| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Hypercholesterolemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Presence of high levels of cholesterol in the blood |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020603 |
| E.1.2 | Term | Hypercholesterolaemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 |
In patients with primary hypercholesterolemia and high cardiovascular risk with LDL-C ≥100 mg/dL (2.59 mmol/L) and ≤160 mg/dL (4.14 mmol/L), to evaluate:
1) at the end of Phase I, the additional LDL-C percentage reduction by switching to coadministered ezetimibe 10 mg + atorvastatin 10 mg compared to atorvastatin 20 mg among patients who are not adequately controlled with atorvastatin 10 mg prior to randomization.
2) at the end of Phase I, the additional LDL-C percentage reduction by switching to coadministered ezetimibe 10 mg + atorvastatin 10 mg compared to rosuvastatin 10 mg among patients who are not adequately controlled with atorvastatin 10 mg prior to randomization. |
|
| E.2.2 | Secondary objectives of the trial |
In patients with primary hypercholesterolemia and high cardiovascular risk with LDL-C ≥100 mg/dL (2.59 mmol/L) and ≤160 mg/dL (4.14 mmol/L), to evaluate:
1) at the end of Phase II, the additional LDL-C percentage reduction by switching to coadministered ezetimibe 10 mg + atorvastatin 20 mg compared to atorvastatin 40 mg among patients who are not adequately controlled with atorvastatin 10 mg prior to randomization and not adequately controlled with atorvastatin 20 mg during Phase I
2) at the end of Phase II, the additional LDL-C percentage reduction by switching to coadministered ezetimibe 10 mg + atorvastatin 20 mg compared to rosuvastatin 20 mg among patients who are not adequately controlled with atorvastatin 10 mg prior to randomization and who are not adequately controlled with rosuvastatin 10 mg during Phase I
Please refer to protocol for the rest of the secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women ≥18 and <80 years of age.
2. Patient understands the study procedures, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
3. Patient is at high cardiovascular risk (determined by a preliminary Cardiovascular Risk Assessment using historical lab values) and one of the following conditions are met:
- Naïve to lipid-lowering therapy (or have been off such therapy for ≥6 weeks prior to Visit 1) and has a historical LDL-C value approximately within the range noted in the protocol*
OR
- Currently taking stable dose of a statin, ezetimibe, or statin + ezetimibe combination listed below with LDL-C lowering efficacy equivalent to or less than atorvastatin 10 mg and has a historical LDL-C value approximately within the range noted in the protocol.:*
Simvastatin 10, 20 mg
Pitavastatin 1 mg
Atorvastatin 10 mg
Pravastatin 10, 20, 40 mg
Fluvastatin 20, 40, 80 mg
Lovastatin 10, 20, 40 mg
Ezetimibe 10 mg
Ezetimibe 10 mg + Lovastatin 10 mg
Ezetimibe 10 mg + Pravastatin 10 mg
Ezetimibe 10 mg + Fluvastatin 20 mg
4. Patient is willing to maintain an ESC / NCEP ATP III Therapeutic Lifestyle Changes(TLC) or similar cholesterol lowering diet for the duration of the study.
5. A female patient who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the duration of the study. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, condom, vasectomy, and non-cyclical hormonal
contraception.*
6. Female patients who are receiving non-cyclical hormone therapy (including noncyclical hormone replacement therapy or any estrogen antagonist/agonist, or noncyclical oral contraceptives) if maintained on a stable dose and regimen for at least 8 weeks prior to Visit 1 and if willing to continue the same regimen throughout the study.
Patients will be eligible to continue to Visit 3 (Week -1) if they meet the following criteria:
7. Patient has a naïve or on-treatment LDL-C value within the range noted in the protocol at Visit 2 (sample collected at Visit 1).
8. Patient has liver transaminases (ALT and AST) ≤2xULN (sample collected at Visit 1) with no active liver disease at Visit 2.
9. Patient has creatine kinase (CK) levels ≤3xULN at Visit 2 (sample collected at Visit 1).
10. Patient has triglyceride (TG) concentrations ≤350 mg/dL (3.95 mmol/L) at Visit 2 (sample collected at Visit 1).
11. Patient meets 2004 NCEP ATP III / 2006 AHA ACC updated guidelines and 2007 Fourth Joint European Societies recommendations for high risk. Risk criteria are determined by the Framingham calculation (using lipid values obtained at Visit 1)*
- High-risk patients without cardiovascular disease (CVD)* including patients who have (1) diabetes, or (2) multiple risk factors and a 10-year risk for CHD >20% (as determined by the Framingham calculation)
- High-risk patients with cardiovascular disease (CVD)* including patients with established coronary and other atherosclerotic vascular disease
Patients will be eligible to continue to Visit 5 (Week 5) if they meet the following criteria:
12. Patient has completed the 5 week atorvastatin 10 mg run-in period.
13. Patient has at least 75% compliance with run-in medication during the active run-in period (determined by pill count) or, if patients are <75% compliance with run-in medication, they will be permitted to continue if all other criteria are met and site personnel follow-up regularly via telephone to remind them to take study medication.
14. LDL-C level ≥100 mg/dL (2.59 mmol/L) and ≤160 mg/dl (4.14 mmol/L) at Visit 4 (sample collected at Visit 3).
15. Patient has triglyceride (TG) concentrations ≤400 mg/dL (4.52 mmol/L) at Visit 4 sample collected at Visit 3).
Patients will be eligible to continue to Visit 7 (Week 11) if they meet the following criteria:
16. Patient has completed the 6-week double blind treatment period.
17. Notified by IVRS that patient is eligible to proceed directly to Visit 6 and will be part of the Phase II portion of the study based on treatment sequence determined at the randomization visit and/or meeting both blinded lipid criteria listed below:
LDL-C level ≥100 mg/dL (2.59 mmol/L) and ≤160 mg/dl (4.14 mmol/L) at Visit 6 (sample collected at Visit 5). TG level ≤400 mg/dL (4.52 mmol/L) at Visit 6 (sample collected at Visit 5). *
* See protocol for further details |
|
| E.4 | Principal exclusion criteria |
1. Patient is Asian.
2. Patient has hypersensitivity or intolerance to ezetimibe, atorvastatin, rosuvastatin, or any component of these medications, or has a history of significant myopathy or rhabdomyolysis with ezetimibe or any statin.
3. Patient routinely consumes more than 2 alcoholic drinks per day (average >14 alcoholic drinks per week). *
4. Female patient who is pregnant or lactating.
5. Patient has been treated with any other investigational drug within 30 days of Visit 1 (Week -6).
6. Patient has any condition or situation which, in the opinion of the investigator, might have posed a risk to the patient or interfere with participation in the study.
Prohibited Medical Conditions
7. Patient has congestive heart failure defined by NYHA (New York Heart Association) Class III or IV.
8. Patient has had a myocardial infarction, coronary artery bypass surgery, angioplasty, or acute coronary syndrome within 3 months prior to Visit 1.
9. Patient has uncontrolled cardiac arrhythmias or recent significant changes in the patient’s electrocardiogram (ECG) as taken within 6 months prior to Visit 1.
10. Patient has homozygous familial hypercholesterolemia or has undergone LDL-C apheresis.
11. Patient has had a partial ileal bypass, gastric bypass, or other significant intestinal malabsorption.
12. Patient has uncontrolled hypertension (treated or untreated) with systolic blood pressure >160 mmHg or diastolic >100 mmHg at Visit 2 (Week –5). Investigators are encouraged to maximize blood pressure control according to current guidelines.
13. Patient has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 based on the 4-variable MDRD (Modification of Diet in Renal Disease) equation at Visit 1 (as done by the central lab), nephrotic syndrome or other clinically significant renal disease at Visit 1 (Week -6).
14. Patient has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins at Visit 1 (Week -6).*
15. Patient has disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease (e.g. stroke, TIA) and degenerative disease that would limit study evaluation or participation.
16. Patient has poorly controlled Type I or II diabetes mellitus (HbA1c ≥8.5% at Visit 1 or newly diagnosed (within 3 months of Visit 1) and/or patient has recent history of repeated hypoglycemia or unstable glycemic control, or has had a change in treatment of antidiabetic pharmacotherapy or change of ±10 units of insulin, within 2 months of Visit 1 (Week -6).*
17. Patient who is known HIV positive.*
18. Patient has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.*
19. Patient has a history of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy.
Prohibited Therapies
20. Patient is currently taking medications that are potent inhibitors of cytochrome P-450 3A4 (CYP3A4), including systemic azole antifungals (e.g., fluconazole, ketoconazole); erythromycin, clarithromycin or cyclosporine
21. Patient is currently taking other medications that may increase the risk of myopathy, including the combinations of protease inhibitors.*
22. Patient consumes > 5 cups (1.2 L) of grapefruit juice per day.
23. Patient has taken lipid-lowering agents including OTC supplements of fish oils containing >900 mg/day of EPA+DHA, red yeast extract, Cholestin, bile acid sequestrants, HMG-CoA reductase inhibitors or other cholesterol-lowering agents not listed below, ezetimibe/simvastatin and niacin (>200 mg/day) within 6 weeks prior to Visit 1 or fibrates within 8 weeks prior to Visit 1.*
24. Patient is receiving treatment with systemic corticosteroids (intravenous, intramuscular and oral steroids). *
25. Patient is currently treated with psyllium, other fiber-based laxatives, phytosterol margarines, and/or over the counter (OTC) therapies known to affect serum lipid levels, unless treated with a stable regimen for at least 6 weeks prior to Visit 1 (Week -6) and patient agrees to remain on constant regimen for the duration of the study.
26. Patient has been on treatment with orlistat, sibutramine, or other anti-obesity medications and not maintained a stable dose within 1 month prior to study entry or is actively losing weight.
27. Patient is taking any cyclical hormones (e.g., cyclical oral contraceptives, cyclical hormone replacement), including the combination of ethinyl estradiol and norethindrone, within 8 weeks prior to randomization [Visit 4 (Day 1)].
28. Patient requires warfarin treatment and has not been on a stable dose with a stable International Normalized Ratio (INR) for at least 6 weeks prior to Visit 1(Week -6).
* See protocol for further details |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline in LDL-C. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary end point is the comparison of the change in LDL-C from baseline to the end of Phase I (Visit 6) after 6 weeks double-blinded treatment with EZ 10mg + Atorva 10 mg, compared to Atorva 20 mg, or Rosuva 10 mg. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1) Additional percent change from baseline in LDL-C at the end of Phase II; comparison of EZ 10mg + Atorva 20 mg, to Atorva 40 mg, or Rosuva 20 mg
2) Percent of patients reaching LDL-C <100 mg/dL (2.59 mmol/L) at the end of Phase I
3) Percent of patients reaching LDL-C <100 mg/dL (2.59 mmol/L) at the end of Phase II.
4) Percent changes from baseline in TC, TG, HDL-C, Apo B, Apo A-I, non-HDL-C, TC/HDL-C ratio, LDL-C/HDL-C ratio, Apo B/Apo A-I ratio, non-HDL-C/HDL-C ratio and hs-CRP at the end of Phase I.
5) Additional percent changes from baseline in TC, TG, HDL-C, Apo B, Apo A-I, non-HDL-C, TC/HDL-C ratio, LDL-C/HDL-C ratio, Apo B/Apo A-I ratio, non-HDL-C/HDL-C ratio and hs-CRP at the end of Phase II.
6) Safety and tolerability of EZ 10 mg + Atorva 10 mg versus Atorva 20 mg and Rosuva 10 mg and the safety of EZ 10 mg + Atorva 20 mg versus Atorva 40 mg and Rosuva 20 mg.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points will be evaluated at the end of Phase I (Visit 6) following 6 weeks double-blinded treatment with either EZ 10mg + Atorva 10 mg, or Atorva 20 mg, or Rosouva 10 mg, and Phase II (Visit 8), following another 6 weeks double-blinded treatment with either EZ 10mg + Atorva 20 mg, or Atorva 40 mg, or Rosuva 20 mg. |
|
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 6 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 232 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belgium |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Lithuania |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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