| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
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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 |
| E.2.1 Main objective: To evaluate the efficacy of ER niacin/laropiprant 2g relative to placebo on plasma low-density lipoprotein cholesterol (LDL-C) at Week 12 of treatment. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy of ER niacin/laropiprant 2g relative to placebo on plasma concentrations of LDL-C, LDL-C/HDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-I, Total Cholesterol (TC)/HDL-C, TC, and Lp(a) at Week 12 of treatment in all patients and in certain subgroups of patients (c) To assess the percent of patients with triple control at the end of study defined as meeting the NCEP ATP-III LDL-C goal for risk category, as well as having HDL-C ≥ 50 mg/dL (≥1.29 mmol/L) for women or ≥ 40 mg/dL (≥1.04 mmol/L) for men and TG <150 mg/dL (≤1.69 mmol/L) (d) To evaluate the efficacy of ER niacin/laropiprant 1 g relative to placebo on plasma concentrations of LDL-C, LDL-C/HDL-C, HDL-C, TG, non-HDL-C, and TC in all patients at Week 4 of treatment (e) To evaluate the tolerability and safety of ER niacin/laropiprant 2 g across 12 weeks of treatment. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General
1.Patient is male or female ≥18 years of age on day of signing informed consent.
2.Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
3.Contraception for female patients who are of reproductive potential: a female patient who is of reproductive potential agrees to remain abstinent or use (or have their partner use) if required locally 2 acceptable methods of birth control for the duration of the study. An acceptable method of birth control is defined as: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy.
NOTE: A female patient who is not of reproductive potential is eligible without requiring the use of contraception. A female patient/subject who is not of reproductive potential is defined as: one who has either 1) reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum FSH levels in the postmenopausal range as determined by the laboratory, or 12 months of spontaneous amenorrhea), 2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy, or 3) bilateral tubal ligation. NOTE: Patients are permitted to use hormonal contraceptives; however, they are not considered an acceptable form of birth control. Patients using hormonal contraceptives must agree to also use 2 acceptable methods of birth control if locally required as indicated above.
Protocol-Specific
4.Patient has been on a stable dose of a protocol specified LMT (simvastatin, atorvastatin, or rosuvastatin alone or combined/coadministered with ezetimibe) for 6 weeks prior to Visit 1 and agrees to continue on the same LMT and dose for the duration of the study.
NOTE: Patients taking other statins (lovastatin, pravastatin, fluvastatin), bile acid sequestrants, red yeast rice products, prescription omega-3-acid ethyl esthers (e.g., Lovaza™), fibrates or niacin ≥ 250 mg are not eligible.
5.Patient is deemed appropriate for further lipid modification, defined as meeting one or more of the following lipid criteria: a.Elevated LDL-C defined according to NCEP ATP III risk categories as follows:
•High Risk (CHD/CHD risk equivalent): ≥100 mg/dL (≥ 2.59 mmol/L) and <130 mg/dL (<3.37 mmol/L)
•Multiple risk (≥ 2 risk factors): ≥ 130 mg/dL (≥ 3.37 mmol/L) and <160 mg/dL (<4.14 mmol/L)
•Low risk (0-1 risk factor): ≥160 mg/dL (<4.14 mmol/L)
Or: b.HDL-C <40 mg/dL (<1.04 mmol/L) in men or <50 mg/dL (<1.29 mmol/L) in women Or: c.TG ≥ 150 mg/dL (≥ 1.69 mmol/L)
Note: Please see Table 3-1 for recommended retest guidance for TG and LDL-C.
6.Patient has TG levels ≤ 500 mg/dL (≤ 5.65 mmol/L). |
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| E.4 | Principal exclusion criteria |
1.Patient is pregnant, breastfeeding, or expecting to conceive during the study including the 14-day post study follow-up. 2.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. 3.Female patient is expecting to donate eggs during the study, including the 14-day follow-up. 4.Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate. 5.Patient is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study. 6. Patient is currently participating in or has participated in a study with: an investigational compound (non-lipid-modifying) within 30 days of Visit 1, a lipid-modifying compound (investigational or marketed, including statins), within 6 weeks of Visit 1 (fibrate within 8 weeks). 7.Patient has donated and/or received blood as follows:
•donated blood products or has had phlebotomy of >300 mL within 8 weeks prior to signing informed consent.
•intends to give or receive blood products during the study.
•intends to donate more than 250 mL of blood products within 8 weeks following the last study visit.
8.Patient has the following exclusionary laboratory values at Visit 1 (see Table 3-1 for ALT/AST/CK recommended retest guidance).
•Creatinine >2.0 mg/dL (177 micromol/L)
•LT (SGPT) >1.5 x ULN
•AST (SGOT) >1.5 x ULN
•CK >2 x ULN
9.Patient is at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse.
10.Patient was <75% compliant during placebo run-in AND, in the opinion of the investigator, is believed to be unable to maintain at least a 75% compliance with dosing during the active treatment period. Prohibited Medical Conditions
Note: Physician circulars should be followed for the patient’s specific statin therapy.
11.Patient has chronic heart failure defined by the New York Heart Association (NYHA) Classes III or IV, uncontrolled cardiac arrhythmias, or unstable hypertension (systolic blood pressure > 160 mm Hg or diastolic > 100 mm Hg).
12.Patient has Type 1 or Type 2 diabetes mellitus and meets one or more of the following criteria: Patient is poorly controlled (HbA1C >8.5% at Visit 1) Patient is newly diagnosed (within 3 months of Visit 1)Patient has recently experienced repeated hypoglycemia or unstable glycemic control. Patient is taking new or recently adjusted antidiabetic pharmacotherapy (with the exception of ± 10 units of insulin) within 3 months of Visit 1. 13.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: 14.Patient has nephrotic syndrome or other clinically significant renal disease. 15.Patient has active peptic ulcer disease within 3 months of Visit 1. 16.Patient has had an episode of gout within 1 year of Visit 1, unless patient is currently taking allopurinol. 17.Patient has a history of hypersensitivity or allergic reaction to niacin or niacin-containing products.
18.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. 9.Patient has history of ileal bypass, gastric bypass or other significant condition associated with malabsorption.
20. Patient has active or chronic hepatobiliary or hepatic disease.
NOTE: Patients with chronic hepatitis B or C or non-alcoholic steatosis are allowed in the study if ALT and AST are within protocol-specified range at Visit 1.
21. Patient is HIV positive.
Prohibited Medications
22. Patient is currently taking or has taken bile acid sequestrants, niacin ≥250 mg, red yeast rice products (e.g., Cholestin™), prescription omega-3-acid ethyl esthers (e.g., Lovaza™), or excluded statins (lovastatin, pravastatin, fluvastatin) within 6 weeks of Visit 1, or fibrates within 8 weeks of Visit 1.
23. Patient is receiving treatment with systemic corticosteroids (intravenous, injected, and oral steroids) OR systemic anabolic agents.
NOTE: Testosterone supplementation is allowed with a stable regimen for at least 6 weeks prior to randomization (Visit 3). Topical, intra-articular, nasal, inhaled, and ophthalmic steroid therapies are allowed. Intermittent, unplanned use of systemic corticosteroids is acceptable if dose duration does not exceed 14 days. Specific dates of use for intermittent systemic treatment must be recorded appropriately on the eCRF.
24. Patient consumes more than 3 alcoholic drinks on any given day or more than 14 drinks per week. Definition of alcoholic drink available in the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy parameter is the percent change from baseline in LDL-C following 12 weeks of active treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 Visit of the Last 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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