| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Hypercholesterolemia & Mixed Dyslipdemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Abnormal blood cholesterol levels |
|
| 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 | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| 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 |
Evaluate the LDL-C-lowering effects of ERN/LRPT/SIM 2 g/20 mg compared to ERN/LRPT 2 g coadministered with simvastatin 20 mg.
Hypothesis: ERN/LRPT/SIM 2 g/20 mg is equivalent to ERN/LRPT 2 g coadministered with simvastatin 20 mg in reducing LDL-C.
Note: For LDL-C primary hypothesis, the criterion for bioequivalence is that the 95%
confidence interval (CI) of the difference in percent change from baseline between the two treatments falls within ±4%. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate the HDL-C-raising effects of ERN/LRPT/SIM 2 g/20 mg compared to
ERN/LRPT 2 g coadministered with simvastatin 20 mg.
Hypothesis: ERN/LRPT/SIM 2 g/20 mg is equivalent to ERN/LRPT 2 g coadministered with simvastatin 20 mg in raising HDL-C.
Note: For HDL-C secondary hypothesis, the criterion for bioequivalence is that the 95% confidence interval (CI) of the difference in percent change from baseline between the two treatments falls within ±4%.
2. Evaluate the tolerability of ERN/LRPT/SIM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female ≥18 and ≤85 years of age on day of signing informed consent.
2. A female patient must meet ONE of the following:
a. Of reproductive potential and agrees to remain abstinent* or use (or have their partner use) 2 acceptable methods of birth control for the study duration. An acceptable method of birth control is defined as:
intrauterine device (IUD)
diaphragm with spermicide
condom
vasectomy
non-cyclical hormonal contraception – must have been on a stable dose for greater than 6 weeks prior to Visit 1 and agree to remain on the same regimen for the duration of the study
contraceptive sponge (with spermicide) is acceptable as a single method of birth control but requires one of the following as a second method:
intrauterine device (IUD), diaphragm, condom or vasectomy
3. Patient has a history of primary hypercholesterolemia or mixed dyslipidemia.
Note: Determined by medical history, historical and/or current lab values, and Investigator’s judgment.
4. Patient meets one of the following criteria at Visit 2:
Patient is high risk (CHD or CHD risk equivalent based on NCEP ATP III guidelines) AND has LDL-C ≤ 190 mg/dL (≤4.91 mmol/L).
Patient is NOT high risk (based on NCEP ATP III guidelines) AND has LDL-C ≤240 mg/dL (≤6.21 mmol/L).
5. Patient meets one of the following triglyceride (TG) criteria at Visit 2:
a. Patient who is on niacin, statin, or fibrate must have TG <500 mg/dL (<5.65
mmol/L).
b. Patient who is not on an LMT or on LMT other than niacin, statin, or fibrate must
have TG <600 mg/dL (<6.77 mmol/L).
Please refer to protocol for complete list |
|
| E.4 | Principal exclusion criteria |
General
1. Patient consumes more than 3 alcoholic drinks on any given day or more than 14 drinks per week.
2. Patient has the following exclusionary central laboratory values. Creatinine clearance (eGFR) <30 mL/min (0.50 mL/s) ALT (SGPT) >1.5 x upper limit of normal (ULN) AST (SGOT) >1.5 x ULN CK >2 x ULN
3. Patient is high risk (CHD or CHD risk equivalent based on NCEP ATP III) AND is on a LMT at Visit 1. Note: High risk patients not currently being treated with a LMT at Visit 1 are eligible.
4. Patient is on simvastatin 40 mg, or another LMT dose of equivalent or greater LDLC lowering
efficacy than that of simvastatin 40 mg.
5. Patient with Type 1 or Type 2 diabetes mellitus and:
is on statin therapy
is poorly controlled (HbA1C>8%)
is newly diagnosed (within 3 months of Visit 1)
has recently experienced repeated hypoglycemia or unstable glycemic control
is taking new or recently adjusted anti-diabetic pharmacotherapy (with the exception of ≤ ± 10 units of insulin) within 3 months of Visit 1
6. Patient currently engages in, or during the study plans to engage, in vigorous exercise
or an aggressive diet regimen. For example, patient has experienced weight change or
has lost/gained more than 5% of body weight within 3 months prior to randomization.
7. Patient has uncontrolled endocrine or metabolic disease known to influence serum
lipids or lipoproteins (i.e., secondary causes of hyperlipidemia such as hyper- or hypothyroidism):
Hyperthyroidism is defined as having a TSH below the central laboratory’s lower limit of the normal reference range (<0.30 mclU/ml)
Note: For patients on thyroid hormone replacement treatment at the time of screening, there is no lower TSH threshold for entry. The patient must have been on a stable dose of thyroid hormone therapy for ≥6 weeks prior to the randomization visit.
Hypothyroidism is defined as having a TSH >20% above the central laboratory’s upper limit of the normal reference range (>6.0 mclU/ml)
8. Patient has nephrotic syndrome or other clinically significant renal disease.
9. Patient has chronic heart failure defined by the New York Heart Association (NYHA) Classes III or IV, uncontrolled/unstable cardiac arrhythmias, or poorly controlled hypertension (systolic blood pressure >160 mm Hg or diastolic >100 mm Hg
Note: The anti-hypertensive medications of a patient can be managed during the screening period and BP measurements can be repeated at subsequent visits prior to randomization.
10. Patient has had active peptic ulcer disease ≤3 months of Visit 1.
11. Patient has had an episode of gout within 1 year of Visit 1, and is not on any medication to control gout.
12. Patient has a history of hypersensitivity or allergic reaction to niacin, simvastatin,
niacin/laropiprant or other niacin-containing products.
13. Patient has history of myocardial infarction, stroke, coronary artery bypass surgery or
other revascularization procedure, unstable angina or angioplasty within 3 months of
Visit 1.
14. Patient has arterial bleeding.
15. Patient has history of ileal bypass, gastric bypass or other significant condition associated with malabsorption or rapid weight loss within 18 months of Visit 1.
16. Patient has active or chronic hepatobiliary or hepatic disease.
17. Patient has taken niacin >50 mg/day, bile-acid sequestrants, HMG-CoA reductase
inhibitors, ezetimibe, CHOLESTIN , and other red yeast rice products and other red yeast products within 6 weeks or fibrates within 8 weeks of randomization visit (Visit
3).
18. 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.
Please refer to protocol for complete list |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Percent change from baseline at the end of the 8-week treatment period in LDL-C.
0524B |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| end of 8 week treatment period |
|
| E.5.2 | Secondary end point(s) |
| Percent change from baseline at the end of the 8-week treatment period in HDL-C. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| end of 8 week treatment period |
|
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Canada |
| Chile |
| Czech Republic |
| Germany |
| Guatemala |
| Hungary |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Romania |
| Russian Federation |
| Slovakia |
| Ukraine |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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