E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with primary hypercholesterolemia currently taking atorvastatin (80mg), simvastatin (80mg) or rosuvastatin (40mg) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058108 |
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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 |
The primary objective is to evaluate the change in low-density lipoprotein cholesterol (LDL-C) in subjects with primary hypercholesterolemia treated with TAK-475 100 mg QD or placebo QD when co-administered with high dose atorvastatin, rosuvastatin, or simvastatin after 24 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• to evaluate safety and tolerability (adverse events [AEs], safety laboratory tests, physical exam [PE], vital signs, best corrected visual acuity [BCVA] and electrocardiogram[ECG])
• to evaluate changes in calculated LDL-c, non-HDL-c (TC minus HDL-c), TC, Apo B, TGs, HDL-c, Apo A1, VLDL-c, derived ratio variables LDL-c/HDL-c, TC/HDL-c and Apo B/Apo A1.
• to evaluate change in hs-CRP.
• to evaluate the percentage of subjects who achieve LDL-C concentrations of <130, <100 and <70 mg/dL at the final visit, until discontinuation of the 100mg dose level.
• the long-term safety of treatment with TAK-475 at 100mg in this population during the open-label extension period at 100 mg.
• the long-term safety of treatment with TAK-475 at 50mg, following down-titration from 100mg dose level,in this population during the open-label extension period. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult male or female subjects (non-pregnant and non-lactating) who are at least 18 years of age, who meet the following lipid criteria:
• Prior to Randomization, the subject must have a mean LDL-C ≥100 mg/dL (2.59 mmol/L) for 2 consecutive samples (at least 1 week apart). The difference between the two individual LDL-C values must not exceed 15% of the higher value
• Prior to Randomization, the subject must have mean triglycerides ≤400 mg/dL (4.52 mmol/L) for 2 consecutive samples (at least 1 week apart). The upper value for either sample must be ≤450 mg/dL (5.1 mmol/L)
The subject must be taking the highest recommended dose of an HMG-CoA reductase inhibitor once daily for at least 4 weeks prior to Visit 1. Subjects who are on a stable regimen of ezetimibe, in addition to their HMG-CoA reductase inhibitor will be allowed to participate in the study while continuing the ezetimibe. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will not qualify for entry into the study:
• if female, are pregnant, lactating, intend to become pregnant during the course of the study, or are unwilling to use acceptable contraception for the course of the study
• have elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>1.5 times the upper limit of normal [ULN]), active liver disease, jaundice, or a history of liver disease
• has serum creatinine >133 mmol/L (1.5 mg/dL);
• have elevated creatine phosphokinase (>3 times ULN);
• has diabetes, with an HbA1c >8% at Visit 1;
• have a history of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, percutaneous coronary intervention, coronary or peripheral arterial surgery (bypass graft surgery) in the 6 months prior to Visit 1;
• have fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain;
• have a known hypersensitivity or history of adverse reaction to atorvastatin, rosuvastatin, or simvastatin;
• has inflammatory bowel disease or any other malabsorption syndrome or have had gastric bypass or another surgical procedure for weight loss;
• have uncontrolled hypertension despite medical treatment (defined as mean resting diastolic blood pressure >100 mm Hg or mean resting systolic blood pressure >160 mm Hg) at Visit 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable for this study is plasma LDL-C.
The secondary efficacy variables are other lipid parameters including calculated LDL-c, non-HDL-c (TC minus HDL-c), TC, Apo B, TGs, HDL-c, Apo A1, VLDL-c, derived ratio variables LDL-c/HDL-c, TC/HDL-c and Apo B/Apo A1, and hs-CRP. |
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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 | 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) | 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 |
Open label extension at the end of 24 weeks treatment |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |