Evaluation of the Duration of Therapy for Thrombosis in Children

Children (birth to 21 years of age, inclusive) with first-episode venous thrombosis in
association with a reversible clinical trigger (key exclusions: history of cancer; severe
thrombophilia state disclosed) are enrolled and prescribed anticoagulation according to the
clinical standard of care and American College of Physicians (Chest journal) 2012
recommendations. At the 6 week (post-diagnosis) follow-up visit, repeat radiologic imaging is
performed to determine residual thrombus burden and its degree of occlusion. In addition,
those subjects with antiphospholipid antibodies (APA) disclosed at enrollment will undergo
repeat APA testing.

Patients with residual occlusive thrombosis or persistent APA are excluded from
randomization, and followed on parallel cohort arms (observational), with conventional
anticoagulation durations. All other patients are randomized to a total anticoagulant
duration of 6 weeks versus 3 months. Children are followed for primary efficacy endpoints of
symptomatic recurrent venous thromboembolism (VTE) and primary safety endpoints of
clinically-relevant bleeding (major plus clinically-relevant non-major, as per International
Society of Thrombosis and Haemostasis Scientific and Standardization Committee [Journal of
Thrombosis & Haemostasis] 2012 definitions/recommendations).

Children are followed through 2 years (with primary endpoint at 1 year). Those with deep
venous thromboses affecting venous return from the limbs also undergo standardized
post-thrombotic syndrome (PTS) outcome assessment using the Manco-Johnson pediatric PTS
instrument.

The non-inferiority analysis uses a bivariate endpoint approach, modeling the inherent
clinical trade-off between the risks of recurrent VTE and bleeding. The trial will enroll 750
children across 40 participating centers, and allows for a 25% rate of exclusion from the
per-protocol population due to randomization non-eligibility (i.e. parallel cohort),
withdrawal/loss to follow-up, and protocol non-adherence.

A sub-study, completed in late 2013, used investigational dalteparin in lieu of formulary low
molecular weight heparin (typically enoxaparin) in those children who were clinically
prescribed a low molecular weight heparin for sub-acute anticoagulation. The goal of this
sub-study was to report dose-finding and outcomes data in children treated with dalteparin
for VTE. Outcomes in these patients were qualitatively compared with those of patients who
received enoxaparin, warfarin, or other anticoagulants for sub-acute anticoagulation. This
portion of the study was an industry-sponsored investigator-initiated sub-study with an
investigator-held IND. Since the closure of the sub-study, the overall Kids-DOTT study is no
longer conducted under an Investigational New Drug (IND) application.

Principal aims and hypotheses:

Specific Aim #1: To evaluate the efficacy and safety of shortened-duration (6 weeks total)
versus conventional-duration (3 months total) anticoagulation for first-episode, provoked,
acute venous thrombosis among children in whom thrombus resolution/non-occlusion (i.e.
established blood flow) is evident after the initial 6 weeks of anticoagulant therapy

Hypothesis: Among children with first-episode, provoked, acute venous thrombosis in whom
thrombosis is resolved or non-occlusive at six weeks follow-up, a shortened duration of
anticoagulation (total six weeks; i.e. no further therapy) is non-inferior in efficacy to the
conventional duration (total three months) of anticoagulation with respect to the risk of
symptomatic recurrent VTE at 1 year, and is superior in safety with respect to the risk of
clinically-relevant bleeding.(The hypothesis will also be tested in secondary analysis at 2
years, using the same efficacy and safety outcomes as for the 1 year primary analysis.)

Specific Aim #2: To determine whether outcomes of first-episode, provoked, acute venous
thrombosis (specifically, with respect to recurrent VTE and PTS) among children treated with
conventional-duration (3 months total) anticoagulation differ between those with and without
thrombus resolution/non-occlusion at 6 weeks.

Hypothesis: Among children with first-episode, provoked, acute venous thrombosis treated with
conventional-duration (3 months total) anticoagulation, the cumulative incidences of
recurrent VTE and PTS are significantly lower among those in whom thrombus
resolution/non-occlusion was, versus was not, evident after the initial 6 weeks of
anticoagulant therapy.

Specific Aim #3: To establish a clinical trial-derived plasma and nucleic acids biorepository
for future proteomic, genomic, and metabolomic investigations of predictors and modulators of
VTE outcomes in children.

Specific Aim #4 (Exploratory Aim): To evaluate whether the effect of treatment duration on
the risks of symptomatic recurrent VTE and clinically-relevant bleeding in children with
first-episode, provoked, acute venous thrombosis differs substantively between subgroups
defined by type of sub-acute anticoagulant therapy in real-world clinical use (all prescribed
clinically, with the exception of investigational dalteparin, which was prescribed under an
investigator-held IND through December 2013).

Inclusion Criteria:

1. Children (birth to <21 years of age) with radiologically-confirmed acute venous
thrombosis in the past 30 days

2. In the opinion of the investigator, the venous thrombosis was a provoked (i.e.,
non-spontaneous) event (e.g.: hospitalization; Central venous catheterization;
infection; dehydration; surgery; trauma; immobility; use of estrogen-containing oral
contraceptive pills; flare of autoimmune/rheumatologic condition).

Exclusion Criteria:

1. Prior episode of VTE

2. Malignancy that, in the opinion of the treating oncologist, is not in remission, or
for which chronic anticoagulation is being administered/anticipated to be initiated
within 6 months (note: remission may exist on or off anti-neoplastic therapy)

3. Systemic lupus erythematosus

4. Pulmonary embolism that is not accompanied by DVT or is more proximal than segmental
branches of the pulmonary artery

5. Use of, or intent to use, thrombolytic therapy

6. History of congenital cardiac disease for which chronic anticoagulation is being
administered/ anticipated to be initiated within 6 months (e.g., for select patients
or centers, in the setting of a single or hypoplastic ventricle or
surgically-established cardiac shunt)

7. Moderate/severe anticoagulant deficiency as defined by any one of the following:

1. protein C <20 IU/dL if patient is ≥3 months of age, or protein C below lower
limit of detection if patient is <3 months of age;

2. antithrombin <30 IU/dL if patient is ≥3 months of age, or antithrombin below
lower limit of detection if patient is <3 months of age;

3. protein S (free antigen or activity) <20 IU/dL.