| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Inhibiting the progression of atherosclerosis in patients with carotid arteries stenosis and dyslipidemia. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inhibiting the progression of atherosclerosis in patients with carotid arteries stenosis and dyslipidemia. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007687 |
| E.1.2 | Term | Carotid artery stenosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of nicotinic acid used in combination with simvastatin at a dose of 20 mg daily in comparison to simvastatin administered at a dose of 40 mg daily in inhibiting the progression of atherosclerotic lesions after 6 months of therapy in patients with carotid artery stenosis and dyslipidemia. |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the influence of nicotinic acid used in combination with simvastatin at a dose of 20 mg daily on serum lipid fractions concentrations in comparison to simvastatin administered at a dose of 40 mg daily.
2. To evaluate the influence of nicotinic acid used in combination with simvastatin at a dose of 20 mg daily on frequency of major cardiovascular events in comparison to simvastatin administered at a dose of 40 mg daily.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Caucasian men and women aged ≥ 18 years;
2. Stenosis of at least one internal carotid artery (ICA) < 70% assessed by carotid arteries ultrasound;
3. LDL-C level > 100 mg / dL (> 2.5 mmol / L) despite taking simvastatin 20 mg daily or equivalent dose of another statin for at least last 28 days;
4. LDL-C level > 115 mg / dl (> 3 mmol / L) in patients not taking any statin over the last 28 days;
5. Patients capable of understanding and following the study procedures;
6. Signing of Informed Consent Form to participate the study before the qualification procedures begin.
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| E.4 | Principal exclusion criteria |
1. Known allergy and/or hypersensitivity to nicotinic acid and/or its derivatives and/or to any study product excipients;
2. Known allergy and/or hypersensitivity to simvastatin and/or its derivatives and/or to any study product excipients;
3. Pregnancy or lactation period in females;
4. Stenosis of at least one internal carotid artery (ICA) ≥ 70% assessed by carotid arteries ultrasound;
5. Symptomatic stenosis of any carotid artery, regardless of the stenosis degree;
6. Patients scheduled to undergo invasive treatment of any carotid artery: carotid endarterectomy (CEA) or cartoid artery stenting (CAS);
7. History of previous CEA or CAS of any carotid artery;
8. Hypotension (systolic blood pressure < 100 mmHg at screening and/or at any time within 3 months prior to enrolment);
9. Uncontrolled hypertension – systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening and/or at any time within 3 months prior to enrolment;
10. Unstable angina pectoris;
11. Heart failure (NYHA III-IV);
12. Symptomatic stenosis or symptomatic aortic regurgitation;
13. Renal failure - estimated creatinine clearance < 30 ml/min or estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 or the need for dialysis;
14. Active liver disease or persistent and unexplained aminotransferases elevations (AST and /or ALT) exceeding the upper limit of normal range;
15. Aminotransferases levels (AST and/or ALT) exceeding > 3 times the upper limit of normal range;
16. Jaudince;
17. Ascites found in physical examination;
18. Active peptic ulcer disease;
19. Gout or uric acid levels above the upper limit of normal range;
20. Primary, hereditaryl, monogenic, homo- or heterozygotic familiar dyslipidemia
21. Triglycerides level > 400 mg/dl (> 4.6 mmol/l);
22. Individual or familiar anamnesis of hereditary muscular system disorders;
23. History of statins- or fibrates-induced muscle toxicity;
24. Inflammatory muscle diseases;
25. Clinical symptoms of myopathy;
26. CK activity exceeds 5 times the upper limit of the normal range;
27. Type 1 diabetes or diabetes mellitus with a known etiology (secondary);
28. The percentage of glycated hemoglobin ≥ 12.0;
29. Free thyroxine (FT4) concentration below the lower limit of normal range;
30. Glaucoma;
31. History of malignant neoplastic disease that has not been in remission for at least 5 years at screening;
32. Taking fibrates, ion exchange resins, or ezetimibe within 90 days prior to enrollment;
33. Systemic administration of following drugs, if it is not possible to stop taking those drugs during study;
• antifungal drugs: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole;
• antibacterial drugs: erythromycin, clarithromycin, telithromycin, fusidic acid;
• antiviral drugs: HIV protease inhibitors (eg. Nelflinawir), kobicystatu, boceprevir, telaprevir;
• medicines used in cardiovascular system diseases: amiodarone, dronedarone, verapamil, ranolazine;
• nefazodone, cyclosporine, danazol, lomitapide;
• vitamin K antagonists (eg. Acenocoumarol, warfarin, phenprocoumon);
• non-investigational medicinal product containing nicotinic acid, nicotinic acid or nicotinamide preparations (vitamin. B3 vitamin. PP) or other nicotinic acid derivatives (eg. hydroxymethylamide of nicotinic acid, inositol hexanicotinate);
• preparations containing polyunsaturated fatty acids, ω-3.
34. Participation in any clinical trial within 90 days prior to enrollment;
35. Severe subjects who are known or suspected to be drug dependent and alcohol abusers (more than 2 standard units of alcohol per day);
36. Serious physical or mental concomitant disease that according to the Investigator might hamper the realization of the trial according to the protocol or the evaluation of efficacy and safety
37. Any reason the subject is considered by the Investigator to be an unsuitable candidate to participate in the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in common carotid arteries intima-media thickness, assessed by ultrasound, after 6 months of the therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. When subject abandonment of treatment.
2. On the last medical examination. |
|
| E.5.2 | Secondary end point(s) |
Groups will be compared for:
1. Change in LDL cholesterol level (LDL-C);
2. Change in HDL cholesterol level (HDL-C);
3. Change in non-HDL cholesterol level (non-HDL-C);
4. Change in total cholesterol (TC);
5. Change in triglycerides level (TG);
6. Major cardiovascular events (composite endpoint):
• brain stroke (ischemic, hemorrhagic, indefinite);
• transient (cerebral) ischemic attack (TIA);
• myocardial infarction;
• brain stroke mortality;
• myocardial infarction mortality;
• sudden cardiac death
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. When the study will be finished.
2. When subject abandonment of treatment.
3. On the last medical examination. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last phone call between the Investigator and the patient |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
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