Clinical Trials Register

Summary
EudraCT Number:	2013-001517-32
Sponsor's Protocol Code Number:	K-877-201
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-07-26
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2013-001517-32

A.3

Full title of the trial

A dose finding study to assess the safety and efficacy of K-877 in patients with statin-controlled LDL-C but abnormal lipid levels

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

To find a safe and effective dose of K-877 for targeted patients

A.4.1

Sponsor's protocol code number

K-877-201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kowa Research Europe
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Kowa Research Europe
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kowa Research Europe
B.5.2	Functional name of contact point	Yusuke Senko
B.5.3	Address:
B.5.3.1	Street Address	105 Wharfedale Road
B.5.3.2	Town/ city	Winnersh Triangle, Wokingham
B.5.3.3	Post code	RG41 5RB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+440118922 9000110
B.5.6	E-mail	ysenko@kowa.co.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	K-877
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	848259–27–8
D.3.9.2	Current sponsor code	K-877
D.3.9.3	Other descriptive name	K-877
D.3.9.4	EV Substance Code	SUB119482
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

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

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 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), very low density lipoprotein (VLDL 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 Week 12
•To measure PK parameters in a subset of patients per dose group

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 above the NCEP ATP III target (see Note 2 below):
• LDL C <70 or <100 mg/dL for patients with CHD or CHD equivalent
• LDL C <130 mg/dL for patients with multiple risk factors
• LDL C <160 mg/dL 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 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 and ≤500 mg/dL
Note: If the patient fails to meet this criterion at 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 for men and ≤55 mg/dL 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 level in menopausal range 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

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 [HbA1c] >10%)
6. Patients who are receiving insulin or insulin analog 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 the normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at any screening visit
9. Patients with a creatine kinase (CK) level >3 × ULN at screening
10. Patients with hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormalities, eg, persistent increase in serum transaminase), gall bladder disease, or pancreatitis
11. Patients with a history of drug or alcohol abuse; allowed amounts are 20 g for women and 30 g for men per day (see Appendix D for details on calculating alcohol use)
12. Patients who have a hypersensitivity/intolerance to PPARα agonists or statins, contraindications as per approved statin Summary of Product Characteristics (SPC)
13. Patients who had MI, 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, 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 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. Patient has a high possibility they will not be compliant with the requirements of the protocol
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

12 weeks

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, 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, 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/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

12 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

LVLS

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

350

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

350

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-09-23

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