Functional Milk Supplementation to Reduce In-Stent Restenosis in STEMI Patients (SMASOEA Trial) (SMASOEA)

Effects of Functional Bovine Milk Supplementation on Coronary In-Stent Restenosis and Major Adverse Cardiovascular Events in STEMI Patients Undergoing Primary PCI: A Randomized, Double-Blind, Controlled Trial

This randomized, double-blind, controlled clinical trial will evaluate the effects of daily supplementation with functionalized bovine milk, enriched with bioactive peptides and optimized lipid profile, on coronary in-stent restenosis and major adverse cardiovascular events (MACE) in patients with first ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation. Participants will be randomly assigned to receive either functionalized milk or an isocaloric non-functional milk for 12 months, in addition to standard secondary prevention care. The primary endpoint is the incidence of in-stent restenosis at 12 months, assessed by coronary computed tomography angiography (CCTA). Secondary endpoints include MACE occurrence, metabolic and inflammatory biomarkers, oxidative stress markers, serum sirtuins, metabolomic profiles, and myocardial injury evaluated by cardiac positron emission tomography (PET). The study aims to determine whether functionalized milk can improve cardiovascular outcomes and modulate pathophysiological mechanisms after STEMI.

Study Overview

• Status: Not yet recruiting
• Conditions: In-stent Restenosis; ST-elevation Myocardial Infarction (STEMI)
• Intervention / Treatment: Dietary supplement: Functional Bovine Milk; Dietary supplement: Non-Functional Bovine Milk

Detailed Description

Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Despite advances in percutaneous coronary intervention (PCI) and the use of drug-eluting stents (DES), in-stent restenosis (ISR) continues to occur, driven by neointimal hyperplasia, vascular inflammation, and metabolic dysregulation. Nutritional interventions with specific bioactive compounds may offer an innovative adjunct to secondary prevention strategies.

This investigator-initiated, randomized, double-blind, controlled trial will assess whether functionalized bovine milk (FM) - standardized to contain a defined profile of bioactive peptides with antihypertensive, anti-thrombotic, anti-inflammatory, antioxidant, and plaque-stabilizing properties - can reduce ISR incidence and improve cardiovascular outcomes in patients with a first ST-elevation myocardial infarction (STEMI) treated with PCI and DES.

A total of 140 eligible patients will be randomized 1:1 to receive FM or an isocaloric non-functional milk (NFM) for 12 months, in addition to guideline-directed secondary prevention care. Both products will be organoleptically matched, blinded by coded packaging, and supplied in equal volumes.

The primary endpoint is the proportion of patients with ISR at 12 months, as measured by coronary computed tomography angiography (CCTA). Secondary endpoints include the composite of major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure), changes in insulin secretion and sensitivity, systemic inflammatory markers (hsCRP, IL-6, TNF-α), oxidative stress parameters, serum sirtuins, and metabolomic/lipidomic profiles obtained through LC-MS and GC-MS. Myocardial injury and viability will also be quantified by cardiac positron emission tomography (PET) at baseline and at study completion.

Adherence will be monitored through dietary records, packaging return counts, and optional biochemical markers. An independent Data Safety Monitoring Board (DSMB) will oversee patient safety and trial conduct. The study is powered to detect a 50% relative reduction in ISR (from 30% to 15%) with 80% power and a two-sided alpha of 0.05.

If positive, the trial will provide robust clinical evidence for the incorporation of a standardised functional dairy product into secondary prevention dietary guidelines for post-STEMI patients, potentially addressing both residual inflammatory risk and metabolic contributors to recurrent events.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: raffaele Male (M) Marfella, MD, PhD; Phone Number: +390815664174; Email: raffaele.marfella@unicampania.it
• Study Contact Backup: Name: raffaele Sardu, MD, PhD; Phone Number: +393391639624; Email: celestino.sardu@unicampania.it

Study Locations

• Italy
  • Naples, Italy, 80138
    • Università degli Studi della Campania "Luigi Vanvitelli" - Dipartimento di Scienze Mediche e Chirurgiche Avanzate
    • Contact: Raffaele Male (M) Marfella, MD, PhD; Phone Number: 3391639624; Email: raffaele.marfella@unicampania.it
    • Contact: Celestino Sardu, MD, PhD; Phone Number: +393336664543; Email: celestino.sardu@unicampania.it
    • Principal Investigator: raffaele Marfella, MD, PhD
    • Sub-Investigator: Celestino Sardu, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-80 years
• First ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) and drug-eluting stent implantation within the previous 4 weeks
• Stable clinical condition at enrollment
• Willingness to adhere to study procedures and dietary supplementation for 12 months
• Signed informed consent

Exclusion Criteria:

• Previous myocardial infarction or coronary revascularization
• Cardiogenic shock or severe heart failure (NYHA class IV)
• Severe renal impairment (eGFR <30 mL/min/1.73m²) or dialysis
• Active malignancy or life expectancy <1 year
• Known lactose intolerance or allergy to milk proteins
• Participation in another interventional clinical trial in the last 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Functional Milk Group; Participants will receive daily supplementation with functionalized bovine milk enriched with bioactive peptides and optimised lipid profile, in addition to guideline-directed secondary prevention therapy, for 12 months.	Dietary supplement: Functional Bovine Milk; Functional milk product enriched with standardised bioactive peptides, provided daily for 12 months.
Experimental: Non-Functional Milk Group; Participants will receive daily supplementation with an isocaloric non-functional bovine milk matched in appearance, taste, and packaging to the functionalized milk, in addition to guideline-directed secondary prevention therapy, for 12 months.	Dietary supplement: Non-Functional Bovine Milk; Standard bovine milk with identical caloric and macronutrient profile to the functionalized milk, without enrichment, provided daily for 12 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of In-Stent Restenosis at 12 Months	Proportion of patients presenting in-stent restenosis (ISR) as assessed by coronary computed tomography angiography (CCTA) at 12 months after index percutaneous coronary intervention (PCI) with drug-eluting stent.	12 months after PCI
Major Adverse Cardiovascular Events (MACE)	Composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure.	12 months after PCI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Inflammatory Biomarkers	Change in hsCRP levels (mg/L)	12 months after PCI
Change in Oxidative Stress Parameters	Change from baseline in Change in plasma malondialdehyde (µmol/L).	12 months after PCI
Change in Serum Sirtuin Levels	Change from baseline in serum sirtuins as measured by ELISA.	12 months after PCI
Metabolomic Profile Changes	Variations in plasma metabolomic profiles assessed by LC-MS and GC-MS.	12 months after PCI
Cardiac PET Imaging Parameters	Change in myocardial perfusion and viability assessed by positron emission tomography.	12 months after PCI
Change in inflammatory markers	Change in IL-6 levels (pg/mL)	12 months after PCIr PCI
Change in inflammatory markers	Change in TNF-α levels (pg/mL)	12 months after PCI
Change in Oxidative Stress parameters	Change in 8-isoprostane levels (pg/mL)	12 months after PCI

Collaborators and Investigators

• Sponsor: Raffaele Marfella
• Collaborators: Ministry of Health, Italy

Publications and helpful links

General Publications

• Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO, King JC, Mente A, Ordovas JM, Volek JS, Yusuf S, Krauss RM. Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Aug 18;76(7):844-857. doi: 10.1016/j.jacc.2020.05.077. Epub 2020 Jun 17.
• Lamarche B, et al. Dairy products and cardiovascular health: How strong is the evidence? J Am Coll Cardiol. 2016;67(12):1472-1489. doi:10.1016/j.jacc.2015.06.079. PMID: 27012404.
• Lordan R, Tsoupras A, Zabetakis I. Milk and dairy consumption: A review of cardiovascular health benefits and risks. Nutrients. 2018;10(8):993. doi:10.3390/nu10080993. PMID: 30087292.

Helpful Links

• Università degli Studi della Campania "Luigi Vanvitelli"
• Ministero dell'Agricoltura, della Sovranità Alimentare e delle Foreste (MASAF)
• National Institutes of Health

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: August 12, 2025
• First Submitted That Met QC Criteria: September 9, 2025
• First Posted (Actual): September 16, 2025

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Inflammation; ST-Elevation Myocardial Infarction
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Infarction; Necrosis; Myocardial Ischemia; Myocardial Infarction; Ischemia; Pathological Conditions, Signs and Symptoms; ST Elevation Myocardial Infarction; Inflammation
• Other Study ID Numbers: SMASOEA-STEMI-FM01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The decision to share individual participant data (IPD) has not yet been finalized. Data sharing will depend on ethical approval, participant consent, and compliance with applicable privacy regulations (including GDPR). If sharing is approved, anonymized datasets and related documentation may be made available to qualified researchers upon reasonable request, after publication of the primary results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No