Clinical Trials Register

Summary
EudraCT Number:	2009-012581-32
Sponsor's Protocol Code Number:	SB-480848/033
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-11-26
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

Netherlands - Competent Authority

A.2

EudraCT number

2009-012581-32

A.3

Full title of the trial

A Clinical Outcomes Study of Darapladib versus Placebo in Subjects Following Acute Coronary Syndrome to Compare the Incidence of Major Adverse Cardiovascular Events (MACE).
(Short title: The Stabilization Of pLaques usIng Darapladib- Thrombolysis In Myocardial Infarction 52 [SOLID-TIMI 52] Trial)

A.3.1

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

Study of darapladib in the prevention of heart attacks, stroke and death in patients who suffered a heart attack.

A.3.2

Name or abbreviated title of the trial where available

SOLID-TIMI 52

A.4.1

Sponsor's protocol code number

SB-480848/033

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01000727

A.5.4

Other Identifiers

Name:

SOLID-TIMI 52

Number:

SOLID-TIMI 52

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	GlaxoSmithKline Research & Development, Ltd
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	GlaxoSmithKline
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	GlaxoSmithKline
B.5.2	Functional name of contact point	GSK Clinical Support Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	GlaxoSmithKline, Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 (0) 20 8990 4466
B.5.5	Fax number	+44 (0) 20 8990 4968
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	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.3.1	Product name	darapladib
D.3.2	Product code	SB-480848
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.3.8	INN - Proposed INN	darapladib
D.3.9.2	Current sponsor code	SB-480848
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	160
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

after recent Acute Coronary Syndrome (ACS)

E.1.1.1

Medical condition in easily understood language

heart attacks caused by disease of the heart blood vessels

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10051592
E.1.2	Term	Acute coronary syndrome
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate clinical efficacy of longterm treatment with Darapladib Enteric Coated Tablets, 160 mg (oral once daily dose) as compared with placebo when added to standard of care in an ACS patient population on the incidence of first occurrence of the composite of major coronary events (i.e., CHD death, non-fatal MI, or urgent coronary revascularization for myocardial ischemia).

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate the efficacy of darapladib on major adverse cardiovascular events (MACE: cardiovascular (CV) death, non-fatal MI, or non-fatal stroke); the individual components of MACE; the individual components of major coronary events; total coronary events (defined as CHD death, non-fatal MI, urgent and non-urgent coronary revascularization, or hospitalization for unstable angina (UA)); any coronary revascularization procedures; the composite of all-cause mortality, non-fatal MI and non-fatal stroke; the composite of CHD death and non-fatal MI; and all-cause mortality. Additional safety and efficacy parameters, including relations to and changes of biomarkers of CV risk, genetics, health economic outcomes, and adverse events (AEs), will also be valuated.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Substudies:
Primary objective is to establish a population PK model adequate to describe the time-course and variability of plasma darapladib concentrations following repeat dose administration of Darapladib Enteric Coat Tablets, 160 mg in patients with ACS.
Secondary objective is to establish a population PK/PD model adequate to describe the relationship between plasma darapladib concentration and plasma Lp-PLA2 activity following repeat dosing of Darapladib Enteric Coat Tablets, 160 mg in patients with ACS.

Pharmacogentic analysis substudy to explore the:
Relationship between genetic variants and the PK and/or PD of darapladib or related drugs.
Relationship between genetic variants and safety and/or tolerability of darapladib or related drugs.
Relationship between genetic variants or genetically defined disease subtypes to clinical efficacy of darapladib and clinical study outcomes.

E.3

Principal inclusion criteria

1. Signed written informed consent prior to beginning study-related procedures
2. Male or female aged at least 18 years, inclusive, at randomization. Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator and in
accordance with local practice in relation to adequate contraception. In Taiwan, subjects must be aged at least 20 years, inclusive, at randomization.
3. Hospitalisation for ACS (unstable angina, non-ST segment elevation MI, or ST segment elevation MI) ≤30 days prior to randomization:
a. Unstable angina (UA) is defined as ischemic chest discomfort (or equivalent) that occurs at rest with at least 1 episode lasting ≥10 minutes and is accompanied by new or presumably new ST segment deviation [transient (<20 minutes)
elevation ≥0.1mV or dynamic horizontal/down-sloping depression ≥0.05mV)] in at least 2 contiguous leads without diagnostic biochemical changes in cardiac enzymes (serum troponin I or T, or creatine kinase-MB).
b. Non-ST segment elevation MI (NSTEMI) is defined as ischemic chest discomfort (or equivalent) that occurs at rest with at least 1 episode lasting ≥10 minutes and is accompanied by a diagnostic elevation in cardiac biomarkers of myocardial injury (serum troponin I or T, or creatine kinase-MB ) above the upper limit of normal without persistent ST segment elevation.
c. ST segment elevation MI (STEMI) is defined as prolonged symptoms of ischemic chest discomfort (or equivalent) at rest (with at least 1 episode lasting >20 min) and new or presumably new electrocardiographic changes (persistent ST
segment elevation ≥0.1 mV in ≥2 contiguous precordial leads or ≥2 adjacent limb leads or new LBBB) that are accompanied by a diagnostic elevation in cardiac biomarkers (serum troponin I or T, or creatine kinase-MB) above the upper limit
of normal.
4. All subjects must also have at least one of the following additional predictors of cardiovascular risk:
a. age ≥60 years at randomization.
b. history of documented MI prior to qualifying ACS event.
c. diabetes mellitus requiring pharmacotherapy.
d. significant renal dysfunction (defined as estimated glomerular filtration rate [eGFR] ≥30 and ≤59 mL/min per 1.73 m2).
e. polyvascular disease manifested in this ACS population as coexistent clinically diagnosed arterial disease in at least 1 peripheral arterial territory, defined as:
• cerebrovascular disease defined as carotid artery disease or as prior ischemic stroke that occured >3 months prior to randomization.
OR
• peripheral arterial disease (PAD)
5. The subject must be clinically stable for 24 hours prior to randomization (clinical stability is defined as the absence of chest pain, hemodynamic instability [e.g., hypotension, requirement for inotropic therapy], or significant arrhythmia [e.g., arrhythmia requiring treatment]).
6. For subjects in whom a PCI is planned as part of management for the qualifying ACS event, the subjects should undergo PCI prior to randomization whenever possible.

E.4

Principal exclusion criteria

1. Clinical or laboratory manifestations of ACS (e.g., chest pain, ECG changes or increase in cardiac enzymes) that is not believed to be thrombotic in origin or is believed to be secondary to other apparent illness (e.g., sepsis, profound anemia,
tachycardia, hypertensive emergency or decompensated heart failure).
2. Absence of obstructive coronary artery disease (i.e., at least one stenosis [>50%] in a major vessel, major branch or bypass graft) based on angiography, if performed, between the time of presentation with ACS and randomization (NOTE: if all stenoses are succesfully treated by PCI, the patient is still eligible).
3. Planned coronary artery bypass graft (CABG) surgery or CABG surgery performed following the qualifying event and prior to randomization.
4. Cirrhosis: known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones) unstable liver disease (defined by the presence of any of the following felt by the investigator to be related to liver disease and not to other disease processes: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice) or evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase >1.5 x upper limit of normal [ULN]; or alanine aminotransferase (ALT) >2.5 x ULN) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
5. Severe renal impairment (e.g., patients with an eGFR <30 mL/min/1.73 m2 or receiving chronic dialysis) or history of nephrectomy or kidney transplant (regardless of renal function).
6. Current severe heart failure (New York Heart Association [NYHA] class III or IV).
7. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy.
8. Any life-threatening condition with life expectancy <2 years, other than vascular disease, that might prevent the subject from completing the study.
9. Severe asthma that is poorly controlled on pharmacotherapy.
10. Positive pregnancy test (all female subjects of childbearing potential must have a urine or serum β-human chorionic gonadotropin [hCG] pregnancy test performed within 7 days prior to randomization) or is known to be pregnant or lactating.
11. History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses.
12. Alcohol or drug abuse within the past 6 months. Current mental condition
(psychiatric disorder, senility or dementia), which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study.
13. Current or planned chronic administration of strong oral or injectable cytochrome P- 450 isoenzyme 3A4 (CYP3A4) inhibitors.
14. Subjects with 2 known birth parents of at least 50% Japanese, Chinese, or Korean ancestry (or if unknown, a reasonable likelihood of such ancestry) must have a blood sample collected for assessment of Lp-PLA2 activity by the central laboratory prior to randomization. Those with Lp-PLA2 activity ≤20 nmol/min/mL will be excluded from participation in the study.
15. Previous exposure to darapladib (SB-480848).
16. Use of another investigational product within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of darapladib or matching placebo.
17. Currently in a study of an investigational device.
18. Any other reason the investigator deems the subject to be unsuitable for the study.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the time to the first occurrence of any
component of the composite of major coronary events that include CHD death, non-fatal MI, or urgent coronary revascularization for myocardial ischemia in an ACS patient population.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time to the first occurrence

E.5.2

Secondary end point(s)

• The composite measure of MACE that includes CV death, non-fatal MI, or non-fatal stroke.
• Individual components of MACE (CV death, MI [fatal and non-fatal],
stroke [fatal and non-fatal]).
• Individual components of major coronary events (CHD death, MI [fatal and non-fatal], urgent coronary revascularization for myocardial ischemia).
• The composite measure of total coronary events that include CHD
death, non-fatal MI, hospitalization for UA, or any coronary
revascularization procedure (excluding percutaneous coronary
intervention [PCI] planned prior to randomization but performed after randomization).
• Any coronary revascularization procedures (excluding PCI planned
prior to randomization but performed after randomization).
• Any component of the composite of all-cause mortality, non-fatal MI, or non-fatal stroke
• The composite of CHD death and non-fatal MI
• All cause mortality.

E.5.2.1

Timepoint(s) of evaluation of this end point

First Occurence

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

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

330

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

Belgium

Bulgaria

Canada

China

Denmark

France

Italy

Netherlands

New Zealand

Romania

Slovakia

Argentina

Australia

Chile

Colombia

Czech Republic

Germany

Hungary

India

Korea, Democratic People's Republic of

Spain

Thailand

Israel

Peru

Philippines

Poland

Russian Federation

South Africa

Taiwan

Turkey

Ukraine

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

The trial should end with the last subject's in-clinic follow-up visit .

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