| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Metabolic syndrome as defined by the ATP III criteria
Síndrome metabólico, tal como se define por criterios de la ATP III |
|
| 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 | 10052066 |
| E.1.2 | Term | Metabolic syndrome |
|
| 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 compare postprandial endothelial function (pre-meal minus post-meal) measured by brachial artery flow-mediated dilation (FMD) after 6 weeks of treatment with ezetimibe/simvastatin (10 mg/10 mg) combination tablet versus simvastatin 80 mg tablet. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare postprandial endothelial function (pre-meal minus post-meal) measured by finger plethysmography (ENDOPAT) after 6 weeks of treatment with ezetimibe/simvastatin (10 mg/10 mg) combination tablet versus simvastatin 80 mg tablet.
2. To compare pre-meal endothelial function assessed by brachial artery flow-mediated dilation (FMD) after 6 weeks of treatment with ezetimibe/simvastatin (10 mg/10 mg) combination tablet versus simvastatin 80 mg tablet.
3. To compare pre-meal endothelial function assessed by finger plethysmography (ENDOPAT) after 6 weeks of treatment with ezetimibe/simvastatin (10 mg/10 mg) combination tablet versus simvastatin 80 mg tablet. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients should fulfill the diagnostic criterium of abdominal adiposity according to the modified 2005 AHA/NHLBI Scientific Statement
Males: waist circumference ?102 cm (?40 in)
Note: For male Asian Americans (as reported by the patient), waist circumference ?90 cm (?35 in)
Females: waist circumference (?35 in)
Note: For female Asian Americans (as reported by the patient), waist circumference ?80 cm (?31 in)
2. Patient has a diagnosis of metabolic syndrome according to the modified 2005 AHA/NHLBI Scientific Statement which include in addition to abdominal adiposity 2 of the following 4 risk factors.
i) Triglycerides (TG)
TG ?150 mg/dL (?1.7 mmol/L)
ii) HDL Cholesterol
Males: HDL-C <40 mg/dL (<1.03 mmol/L)
Females: HDL-C <50 mg/dL (<1.3 mmol/L)
iii) Bloodpressure
Systolic Bloodpressure ?130 mm Hg or
Diastolic Bloodpressure ?85 mm Hg
iv) Fasting glucose
?100 mg/dL (?5.55 mmol/L)
3. Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
4. Patient is a male or female of 18-79 years of age on the day of signing informed consent.
5. Patient is willing to maintain a stable diet for the duration of the study.
6. Patient is a postmenopausal female who is not receiving hormone therapy (including cyclic and non-cyclical hormone replacement therapy or any estrogen antagonist/agonist). Postmenopausal status is defined as (1) no menses for ?1 year but <3 years and confirmed by FSH levels elevated into the postmenopausal range (as defined by the designated laboratory) or (2) no menses for at least 3 years.
7. Patient is ?naïve? to lipid-lowering therapy. (?naïve?, for the purposes of this protocol, is defined as not being treated with statin, fibrate, niacin, ezetimibe or other lipid-lowering drugs for at least 3 months prior to Visit 1 (Week -2).
8. Patient has a baseline fasting LDL-C level of ?100 mg/dL (?2.59 mmol/L) and <220 mg/dL (<5.69 mmol/L), and TG level <400 mg/dL (<4.52 mmol/L) at Visit 1 (Week -2). |
|
| E.4 | Principal exclusion criteria |
1.Patient weighs (>159 kg).
2.Patient has a hypersensitivity or intolerance to ezetimibe or simvastatin or any component of these medications.
3.Patient consumes more than 14 alcoholic drinks per week.
4.Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent.
5.Patient has smoked <3 months from study start or smoking history > 10 packyears
6.Patient has exclusionary laboratory values at Visit 1 as listed in the table below:
liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST])> 1.5 X ULN with no active liver disease
Glucose > 7.0 mmol/L (126 mg/dL)
Creatine kinase (CK) > 2 X ULN
Albumin:creatinine ratio >34
TSH <0.3 mcIU/mL or > 5.0 mcIU/mL
7.Patient has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the patient?s participation for the full duration of the study, such that it is not in the best interest of the patient to participate.
8.Patient has congestive heart failure.
9.Patient has atherosclerotic vascular disease.
10.Patient has acute or chronic coronary heart disease.
11.Patient has a history of pre-eclampsia < 6 years prior to Visit 1.
12.Patient has had a partial ileal bypass, gastric bypass or gastric banding.
13.Patient has celiac disease or other significant intestinal malabsorption.
14.Patient has untreated and uncontrolled hypertension with systolic blood pressure >160 mm Hg or diastolic >100 mm Hg at Visit 1(Week -4/-3).
15.Patient has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 based on the 4-variable (age, race, gender and creatinine) MDRD (Modification of Diet in Renal Disease) equation at Visit 1 (as done by the central lab), history of nephrotic syndrome or other clinically significant renal disease at Visit 1 (Week -4/-3).
17.Patient has diabetes mellitus defined as a history of diabetes or fasting serum glucose >126 mg/dL.
19.Patient is known to be HIV positive.
20.Patient has a history of malignancy ? 5 years prior to signing informed consent, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer.
21.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 or dependence.
22.Patient has a history of mental instability or major psychiatric illness not adequately controlled and stable on pharmacotherapy.
23.Patient has Raynauds Syndrome.
24.Patient has significant aortic coarctation.
25.Patient has significant deformity of fingers of either hand prohibiting use of the same digit on both hands for ENDOPAT.
26.Patient has had a mastectomy or is going to have one during the study period.
27.Patient has a history of upper extremity thrombosis
28.Patient is currently taking any antihypertensive or vasoactive medications. This includes standard antihypertensive drug therapies and nitrates.
29.Patient is currently taking any potent inhibitor of cytochrome P450 3A4 (CYP3A4), such as: itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone.
30.Patient is currently taking therapies that could increase the risk of myopathy, such as: verapamil, amiodarone, or trandolapril/verapamil.
31.Patient is currently taking cyclosporine, danazol or fusidic acid.
32.Patient consumes >1 liter of grapefruit juice per day.
33.Patient has taken lipid-lowering agents including OTC supplements of fish oils containing > 200 mg/day of EPA+DHA (for example, 1g of cod liver oil contains 0.19g of EPA+DHA, and does not exceed the RDA for vitamins A and D), red yeast rice extract, Cholestin®, bile-acid sequestrants, HMG-CoA reductase inhibitors (statins) or ezetimibe or niacin or fibrates taken within 3 months prior to study entry.
34.Patient is receiving treatment with systemic corticosteroids (intravenous, intramuscular and oral steroids) or has received within 6 weeks prior to randomization (Visit 3).
35.Patient has been on treatment with orlistat, sibutramine, rimonabant or other anti-obesity medications within 3 months prior to study entry or is actively losing weight.
36.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 2 (Week -2) and patient agrees to remain on constant regimen for the duration of the study.
38.It is not possible to obtain a FMD measurement of sufficient quality at screening (Visit 1)
39.Patient is known to have or has a history of Obstructive Sleep Apnea Syndrome (OSAS) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Endpoints
The primary efficacy endpoint is the delta between pre-meal and post-meal FMD (FMD pre-meal minus FMD 4 hours post-meal) following 6 weeks of treatment with simvastatin 10 mg combined with ezetimibe 10 mg or simvastatin 80 mg monotherapy.
Secondary efficacy endpoint include the delta of pre-meal and post-meal (pre-meal minus post-meal) of finger plethysmography (ENDOPAT) after 6 weeks of treatment. In addition, a within group comparison will be made from pre to post meal changes in FMD and ENDOPAT in both groups. The pre-meal FMD and ENDOPAT measurement after 6 weeks of treatment, pre-meal and post-meal, AUC and AUIC of lipids, apolipoproteins, and lipoprotein compositional changes (e.g., LDL-C, total cholesterol (TC), TG, free fatty acids, HDL-C, non-HDL-C, Apo A-1, Apo B48 and B100, inflammatory markers, oxysterols, and phytosterols) will also be examined. Finally, differences in autonomic tone measured by Heart Rate Variability (HRV) (lnLF, lnHF and HF/LF ratio) and the relation with changes in vascular reactivity (FMD and ENDOPAT) will be assessed.
Safety Endpoints
Safety will be assessed primarily by clinical and statistical review of all safety parameters, including adverse experiences (AEs), laboratory values and vital signs occurring during the treatment period. The safety analysis will focus on the percentage of patients with one or more AEs (overall), drug-related AEs, serious AEs, discontinuations due to an AE and the percentage of patients with elevation in ALT or AST (>3xULN) and CK(>10xULN). Pre-meal and post-meal inflammatory and endothelial markers (IL-6, PAI-1, vwF and E-selectin), Pre-meal and post-meal hormones (adiponectin and insulin) will be also be examined. |
|
| 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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.8.3 |
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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
