The UNBLOCK Study: Utilization of Bivalirudin On Clots in Kids

This will be an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy
study of bivalirudin in children 6 months to 18 years of age with deep vein thrombosis. The
specific aims are as follows:

1. Pharmacodynamic analysis based on the activated partial thromboplastin time (aPTT) will
be performed and the best bolus dose and initial infusion dose of bivalirudin will be
determined for 3 age cohorts of children.

2. Pharmacokinetic analysis of bivalirudin will be determined based on bivalirudin plasma
levels in the same 3 age cohorts.

3. Comparison of pharmacokinetics with pharmacodynamics will be performed to determine
whether the aPTT is an adequate surrogate for plasma bivalirudin levels.

4. The rate of clot resolution within 48-72 hours will be determined.

5. The safety of bivalirudin will be determined by assessing for major and minor bleeding
and other adverse events.

A total of 30 patients will be enrolled in this study. They will be divided into 3 groups
according to their age range (6 months-age to > 5, 5 to > 12 years and 12 to >18 years). The
patient must have a deep vein thrombosis (clot in an artery or vein) that has been seen on
an imaging test. After receiving the study drug, the subjects will then have blood tests at
specific timepoints to measure how the drug is effecting the body and how the drug is acting
once it is in the body. Based upon the levels of the blood tests, the dose of the study drug
may be adjusted or stopped. The subject will continue on the drug until the clot is
dissolved, the subject is prescribed a different anticoagulant or the physician or parents
decide to remove the child off of the study. The drug will also be discontinued if any
excessive bleeding or severe side effects related to the drug are observed. A follow up
imaging study will be performed on all patients 48-72 hours after the drug was started. If
the clot is still present at this time, another imaging study will be done at 30 days after
the drug was given. The subjects will continue to have lab tests twice weekly for about 3
weeks to monitor for the effects of the drug. After completion of the study, the patient
will undergo a study exit physical exam between 20-40 days after the drug was stopped.

Inclusion Criteria:

- Children > 6 months to < 18 years of age.

- Deep vein thrombosis demonstrated by objective testing (Duplex ultrasonography,
venography, CT venography, MR venography, echocardiography). This imaging must be
performed within 72 hours prior to initiation of study drug if no other
anticoagulation has been started. If receiving other anticoagulation prior to start
of study drug, imaging must be performed within 24 hours of study drug initiation.

- Informed consent and assent from parent/guardian/patient

Exclusion Criteria:

- Treatment of present thrombus with thrombolytic agent.

- Treatment of present thrombus with another anticoagulant for more than 48 hours (low
dose heparin for maintenance of venous or arterial catheter patency is allowed).

- Baseline prothrombin time (PT) which is more than 3 seconds above the upper limit of
normal or baseline activated partial thromboplastin time (aPTT) which is more than 5
seconds above the upper limit of normal.

- Creatinine which is more than 20% above the upper limit of normal for age.

- Presence of a known bleeding disorder.

- Active bleeding.

- Planned invasive procedure within 3 days.

- Known pregnancy