International randomized double blind clinical study evaluating the efficacy and safety of clopidogrel 0.2mg/kg once daily versus placebo in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt (e.g. modified Blalock Taussig shunt)

There is no consistent approach in preventing complications after
systemic-to-pulmonary artery shunts. Initial treatment with unfractionated
Heparin followed by ASA (1 to 10 mg/kg/d) is sometimes used. Children who
develop shunt occlusion usually require further intervention, including
thrombolytic therapy and/or stenting or surgical revision.

Although the therapeutic benefit of ASA as an antiplatelet drug has never been
formally evaluated in children, it is common practice in some centers to use
this drug in systemic-to-pulmonary artery shunt patients. The registry
previously discussed, also showed that despite lack of evidence to support ASA
efficacy, aspirin was used in 80% of the cases in this series of 1004 patients,
at doses from less than 20 mg to more than 40 mg, and appeared to be associated
with a lower risk of death after all of these palliative procedures, whatever
the specific underlying cyanotic disease or the shunt type (1)

Nevertheless, chronic use of ASA cannot be mandated given the absence of formal
demonstration of its efficacy and clinical benefit. Therefore, in the absence
of any standardized anticoagulation or antiplatelet regimen for patients having
systemic-to-pulmonary artery shunts, clinical trials with such drugs are
warranted in this
high-risk patient population.

The potential that clopidogrel treatment could fulfill an unmet medical need in
patients with a BTS or any systemic-to-pulmonary artery shunt led to a clinical
development program that was established and initiated under the rules
described in a formal Written Request from the United States Food and Drug
Administration (FDA).

The current study (CLARINET) is a prospective, multinational, randomized,
double-blind, placebo-controlled, two parallel group clinical study to
determine efficacy and safety of 0.2mg/kg/day of clopidogrel in neonates or
infants with cyanotic congenital heart disease palliated with a
systemic-to-pulmonary artery shunt. Neonates (age less than or equal to 30 days
at the time of randomization) or infants (age less than or equal to 92 days at
the time of randomization) will be randomized to clopidogrel or placebo as
early as possible after shunt placement and followed up to the earliest of
shunt thrombosis or next surgical procedure for correction of the congenital
heart disease, or death, or 1 year (365 days) of age, or common study end-date
(CSED) defined as a date when it is projected that 174 primary events will have
occurred.

(1) Li JS, Berezny KB, Yow E: Influence of aspirin use on mortality in infants
with cyanotic congenital heart disease palliated with a systemic-to-pulmonary
artery shunt: a multicenter, international registry. Abstract AHA 2005.

Primary:
To evaluate the efficacy of 0.2 mg/kg/day of clopidogrel versus placebo for the
reduction of all-cause mortality and shunt-related morbidity in neonates or
infants with cyanotic congenital heart disease palliated with a
systemic-to-pulmonary artery shunt.

Secondary:
To assess the safety of clopidogrel in the study population.

Prospective, multinational, randomized, double-blind, placebo-controlled, two
parallel group clinical study.
It is expected to enroll 490 patients in 130 sites worldwide to reach 174
events.

Patients will be randomized to either clopidogrel 0.2 mg/kg or placebo.
Patients may receive concomitant background therapy, with or without acetyl
salicylic acid (ASA), as per usual practice at each site.

Medical office visits for efficacy and safety assessment are scheduled at
baseline and at 4 weeks, 12 weeks, 24 weeks, 36 weeks and at final visit.

Final visit is defined as the earliest of shunt thrombosis or next surgical
procedure for correction of the congenital heart disease, or death, or 1 year
(365 days) of age, or common study end-date (CSED) defined as a date when it is
projected that 174 primary events will have occurred.

Contacts (at minimum by telephone) are scheduled every 2 weeks until 12 weeks
visit and every 4 weeks thereafter for adjustment of the study drug dose to be
administered with respect to patient's weight.