Clinical Trials Register

Summary
EudraCT Number:	2006-002942-12
Sponsor's Protocol Code Number:	P04737
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-09-26
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

Finland - Fimea

A.2

EudraCT number

2006-002942-12

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of SCH 530348 in Addition to Standard of Care in Subjects With a History of Atherosclerotic Disease: Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P - TIMI 50)

A.3.1

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

Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis.

A.3.2

Name or abbreviated title of the trial where available

TRA 2°P - TIMI 50

A.4.1

Sponsor's protocol code number

P04737

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00526474

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	Schering Plough Research Institute, A Division of Schering Corporation
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	Schering Plough Research Institute, A Division of Schering Corporation
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	Schering Plough Research Institute, A Division of Schering Corporation
B.5.2	Functional name of contact point	Dr. Gail Berman
B.5.3	Address:
B.5.3.1	Street Address	126 E. Lincoln Ave. PO Box 2000
B.5.3.2	Town/ city	Rahway, NJ
B.5.3.3	Post code	07065
B.5.4	Telephone number	732 594-1269
B.5.5	Fax number	732 594-3690

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	SCH 530348 bisulfate Tablet
D.3.2	Product code	SCH 530348
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.3.9.1	CAS number	705260-08-8
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	2.5
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

Documented coronary artery disease, postischemic cerebrovascular disease or peripheral artery disease.

E.1.1.1

Medical condition in easily understood language

Heart disease, stroke and peripheral arterial disease

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	13.1
E.1.2	Level	PT
E.1.2	Classification code	10043634
E.1.2	Term	Thrombosis prophylaxis
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 is to evaluate the hypothesis that SCH 530348 added to standard of care will reduce the incidence of atherothrombotic ischemic events relative to standard of care alone, as measured by the composite of cardiovascular (CV) death, myocardial infarction (MI), stroke, and urgent coronary revascularization (revasc).

E.2.2

Secondary objectives of the trial

Key secondary obj: evaluate benefit with respect to the composite of CV death, MI, & stroke. Other efficacy obj: eval occurrences of: 1. all-cause death, MI, stroke & urgent coronary revasc 2. CV death & MI 3. CV death, MI, stroke, urgent coronary revasc, or urgent hospitalization for vascular cause of ischemic nature 4. all-cause death, MI, stroke, any revasc (incl amputation for ischemic limb) 5. CV death, MI, stroke, revasc (incl amputation for ischemic limb) or urgent hospitalization for vascular cause of ischemic nature 6. individual components of composite primary efficacy endpt 7. all-cause death.See Protocol for suppl efficacy obj. Safety obj: eval occurrences of: 1. composite of moderate & severe bleeding events according to GUSTO 2. clinically significant bleeding defined as TIMI major/minor bleeding, bleeding that requires unplanned medical or surgical treatment or lab eval even if it does not meet criteria for TIMI major/minor bleeding.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject may be of either sex and any race, and must be at least 18 years old.
2. Subject must have evidence or a history of atherosclerosis involving the coronary, cerebral, or peripheral vascular systems as follows:
a. CAD as indicated by a history of presumed spontaneous MI [hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI (eg, due to profound anemia or hypertensive emergency, troponin increase in sepsis)] ≥ 2 weeks but ≤ 12 months prior, or
b. ischemic (presumed thrombotic) CVD as indicated by a history of ischemic stroke (hospitalized with final diagnosis of nonhemorrhagic stroke) [includes completion of a standard evaluation for stroke in an acute care facility or stroke clinic without hospital admission] ≥2 weeks but ≤ 12 months prior, or
c. PAD as indicated by a history of intermittent claudication and
I. a resting ankle/brachial index of (ABI) of <0.85, or
II. amputation, peripheral bypass, or peripheral angioplasty of the extremities secondary to ischemia (note that enrollment of subjects entering with qualifying PAD will end when the total of the subset of subjects reaches ~ 15% of the planned total enrollment; investigators will be told when to stop enrollment of these subjects)

3. Subject must be willing and able to give appropriate informed consent.

4. A woman of child-bearing potential who is currently sexually active must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 2 months after stopping the medication. Highly effective methods of birth control are defined as those that result in a low failure rate (ie, <1% per year) when used consistently and correctly, such as hormonal implants, injectables, combined oral contraceptives, hormonal intrauterine devices, sexual abstinence, or surgical sterilization (eg, vasectomy of male partner).

5. A woman of child-bearing potential who is not currently sexually active must agree to use a medically accepted method of contraception should she become sexually active while participating in the study.

E.4

Principal exclusion criteria

1. Clinically unstable at the time of enrollment
2. Any planned coronary revascularization or peripheral intervention
3. Concurrent or anticipated treatment with warfarin (or derivatives, eg, phenprocoumon), oral factor Xa inhibitor, or oral direct thrombin inhibitor after enrollment. (Note 1: If a subject is taking warfarin during determination of eligibility, and the investigator is willing to stop the subject's treatment with warfarin immediately, and the subject is not otherwise disqualified from participation, then the subject may receive randomized assignment of study drug)(Note 2: A subject who was not using warfarin/derivatives and for whom use was not anticipated, but who subsequently requires warfarin/derivatives after randomized assignment of study drug may continue treatment with warfarin/derivatives and randomized study drug, except when aspirin /thienopyridine/warfarin concurrent therapy is needed & thienopyridine cannot be discontinued)
4. Concurrent or anticipated treatment with a potent inducer (eg, rifampin) or potent inhibitor (eg, ketoconazole, erythromycin) of CYP3A4 isoenzymes (detailed list will be supplied to investigator). (Note: A subject who was not using a potent 3A4 inducer or potent inhibitor and/or for whom such therapy was not anticipated, but requires such therapy after randomization may receive such therapy as follows:
a. potent 3A4 inducer - continue study drug until therapy with inducer ends or until inducer therapy extends beyond 4 weeks, then discontinue study drug;
b. potent 3A4 inhibitor - interrupt study drug treatment until inhibitor therapy ends or until inhibitor therapy extends beyond 4 weeks, then discontinue study drug)
5. History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment
6. History at any time of intracranial hemorrhage (except "microhemorrhage" [eg, as detected on T2-weighted MRI]), intracranial or spinal cord surgery, or a central nervous system tumor or aneurysm
7. Documented sustained severe hypertension (systolic blood pressure >200mmHg or diastolic blood pressure >110mmHg) at enrollment or within the previous 10 days
8. Severe valvular heart disease, as defined by the American College of Cardiology/American Heart Association
9. History within 2 weeks prior to enrollment of major surgery other than mentioned above or of ischemic (presumed thrombotic) stroke
10. Known platelet count <100,000/mm3 within 30 days before enrollment
11. Known active hepatobiliary disease or known unexplained persistent increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) activity to two times or more the upper limit of the reference range (upper limit of "normal" [≥2xULN]
12. Any serious illness or any condition that the investigator feels would (a) pose a significant hazard to the subject if investigational therapy were initiated, or (b) would limit the prognosis of the subject, regardless of investigational therapy.
13. Any serious medical comorbidity (eg, active malignancy) such that the subject's life expectancy is <24 months
14. Previous participation in the current study
15. Current participation in any other study of investigational therapy, or participation in such a study within the last 30 days
16. Known hypersensitivity to any component of the current investigational product
17. Subject is a woman who is breast-feeding, pregnant, or who intends to become pregnant (affirm that a female subject of child-bearing potential is not pregnant before enrollment)
18. Subject is part of the staff personnel directly involved with this study, or is a family member of the investigational staff
19. Known current substance abuse at the time of enrollment

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of the study is the first occurrence of any component of the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization.

E.5.1.1

Timepoint(s) of evaluation of this end point

First occurrence of any component of the composite primary endpoint

E.5.2

Secondary end point(s)

Key secondary endpoint (EP): first occurrence of any component of the composite of CV death, MI, & stroke. Other efficacy EPs: first occurrence of any component of the following composites or individual components:
1 all-cause death, MI, stroke & urgent coronary revasc
2. CV death & MI
3. CV death, MI, stroke, urgent coronary revasc, or urgent hospitalization for vascular
cause of ischemic nature
4. all-cause death, MI, stroke, any revasc (incl amputation for ischemic limb)
5. CV death, MI, stroke, revasc (incl amputation for ischemic limb) or urgent hospitalization for vascular
cause of ischemic nature
6. individual components of composite primary efficacy EP
7. all-cause death. See Protocol for suppl efficacy EPs.Safety EPs: the first occurrence of any component of:
1. composite of moderate &/or severe bleeding events according to GUSTO
2. clinically significant bleeding
defined as TIMI major/minor bleeding, bleeding that requires unplanned medical or surgical treatment or lab eval even if it does not meet criteria for TIMI major/minor bleeding.

E.5.2.1

Timepoint(s) of evaluation of this end point

First occurrence of any component of the of the composites or individual components

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

Yes

E.6.11

Pharmacogenomic

Yes

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.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

450

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

Canada

Chile

China

Colombia

Hong Kong

Israel

Japan

Malaysia

New Zealand

Peru

Singapore

South Africa

Taiwan

Turkey

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

The trial continues until a statistically calculated minimum number of primary and key secondary efficacy endpoint events have been observed and all subjects have participated for at least 1 year.

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	16500
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	10000
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
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	12150
F.4.2.2	In the whole clinical trial	27000

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

2007-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-12-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-12-16

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