The primary hypotheses in this study is that a cangrelor infusion will maintain target levels of platelet inhibition (> 60% inhibition) after discontinuation of a thienopyridine (clopidogrel or ticlopidine) in patients waiting for surgery.
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint for this trial is maintenance of platelet inhibition in
80% of patient samples above 60% as determined by VerifyNowTM P2Y12 point of
care assay measured during cangrelor infusion prior to surgery.
Secondary outcome
The main safety endpoint of the trial is the absence of excessive CABG-related
bleeding. Excessive CABG-related bleeding is defined as the ccurrence of the
combination of any one of the following 3 components during the CABG procedure
through hospital discharge:
• Surgical re-exploration
• 24 hour CT output of >1.5 liters
• Incidence of PRBC transfusions > 4 units
Additional secondary endpoints of this trial are:
• Difference between cangrelor and placebo treatment in term of percentage of
total patient samples which maintains at least 60% platelet inhibition as
determined by VerifyNowTM P2Y12 point of care assay
• Percentage of patients who maintains at least 60% platelet inhibition in
their last ontreatment sample before the surgery.
• CABG-related bleeding (TIMI, GUSTO, ACUITY) up to 7 days post CABG or
discharge whichever occurs first.
• All blood product transfusions up to 7 days post CABG or discharge, whichever
is sooner.
Additional safety observations will include:
• Incidence of bleeding from randomization until discontinuation of study drug
(TIMI, GUSTO, ACUITY)
• Incidence of the combination of the combined ischemic endpoint of death, MI,
stroke or need for urgent revascularization within 30 days following surgery
• Incidence of the combined ischemic endpoint of death, MI, stroke or need for
urgent revascularization from the time of randomization until discontinuation
of study drug.
• Incidence of adverse events and serious adverse events up to 7 days post CABG
or discharge whichever occurs first.
Background summary
Dual antiplatelet therapy with clopidogrel and aspirin reduces clinical
ischemic events and improves outcomes for patients with acute coronary
syndromes (ACS). However, as both aspirin and clopidogrel are irreversible
platelet antagonists that inhibit platelet function for the live of the
platelet concerns about bleeding for patients who might require coronary artery
bypass grafting (CABG) have limited adoption of upstream dual anti-platelet
therapy. Also, as current ACC/AHA and Society of Thoracic Surgeons (STS)
guidelines recommend cessation of clopidogrel before non-emergent cardiac
surgical procedures in order to minimize bleeding risks length of stay is also
potentially impacted by the choice of initiating clopidogrel at presentation.
On the other hand, while there are risks associated with early initiation of
irreversible antiplatelet therapy in ACS patient requiring surgical
revascularization suggest that there is also a benefit of P2Y12 inhibition in
terms of decreased thrombotic events prior to CABG. Therefore, even though
clopidogrel treatment prior to CABG does increase bleeding to its
irreversibility, platelet P2Y12 inhibition does appear to prevent ischemic
events in patients requiring CABG.
There are other clinical situations in which the ability to maintain adequate
P2Y12 inhibition with rapid reversibility would be desirable. For instance,
patients with indwelling drugeluting stents are maintained on aspirin and
clopidogrel to prevent stent thrombosis. Should these patients require a
surgical procedure, cessation of clopidogrel increases the risk for ischemic
events or stent thrombosis, while maintaining irreversible platelet inhibition
with aspirin and a thienopyridine leads to unacceptable operative bleeding
risk. Additionally, cessation of clopidogrel may increase the incidence of
ischemic events in the short-term due to a *rebound* effect of platelet
activation. Currently, no short-acting platelet inhibitors are available which
allow maintenance of platelet inhibition before surgery without increasing
bleeding complications at the time of surgery. Potentially, effective platelet
inhibition with an ultra short-acting platelet inhibitor during the period of
clopidogrel withdrawal may protect patients from ischemic events and cangrelor
also preserve normal hemostasis at the time of surgery. We hypothesize that the
reversible, ultra short-acting P2Y12 platelet inhibitor cangrelor may be a safe
and effective drug to bridge patients from the irreversible platelet inhibitors
clopidogrel or ticlopidine to the time of surgery.
Study objective
The primary hypotheses in this study is that a cangrelor infusion will maintain
target levels of platelet inhibition (> 60% inhibition) after discontinuation
of a thienopyridine (clopidogrel or ticlopidine) in patients waiting for
surgery.
Study design
This study will be a Phase II, prospective, randomized, double-blind,
multi-center trial in patients who discontinue thienopyridine and are
undergoing non-emergent coronary artery bypass grafting (CABG). The trial will
consist of two stages.
Stage I: Open label lead-in period:
Cangrelor IV infusion, will be administered to cohort of 5 patients at a time
in a step-wise fashion at pre-determined doses (0.5 µg/kg/min, 0.75 µg/kg/min,
1.0 µg/kg/min and 1.5 µg/kg/min) until percent platelet inhibition as measured
by VerifyNowTM P2Y12 is > 60% in 80% of samples or a dose of 2.0 µg/kg/min is
reached.
The first set of patients will receive an infusion of 0.5 µg/kg/min. If
platelet inhibition as measured by VerifyNowTM P2Y12 is not > 60%, in greater
than 80% of patient samples the second set of 5 patients will be administered a
0.75 µg/kg/min IV infusion. If platelet inhibition as measured by VerifyNowTM
P2Y12 is again not consistently > 60%, the third set of 5 patients will be
administered a 1.0 µg/kg/minute infusion, followed by a fourth set of 5
patients who will receive a 1.5 µg/kg/minute infusion, if needed. If platelet
inhibition as measured by VerifyNowTM P2Y12 is still <= 60% the decision will be
made to use a 2.0 µg/kg/min.
Stage II: Blinded, randomized period:
A single infusion dose of cangrelor or matching placebo ranging from 0.5 µg/
kg/min to 2.0 µg/kg/min IV infusion (depending on the results of the Stage I
evaluation) or matching placebo.
Up to 200 patients will be randomized at approximately 30 centers globally.
Informed consent will be obtained from patients meeting the inclusion criteria
before the initiation of any study specific procedures. Eligible patients will
be randomized to receive cangrelor plus standard of care (SOC) versus placebo
plus SOC in a 1:1 ratio.
Patients will be randomized into two arms, to enroll concurrently. In the first
arm, patients will receive only standard of care, in which the thienopyridine
is discontinued after the need for surgery has been determined and a placebo
infusion is administered. In the second arm, a
cangrelor infusion will be started in addition to SOC when the thienopyridine
has been discontinued after the need for surgery has been determined. The
infusions (cangrelor or matching placebo) will continue throughout the
pre-operative period. It is recommended that patients wait 5 days after
discontinuation of clopidogrel before undergoing surgery (in accordance with
ACC/AHA and STS guidelines), but the timing of surgery will be left to the
discretion of the investigator with an allowed maximum of 7 days of infusion.
The Data Safety Monitoring Board (DSMB) chairman will perform a dose
confirmation analysis following enrollment of the first 20 patients in Stage
II.
Intervention
not applicable
Study burden and risks
Seven Phase I, five Phase II and two Phase III studies have been completed to
date, in which approximately 7600 subjects were exposed to cangrelor. The main
risk associated with anti-platelet therapy is bleeding. Preclinical studies
demonstrated renal toxicity in rats when administered by IV infusion at a dose
of 25 µg/kg/min for 1 month or in dogs administered at the dose of 60 µg/kg/min
for 1 week. The histopathological changes were, however, completely reversible
in animals one-month after cessation of similar cangrelor infusions. The early
signs of renal toxicity can be monitored (increase in plasma serum creatinine
levels) before histopathological changes are observed. Relevant risks and
benefits of cangrelor are fully described in the cangrelor Investigator
Brochure (cangrelor Investigator*s Brochure, 2010).
8 Sylvan Way
NJ 07054 Parsippany
US
8 Sylvan Way
NJ 07054 Parsippany
US
Listed location countries
Age
Inclusion criteria
1. Provide written informed consent before initiation of any study related procedures.
2. Be at least 18 years of age.
3. Anticipate non-emergent coronary artery bypass graft (CABG) surgery, either *onpump* or *off-pump,* no sooner than 48 hours from randomization but no longer than 7 days from randomization, with patient to remain hospitalized until planned CABG.
4. Have received a thienopyridine (at least 75 mg of clopidogrel or 500 mg ticlopidine)
within 48 hours prior to enrollment in the study for the treatment of an acute coronary syndrome or as long-term preventative therapy following drug-eluting stent treatment.
Exclusion criteria
1. Confirmed of suspected pregnancy (if woman of child-bearing potential) or lactating females
2. Cerebrovascular accident within one year
3. Intracranial neoplasm or history of intracranial surgery
4. History of bleeding diathesis
5. Thrombocytopenia (platelet count of less than 100,000/µL)
6. Known International Normalized Ratio (INR) greater than 1.5 at screening.
7. Requirement for dialysis treatment (hemodialysis or peritoneal)
8. Estimated Glomeular filtration rate eGFR <30 ml/min
9. Administration of abciximab within 24 hours of randomization or administration of
eptifibitide or tirofiban within 12 hours of randomization.
10. Plans to continue oral anticoagulant, thienopyridine or GPIIb/IIIa antagonist therapy
in the pre-operative period.
11. Need of planned concomitant valvular heart surgery
12. Refusal to receive blood transfusion
13. Receipt of fibrinolytic therapy in the 12 hours preceding randomization
14. Allergy, hypersensitivity, or contraindication to cangrelor, mannitol, sorbitol, or
microcrystalline cellulose
15. High likelihood of being unavailable for follow-up
16. Participation in other clinical research studies involving the evaluation of other
investigational drugs or devices within 30 days of randomization
17. Any disease or condition which, in the judgment of the investigator, would place the patient at undue risk by being enrolled in the trial
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 | EUCTR2008-001135-35-NL |
| CCMO | NL31843.100.10 |