| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with primary dyslipidaemia |
|
| 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 |
|
| 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 evaluate the reduction in low-density lipoprotein cholesterol (LDL-c) in subjects with primary dyslipidemia when treated with TAK-475 100 mg OD versus ezetimibe 10 mg OD for 24 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
1). To evaluate the reduction in LDL-c in subjects with primary dyslipidemia when treated with ezetimibe 10 mg versus TAK-475 100 mg administered in combination with ezetimibe 10 mg for 24 weeks.
2). To evaluate the safety and tolerability (AEs, safety laboratory tests, physical examination, vital signs, BCVA and ECG) and the changes in lipid variables: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TGs), very-low density lipoprotein cholesterol (VLDL-c), Apolipoprotein A1 (ApoA1) and Apolipoprotein B (Apo B) and non-HDL. The percentage of the subjects achieving LDL-c levels of <130mg/dL and < 100mg/dL will be evaluated. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male or female aged ≥ 18 years.
2. If female and of child bearing potential, the subject is not pregnant, not lactating, not planning on becoming pregnant between Screening and 30 days following the last dose of study medication, and agrees to use acceptable forms of contraception during the study.
3. The subject has documented history of dyslipidemia (fasting LDL-c levels ≥ 160 mg/dL (≥4.14 mmol/L) and ≤ 220mg/dL (≤ 5.6mmol/L) and triglycerides ≤ 400 mg/dL (4.52 mmol/L) within 30 days prior to Screening. If this is not the case, an initial blood sample should be taken and analyzed at the local laboratory to confirm this. These results should be confirmed at Screening (Visit 1)).
4. Willing and able to comply with a standardized diet (e.g. TLC)
5. Not have taken any lipid lowering therapy for at least 30 days prior to Screening (Visit 1) (see Prohibited Medication section 5.5).
6. Otherwise is in good physical and mental health as determined by a physician (i.e. via medical history and physical examination).
7. Capable of understanding and willing to sign the Informed Consent Form.
8. At Randomization: the subject must have mean fasting LDL-c levels ≥ 130 mg/dL (3.36mmol/L) and ≤ 220 mg/dL (5.6 mmol/L) and mean triglyceride levels ≤ 400 mg/dL (≤ 4.52 mmol/L). The mean values will be calculated from measurements made at Visit 2 (Week -2) and 3 (Week -1) for each subject. In order for the subject to be Randomized, the individual LDL-c values must not differ by more than 15 % of the upper value, and for triglycerides the upper value must be ≤ 450mg/dl (5.0 mmol/L). If the inclusion range is not attained for either triglycerides or LDL-c then the investigator will repeat these assessments at an additional Visit (Visit 3.1). If the LDL and TG criteria then fulfil the above criteria, and the individual value at Visit 3.1 compared to one individual value from Visit 2 or 3 does not differ by more than 15%, then the subject may enter the active treatment phase. |
|
| E.4 | Principal exclusion criteria |
1. ALT or AST level > 1.5 times the upper limit of normal (ULN), active liver disease, jaundice or serum creatinine > 135 μmol/L prior to Screening and/or Randomization. 2. CPK > 3 times the ULN prior to Screening and/or Randomization.
3. A previous history of cancer, other than basal cell carcinoma, that has been in remission for less than 5 years prior to the first dose of study drug. This criterion does not include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.
4. An endocrine disorder, such as Cushing’s Syndrome, hyperthyroidism or inappropriately treated hypothyroidism affecting lipid metabolism. Subjects with hypothyroidism on appropriate replacement therapy (defined as stable thyroid hormone replacement therapy at least 3 months prior to Screening (Visit 1) and TSH levels ≤ 1.5 x ULN) will be eligible for enrolment.
5. A positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject’s verbal report.
6. A positive human immunodeficiency virus (HIV) status or taking retroviral medications, as determined by medical history and/or subject’s verbal report.
7. Unable or unwilling to discontinue excluded medications or to continue stable doses of “stable dose” medications. See Concomitant Medications (Section 5.4).
8. Participated in any other clinical studies with TAK-475, is currently participating in another investigational study, has participated in an investigational study within the past 30 days or, for drugs with a long half life, within a period of less than 5 times the drug’s half life.
9. A known hypersensitivity or history of intolerance to TAK-475 or ezetimibe.
10. A history or presence of clinically significant food allergy that would prevent adherence to the specialized diet.
11. A known heterozygous or homozygous familial hypercholesteroleamia or known Type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia).
12. Fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain and/or discontinuation of HMG-CoA reductase inhibitors due to myalgia at any time.
13. Uncontrolled hypertension despite medical treatment (Stage 2 hypertension defined as mean resting diastolic blood pressure > 100 mmHg or mean resting systolic blood pressure > 160 mmHg) at Screening (Visit 1).
14. Inflammatory bowel or any other malabsorption syndrome or has had gastric bypass surgery or any other surgical procedure for weight loss.
15. Unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.
16. Unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
17. A history of drug abuse (defined as illicit drug use) or a history of high alcohol intake (defined as regular or daily consumption of more than 3 (males) and 2 (females) alcoholic drinks per day) within the previous 2 years.
18. Any other serious disease or condition at Screening Visit 1 or at Randomization that might reduce life expectancy, impair successful management according to the protocol or make the subject an unsuitable candidate to receive study drug.
19. A history of coronary heart disease (CHD) or CHD-risk factors comprised of: 19.1 Diabetes Mellitus type 1 or 2
19.2 History or presence of myocardial infarction, angina pectoris, unstable angina, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft), aortic aneurysm, transient ischaemic attacks or cerebrovascular accident (maximum of 3-5 trial specific diagnostic criteria).
19.3 Multiple risk factors that confer a 10-year risk of CHD >20% based on the Framingham risk score |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable for this study is fasting serum LDL-C concentration.
The secondary efficacy variables for this study are the following lipid parameters:
· TC
· HDL-c
· TG
· VLDL-c
· Apo Al,
· Apo B
· Non-HDL-c
The supportive variables for this study are the following:
· HDL sub fractions (HDL 2 and HDL3)
· Lipoprotein (a)
· LDL/HDL, TC/HDL, Apo B/Apo A1 - derived variables
· High-sensitivity C-reactive protein (hs-CRP)
Safety assessments
· Adverse Events
· Clinical Laboratory Tests
· 12 Lead ECG
· Vital Signs (blood pressure and pulse rate) and weight
· Best Corrected Visual Acuity (BCVA) · Physical Examination |
|
| 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 | Information not present in EudraCT |
| 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 |
|
| 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.8.5 | 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | |
| 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 |
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