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Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT)

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ClinicalTrials.gov Identifier: NCT00687882
Recruitment Status : Recruiting
First Posted : June 2, 2008
Last Update Posted : March 20, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Neil Goldenberg, Johns Hopkins University

May 6, 2008
June 2, 2008
March 20, 2018
March 2008
June 30, 2021   (Final data collection date for primary outcome measure)
Bivariate endpoint. [ Time Frame: 1 Year ]
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).
Efficacy will be evaluated based on the cumulative incidence of symptomatic, radiologically-confirmed recurrent venous thromboembolism and the prevalence/severity of post-thrombotic syndrome, using a standardized validated pediatric outcome instrument. [ Time Frame: 2 Years ]
Complete list of historical versions of study NCT00687882 on ClinicalTrials.gov Archive Site
Prevalence/severity of post-thrombotic syndrome. [ Time Frame: 1 and 2 Years ]
PTS is measured using a standardized validated pediatric outcome instrument (Manco-Johnson instrument). Both PTS and clinically-significant PTS will be captured as secondary endpoints.
  • Safety [ Time Frame: Within Therapy Period ]
  • Efficacy will be evaluated based on the cumulative incidence of symptomatic, radiologically-confirmed recurrent venous thromboembolism and the prevalence/severity of post-thrombotic syndrome, using a standardized validated pediatric outcome instrument. [ Time Frame: 5 Years ]
Not Provided
Not Provided
 
Evaluation of the Duration of Therapy for Thrombosis in Children
Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in Children
The Kids-DOTT trial is a randomized controlled clinical trial whose primary objective is to evaluate non-inferiority of shortened-duration (6 weeks) versus conventional-duration (3 months) anticoagulation in children with first-episode acute venous thrombosis. The first stage of the trial has consisted of a pilot/feasibility component, which then continues as the definitively-powered trial.

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).

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Venous Thrombosis
  • Other: Shortened duration (6 weeks) of anticoagulant therapy
    Subjects with evidence of non-occlusive or resolved thrombus at 6 weeks time will be randomized to receive a total duration of anticoagulant therapy of 6 weeks.
  • Other: Conventional duration (3 months) of anticoagulant therapy
    Subjects with evidence of non-occlusive or resolved thrombus at 6 weeks time will be randomized to receive a total duration of anticoagulant therapy of 3 months.
  • Other: No Intervention
    Subjects with evidence of persistent thrombus at 6 weeks time will remain on anticoagulant therapy for 3-6 months at the discretion of their treating physician.
  • Other: No Intervention
    Subjects with evidence of persistent antiphospholipid antibody at 6 weeks will remain on anticoagulant therapy for 3 months to indefinite duration, at the discretion of their treating physician.
  • Experimental: Intervention: A
    Patients with non-occlusive thrombus or resolved thrombosis at 6 weeks.
    Intervention: Other: Shortened duration (6 weeks) of anticoagulant therapy
  • Active Comparator: B
    Patients with non-occlusive thrombus or resolved thrombosis at 6 weeks.
    Intervention: Other: Conventional duration (3 months) of anticoagulant therapy
  • Parallel Cohort: Persistent Occlusive Thrombosis
    Patients with completely occlusive thrombosis at 6 weeks.
    Intervention: Other: No Intervention
  • Parallel Cohort: Persistent Antiphospholipid Antibody
    Patients with persistent Positive Antiphospholipid Antibody at 6 weeks.
    Intervention: Other: No Intervention

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
815
1250
June 30, 2022
June 30, 2021   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
up to 20 Years   (Child, Adult)
No
Contact: Neil A Goldenberg, MD, PhD 727-767-6886 neil@jhmi.edu
Contact: Frances L Hamblin, MSHS, RN 727-767-2460 Frances.Hamblin@jhmi.edu
Australia,   Austria,   Canada,   Germany,   Israel,   Netherlands,   United States
Argentina,   United Kingdom
 
NCT00687882
IRB00063928
1U01HL130048-01A1 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Plan to Share IPD: No
Neil Goldenberg, Johns Hopkins University
Johns Hopkins All Children's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Neil A Goldenberg, MD, PhD Johns Hopkins All Children's Hospital
Johns Hopkins All Children's Hospital
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP