Clinical trial NCT00687882: Evaluation of the Duration of Therapy for Thrombosis in Children
Official title: Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thrombosis
Keywords: Venous Thromboembolism
Postthrombotic Syndrome
Antithrombotic Therapy
Duration of Therapy
Children
Lead sponsor: Johns Hopkins All Children's Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2008-06-02
Enrollment: 532
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Efficacy Outcome - Occurrence of Symptomatic Recurrent Venous Thromboembolism
timeFrame: 1 Year
measure: Safety Outcome - Occurrence of Clinically-relevant (i.e. Major Plus Clinically-relevant Non-major (CRNM)
timeFrame: 1 year
Secondary outcomes:
measure: Efficacy Outcome 1 - Occurrence of Symptomatic Recurrent Venous Thromboembolism (VTE) or Development of Post Thrombotic Syndrome (PTS) (Composite Endpoint)
timeFrame: 1 year
measure: Efficacy Outcome 2 - Occurrence of Symptomatic Recurrent Venous Thromboembolism (VTE)
timeFrame: 2 years
measure: Efficacy Outcome 3 - Development of Post Thrombotic Syndrome (PTS)
timeFrame: 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Sacramento
country: United States
facility: UC Davis Children's Center
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital UCSD
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: George Washington University, Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University / Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Stead Family Children's Hospital
state: Iowa
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Medicine
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan, Wayne State University
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Grand Rapids
country: United States
facility: Helen Devos Children's Hospital
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Kalispell
country: United States
facility: Glacier View
state: Montana
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: Ithaca
country: United States
facility: Cornell University
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: NewYork-Presbyterian
state: New York
city: Rochester
country: United States
facility: Golisano Children's Hospital
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Hershey
country: United States
facility: Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: St. Christopher's Hospital for Children
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: Palmetto Health
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital (Baylor)
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System University Hospital
state: Virginia
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Wauwatosa
country: United States
facility: Medical College of Wisconsin, Blood Center of Wisconsin
state: Wisconsin
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Vienna
country: Austria
facility: Medizinishe Universitat Wien
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Hamilton
country: Canada
facility: McMaster Childrens Hospital
state: Ontario
city: Toronto
country: Canada
facility: SickKids
state: Ontario
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Jerusalem
country: Israel
facility: Hadassah Hebrew-University Hospital
city: Tel-Aviv
country: Israel
facility: Sheba Medical Center
city: Rotterdam
country: Netherlands
facility: Sophia Children's Hospital
Study officials:
affiliation: Johns Hopkins All Children's Hospital
name: Neil A Goldenberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.