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出境医 / 临床实验 / Ezetimibe-Simvastatin Evaluation Study (ZEUS)

Ezetimibe-Simvastatin Evaluation Study (ZEUS)

Study Description
Brief Summary:
The study purpose is to assess the efficacy of the fixed combination of ezetimibe-simvastatin in patients with hypercholesterolemia not responding to statin monotherapy in achieving the blood plasma LDL-C target as defined by the ESC / EAS Guideline, of 2016.

Condition or disease
Hypercholesterolemia Hyperlipidemias Statin Monotherapy Response

Detailed Description:

The additional study objectives are:

  1. To evaluate the efficacy of a fixed combination of ezetimibe-simvastatin in patients with hypercholesterolemia to improve the lipid profile (HDL-C ↑, T-CHOL, Triglycerides ↓).
  2. Evaluation of the response of patients with hypercholesterolemia who received a fixed combination of ezetimibe-simvastatin to achieve a target according to the category of total cardiovascular risk to which they belong.
  3. To evaluate the efficacy of a stable combination of ezetimibe and simvastatin in patients with hypercholesterolemia in improving non-HDL-cholesterol (non-HDL-C) levels.
  4. Safety assessment through the recording of Adverse Events during the study.
Study Design
Layout table for study information
Study Type : Observational
Actual Enrollment : 0 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Non-interventional, Multicenter, Clinical Observational Study to Evaluate the Efficacy of a Fixed Combination of Ezetimibe and Simvastatin in Hypercholesterolemic Patients Not Responding to Statin Monotherapy.
Estimated Study Start Date : April 1, 2021
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2021
Arms and Interventions
Outcome Measures
Primary Outcome Measures :
  1. LDL-C [ Time Frame: 3 months ]
    Levels of LDL-C


Secondary Outcome Measures :
  1. Lipidemic profile [ Time Frame: 3 months ]
    HDL-C↑ T-CHOL, Triglycerides measurements

  2. Cardiovascular risk factor [ Time Frame: 3 months ]
    Response of patients vs target of total cardiovascular risk to which they belong.

  3. Adverse Events [ Time Frame: 3 months ]
    Number of Adverse Events during the study.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with hyperlcholesterolaemia - not responders to statin monotherapy.
Criteria

Inclusion Criteria:

  • Patients diagnosed with primary (heterozygous familial and non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia or mixed hyperlipidemia.
  • Patients not properly responded with a statin only.
  • Patients who have not achieved LDL-C with previous treatment.
  • Adult patients who will sign their consent form to participate in the study.

Exclusion Criteria:

  • Patients who have not fully understood the study procedures and have not signed the consent form.
  • Hypersensitivity to the active substances or to any of the excipients of study drug.
  • Pregnancy and breastfeeding.
  • Active liver disease or unexplained persistent increases in serum transaminases.
  • Concomitant administration of potent inhibitors of the CYP3A4 system (agents that increase the AUC approximately 5 times or more) (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfinavir ), boceprevir, telaprevir, nefazodone and combesistate containing medicines.
  • Concomitant administration of gemfibrozil, cyclosporine or danazol.
  • Patients with homozygous familial hypercholesterolaemia (HoFH), concurrent administration of lopithipid with doses of study drug> 10 mg / 40 mg.
Contacts and Locations

Locations
Layout table for location information
Greece
Athens University Hospital
Athens, Greece
Sponsors and Collaborators
Elpen Pharmaceutical Co. Inc.
Tracking Information
First Submitted Date May 10, 2019
First Posted Date May 13, 2019
Last Update Posted Date April 12, 2021
Estimated Study Start Date April 1, 2021
Estimated Primary Completion Date December 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 10, 2019) 		LDL-C [ Time Frame: 3 months ]
Levels of LDL-C
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: May 10, 2019)
  • Lipidemic profile [ Time Frame: 3 months ]
    HDL-C↑ T-CHOL, Triglycerides measurements
  • Cardiovascular risk factor [ Time Frame: 3 months ]
    Response of patients vs target of total cardiovascular risk to which they belong.
  • Adverse Events [ Time Frame: 3 months ]
    Number of Adverse Events during the study.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Ezetimibe-Simvastatin Evaluation Study
Official Title Non-interventional, Multicenter, Clinical Observational Study to Evaluate the Efficacy of a Fixed Combination of Ezetimibe and Simvastatin in Hypercholesterolemic Patients Not Responding to Statin Monotherapy.
Brief Summary The study purpose is to assess the efficacy of the fixed combination of ezetimibe-simvastatin in patients with hypercholesterolemia not responding to statin monotherapy in achieving the blood plasma LDL-C target as defined by the ESC / EAS Guideline, of 2016.
Detailed Description

The additional study objectives are:

  1. To evaluate the efficacy of a fixed combination of ezetimibe-simvastatin in patients with hypercholesterolemia to improve the lipid profile (HDL-C ↑, T-CHOL, Triglycerides ↓).
  2. Evaluation of the response of patients with hypercholesterolemia who received a fixed combination of ezetimibe-simvastatin to achieve a target according to the category of total cardiovascular risk to which they belong.
  3. To evaluate the efficacy of a stable combination of ezetimibe and simvastatin in patients with hypercholesterolemia in improving non-HDL-cholesterol (non-HDL-C) levels.
  4. Safety assessment through the recording of Adverse Events during the study.
Study Type Observational
Study Design Observational Model: Other
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Patients with hyperlcholesterolaemia - not responders to statin monotherapy.
Condition
  • Hypercholesterolemia
  • Hyperlipidemias
  • Statin Monotherapy Response
Intervention Not Provided
Study Groups/Cohorts Not Provided
Publications *
  • Reiner Ž, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegría E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs RH, Kjekshus JK, Perrone Filardi P, Riccardi G, Storey RF, David W; Clinical Practice Guidelines Committee of the Spanish Society of Cardiology. [ESC/EAS Guidelines for the management of dyslipidaemias]. Rev Esp Cardiol. 2011 Dec;64(12):1168.e1-1168.e60. doi: 10.1016/j.recesp.2011.09.014. Review. Spanish.
  • Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WMM, Vlachopoulos C, Wood DA, Zamorano JL, Cooney MT; ESC Scientific Document Group. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016 Oct 14;37(39):2999-3058. doi: 10.1093/eurheartj/ehw272. Epub 2016 Aug 27.
  • M. Elisaf, Chr. Pitsavos, Ev. Liberopoulos, K. Tziomalos, V. Athyros. Updated guidelines of the Hellenic Society of Atherosclerosis for the diagnosis and treatment of dyslipidemia. Hellenic Journal of Atherosclerosis (2014) 5: 151-163
  • D. B. Panagiotakos. Cardiovascular Disease Risk Models. Hellenic Journal of Atherosclerosis (2013) 4: 151-157
  • Panagiotakos DB, Fitzgerald AP, Pitsavos C, Pipilis A, Graham I, Stefanadis C. Statistical modelling of 10-year fatal cardiovascular disease risk in Greece: the HellenicSCORE (a calibration of the ESC SCORE project). Hellenic J Cardiol. 2007 Mar-Apr;48(2):55-63.
  • Walker JF. Simvastatin: the clinical profile. Am J Med. 1989 Oct 16;87(4A):44S-46S.
  • Simons LA. Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks. The Principal Investigators. Clin Cardiol. 1993 Apr;16(4):317-22.
  • Rabelink AJ, Hené RJ, Erkelens DW, Joles JA, Koomans HA. Effects of simvastatin and cholestyramine on lipoprotein profile in hyperlipidaemia of nephrotic syndrome. Lancet. 1988 Dec 10;2(8624):1335-8.
  • Shankar PK, Bhat R, Prabhu M, Reddy BP, Reddy MS, Reddy M. Efficacy and tolerability of fixed-dose combination of simvastatin plus ezetimibe in patients with primary hypercholesterolemia: Results of a multicentric trial from India. J Clin Lipidol. 2007 Aug;1(4):264-70. doi: 10.1016/j.jacl.2007.07.009. Epub 2007 Jul 27.
  • Nußbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G. Ezetimibe-Statin Combination Therapy. Dtsch Arztebl Int. 2016 Jul 1;113(26):445-53. doi: 10.3238/arztebl.2016.0445.
  • Mikhailidis DP, Sibbring GC, Ballantyne CM, Davies GM, Catapano AL. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 2007 Aug;23(8):2009-26.
  • Chenot F, Montant PF, Marcovitch O, Blaimont M, de Meester A, Descamps OS. Co-administration of ezetimibe and simvastatin in acute myocardial infarction. Eur J Clin Invest. 2007 May;37(5):357-63.
  • Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002 Dec 18;40(12):2125-34.
  • Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3.
  • M.Elisaf, A.Kei, T.Alexandrides, E. Liberopoulos. The impact of improve-it study. Hellenic Journal of Atherosclerosis 6: 153-154
  • Ahmed O, Littmann K, Gustafsson U, Pramfalk C, Öörni K, Larsson L, Minniti ME, Sahlin S, Camejo G, Parini P, Eriksson M. Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients. J Am Heart Assoc. 2018 Dec 18;7(24):e009876. doi: 10.1161/JAHA.118.009876.
  • Bove M, Fogacci F, Cicero AFG. Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia. Expert Opin Drug Metab Toxicol. 2017 Oct;13(10):1099-1104. doi: 10.1080/17425255.2017.1381085. Epub 2017 Sep 26. Review.
  • Abramson J, Rosenberg HG, Jewell N, Wright JM. Safety and efficacy of statins. Lancet. 2017 Mar 18;389(10074):1097. doi: 10.1016/S0140-6736(17)30713-4.
  • Robinson JG. Nonstatins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Role in Non-Familial Hypercholesterolemia. Prog Cardiovasc Dis. 2016 Sep - Oct;59(2):165-171. doi: 10.1016/j.pcad.2016.07.011. Epub 2016 Aug 4. Review.
  • Kei A, Elisaf MS. Nicotinic acid: clinical considerations. Expert Opin Drug Saf. 2012 Jul;11(4):551-64. doi: 10.1517/14740338.2012.682981. Epub 2012 May 7. Review.
  • A. Kei, M.Elisaf. Current role of fibrates in the treatment of dyslipidemia. Hellenic Journal of Atherosclerosis 5(2): 106-11
  • Bohula EA, Wiviott SD, Giugliano RP, Blazing MA, Park JG, Murphy SA, White JA, Mach F, Van de Werf F, Dalby AJ, White HD, Tershakovec AM, Cannon CP, Braunwald E. Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2017 Dec 19;136(25):2440-2450. doi: 10.1161/CIRCULATIONAHA.117.029095. Epub 2017 Sep 30.
  • Ghanim H, Green K, Abuaysheh S, Patel R, Batra M, Chaudhuri A, Makdissi A, Kuhadiya ND, Dandona P. Ezetimibe and simvastatin combination inhibits and reverses the pro-inflammatory and pro-atherogenic effects of cream in obese patients. Atherosclerosis. 2017 Aug;263:278-286. doi: 10.1016/j.atherosclerosis.2017.06.010. Epub 2017 Jun 7.
  • Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol. 1992 Jan-Mar;2(1-2):23-8.
  • Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W; Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001 Sep 4;104(10):1108-13.
  • Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetière P, Jousilahti P, Keil U, Njølstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM; SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003 Jun;24(11):987-1003.
  • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97.
  • Suchy D, Łabuzek K, Stadnicki A, Okopień B. Ezetimibe--a new approach in hypercholesterolemia management. Pharmacol Rep. 2011;63(6):1335-48. Review.
  • Al-Shaer MH, Choueiri NE, Suleiman ES. The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia. Lipids Health Dis. 2004 Oct 7;3:22.
  • Gazi IF, Mikhailidis DP. Non-low-density lipoprotein cholesterol-associated actions of ezetimibe: an overview. Expert Opin Ther Targets. 2006 Dec;10(6):851-66. Review.
  • Jankowski P, Loster M, Kawecka-Jaszcz K. Ezetimibe: New perspectives in lipid lowering treatment. Cardiol J. 2007;14(3):232-7.
  • Kostapanos MS, Mikhailidis DP, Elisaf MS. Adding ezetimibe to statin treatment: is LDL-C lowering the only benefit? Future Cardiol. 2012 Nov;8(6):813-7. doi: 10.2217/fca.12.64.
  • Kostapanos MS, Elisaf MS, Mikhailidis DP. Ezetimibe - a new approach in hypercholesterolemia management. Pharmacol Rep. 2012;64(4):997-8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Withdrawn
Actual Enrollment
 (submitted: April 8, 2021) 		0
Original Estimated Enrollment
 (submitted: May 10, 2019) 		2000
Estimated Study Completion Date December 30, 2021
Estimated Primary Completion Date December 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients diagnosed with primary (heterozygous familial and non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia or mixed hyperlipidemia.
  • Patients not properly responded with a statin only.
  • Patients who have not achieved LDL-C with previous treatment.
  • Adult patients who will sign their consent form to participate in the study.

Exclusion Criteria:

  • Patients who have not fully understood the study procedures and have not signed the consent form.
  • Hypersensitivity to the active substances or to any of the excipients of study drug.
  • Pregnancy and breastfeeding.
  • Active liver disease or unexplained persistent increases in serum transaminases.
  • Concomitant administration of potent inhibitors of the CYP3A4 system (agents that increase the AUC approximately 5 times or more) (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfinavir ), boceprevir, telaprevir, nefazodone and combesistate containing medicines.
  • Concomitant administration of gemfibrozil, cyclosporine or danazol.
  • Patients with homozygous familial hypercholesterolaemia (HoFH), concurrent administration of lopithipid with doses of study drug> 10 mg / 40 mg.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Greece
Removed Location Countries  
 
Administrative Information
NCT Number NCT03947866
Other Study ID Numbers 2019-SMEZ-EL-103
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Elpen Pharmaceutical Co. Inc.
Study Sponsor Elpen Pharmaceutical Co. Inc.
Collaborators Not Provided
Investigators Not Provided
PRS Account Elpen Pharmaceutical Co. Inc.
Verification Date April 2021

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