| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| dyslipidemia (eg hyperlipidaemia, hypertriglyceridaemia) |
|
| E.1.1.1 | Medical condition in easily understood language |
| abnormally high lipid levels |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020667 |
| E.1.2 | Term | Hyperlipidemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 assess the dose response of the following parameters:
•% change in non high density lipoprotein cholesterol (non HDL C) from baseline to Week 12
•% change in TG from baseline to Week 12
To assess the safety and tolerability of K 877 in patients with residual cardiovascular risk despite statin controlled LDL C concentration as particularly evaluated by:
•Change and % change in serum creatinine from baseline to Week 12
•Change and % change in homocysteine from baseline to Week 12
|
|
| E.2.2 | Secondary objectives of the trial |
To assess the response of the following parameters:
•% change in HDL-C, total cholesterol (TC), and apolipoprotein (Apo) B from baseline to Wk 12
•% change in Apo A1 and Apo A2 from baseline to Week 12
•% change in LDL-C, small LDL particles (small and dense LDL), very low density lipoprotein (VLDL-C) (calculated as TC - LDL-C - HDL-C), Apo B48, Apo B100, Apo C2, Apo C3, adiponectin, fibroblast growth factor 21 (FGF21), high sensitivity C reactive protein (hsCRP), lecithin cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP) mass and activity, proprotein convertase subtilisin/kexin type 9 (PCSK9) mass, HDL function (reverse cholesterol transport, HDL driven endothelial production of nitric oxide, Ion mobility analysis, HDL sub fractions (including pre beta HDL) and lipid and lipoprotein ratios TC/HDL C, non HDL C/HDL C, Apo B/Apo A1, LDL C/Apo B, and Apo C3/Apo C2, from baseline to Wk 12
To measure PK parameters in a subset of patients per dose group |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients who meet the following criteria at screening will be eligible to participate in the study:
1. Able to understand and comply with study procedures and give written informed consent
2. Aged>=18 years
3. Have no clinically significant abnormal findings on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG) and clinical laboratory profiles of both blood and urine that would impair participation or safety in the trial or clinically relevant abnormal findings that in the opinion of the investigator could interfere with the objectives of the study or the safety of the patient
4. After treatment with stable statin therapy for at least 12 weeks prior to screening, have a screening LDL-C of no more than 10 mg/dL (0.259 mmol/L) above the NCEP ATP III target (see Note 2 below):
- LDL-C<70 mg/dL (1.81 mmol/L) or <100 mg/dL (2.59 mmol/L) for patients with coronary heart disease (CHD) or CHD equivalent
- LDL-C<130 mg/dL (3.36 mmol/L) for patients with multiple risk factors
- LDL-C<160 mg/dL (4.14 mmol/L) for patients with 0-1 risk factor
Note 1: Any statin approved by the regulatory authority in the respective country is allowed, with the exception of pravastatin, lovastatin, and fluvastatin
Note 2: If LDL-C is greater than 10 mg/dL (0.259 mmol/L) above target, patients are only eligible for the study if they are on the maximum allowable statin dose as per approved SPC in the respective country or on the maximum dose tolerated by the respective patient.
5. Fasting TG value at screening is>=175 mg/dL (1.97 mmol/L) and<=500 mg/dL (5.65 mmol/L) Note: If the patient fails to meet this criterion at Screening Visit (SV) 1, a fasting re-test of TG will be allowed at a second SV
6. HDL-C value at screening is<=50 mg/dL (1.30 mmol/L) for men and<=55 mg/dL (1.43 mmol/L)for women
7. Women may be enrolled if all 3 of the following criteria are met:
They are not pregnant
They are not breastfeeding and
They do not plan on becoming pregnant during the study
8. Women of childbearing potential must have a negative urine pregnancy test at screening. Women are not considered to be of childbearing potential if they meet 1 of the following criteria as documented by the investigator:
- They have had a hysterectomy or tubal ligation at minimum 1 cycle prior to signing the Informed Consent Form
- They are post-menopausal, defined as >=1 year since their last menstrual period for women >= 55 years of age or >=1 year since their last menstrual period and have a follicle-stimulating hormone (FSH) level in menopausal range (defined as > 40 miU/mL) for women < 55 years of age
9. Women of childbearing potential must agree to use an effective method of contraception from screening to the end of the study. Effective methods of contraception are those contraceptive methods with a Pearl index of <1 used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives or intrauterine devices)
10. Male study participants will be required to use condoms with a spermicide during sexual intercourse from screening to the end of the study, even if their sexual partner is or may be pregnant |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from participation in the study if any of the following criteria apply:
1. Patients who require other lipid lowering treatments in addition to study drug (K-877) and statin
2. Patients with body mass index ≥40 kg/m2
3. Patients with homozygous familial hypercholesterolaemia (heterozygous is permitted) or familial hypoalphalipoproteinaemia
4. Patients with type 1 diabetes mellitus
5. Patients with poorly controlled type 2 diabetes mellitus (haemoglobin A1c >10%)
6. Patients who are receiving insulin or insulin analogue treatment except for stable basal insulin therapy with a single insulin
7. Patients with moderate or severe renal impairment (ie, estimated glomerular filtration rate <50 mL/min/1.73m2) at screening
8. Patients with serious liver dysfunction; liver function test values >3 × upper limit of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening
9. Patients with a creatine kinase level >3 × ULN at screening
10. Patients with hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormalities), gall bladder disease or pancreatitis
11. Patients with a history of drug or alcohol abuse; allowed amounts of alcohol are an average of 20 g for women and 30 g for men per day as consumed in the course of a week
12. Patients who have a hypersensitivity/intolerance to peroxisome proliferator-activated receptor α agonists or statins, or for whom statins are contraindicated as per approved statin SPC
13. Patients who had myocardial infarction, artery angioplasty, bypass graft surgery or severe/unstable angina pectoris within 3 months prior to screening
14. Patients who had symptomatic cerebrovascular disease including cerebrovascular haemorrhage, ischaemia (including transient ischaemic attack), or carotid endarterectomy within 3 months of screening
15. Patients with symptomatic heart failure (New York Heart Association class III or IV)
16. Patients who have uncontrolled hypertension (seated systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg); Note: An average of 3 readings within an adequate time interval during the study visit may be used to determine blood pressure level
17. Patients who have used lipid modifying treatment other than statins within the 28 days prior to screening
18. Patients with a history of chronic active hepatitis B or hepatitis C or known to be infected with human immunodeficiency virus (HIV) 1 or HIV 2
19. Patients with known muscular or neuromuscular disease
20. Patients with known active or history (<10 years from previous event) of neoplastic disease (excluding basal cell cancer) or patients who may need to take antineoplastic treatment during the study period
21. Patients with uncontrolled hypothyroidism or hyperthyroidism
Note: controlled thyroid disease (normal serum thyroid stimulating hormone [TSH] and stable therapy for at least 3 months) is permitted
22. Patients who have participated in any other clinical studies within 3 months of screening
23. Patients who have experienced a loss of more than 400 mL of blood during the 3 months prior to screening, eg, as a blood donor
24. Patients with a clinically relevant abnormal history, physical examination findings, 12 lead ECG, or laboratory values at screening that in the opinion of the investigator could interfere with the objectives of the study or the safety of the patient
25. Patients with a high possibility they will not be compliant with the requirements of the protocol (eg uncooperative attitude, inability to return for follow up visits and unlikelihood of completing the study)
26. Patients who have a mental condition rendering them unable to understand the nature, scope, and possible consequences of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoints of the study include the following:
• % change in non HDL C from baseline to Week 12
• % change in TG from baseline to Week 12
For the primary endpoints, non HDL C and TG, the primary analysis will be carried out using an analysis of covariance (ANCOVA) model with percent change from baseline to Week 12, baseline non HDL C, and baseline TG values as covariates, respectively. The superiority of K 877 groups compared to placebo will be assessed by Dunnett’s test, which will be performed separately for once daily (QD) and twice daily (BID) groups. As a secondary analysis, the dose response relationship in K 877 QD group and BID group will be separately assessed with a contrast method with the ANCOVA model. In addition, the difference between all groups will be assessed with the ANCOVA model. The primary efficacy analysis will be performed on the ITT and Per Protocol Populations.
The primary efficacy analysis will use the MMRM model for missing data imputation. Sensitivity analysis with LOCF method will be performed. Other possible solutions for the missing data imputation will also be explored, such as repeated measurements at Week 4, Week 8, and Week 12 with compound symmetry covariance structure and repeated measurements at Week 8 and Week 12 with compound symmetry covariance structure.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include the following:
• % change in HDL C, TC, and Apo B from baseline to Week 12
• % change in Apo A1 and Apo A2 from baseline to Week 12
• % change in LDL C, small LDL particles (small and dense LDL), VLDL C (calculated as TC - LDL-C - HDL-C), Apo B48, Apo C2, Apo C3, adiponectin, FGF21, hsCRP, LCAT, CETP mass and activity, PCSK9 mass, HDL function (reverse cholesterol transport, HDL driven endothelial production of nitric oxide, Ion mobility analysis, 2 D gel analysis for HDL sub fractions including pre beta HDL, Calculation: TC/HDL C, non HDL C/HDL C, Apo B/Apo A1, LDL C/Apo B, Apo B100, and Apo C3/C2 from baseline to Week 12
The secondary efficacy endpoints will be analysed using the same statistical method used for the primary analysis; however, Dunnett’s test will not be used to evaluate the superiority of the K 877 groups to the placebo group. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | No |
| 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 |
| Czech Republic |
| Denmark |
| Germany |
| Hungary |
| Netherlands |
| Poland |
| Russian Federation |
| Sweden |
| United Kingdom |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
