Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in Children
N/A
20 Years
Both
Venous Thrombosis
Trial Information
Prospective Multi-Center 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 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 [J Thromb Haemost] 2012
definitions/recommendations).
Children are followed through 2 years. 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 26 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 to be completed in late 2013 uses investigational dalteparin in lieu of
formulary low molecular weight heparin (typically enoxaparin) in those children who are
clinically prescribed a low molecular weight heparin for sub-acute anticoagulation. The
goal of this sub-study is to report dose-finding and outcomes data in children treated with
dalteparin for VTE. Outcomes in these patients will be qualitatively compared with those of
patients who receive enoxaparin or warfarin for sub-acute anticoagulation. This is an
industry-sponsored investigator-initiated sub-study with an investigator-held IND.
Hypotheses:
Principal Study hypothesis 1: Among children with first-episode acute venous thrombosis in
whom thrombus is not persistently occlusive following the initial 6 week period of
anticoagulant therapy, shortened-duration anticoagulation (6 weeks total) is non-inferior to
conventional-duration anticoagulation (3 months total).
Secondary Hypothesis 1: Among children with first-episode acute venous thrombosis treated
with conventional-duration (3 months total) anticoagulation, the cumulative incidences of
recurrent VTE and PTS at 2 years are significantly lower among those in whom thrombus
resolution/non-occlusion was, versus was not, evident after the initial 6 weeks of
anticoagulant therapy.
Secondary Hypothesis 2: Among children with first-episode venous thrombosis in whom
persistent antiphospholipid antibody positivity is evident at 6 and 12 weeks post-diagnosis,
the total duration of anticoagulant therapy (over the range of 3 months to indefinite
duration, as determined clinically in routine care) is not a significant predictor of
recurrent VTE or PTS at 2 years in the study population.
Secondary Hypothesis 3: Among children with first-episode acute venous thrombosis treated
with a conventional duration of anticoagulation, the relative risk of PTS at 2 years is
lower for LMWH (e.g. dalteparin and enoxaparin) as extended (i.e., sub-acute) anticoagulant
therapy than for warfarin, after adjustment for persistent occlusion vs.
non-occlusion/resolution of thrombus following the initial 6-week therapy period.
Inclusion Criteria:
- Children, aged 0- <21 years at time of enrollment
- Recently-diagnosed (i.e., within 30 days of radiologic diagnosis) of first-
episode acute venous thrombosis
Exclusion Criteria:
- 1) Any one of the following:
1. history of premature birth, if corrected (i.e., post-conceptional) age < 36
weeks (including gestation) at time of enrollment;
2. pregnancy at time of enrollment (N.B.: development of pregnancy while on study
will constitute post-enrollment exclusion from the study, although any data
collected to that time will be retained given the intent-to-treat analytic
approach);
3. known pulmonary embolism complicating this first-episode venous thrombosis;
4. uncorrected anatomic vascular defect, including May-Thurner anomaly, cervical
rib, and atretic IVC;
5. use of thrombolytic therapy (i.e. tPA) in the treatment of this first-episode
venous thrombosis;
6. chronic inflammatory condition/disease, other than diabetes mellitus;
7. prior episode of treated VTE;
8. antiphospholipid antibody persistent at 6 weeks (anticardiolipin IgM ≥ 20,
anti-beta-2-glycoprotein-1 IgG or IgM ≥ 10, or lupus anticoagulant positive by
local laboratory parameters, e.g. LA1/LA2 ratio ≥ 1.2 by dRVVT);
9. combined elevation of factor VIII > 150 IU/dL and D-dimer > 500 ng/mL at
diagnosis in patients with veno-occlusive DVT involving the extremities, iliac
veins, IVC, subclavian vein, brachiocephalic vein, innominate vein, or SVC;
10. history of malignancy;
11. no identifiable clinical risk factor for thrombosis (i.e., episode is
spontaneous);
12. homozygous factor V Leiden mutation;
13. homozygous prothrombin 20210 mutation;
14. protein C below lower limit of normal values for age (local laboratory, if
patient is < 3 months of age) or protein C less than 40% (IU/dL)if the patient
is ≥ 3 months of age;
15. protein S below 40% (IU/dL);
16. antithrombin below lower limit of normal values for age (local laboratory, if
patient is < 3 months of age) or antithrombin less than 60 % (IU/dL) if the
patient is 3 months of age or older at time of enrollment for patients who will
be treated with dalteparin (FRAGMIN®);
17. Two or more separate, non-contiguous thrombi simultaneously;
18. Systemic lupus erythematosus (SLE);
19. DALTEPARIN SUBSTUDY ONLY: estimated creatinine clearance <60ml/min. or the
patient weighs 8 kg at the time of enrollment.
- OR
- 2) At least three of the following:
1. first-degree family history of VTE (full sibling or biological parent treated
for VTE before 50 years of age);
2. thrombophilia traits at most recent assessment prior to enrollment as follows
(each counted individually as one risk factor):
1. factor V Leiden mutation;
2. prothrombin 20210 mutation;
3. protein C below lower limit of normal values for age (local laboratory, if
patient is < 3 months of age), or protein C less than 40% (IU/dL) if
patient is ≥ 3 months);
4. protein S below 40%;
5. antithrombin below lower limit of normal values for age (local laboratory,
if patient is < 3 months of age) or antithrombin less than 60% (IU/dL) if
patient is ≥ 3 months);
6. homocysteine ≥ 14 microM;
7. antiphospholipid antibody positive at enrollment; (anticardiolipin IgM ≥
20); GPL/MPL, anti-beta-2- glycoprotein-1 IgG or IgM ≥ 10 GPL/MPL, or lupus
anticoagulant positive by local laboratory parameters,e.g.LA1/LA2 ration ≥
1.2 by dRVVT).
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment
Outcome Measure:
Bivariate endpoint.
Outcome Description:
Primary efficacy endpoint is the risk of symptomatic, radiologically-confirmed recurrent venous thromboembolism. Primary safety endpoint is clinically-relevant bleeding (major + clinically-relevant non-major).
Outcome Time Frame:
2 Years
Safety Issue:
Yes
Principal Investigator
Neil A Goldenberg, MD, PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Colorado Denver Health Sciences Center
Authority:
United States: Food and Drug Administration
Study ID:
03-0585
NCT ID:
NCT00687882
Start Date:
March 2008
Completion Date:
December 2018
Related Keywords:
- Venous Thrombosis
- Venous Thromboembolism
- Postthrombotic Syndrome
- Antithrombotic Therapy
- Duration of Therapy
- Children
- Thrombosis
- Venous Thrombosis
- Venous Thromboembolism
Name | Location |
|---|---|
| Michigan State University | East Lansing, Michigan 48824 |
| All Children's Hospital | St. Petersburg, Florida 33701 |
| Phoenix Children's Hospital | Phoenix, Arizona 85016-7710 |
| Nationwide Children's Hospital | Columbus, Ohio 43205-2696 |
| Duke University | Durham, North Carolina 27710 |
| Vanderbilt University | Nashville, Tennessee 37232-6305 |
| University of Texas Southwestern | Dallas, Texas 75390 |
| Cook Children's Hospital | Fort Worth, Texas 76104 |
| University of Colorado School of Medicine | Aurora, Colorado |
| Rady Children's Hospital UCSD | San Diego, California 92123 |
| George Washington University, Children's National Medical Center | Washington, District of Columbia 20010 |
| Children's Hospital of Michigan, Wayne State University | Detroit, Michigan 48201 |
| Texas Children's Cancer Center, Baylor College of Medicine | Houston, Texas 77030 |
| Medical College of Wisconsin, Blood Center of Wisconsin | Wauwatosa, Wisconsin 53226 |
