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

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.

Study Overview

• Status: Completed
• Conditions: Venous Thrombosis
• Intervention / Treatment: Other: Shortened duration (6 weeks) of anticoagulant therapy; Other: Conventional duration (3 months) of anticoagulant therapy; Other: No Intervention; Other: No Intervention

Detailed Description

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 compare the composite efficacy 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., 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 to the conventional duration (total three months) of anticoagulation with respect to a composite efficacy endpoint comprised of the 1-year risk of symptomatic recurrent VTE or PTS. (The hypothesis will also be tested in secondary analysis at 2 years.)

Specific Aim #3: 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 #4: 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 #5: To investigate whether duration of anticoagulation (over the range of 3 months to indefinite duration, as determined clinically in routine care) on influences the risks of symptomatic recurrent VTE and clinically-relevant bleeding among children with first-episode, provoked, acute venous thrombosis in whom persistent antiphospholipid antibody (APA) positivity is evident at 6- and 12 -weeks post-diagnosis.

Hypothesis: Among children with first-episode, provoked, acute venous thrombosis in whom persistent APA positivity is evident at 6- and 12 -weeks post-diagnosis, duration of anticoagulant therapy is not a predictor of symptomatic recurrent VTE but is directly related to the risk of clinically-relevant bleeding.

Specific Aim #6 (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).

• Study Type: Interventional
• Enrollment (Actual): 608
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
• Austria
  • Vienna, Austria
    • Medizinishe Universitat Wien
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Stollery Children's Hospital
  • Ontario
    • Hamilton, Ontario, Canada
      • McMaster Childrens Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • SickKids
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • Montreal Children's Hospital
• Israel
  • Jerusalem, Israel
    • Hadassah Hebrew-University Hospital
  • Tel-Aviv, Israel
    • Sheba Medical Center
• Netherlands
  • Rotterdam, Netherlands
    • Sophia Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital Orange County
    • Palo Alto, California, United States, 34304
      • Stanford Medicine
    • Sacramento, California, United States, 95817
      • UC Davis Children's Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital UCSD
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • George Washington University, Children's National Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33124
      • University of Miami
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University / Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Stead Family Children's Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan, Wayne State University
    • East Lansing, Michigan, United States, 48824
      • Michigan State University
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Montana
    • Kalispell, Montana, United States, 59901
      • Glacier View
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Bronx, New York, United States, 10467-2403
      • The Children's Hospital at Montefiore
    • Ithaca, New York, United States, 14850
      • Cornell University
    • New Hyde Park, New York, United States, 11040
      • Cohen Children's Medical Center
    • New York, New York, United States, 10032
      • NewYork-Presbyterian
    • Rochester, New York, United States, 14642
      • Golisano Children's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital (Baylor)
  • Utah
    • Salt Lake City, Utah, United States, 81432
      • Primary Children's Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System University Hospital
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • Medical College of Wisconsin, Blood Center of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Children (birth to <21 years of age) with radiologically-confirmed acute deep 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 (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. Chronic anticoagulant at prophylactic dosing is being or will be administered beyond 6 months post VTE diagnosis

7. Moderate/severe anticoagulant deficiency (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention: A; Patients with non-occlusive thrombus or resolved thrombosis at 6 weeks.	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.
Active Comparator: B; Patients with non-occlusive thrombus or resolved thrombosis at 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: Parallel Cohort: Persistent Occlusive Thrombosis; Patients with completely occlusive thrombosis at 6 weeks.	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.
Other: Parallel Cohort: Persistent Antiphospholipid Antibody; Patients with persistent Positive Antiphospholipid Antibody at 6 weeks.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy outcome - Occurrence of symptomatic recurrent venous thromboembolism	Occurrence of symptomatic recurrent venous thromboembolism. Primary safety endpoint is occurrence of clinically-relevant bleeding (major + clinically-relevant non-major) bleeding.	1 Year
Safety outcome - Occurrence of clinically-relevant (i.e. major plus clinically-relevant non-major [CRNM]	Occurrence of clinically-relevant (i.e. major plus clinically-relevant non-major [CRNM] bleeding	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy outcome 1 - Occurrence of symptomatic recurrent venous thromboembolism (VTE) or development of Post Thrombotic Syndrome (PTS) (composite endpoint)	Occurrence of symptomatic recurrent venous thromboembolism (VTE) or development of Post Thrombotic Syndrome (PTS) (composite endpoint)	1 year
Efficacy outcome 2 - Occurrence of symptomatic recurrent venous thromboembolism (VTE)	Occurrence of symptomatic recurrent venous thromboembolism (VTE)	2 years
Efficacy outcome 3 - Development of Post Thrombotic Syndrome (PTS)	Development of Post Thrombotic Syndrome (PTS)	1 year
Efficacy outcome 4 - Development of Post Thrombotic Syndrome (PTS)	Development of Post Thrombotic Syndrome (PTS)	2 years

Collaborators and Investigators

• Sponsor: Johns Hopkins All Children's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Neil A Goldenberg, MD, PhD, Johns Hopkins All Children's Hospital

Publications and helpful links

General Publications

• Goldenberg NA, Tripputi M, Crowther M, Abshire TC, DiMichele D, Manco-Johnson MJ, Hiatt WR. The "parallel-cohort RCT": Novel design aspects and application in the Kids-DOTT trial of pediatric venous thromboembolism. Contemp Clin Trials. 2010 Jan;31(1):131-3. doi: 10.1016/j.cct.2009.11.006. Epub 2009 Nov 24.
• Kittelson JM, Spyropoulos AC, Halperin JL, Kessler CM, Schulman S, Steg G, Turpie AG, Cutler NR, Hiatt WR, Goldenberg NA; Antithrombotic Trials Leadership and Steering (ATLAS) Group. Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach. J Thromb Haemost. 2013 Aug;11(8):1443-8. doi: 10.1111/jth.12324.
• Goldenberg NA, Abshire T, Blatchford PJ, Fenton LZ, Halperin JL, Hiatt WR, Kessler CM, Kittelson JM, Manco-Johnson MJ, Spyropoulos AC, Steg PG, Stence NV, Turpie AG, Schulman S; Kids-DOTT Trial Investigators. Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings. J Thromb Haemost. 2015 Sep;13(9):1597-605. doi: 10.1111/jth.13038. Epub 2015 Aug 11.
• Goldenberg NA, Kittelson JM, Abshire TC, Bonaca M, Casella JF, Dale RA, Halperin JL, Hamblin F, Kessler CM, Manco-Johnson MJ, Sidonio RF, Spyropoulos AC, Steg PG, Turpie AGG, Schulman S; Kids-DOTT Trial Investigators and the ATLAS Group. Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial. JAMA. 2022 Jan 11;327(2):129-137. doi: 10.1001/jama.2021.23182. Erratum In: JAMA. 2022 Mar 22;327(12):1188.

Helpful Links

• https://www.hopkinsallchildrens.org/academics/research/multicenter-studies/kids-dott

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): January 5, 2021
• Study Completion (Actual): February 15, 2022

Study Registration Dates

• First Submitted: May 6, 2008
• First Submitted That Met QC Criteria: May 28, 2008
• First Posted (Estimate): June 2, 2008

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Children; Venous Thromboembolism; Antithrombotic Therapy; Postthrombotic Syndrome; Duration of Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Anticoagulants
• Other Study ID Numbers: IRB00063928; 1U01HL130048-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No