Evaluation of the Duration of Therapy for Thrombosis in Children

Venous Thrombosis Clinical Trial

— Kids-DOTT  

Official title:

Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in Children

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00687882
• Other study ID #: IRB00063928
• Secondary ID: 1U01HL130048-01A
• Status: Completed
• Phase: Phase 3
• Start date: March 2008
• Est. completion date: February 15, 2022

Study information

• Verified date: January 2022
• Source: Johns Hopkins All Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 608
• Est. completion date: February 15, 2022
• Est. primary completion date: January 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 20 Years

Eligibility

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.

Related Conditions & MeSH terms

• Thrombosis
• Venous Thrombosis

Intervention

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Parkville	Victoria
Austria	Medizinishe Universitat Wien	Vienna
Canada	Stollery Children's Hospital	Edmonton	Alberta
Canada	McMaster Childrens Hospital	Hamilton	Ontario
Canada	Montreal Children's Hospital	Montréal	Quebec
Canada	SickKids	Toronto	Ontario
Israel	Hadassah Hebrew-University Hospital	Jerusalem
Israel	Sheba Medical Center	Tel-Aviv
Netherlands	Sophia Children's Hospital	Rotterdam
United States	Akron Children's Hospital	Akron	Ohio
United States	Emory University / Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins Medicine	Baltimore	Maryland
United States	University of Alabama Birmingham	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	The Children's Hospital at Montefiore	Bronx	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System University Hospital	Charlottesville	Virginia
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Palmetto Health	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern	Dallas	Texas
United States	Children's Hospital of Michigan, Wayne State University	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	Michigan State University	East Lansing	Michigan
United States	Helen Devos Children's Hospital	Grand Rapids	Michigan
United States	Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital (Baylor)	Houston	Texas
United States	Indiana Hemophilia and Thrombosis Center	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa Stead Family Children's Hospital	Iowa City	Iowa
United States	Cornell University	Ithaca	New York
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Glacier View	Kalispell	Montana
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Cohen Children's Medical Center	New Hyde Park	New York
United States	NewYork-Presbyterian	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital Orange County	Orange	California
United States	Stanford Medicine	Palo Alto	California
United States	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Golisano Children's Hospital	Rochester	New York
United States	UC Davis Children's Center	Sacramento	California
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Rady Children's Hospital UCSD	San Diego	California
United States	George Washington University, Children's National Medical Center	Washington	District of Columbia
United States	Medical College of Wisconsin, Blood Center of Wisconsin	Wauwatosa	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins All Children's Hospital	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Israel,  Netherlands, 

References & Publications (3)

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. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Efficacy outcome 2 - Occurrence of symptomatic recurrent venous thromboembolism (VTE)	Occurrence of symptomatic recurrent venous thromboembolism (VTE)	2 years
Secondary	Efficacy outcome 3 - Development of Post Thrombotic Syndrome (PTS)	Development of Post Thrombotic Syndrome (PTS)	1 year
Secondary	Efficacy outcome 4 - Development of Post Thrombotic Syndrome (PTS)	Development of Post Thrombotic Syndrome (PTS)	2 years

External Links

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