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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT06129526
Other study ID # EPA-UOI 2023
Secondary ID
Status Not yet recruiting
Phase Phase 4
First received
Last updated
Start date December 2023
Est. completion date December 2024

Study information

Verified date November 2023
Source University of Ioannina
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Investigation of the efficacy and safety of an Eicosapentaenoic acid (EPA) supplement versus a placebo supplement on plasma triglyceride levels as well as inflammatory, thrombotic, endothelial and platelet activation markers, in patients with type-2 diabetes mellitus (DM-2).


Description:

The conflicting results of previous clinical trials regarding the clinical efficacy of omega-3 fatty acids, such as the STRENGTH and REDUCE-IT studies, as well as the published comments for the placebo used in the REDUCE-IT study (mineral oil), highlight the need for additional studies (pharmacodynamic, clinical, and basic research studies). The SEASIDE (Study of the Effect of Eicosapentaenoic acid, EPA, on Markers of Atherothrombosis in Patients with Type-2 Diabetes) is a phase 4 clinical study, aiming to investigate the efficacy of the dietary supplement EPAVasc, consisted of 1,875mg EPA / 125mg Docosahexaenoic acid (DHA) / 3.75μg Vitamin D / 12mg tocopherol, in reducing the plasma levels of triglycerides, markers of inflammation, coagulation, and platelet as well as endothelial functionality, in high or very high cardiovascular risk DM-2 patients, as compared with the administration of a placebo dietary supplement (Corn Oil). The safety of administering the above EPA supplementation to these patients will be also investigated. This study is expected to significantly advance the existing knowledge regarding the efficacy of EPA in reducing important cardiovascular risk biomarkers in high or very high cardiovascular risk DM-2 patients.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 450
Est. completion date December 2024
Est. primary completion date September 2024
Accepts healthy volunteers No
Gender All
Age group 50 Years and older
Eligibility Inclusion Criteria: The study will enroll DM-2 patients at high or very high cardiovascular risk, aged = 50 years. Patients should have at least one additional cardiovascular risk factor (such as smoking, hypertension, HDL-cholesterol =40 mg/dL for Men, or =50mg/dL for Women, high-sensitivity C-reactive protein (hs-CRP)> 3mg/L, renal dysfunction (CrCl 30-60 mL/min), Ankle-Brachial Index (ABI) <0.9 (without symptoms of intermittent claudication). In addition, patients enrolled in the study will exhibit triglyceride levels >135 mg/dL and <500 mg/dL, despite adherence to the dietary recommendations given for their disease. These recommendations should be followed by all patients during the study. In addition to antidiabetic treatment, patients will receive statin or statin-ezetimibe combination therapy for at least 4 weeks prior to the first visit and should have LDL-cholesterol levels <100mg/dL. Antidiabetic and hypolipidemic treatment will remain unchanged during the study. All patients will sign a written informed consent prior to their inclusion in the study. Exclusion Criteria 1. Patients with a history (= 12 months) of acute coronary syndrome (ACS) or ischemic stroke who are receiving antiplatelet therapy. 2. Patients with peripheral arterial disease or carotid artery disease (>50% stenosis by DOPPLER ultrasound criteria) receiving antiplatelet therapy. 3. Patients receiving monotherapy with any antiplatelet agent. 4. Patients with atrial fibrillation receiving any anticoagulation, or patients with a history of cardioembolic ischemic stroke or hemorrhagic stroke. 5. Patients with severe heart failure, (NYHA IV). 6. Patients with laboratory or clinically diagnosed severe active liver disease or liver failure (child-Pugh staging, score = 5) or renal failure (eGFR < 30ml/min). 7. Patients with cancer, receiving any anticancer treatment. 8. Patients who are planned to undergo any surgical procedure. 9. Exclusion criteria will also include a. HbA1c levels >10.0%, b. history of acute or chronic pancreatitis, c. known hypersensitivity to fish or shellfish or to the components of the study product or placebo.

Study Design


Intervention

Dietary Supplement:
EPAVasc
EPAVasc: 1,875mg EPA / 125mg DHA / 3.75µg Vitamin D / 12mg tocopherol
Corn Oil
Corn Oil

Locations

Country Name City State
Greece Atherothrombosis Research Centre / Laboratory of Biochemistry, University of Ioannina Ioannina Epirus

Sponsors (2)

Lead Sponsor Collaborator
University of Ioannina LIBYTEC Pharmaceutical S.A.

Country where clinical trial is conducted

Greece, 

References & Publications (30)

ASCEND Study Collaborative Group; Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018 Oct 18;379(16):1540-1550. doi: 10.1056/NEJMoa1804989. Epub 2018 Aug 26. — View Citation

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10. — View Citation

Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB, Le VT, May HT, Shaikh K, Shekar C, Roy SK, Tayek J, Nelson JR. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020 Oct 21;41(40):3925-3932. doi: 10.1093/eurheartj/ehaa652. — View Citation

Calder PC. Mechanisms of action of (n-3) fatty acids. J Nutr. 2012 Mar;142(3):592S-599S. doi: 10.3945/jn.111.155259. Epub 2012 Jan 25. — View Citation

Cholewski M, Tomczykowa M, Tomczyk M. A Comprehensive Review of Chemistry, Sources and Bioavailability of Omega-3 Fatty Acids. Nutrients. 2018 Nov 4;10(11):1662. doi: 10.3390/nu10111662. — View Citation

de Carvalho CCCR, Caramujo MJ. The Various Roles of Fatty Acids. Molecules. 2018 Oct 9;23(10):2583. doi: 10.3390/molecules23102583. — View Citation

Fialkow J. Omega-3 Fatty Acid Formulations in Cardiovascular Disease: Dietary Supplements are Not Substitutes for Prescription Products. Am J Cardiovasc Drugs. 2016 Aug;16(4):229-239. doi: 10.1007/s40256-016-0170-7. — View Citation

Goel A, Pothineni NV, Singhal M, Paydak H, Saldeen T, Mehta JL. Fish, Fish Oils and Cardioprotection: Promise or Fish Tale? Int J Mol Sci. 2018 Nov 22;19(12):3703. doi: 10.3390/ijms19123703. — View Citation

Grayling MJ, Mander AP, Wason JMS. Blinded and unblinded sample size reestimation in crossover trials balanced for period. Biom J. 2018 Sep;60(5):917-933. doi: 10.1002/bimj.201700092. Epub 2018 Aug 3. — View Citation

Harden M, Friede T. Sample size calculation in multi-centre clinical trials. BMC Med Res Methodol. 2018 Nov 29;18(1):156. doi: 10.1186/s12874-018-0602-y. — View Citation

Innes JK, Calder PC. Marine Omega-3 (N-3) Fatty Acids for Cardiovascular Health: An Update for 2020. Int J Mol Sci. 2020 Feb 18;21(4):1362. doi: 10.3390/ijms21041362. — View Citation

Kalantzi K, Tentolouris N, Melidonis AJ, Papadaki S, Peroulis M, Amantos KA, Andreopoulos G, Bellos GI, Boutel D, Bristianou M, Chrisis D, Dimitsikoglou NA, Doupis J, Georgopoulou C, Gkintikas SA, Iraklianou S, Kanellas Kappa, Kotsa K, Koufakis T, Kouroglou M, Koutsovasilis AG, Lanaras L, Liouri E, Lixouriotis C, Lykoudi A, Mandalaki E, Papageorgiou E, Papanas N, Rigas S, Stamatelatou MI, Triantafyllidis I, Trikkalinou A, Tsouka AN, Zacharopoulou O, Zoupas C, Tsolakis I, Tselepis AD. Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel-Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events. J Am Heart Assoc. 2021 Jan 5;10(1):e018184. doi: 10.1161/JAHA.120.018184. Epub 2020 Dec 17. — View Citation

Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010 Nov 18;363(21):2015-26. doi: 10.1056/NEJMoa1003603. Epub 2010 Aug 28. — View Citation

Liu Y, Xu H. Sample size re-estimation for pivotal clinical trials. Contemp Clin Trials. 2021 Mar;102:106215. doi: 10.1016/j.cct.2020.106215. Epub 2020 Nov 18. — View Citation

Maki KC, Johns C, Harris WS, Puder M, Freedman SD, Thorsteinsson T, Daak A, Rabinowicz AL, Sancilio FD. Bioequivalence Demonstration for Omega-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance. Clin Ther. 2017 Mar;39(3):652-658. doi: 10.1016/j.clinthera.2017.01.019. Epub 2017 Feb 8. — View Citation

Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-32. doi: 10.1056/NEJMoa1811403. Epub 2018 Nov 10. — View Citation

Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundstrom T, Agrawal R, Menon V, Wolski K, Nissen SE. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2268-2280. doi: 10.1001/jama.2020.22258. — View Citation

Ntalas IV, Kalantzi KI, Tsoumani ME, Bourdakis A, Charmpas C, Christogiannis Z, Dimoulis N, Draganigos A, Efthimiadis I, Giannakoulas G, Giatrakos I, Giogiakas V, Goumas G, Hatziathanasiou G, Kazakos E, Kipouridis N, Konstantinou S, Milionis H, Nikolopoulos D, Peltekis L, Prokopakis N, Sinteles I, Stroumbis C, Terzoudi K, Thoma M, Tsilias K, Vakalis I, Vardakis K, Vasilakopoulos V, Vemmos K, Voukelatou M, Xaraktsis I, Panagiotakos DB, Goudevenos JA, Tselepis AD. Salts of Clopidogrel: Investigation to Ensure Clinical Equivalence: A 12-Month Randomized Clinical Trial. J Cardiovasc Pharmacol Ther. 2016 Nov;21(6):516-525. doi: 10.1177/1074248416644343. Epub 2016 Apr 14. — View Citation

Ntalas IV, Kalantzi KI, Tsoumani ME, Vakalis JN, Vasilakopoulos V, Vardakis K, Vemmos KN, Voukelatou M, Giannakoulas G, Giatrakos I, Giogiakas V, Goumas G, Dimoulis N, Draganigos A, Efthimiadis I, Thoma M, Kazakos E, Kipouridis N, Konstantinou S, Bourdakis A, Nikolopoulos D, Peltekis L, Prokopakis N, Sinteles I, Stroumbis CS, Terzoudi K, Tsilias K, Xaraktsis I, Charmpas C, Hatziathanasiou G, Christogiannis Z, Panagiotakos DB, Goudevenos JA, Tselepis AD. Generic Clopidogrel Besylate in the Secondary Prevention of Atherothrombotic Events: A 6-month Follow-up of a Randomised Clinical Trial. Curr Vasc Pharmacol. 2015;13(6):809-18. doi: 10.2174/1570161113666150316220515. — View Citation

Preston Mason R. New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease. Curr Atheroscler Rep. 2019 Jan 12;21(1):2. doi: 10.1007/s11883-019-0762-1. — View Citation

Ryan, Thomas P. 2013. Sample Size Determination and Power. John Wiley & Sons. New Jersey.

Sherratt SCR, Juliano RA, Mason RP. Eicosapentaenoic acid (EPA) has optimal chain length and degree of unsaturation to inhibit oxidation of small dense LDL and membrane cholesterol domains as compared to related fatty acids in vitro. Biochim Biophys Acta Biomembr. 2020 Jul 1;1862(7):183254. doi: 10.1016/j.bbamem.2020.183254. Epub 2020 Mar 2. — View Citation

Shibabaw T. Omega-3 polyunsaturated fatty acids: anti-inflammatory and anti-hypertriglyceridemia mechanisms in cardiovascular disease. Mol Cell Biochem. 2021 Feb;476(2):993-1003. doi: 10.1007/s11010-020-03965-7. Epub 2020 Nov 11. — View Citation

Tsoumani ME, Kalantzi KI, Dimitriou AA, Ntalas IV, Goudevenos IA, Tselepis AD. Antiplatelet efficacy of long-term treatment with clopidogrel besylate in patients with a history of acute coronary syndrome: comparison with clopidogrel hydrogen sulfate. Angiology. 2012 Oct;63(7):547-51. doi: 10.1177/0003319711427697. Epub 2011 Dec 5. — View Citation

Tsoumani ME, Kalantzi KI, Dimitriou AA, Ntalas IV, Goudevenos IA, Tselepis AD. Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. Comparison with clopidogrel hydrogen sulfate. Expert Opin Pharmacother. 2012 Feb;13(2):149-58. doi: 10.1517/14656566.2012.644536. Epub 2011 Dec 21. — View Citation

Wang P, Chow SC. Sample size re-estimation in clinical trials. Stat Med. 2021 Nov 30;40(27):6133-6149. doi: 10.1002/sim.9175. Epub 2021 Aug 25. — View Citation

Watanabe T, Ando K, Daidoji H, Otaki Y, Sugawara S, Matsui M, Ikeno E, Hirono O, Miyawaki H, Yashiro Y, Nishiyama S, Arimoto T, Takahashi H, Shishido T, Miyashita T, Miyamoto T, Kubota I; CHERRY study investigators. A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins. J Cardiol. 2017 Dec;70(6):537-544. doi: 10.1016/j.jjcc.2017.07.007. Epub 2017 Aug 31. — View Citation

Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr. 2002 Nov;76(5):1007-15. doi: 10.1093/ajcn/76.5.1007. — View Citation

Yagi S, Fukuda D, Aihara KI, Akaike M, Shimabukuro M, Sata M. n-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease. J Atheroscler Thromb. 2017 Oct 1;24(10):999-1010. doi: 10.5551/jat.RV17013. Epub 2017 Aug 24. — View Citation

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S0140-6736(07)60527-3. Erratum In: Lancet. 2007 Jul 21;370(9583):220. — View Citation

* Note: There are 30 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary The percentage (%) change in plasma levels of triglycerides and markers of inflammation, coagulation, endothelial cell and platelet activation. The primary composite efficacy endpoint is the percentage (%) change in each participant in plasma levels of triglycerides and markers of inflammation, coagulation, endothelial cell and platelet activation, comparing the placebo supplement and the investigating supplement. 3 months
Primary Number of participants who suffer from bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria during the entire follow-up period. The Primary safety endpoint is major bleeding according to BARC (Bleeding Academic Research Consortium) criteria. 3 months
Secondary The percentage (%) change in plasma levels of triglycerides. The secondary efficacy endpoint is the (%) change in triglyceride levels of each participant. 3 months
Secondary The percentage (%) change in markers of inflammation. The secondary efficacy endpoint is the (%) change in markers of inflammation, specifically Interleukin-1beta (IL-1ß) (pg/ml) and Interleukin-6 (IL-6) (pg/ml). 3 months
Secondary The percentage (%) change in markers of coagulation. The secondary efficacy endpoint is the (%) change in markers of coagulation specifically Tissue Factor (pg/ml) and Thrombin Time (sec). 3 months
Secondary The percentage (%) change in markers of endothelial cell activation. The secondary efficacy endpoint is the (%) change in markers of endothelial cell activation specifically Monocyte Chemotactic Protein-1 (MCP-1) (pg/ml), Vascular Endothelial Cell Adhesion Molecule-1 (VCAM-1) (ng/mL) and von Willebrand Factor (vWF) (mIU/ml). 3 months
Secondary The percentage (%) change in markers of platelet activation. The secondary efficacy endpoint is the (%) change in markers of platelet activation specifically soluble P-selectin (sP-selectin) (ng/ml), sCD40L (pg/ml) and Thromboxane A2 (TxA2) (pg/ml). 3 months
Secondary Number of participants who suffer from the secondary safety end points which are Atrial fibrillation, Palpitations, Arrhythmias, Heart failure, Pneumonia, Peripheral edema, Diarrhea. Secondary safety endpoints are Atrial fibrillation, Palpitations, Arrhythmias, Heart failure, Pneumonia, Peripheral edema, Diarrhea. 3 months
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