| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with primary dyslipidaemia currently taking simvastatin 20mg or 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 of this trial is to evaluate the reduction in LDL-c in subjects with primary dyslipidemia when treated with TAK-475 50 mg OD, TAK-475 100 mg OD or placebo OD when co-administered with simvastatin 20 or 40 mg OD for 24 weeks. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are to evaluate the effects of TAK-475 50 mg OD, TAK-475 100 mg OD or placebo OD when co-administered with simvastatin 20 or 40 mg OD for 24 weeks on
· other lipids variables (see section 4.2.)
· the overall safety and tolerability after 24 weeks of treatment.
· percentage of subjects who achieve LDL-c concentrations of <70, <100, <130 mg/dL at the final visit.
· plasma concentration-time profile of TAK-475, M-I, M-II
· to identify subject factors (covariates) which affect the apparent clearance of the drug.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
At Screening (Visit 1) in order to be eligible for enrolment subjects must be/have:
1) Read and understood the patient information sheet and signed the Written Informed Consent
2) Male or female, aged ≥ 18 years old
3) • Documented history of stable dyslipidemia with or without cardiovascular risk factors but without diabetes type 1 or 2
• The most recent value of LDL-c ≥100 mg/dL (2.59 mmol/L) and ≤190 mg/dL (4.92 mmol/L) and triglyceride levels ≤ 400 mg/dL (4.5 mmol/L), within 6 months prior to Screening. If no value is available, then confirm acceptability for enrolment from result on sample taken at screening visit 1.
5) On a stable dose of simvastatin, either 20 mg or 40 mg for at least 4 weeks previous to Screening Visit 1
6) Currently stable for at least 4 weeks on a standardized diet (e.g. Therapeutic Lifestyle Change Diet (TLC) and is willing and able to comply with it for the duration of the study
7) If female and of childbearing potential, the subject is not pregnant, not lactating or 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
8) In good physical and mental health as determined by a physician (i.e., via medical history and physical examination).
At Randomisation (Visit 4) in order to be randomized subjects must have fulfilled the above criteria and have:
9) Mean LDL-c levels ≥ 100 mg/dL (2.59 mmol/L) and ≤ 170 mg/dL (4.40 mmol/L), and mean triglyceride levels ≤ 400 mg/dL (4.5 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 difference between the two individual values must not differ by more than 15% of the upper value for LDL-c and the upper value for triglycerides for either sample must be ≤ 450 mg/dL (5.1 mmol/L).
If the inclusion range is not attained for either LDL-c or triglycerides levels then the investigator will repeat these assessments at an additional Visit (Visit 3.1). If the LDL-c and triglycerides level then fulfil the above criteria at two consecutive visits at least 1 week apart, then the subject may enter the active phase of treatment.
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| E.4 | Principal exclusion criteria |
Main Criteria for Exclusion:
1. Between screening and randomisation,
(i) ALT or AST level >1.5 times the upper limit of normal (ULN). However, if a repeat test is <1.5 x ULN then contact the Takeda Safety Contact for consideration of inclusion – see Section 6.3.1,
(ii) serum creatinine >133 μmol/L (>1.5mg/dL) or
(iii) CPK >3 times the upper limit of normal (ULN)
2. Active liver disease, gallbladder disease (with or without cholelithiasis) or jaundice
3. A positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject’s verbal report.
4. A positive human immunodeficiency virus status or is taking anti-retroviral medications, as determined by medical history and/or subject’s verbal report.5. A known hypersensitivity or history of intolerance to TAK-475 or simvastatin.
6. Type 1 or 2 diabetes
7. History of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft surgery), in the 6 months prior to Screening, Visit 1.
8. A previous history of cancer, 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.
9. 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. If the subject’s TSH >1.5 x ULN, a free thyroxine T4 level will be determined. If the free thyroxine T4 is within normal limits for that subject, the subject may continue in the study.
10. A known heterozygous or homozygous familial hypercholesterolemia or known Type III hyperlipoproteinemia (familial dysbetalipoproteinemia).
11. Fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain
12. 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 Screening Visit 1.
13. Inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.
14. Unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.
15. Unable or unwilling to discontinue excluded medications or to continue stable doses of “stable dose” medications or would require treatment with any excluded medication during the study. See Prohibited Medications Section 5.4
16. Currently participating in another investigational study or 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.
17. Unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
18. 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 past 2 years.
19. Any other serious disease or condition at Screening or at Randomisation that might reduce life expectancy, impair successful management according to the protocol or make the subject an unsuitable candidate to receive study drug.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The safety assessments include the following variables:
· Adverse events
· Clinical Laboratory Tests
· Physical Examination
· 12-lead electrocardiogram (ECG)
· Weight
· Vital Signs
· Best Corrected Visual Acuity (BCVA)
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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 | Yes |
| 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 | 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.8.6 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 | 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
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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 | 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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