Kids DOTT Trial

Principal Investigator: Anupam Verma
Keywords: Thrombosis , Children , DOTT Department: Pediatric Administration
IRB Number: 00074534 Co Investigator:  
Specialty: Hematology/BMT
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Rebbecca Hanshew
Rebbecca.Perez@hsc.utah.edu
801-213-9105

Brief Summary

The main purpose of the Kids-DOTT trial is to provide key evidence for the optimal duration of anticoagulant therapy venous for thrombosis in children, given that the conventional duration of such therapy in children is derived solely from evidence in adult venous thromboembolism (VTE) trials. To fulfill this purpose, a multicenter randomized controlled trial (RCT) is necessary and herein described. Because of the large scope of this trial, an additional purpose, during the vanguard study was to provide evidence of feasibility of the trial via an initial internal/nested pilot/feasibility phase. Metrics were established during the vanguard study that would allow for advancement into the "rest of trial phase", for trial completion.

The Kids-DOTT trial specifically addresses the population of children with first-episode venous thrombosis in whom clinical characteristics do not indicate an a priori heightened risk for developing recurrent VTE or the post-thrombotic syndrome (PTS). As such, this trial adopts a rational, risk-stratified approach to antithrombotic therapy in children. In particular, it excludes those few patients in whom findings on initial diagnostic evaluation warrant a prolonged duration of anticoagulation (e.g., spontaneous/idiopathic event, prior VTE, underlying cancer, severe hypercoagulable state), and then takes advantage of an additional clinical factor (early thrombus resolution/non-occlusion), in order to target a group of children who are most likely to realize a net benefit (from the risk/benefit perspective) of shortened-duration anticoagulation. Over 90% of VTE in children are classified as “provoked” (non-spontaneous), meaning that they have been provoked by the presence or insertion of a central venous catheter, recent hospitalization, surgery, trauma, immobility, infection, dehydration, flare of autoimmune condition, oral contraceptive use, etc.

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.

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.

Specific Aim #3: 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 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).

Specific Aim #4: To establish a clinical trial-derived plasma and nucleic acids biorepository for future "omics" (e.g. proteomic, genomic, and metabolomics) investigations of predictors and modulators of VTE outcomes in children.

Specific Aim #5 (exploratory): 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)

For the internal/nested pilot/feasibility study completed during the vanguard phase of the trial, the specific aims were as follow:

(1) To provide pilot data on the proportion of children studied with acute thrombosis who exhibit thrombus resolution/non-occlusion (i.e., established blood flow) following 6 weeks of standard anticoagulant therapy, the occurrence of recurrent VTE and PTS in children studied, and the frequency of study drop-out;

(2) To evaluate the feasibility of web-based enrollment, randomization, and data collection over a 2-year follow-up period among participating sites;

(3) To determine the concordance (measured as percent agreement and κ) in the finding of completely occlusive thrombosis at the 6 week repeat imaging study (i.e., principal randomization criterion) for the reading by the blinded central adjudicating radiologist in comparison to the local clinical radiology report.

 

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

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:

a. 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;

b. 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;

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

NOTE regarding pregnancy:

A patient who develops a DVT while pregnant who has no other provoking factor beyond the pregnancy will remain ineligible for this study. A patient who had previously met eligibility criteria and has completed treatment for her DVT and then becomes pregnant can remain enrolled on study for long-term follow-up purposes. If a patient is enrolled on study and is still on anticoagulant treatment when she becomes pregnant, she will be retained in the study on the allocated treatment duration arm so long as the primary hematologist believes that this is clinically appropriate; else she will be withdrawn from the study and treated with the clinically-indicated duration of anticoagulation.