The primary objective of this study is to demonstrate non-inferiority by pharmacodynamic (PD) analysis of the prasugrel 5-mg maintenance dose (MD) in aspirin-treated subjects >=75 years of age with stable coronary artery disease (CAD) versus the…
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Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Criteria for Evaluation:
Efficacy: No clinical efficacy measures will be collected in this study.
Safety: Laboratory measures, adverse events.
Pharmacokinetic: Blood samples will be collected for the determination of
plasma concentrations of the prasugrel active metabolite (R-138727) and the
clopidogrel active metabolite (R-130964). Inactive metabolites of prasugrel and
clopidogrel will not be analysed in this study.
Pharmacodynamic: LTA (ADP, AA, collagen and/or SDF-1β); VerifyNow® P2Y12; VASP;
flow cytometric markers at prespecified sites;
Secondary outcome
-
Background summary
The TRITON-TIMI 38 Phase 3 clinical trial (Study TAAL) revealed significantly
reduced rates of ischaemic events on prasugrel therapy compared to clopidogrel
for the composite endpoint of CV death, MI, or stroke in subjects with acute
coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI);
however, with prasugrel there was a greater risk of bleeding identified in very
elderly (>=75 years of age) subjects. Reducing the prasugrel maintenance dose
(MD) to 5 mg in subjects >=75 years of age is expected to reduce exposure to
prasugrel*s active metabolite to a range that will lower the risk of bleeding
while providing efficacy comparable to that of 10-mg prasugrel MD in subjects
<75 years of age (there are no direct efficacy outcomes for this study).
The use of prasugrel in patients >=75 years of age is generally not recommended
in the European Union (EU). If, after a careful individual benefit/risk
evaluation by the prescribing physician, treatment is deemed necessary in the
patients age group >=75 years, then following a 60-mg loading dose a reduced
maintenance dose (MD) of 5 mg should be prescribed, in accordance with the
European Summary of Product Characteristics (EU SPC). The use of prasugrel is
generally not recommended in these patients in the United States (US) as well,
except in high-risk situations (patients with diabetes or history of myocardial
infarction) where its effect appears to be greater and its use may be
considered, in accordance with the US Package insert (USPI).
There is currently a lack of clinical data on the prasugrel 5-mg MD in subjects
who are >=75 years of age. This study, which is a post-marketing commitment
based on the Committee for Medicinal Products for Human Use (CHMP) review of
the prasugrel marketing authorisation application, will test the hypothesis
that a prasugrel 5-mg MD in the very elderly will achieve a non-inferior
pharmacodynamic (PD) effect to a 10-mg MD in younger subjects. This study will
provide further support for the prasugrel 5-mg MD recommendation in subjects
>=75 years of age. In addition, the approved clopidogrel 75-mg MD will be
compared with the 5-mg and 10-mg MD of prasugrel.
Study objective
The primary objective of this study is to demonstrate non-inferiority by
pharmacodynamic (PD) analysis of the prasugrel 5-mg maintenance dose (MD) in
aspirin-treated subjects >=75 years of age with stable coronary artery disease
(CAD) versus the prasugrel 10-mg MD in aspirin-treated subjects >=45 to <65
years of age with stable CAD, as assessed by maximum platelet aggregation (MPA)
to 20 µM ADP measured with light transmission aggregometry (LTA) at the
pre-dose trough on day 12±2 of the MD period (Study Period 1).
The secondary objectives of the study are:
• To compare the PD between MD regimens (5 mg prasugrel, 10 mg prasugrel, and
75 mg clopidogrel) when co-administered with aspirin, as measured by LTA (MPA),
VerifyNow® P2Y12 (PRU, device reported % inhibition) and VASP (PRI) within each
age group (subjects >=75 years of age and subjects >=45 to <65 years of age).
• To compare the PD within MD regimens (5 mg prasugrel, 10 mg prasugrel, and 75
mg clopidogrel) when co-administered with aspirin, as measured by LTA (MPA),
VerifyNow® P2Y12 (PRU, device reported % inhibition) and VASP (PRI) between
subjects >=75 years of age and subjects >=45 to <65 years of age.
• To compare the PK of exposure to prasugrel's and clopidogrel's active
metabolites and their relations to PD measurements between subjects >=75 years
and subjects >=45 to <65 years of age.
• To compare the PD between MD regimens (5 mg prasugrel, 10 mg prasugrel, and
75 mg clopidogrel) as assessed by exploratory analyses of other LTA agonists
(for example, collagen and stromal cell-derived factor beta [SDF-1β]) within
each age group.
• To compare the PD within MD regimens, as assessed by exploratory analyses of
other LTA agonists (for example, collagen and SDF-1β) between subjects >=75
years of age and subjects >=45 to <65 years of age.
• To assess the safety and tolerability of each MD regimen (5 mg prasugrel, 10
mg prasugrel, and 75 mg clopidogrel) when co-administered with aspirin in
subjects with stable CAD >=75 years of age and >=45 to <65 years of age.
• To compare MD regimens as assessed by exploratory analyses of flow cytometric
markers (for example, CD11b Ligand, P-selectin, CD 40 Ligand, CD184, CD69,
CD58, IFFITM1, PRKRA, C4 complement deposition, microparticles, platelet size,
and PAC-1 Mab). Note: These exploratory flow cytometric markers will be
collected only at prespecified sites.
Study design
This Phase 1b study will be a multi-center, partially-blinded study
(single-blind for subjects in Period 1; double-blind in Periods 2 and 3),
double-dummy (5 mg, 10 mg prasugrel, 75 mg clopidogrel with matching placebo),
parallel group (two population arms), active comparator, multiple dose (30-42
days total), randomised sequence, 3-period (first period fixed and the
remaining two periods crossover within each population arm) study design (3
periods of 12±2 days without intervening or terminal washout periods) in
aspirin-treated subjects with stable coronary artery disease.
Intervention
Physical examination (1x during this study), ECG (1x), vbody weight and length
(1x) viital signs (5x).
Subjects of this study will not be submitted to a behavioural change.
Questionnaires will not be taken. Diares will not be kept.
Study burden and risks
Risks associated with study drug Prasugrel
Prasugrel has been taken by around 10,500 patients in clinical trials and is
already approved in Europe as medication for patients with Acute Coronary
Syndrome, however it has been tested as a treatment for stable Coronary Artery
Disease only by a limited number of people. This medication is not yet approved
on the market in the Netherlands.
The most common side effect is bleeding. The following examples may be signs of
bleeding: Blood in the Urine; Blood in the Stool; Uncontrollable bleeding
Additional common side effects: Bleeding in the stomach or bowels, bleeding
from a needle puncture site, Nose bleeds, Small red bruises on the skin
(ecchymoses), Blood in urine
Hematoma (bleeding under the skin at the site of an injection, or into a
muscle, causing swelling)
There are additional uncommon side effects of which your study doctor can tell
you more if you would like to.
Risks associated with comparator drug Clopidogrel
The most common side effect is bleeding. Bleeding may occur for example as
bleeding in the stomach or bowels, bruising, haematoma, nose bleed, blood in
the urine, bleeding in the eye or prolonged bleeding. Common side effects are:
Diarrhoea, abdominal pain, indigestion or heartburn.
There are additional uncommon side effects of which study doctor can tell you
more if would like to.
Risks and Discomforts associated with Aspirin
Aspirin may have undesirable side effects. People who are allergic to
acetylsalicylic acid, or have asthma, persisting or recurring stomach problems
(such as heartburn, upset stomach or stomach pain), ulcers, or bleeding
problems should not take aspirin unless directed by a doctor.
Do not use aspirin if you are taking a prescription drug for thinning the
blood, diabetes, gout, or arthritis, unless directed by a doctor. Combining
aspirin or similar drugs with oral anti-diabetes drugs can decrease blood sugar
levels more than expected.
Possible side effects of aspirin include stomach pain or discomfort,
indigestion, heartburn, nausea, or vomiting. Less common side effects include
unusual bleeding or bruising, black stools, severe diarrhea, ringing in the
ears, severe headache, dizziness, drowsiness, confusion, changes in vision,
changes in behavior, excessive sweating, and increased thirst.
The combination of study drug with other drugs prescribed for your condition
may have other unknown risks or possible harmful interaction.
Risks associated with study procedures
Blood Sampling
As a result of blood sampling you might feel pain or be light-headed. You may
experience some temporary discomfort, bleeding, bruising, or rarely, infection,
at the site of a needle puncture you receive during the drawing of blood
samples. The study blood draws might also increase the risk of anaemia caused
by study medications.
ECG
The ECG is a painless procedure that requires you to lie still for a few
minutes while electrodes are attached to your chest to record the activity of
your heart. The ECG leads placed on your skin may cause slight discomfort
during placement and removal. Some individuals are sensitive to the sticky
patches used during an ECG, which may result in redness and sore skin in those
areas.
In addition to the risks already described, prasugrel and clopidogrel, alone or
in combination with Aspirin®, and the study procedures may have other unknown
risks.
There may also be unknown risks to an embryo, fetus, or nursing infant.
Lilly Corporate Center DC 6076
IN 46285, Indianapolis, Indiana
US
Lilly Corporate Center DC 6076
IN 46285, Indianapolis, Indiana
US
Listed location countries
Age
Inclusion criteria
This study will include male or female aspirin-treated subjects not indicated for a thienopyridine treatment with stable coronary artery disease (CAD) who are at least 45 years of age and who weigh at least 60 kg, with subjects grouped into one of the following: subjects of 75 years of age or older and subjects between 45 and 65 years of age. Stable coronary artery disease is defined as any of the following: Subjects diagnosed with chronic stable angina; prior history of unstable angina (including non-ST-segment elevation myocardial infarction) or acute myocardial infarction (AMI); previous coronary revascularisation including percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or CAD in at least one coronary vessel on previous angiography or noninvasive imaging procedure.;The following inclusion criterion is applicable only to patients enrolled at sites in the
Netherlands:
- Subjects previously treated with clopidogrel and aspirin for at least 1
year and who did not have a bleeding event requiring medical attention
during treatment.
Exclusion criteria
• Unstable coronary artery disease.
• PCI or CABG within the previous 90 days.
• History of refractory ventricular arrhythmias within the last 6 months; an implanted defibrillator device; congestive heart failure within 6 months prior to screening; major surgery, or severe trauma, fracture or organ biopsy within 90 days prior to randomisation.
• Any planned surgical procedure or any coronary revascularisation (surgical or percutaneous) planned within 60 days following randomisation.
• Any known contraindication to treatment with an antiplatelet agent.
• Significant hypertension at the time of screening or randomisation.
• Clinically significant out-of-range values for platelet count or haemoglobin at screening, in the investigator*s opinion, or results of clinical laboratory tests at the time of screening that are judged to be clinically significant for the study population, as determined by the investigator.
• Prior history or presence of significant bleeding disorders, abnormal bleeding tendency, or personal history of coagulation or bleeding disorders.
• Prior history or clinical suspicion of cerebral vascular malformations, intracranial neoplasm, transient ischaemic attack (TIA), or stroke.
• Prior history or presence of thrombocytopenia or thrombocytosis.
• Use of antiplatelet agents (excluding aspirin) *10 days prior to screening; the use (or planned use) of heparin, oral anticoagulants, or fibrinolytic agents within 30 days of screening; or subjects receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) or cyclooxygenase-2 (COX-2) inhibitors that cannot be discontinued for the duration of the study.;The following exclusion criteria are applicable only to patients enrolled at sites in the
Netherlands:
- Prior history or presence of decreased kidney function (as defined by
creatinine clearance <30 mL/min) and/or a diagnosis of end stage renal
disease [ESRD].
- Any bleeding requiring medical attention within the last 2 years prior
to screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-012409-20-NL |
| CCMO | NL32914.100.10 |