Clinical Trials Register

Summary
EudraCT Number:	2010-021627-27
Sponsor's Protocol Code Number:	MK-0524A-133
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-02-02
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2010-021627-27

A.3

Full title of the trial

A Worldwide, Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled 12-Week Study to Evaluate the Efficacy and Safety of Extended Release (ER) Niacin/Laropiprant When Added to Ongoing Lipid-Modifying Therapy in Patients with Primary Hypercholesterolemia or Mixed Dyslipidemia

A.3.1

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

A worldwide placebo-controlled study to evaluate the additional lipid benefits of extended release (ER) niacin/laropiprant when taken with current lipid-modifying therapy in individuals with abnormal lipids

A.4.1

Sponsor's protocol code number

MK-0524A-133

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,
B.5.2	Functional name of contact point	Global Clinical Trial Organisation
B.5.3	Address:
B.5.3.1	Street Address	K15-2310, 2000 Galloping Hill Road
B.5.3.2	Town/ city	Kenilworth
B.5.3.3	Post code	NJ 07033
B.5.3.4	Country	United States
B.5.4	Telephone number	+1908740-2381
B.5.5	Fax number	+1908740-3606
B.5.6	E-mail	david.detoro@merck.com

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	Yes
D.2.1.1.1	Trade name	Tredaptive 1000 mg/20 mg modified-release tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd., Hoddesdon, UK
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	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.3.8	INN - Proposed INN	NICOTINIC ACID
D.3.9.1	CAS number	59-67-6
D.3.9.3	Other descriptive name	pyridine-3-carboxylic acid
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LAROPIPRANT
D.3.9.1	CAS number	571170-77-9
D.3.9.2	Current sponsor code	MK-0524
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	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

Primary Hypercholesterolemia or Mixed Dyslipidemia

E.1.1.1

Medical condition in easily understood language

High blood cholesterol or high concentration of lipids in the blood.

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10020604
E.1.2	Term	Hypercholesterolemia
E.1.2	System Organ Class	100000004861

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10058110
E.1.2	Term	Dyslipidemia
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 evaluate the efficacy of ERN/LRPT 2 g relative to placebo on plasma LDL-C at Week 12 of treatment.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of ERN/LRPT 2 g relative to placebo on plasma concentrations of LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I,
TC:HDL-C, Lp(a), Apo A-I, and TC at Week 12 of treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Protocol-Specific:

1. Patient has a history of primary hypercholesterolemia or mixed dyslipidemia.

2. Patient must meet one of the following risk categories and corresponding LDL-C criteria (detailed definitions of risk categories are in Appendix 6.1) at Visit 2.

Risk Category: Very High Risk
Criteria: Established CHD or other atherosclerotic vascular disease + other significant or multiple risk factors
Acceptable LDL-C Value (Visit 2):≥70 to <130 mg/dL; ≥1.81 to <3.36 mmol/L

Risk Category: High Risk:
Criteria: One of the following:
-CHD
-CHD risk equivalent
Acceptable LDL-C Value (Visit 2):≥100 to <130 mg/dL; ≥2.59 to <3.36 mmol/L

Risk Category: Moderate Risk
Criteria: Non-CHD/Non-CHD Risk Equivalent patient with ≥2 risk factors and Framingham 10-year CHD risk ≤20%
Acceptable LDL-C Value (Visit 2): ≥130 to <160 mg/dL; ≥3.36 to <4.14 mmol/L

3. Patient has TG levels <500 mg/dL (<5.65 mmol/L) at Visit 2.

4. Patient has been on a stable dose of one of the following LMTs for at least 6 weeks prior to Visit 1, and agrees to remain on the same type and dose of LMT for the duration of the study, unless the patient is LMT naive. Patient who is given new therapy (ezetimibe/simvastatin FDC tablet 10/20 mg or rosuvastatin 10 mg or ezetimibe co-administered with any statin) based on investigator’s clinical judgment at Visit 1, must agree to remain on the same type and dose of LMT for the duration of
the study:
-Monotherapy: any statin
-Combination Therapy: ezetimibe/simvastatin FDC tablet
-Co-administration Therapy: any statin co-administered with ezetimibe

General:

5. Patient is male or female and ≥18 years of age on day of signing informed consent.

6. A female patient must meet ONE of the following:

a. Of reproductive potential and agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the study duration. An acceptable method of birth control is defined as:
- intrauterine device (IUD)
- diaphragm with spermicide
- condom
- vasectomy
- oral contraceptive pills (OCPs) – must have been used for at least 2 months prior to randomization.
- contraceptive sponge (with spermicide) is acceptable as a single method of birth control but requires one of the following as a second method: intrauterine device (IUD), diaphragm, condom or vasectomy.

b. Not of reproductive potential is eligible without requiring the use of contraception.

Definition of "not of reproductive potential": one who has either of the
following:
- reached natural menopause, defined as: 6 months of spontaneous amenorrhea with serum FSH levels (at Visit 1) in the postmenopausal range (per central lab) or 12 months of spontaneous amenorrhea.
Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa).
- 6 weeks post surgical ysterectomy, or bilateral oophorectomy with or without hysterectomy.
- Bilateral tubal ligation without subsequent restorative procedure.

7. Patient understands the study’s procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.

E.4

Principal exclusion criteria

Protocol-Specific:

1. Patient has taken a prohibited LMT within 6 weeks of Visit 1. Examples of prohibited LMT include bile acid sequestrants, fibrates (monotherapy, coadministration or combination with other LMT), niacin >50 mg, and red yeast rice products.

2. Patient has had a change to the type or dose of acceptable LMT regimen within 6 weeks of Visit 1.

General:
3. Patient is pregnant, breastfeeding, or expecting to conceive during the study including the 14-day poststudy follow-up.

4. Patient has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical
cancer.

5. Female patient is expecting to donate eggs during the study, including the 14-day follow-up.

6. Patient is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study.

7. Patient has participated in a study, including post-study follow-up, with an investigational compound (non-lipid-modifying) within 30 days of Visit 1 or a lipidmodifying compound (investigational or marketed), within 6 weeks of Visit 1.

8. Patient has donated and/or received blood as follows:

- donated blood products or has had phlebotomy of >300 mL within 8 weeks prior to signing informed consent.
- intends to give or receive blood products during the study.
- intends to donate more than 250 mL of blood products within 8 weeks following the last study visit.

9. Patient has the following exclusionary laboratory values at Visit 2 (Table 3-1 provides retesting guidelines).
- Creatinine clearance (eGFR) <30 mL/min (0.50 mL/s)
- ALT (SGPT) >1.5 x ULN
- AST (SGOT) >1.5 x ULN
- CK >2 x ULN

10. Patient has used recreational or illicit drugs within 1 year of signing informed consent.

11. Patient was <80% compliant with LMT or placebo at Visit 2, AND in the opinion of the investigator, is believed to be unable to maintain at least 80% compliance with dosing during the active treatment period.

Prohibited Medical Conditions

12. Patient has chronic heart failure defined by the New York Heart Association (NYHA) Classes III or IV, uncontrolled cardiac arrhythmias, or poorly controlled hypertension (systolic blood pressure >160 mm Hg or diastolic >100 mm Hg).

13. Patient has Type 1 or Type 2 diabetes mellitus and meets one or more of the following criteria:
- Patient is poorly controlled (HbA1C >8.0% at Visit 1)
- Patient is newly diagnosed (within 3 months of Visit 1)
- Patient has recently experienced repeated hypoglycemia or unstable glycemic control (within 3 months of Visit 1).
- Patient is taking new or recently adjusted antidiabetic pharmacotherapy (with the
exception of ± ≤10 units of insulin) within 3 months of Visit 1.

14. Patient has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia such as hyper- or
hypothyroidism:

15. Patient has nephrotic syndrome or other clinically significant renal disease.

16. Patient has active peptic ulcer disease within 3 months of Visit 1.

17. Patient has a history of hypersensitivity or allergic reaction to niacin or niacincontaining products.

18. Patient has history of myocardial infarction, stroke, coronary artery bypass surgery or other revascularization procedure, unstable angina or angioplasty within 3 months of Visit 1.

19. Patient has arterial bleeding.

20. Patient has a history of ileal bypass, gastric bypass or other significant condition associated with malabsorption or rapid weight loss within 18 months of Visit 1.

21. Patient has active or chronic hepatobiliary or hepatic disease.

Prohibited Concomitant Medications

22. Patient is Chinese and is on simvastatin 80 mg or a product containing simvastatin 80 mg at Visit 1.

23. Patient is receiving treatment with systemic steroids (intravenous, injected, and oral steroids) OR systemic anabolic agents.

24. Patient consumes more than 3 alcoholic drinks on any given day or more than 14 drinks per week. Please see Section 3.2.2 for definition of alcoholic drinks.

25. Patient is taking the following antioxidant vitamins each day:

- Vitamin C in excess of 1500 mg
- Vitamin E in excess of 45 IU for men, 36 IU for women
- Beta Carotene 15000 IU for men, 12000 IU for women

E.5 End points

E.5.1

Primary end point(s)

Efficacy Endpoints:

Percent change from baseline in LDL-C at Week 12.

Exploratory Endpoints:

Percent change from baseline in hsCRP, proportion of patients who achieve LDL-C, HDL-C, and TG target lipid levels (per NCEP ATP III and ESC) and proportion of patients who achieve LDL-C, non-HDL-C, and Apo B targets per ADA/ACC, lipoprotein sub-fractions, exploratory proteomics, DNA, posthoc analysis using biomarker samples.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

E.5.2

Secondary end point(s)

Secondary endpoints include the percent change from baseline in LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I, TC:HDL-C, Lp(a), Apo A-I, and TC, at week 12 and, with LDL-C added, at Week 4. Also included is the proportion of patients who achieve LDL-C target lipid levels (both NCEP ATP III and ESC targets).

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

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

Yes

E.6.13.1

Other scope of the trial description

tolerability

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Argentina

Australia

Brazil

Bulgaria

Canada

Chile

Colombia

Czech Republic

France

Germany

Hungary

India

Israel

Italy

Mexico

Netherlands

New Zealand

Peru

Philippines

Poland

Russian Federation

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

last visit of the last subject

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 years

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