| 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 efficacy of TAK-475 compared to placebo on low-density lipoprotein cholesterol (LDL-c) levels in subjects with Type 2 Diabetes currently treated with doses of other lipid-lowering drugs. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of TAK-475 compared to placebo on total cholesterol (TC),
triglycerides (TGs), high-density lipoprotein cholesterol (HDL-c), very-low densitylipoproteins (VLDL-c), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B), in this population. The percentage of subjects achieving LDL-c levels of <130 mg/dL, <100mg/dL and < 70 mg/dL after 24 weeks of treatment and the overall safety and tolerability will be evaluated. Other secondary objectives are to evaluate the effects of TAK-475 compared to placebo on other lipid variables, high-sensitivity C-reactive protein (hs-CRP), apolipoprotein (a) and Hb A1c.
Blood samples for the determination of biomarkers, including cardiovascular morbidity markers will also be collected. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged ≥ 18 years,
2. Capable of understanding and willing to sign the Informed Consent Form, 3. Documented diagnosis of Type 2 diabetes mellitus for > 6 months (Random
venous plasma glucose ≥ 200 mg/dL (11.1 mmol/L), 2-hour glucose tolerance during a 75g oral glucose tolerance test (OGTT) ≥ 200mg/dL (11.1 mmol/L) or Fasting Plasma Glucose (FPG) ≥126 mg/dL (7 mmol/L)), with stable glycaemic control over a period of at least 3 months and HbA1c of 9.5 % or less.
4. On a stable antidiabetic regimen, which may include oral antidiabetic medication and/or insulin, for at least 3 months prior to Screening (Visit 1).
5. The most recent value of LDL-c ≥ 100 mg/dL (2.59 mmol/L) and triglycerides ≤ 400mg/dl (4.52 mmol/L), within the previous 6 months, currently treated with one of the following lipid-lowering drugs: atorvastatin (10 mg, 20 mg, or 40 mg), simvastatin (20mg or 40 mg), rosuvastatin (10 mg or 20 mg), or fenofibrate (not to exceed 200 mg), and no changes in the medication for at least 4 Weeks before Screening (Visit 1). If no value is available, then confirm acceptability for enrolment from result on sample taken at screening visit 1.
6. The subject is otherwise in good health as determined by a physician (ie, via medical history and physical examination)
7. At Randomisation (Visit 4) in order to be randomised subjects must have fulfilled the above criteria and also have: Mean LDL-cholesterol levels of ≥100mg/dL
(2.59 mmol/L) and mean triglycerides level of ≤ 400 mg/dL (4.52 mmol/L). The mean
values will be calculated from measurements made at Week –2 (Visit 2) and Week –1
(Visit 3) for each subject. For LDL-cholesterol the difference between the two individual values must not differ by more than 15% of the upper value. For triglycerides, the upper value 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 with
TAK-475 100mg or placebo.
8. 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.
9. At Randomisation (Visit 4) in order to be randomised subjects must have fulfilled
the above criteria and also have:
Mean LDL-cholesterol levels of ≥100mg/dL (2.59 mmol/L) and mean triglycerides level of ≤ 400 mg/dL (4.52 mmol/L). The mean values will be calculated from measurements made at Week –2 (Visit 2) and Week –1 (Visit 3) for each subject. For LDL-cholesterol the difference between the two individual values must not differ by more than 15% of the upper value. For triglycerides, the upper value 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 with TAK-475 100mg or placebo. |
|
| E.4 | Principal exclusion criteria |
At Screening (Visit 1) to enter the 4-Week Run-In period the subjects must not be/have:
1. Type 1 Diabetes Mellitus
2. Between screening and randomisation,
(i) ALT or AST level >1.5 times the upper limit of normal (ULN). If a repeat
test is <1.5 times ULN then contact the Takeda Safety Contact for
consideration of inclusion – see Section 6.6.1,
(ii) serum creatinine >133 μmol/L (>1.5mg/dL) or (iii) CPK >3 times the upper limit of normal (ULN)
3. Active liver disease, gallbladder disease (with or without cholelithiasis) or jaundice
4. Positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject’s verbal report
5. Positive human immunodeficiency virus status or is taking anti-retroviral
medications, as determined by medical history and/or subject’s verbal report
6. Known hypersensitivity or intolerance to TAK-475 or to the planned companion medication or its components
7. 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. 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 Lead-In 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. Known heterozygous or homozygous familial hypercholesterolaemia or known Type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia)
11. Fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain
12. Uncontrolled hypertension despite 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 5.5
16. 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. 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, make the subject an unsuitable candidate to receive study drug
20. A history of photoallergic or phototoxic reaction during treatment with a
fibrate or ketoprofen (this applies ONLY if fenofibrate is the planned companion medication). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy: The primary efficacy variable for this study is the fasting direct plasma LDL-c.
Secondary: The secondary efficacy variables are lipid parameters including: non-HDL-c, TC, Apo B, HDL-c, Apo A1, TG, VLDL-c, ratios (LDL-c/HDL-c, TC/HDL-c, Apo
B/Apo A1), hs-CRP and Hb A1c.TC/HDL-c, LDL-c/HDL-c, Apo B/Apo A1 ratios and non-HDL-c will also be derived. Cardiovascular morbidity markers (e.g. Interleukin 6 (IL-6), Oxidazed-LDL, fibrinogen, plasminogen activated inhibitor-1 (PAI-1)) will also be evaluated, if determined.Safety: Safety variables are: Adverse events, clinical chemistry, hematology, urinalysis, electrocardiogram (ECG), vital signs, weight, physical examination and Best Corrected Visual Acuity (BCVA). |
|
| 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 | No |
| 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) | 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 |
|
| 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 |
Print
