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 | No |
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 | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Full Title of Sub-Study: A Randomized, Double-Blind, Placebo-Controlled
Study to Evaluate the Ocular Safety of SCH 530348 in Subjects
Participating in the Schering-Plough P04737 Study (TRASM Secondary
Prevention - Ocular Safety Study)
Sponsor's sub-study number/version/date: P05183 / Amendment #1 /
13 June 2008
Objective: To determine the long term ocular safety of SCH 530348 when
administered in addition to the standard of care for 1 year, with respect
to any changes occurring in the retina, both anatomic and functional, in
subjects with documented atherosclerotic disease.
The overall safety evaluation will include optical coherence tomography
(OCT), best corrected visual acuity (ie, with refraction), fundus
photography, Farnsworth-Munsell 100 hue color testing, and dilated
funduscopic examination.
Primary Endpoint for this study: The incidence of vacuolization in the
inner nuclear layer (INL) of the retina through treatment and follow-up.
Vacuolization is defined as the presence of more than one vacuole
(defined as a clear round structure in the INL of the retina of at least 30
μm in diameter) compared to baseline.
Study Population: Will comprise of subjects with established
atherosclerotic disease. The study will include subjects who meet all the
inclusion criteria and none of the exclusion criteria for the parent
protocol (P04737). In addition, subjects will be excluded from entry if
ANY of the exclusion criteria listed below are met:
1. History or evidence of age-related macular degeneration on baseline
evaluation
2. History of diabetic macular edema, or evidence of treated diabetic
retinopathy on baseline evaluation
3. History or evidence of other retinal diseases, including retinal injury,
on baseline evaluation
4. History or evidence of retinal surgery, including laser
photocoagulation, on baseline evaluation
5. History or evidence of glaucoma on baseline evaluation
6. History or evidence of high intraocular pressure of >22 mm Hg on
baseline evaluation
7. Evidence of center foveal thickness of >190 μm on baseline OCT
examination
8. Presence of vacuoles in the retina on baseline OCT |
|
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 | 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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 2 |
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 | 36 |
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 | 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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
Hong Kong |
Israel |
Japan |
Malaysia |
New Zealand |
Peru |
Singapore |
South Africa |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |