-deoxyguanosine
Time frame: 14, 21, and 28 days of life
Concentrations of 2,3-dinor-iPF2α-III
Time frame: 14, 21, and 28 days of life
Concentrations of 5-iPF2α-VI
Time frame: 14, 21, and 28 days of life
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) - Motor Composite Score
Time frame: 6 and 24 months corrected age
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) Language Composite Score
Time frame: 6 and 24 months corrected age
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-IV) - Cognitive Composite Score
Time frame: 6 and 24 months of corrected age
Ages and Stages Questionnaire, Third Edition (ASQ-3) Total Score
Time frame: 6 and 24 months of corrected age
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2026.
- Background: PubMed 39818239Albiach-Delgado A, Pinilla-Gonzalez A, Cascant-Vilaplana MM, Solaz-Garcia A, Torrejon-Rodriguez L, Lara-Canton I, Parra-Llorca A, Cernada M, Gormaz M, Pertierra A, Tapia C, Iriondo M, Aguar M, Kuligowski J, Vento M. The effect of inhaled nitric oxide treatment on biomarkers of oxidative/nitrosative damage to proteins and DNA/RNA. Free Radic Biol Med. 2025 Feb 16;228:350-359. doi: 10.1016/j.freeradbiomed.2025.01.020. Epub 2025 Jan 14.
- BackgroundRamos-Garcia V, Ten-Doménech I, Moreno-Giménez A, Gormaz M, Parra-Llorca A, Shephard AP, et al. ATR-FTIR spectroscopy for the routine quality control of exosome isolations. Chemometrics and Intelligent Laboratory Systems 2021:104401. https://doi.org/10.1016/j.chemolab.2021.104401.
- Background: PubMed 36836757Buratta S, Urbanelli L, Tognoloni A, Latella R, Cerrotti G, Emiliani C, Chiaradia E. Protein and Lipid Content of Milk Extracellular Vesicles: A Comparative Overview. Life (Basel). 2023 Feb 1;13(2):401. doi: 10.3390/life13020401.
- Background: PubMed 31685268Pisano C, Galley J, Elbahrawy M, Wang Y, Farrell A, Brigstock D, Besner GE. Human Breast Milk-Derived Extracellular Vesicles in the Protection Against Experimental Necrotizing Enterocolitis. J Pediatr Surg. 2020 Jan;55(1):54-58. doi: 10.1016/j.jpedsurg.2019.09.052. Epub 2019 Oct 25.
- Background: PubMed 31713717Miyake H, Lee C, Chusilp S, Bhalla M, Li B, Pitino M, Seo S, O'Connor DL, Pierro A. Human breast milk exosomes attenuate intestinal damage. Pediatr Surg Int. 2020 Feb;36(2):155-163. doi: 10.1007/s00383-019-04599-7. Epub 2019 Nov 12.
- Background: PubMed 28688106Liao Y, Du X, Li J, Lonnerdal B. Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Mol Nutr Food Res. 2017 Nov;61(11). doi: 10.1002/mnfr.201700082. Epub 2017 Aug 15.
- Background: PubMed 32168961Galley JD, Besner GE. The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles. Nutrients. 2020 Mar 11;12(3):745. doi: 10.3390/nu12030745.
- Background: PubMed 35954189Chutipongtanate S, Morrow AL, Newburg DS. Human Milk Extracellular Vesicles: A Biological System with Clinical Implications. Cells. 2022 Jul 30;11(15):2345. doi: 10.3390/cells11152345.
- Background: PubMed 30865991Lonnerdal B. Human Milk MicroRNAs/Exosomes: Composition and Biological Effects. Nestle Nutr Inst Workshop Ser. 2019;90:83-92. doi: 10.1159/000490297. Epub 2019 Mar 13.
- Background: PubMed 33715285Chen W, Chen X, Qian Y, Wang X, Zhou Y, Yan X, Yu B, Yao S, Yu Z, Zhu J, Han S. Lipidomic Profiling of Human Milk Derived Exosomes and Their Emerging Roles in the Prevention of Necrotizing Enterocolitis. Mol Nutr Food Res. 2021 May;65(10):e2000845. doi: 10.1002/mnfr.202000845. Epub 2021 Apr 22.
- Background: PubMed 25206958Zonneveld MI, Brisson AR, van Herwijnen MJ, Tan S, van de Lest CH, Redegeld FA, Garssen J, Wauben MH, Nolte-'t Hoen EN. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. J Extracell Vesicles. 2014 Aug 14;3. doi: 10.3402/jev.v3.24215. eCollection 2014.
- Background: PubMed 17641064Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007 Aug 1;179(3):1969-78. doi: 10.4049/jimmunol.179.3.1969.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Very Preterm Infants (<32 Weeks of Gestation), run by Instituto de Investigacion Sanitaria La Fe at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Julia Kuligowski, PhD (+34961246661, julia.kuligowski@uv.es), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with treatment-related serious adverse events (time frame: From enrollment until term-equivalent age (i.e., up to 40 weeks postmenstrual age)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07402083, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2026.