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

Sponsor

Johns Hopkins All Children's Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT00687882

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

608

Enrollment

Locations

Arms

167.5

Duration (Months)

9.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thrombosis	Other: Shortened duration (6 weeks) of anticoagulant therapy Other: Conventional duration (3 months) of anticoagulant therapy Other: No Intervention Other: No Intervention	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

608 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2008

Actual Primary Completion Date :

Jan 5, 2021

Actual Study Completion Date :

Feb 15, 2022

Arms and Interventions

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: Parallel Cohort: Persistent Antiphospholipid Antibody Patients with persistent Positive Antiphospholipid Antibody at 6 weeks.	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.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Efficacy outcome 1 - Occurrence of symptomatic recurrent venous thromboembolism (VTE) or development of Post Thrombotic Syndrome (PTS) (composite endpoint) [1 year]
Occurrence of symptomatic recurrent venous thromboembolism (VTE) or development of Post Thrombotic Syndrome (PTS) (composite endpoint)
Efficacy outcome 2 - Occurrence of symptomatic recurrent venous thromboembolism (VTE) [2 years]
Occurrence of symptomatic recurrent venous thromboembolism (VTE)
Efficacy outcome 3 - Development of Post Thrombotic Syndrome (PTS) [1 year]
Development of Post Thrombotic Syndrome (PTS)
Efficacy outcome 4 - Development of Post Thrombotic Syndrome (PTS) [2 years]
Development of Post Thrombotic Syndrome (PTS)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 20 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Children (birth to <21 years of age) with radiologically-confirmed acute deep venous thrombosis in the past 30 days
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:

Prior episode of VTE
Malignancy that, in the opinion of the treating oncologist, is not in remission (note: remission may exist on or off anti-neoplastic therapy)
Systemic lupus erythematosus
Pulmonary embolism that is not accompanied by DVT or is more proximal than segmental branches of the pulmonary artery
Use of, or intent to use, thrombolytic therapy
Chronic anticoagulant at prophylactic dosing is being or will be administered beyond 6 months post VTE diagnosis
Moderate/severe anticoagulant deficiency (defined by any one of the following):
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;
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;
protein S (free antigen or activity) <20 IU/dL.

Contacts and Locations

Locations

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