Evaluation of the Duration of Therapy for Thrombosis in Children



Status:Recruiting
Conditions:Cardiology
Therapuetic Areas:Cardiology / Vascular Diseases
Healthy:No
Age Range:Any - 20
Updated:4/6/2019
Start Date:March 2008
End Date:June 30, 2022
Contact:Neil A Goldenberg, MD, PhD
Email:neil@jhmi.edu
Phone:727-767-6886

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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).

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.
We found this trial at
55
sites
1 Perkins Square
Akron, Ohio 44308
(330) 543-1000
Principal Investigator: John Fargo, DO
Phone: 330-543-3805
Akron Children's Hospital From humble beginnings as a day nursery in 1890, Akron Children
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4900 Mueller Boulevard
Austin, Texas 78723
(512) 324-0000
Principal Investigator: Robert Mignacca, MD
Dell Children's Medical Center of Central Texas Welcome to Dell Children
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1720 2nd Ave S
Birmingham, Alabama 35233
(205) 934-4011 
Principal Investigator: Hope Wilson, MD
University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
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3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
 1-513-636-4200 
Principal Investigator: Christina Tarango, MD
Phone: 513-803-9255
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
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11100 Euclid Avenue
Cleveland, Ohio 44106
(216) 844-1000
Principal Investigator: Sanjay Ahuja, MD
Phone: 216-983-3178
Rainbow Babies and Children's Hospital UH Rainbow Babies & Children’s Hospital is a 244-bed, full-service...
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Cleveland, OH
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700 Childrens Drive
Columbus, Ohio 43205
(616) 722-2000
Principal Investigator: Sarah O'Brien, MD
Phone: 614-355-1201
Nationwide Children's Hospital At Nationwide Children’s, we are creating the future of pediatric health care....
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Columbus, OH
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Durham, North Carolina 27710
(919) 684-8111
Duke University Younger than most other prestigious U.S. research universities, Duke University consistently ranks among...
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807 Childrens Way
Jacksonville, Florida 32207
(904) 697-3600
Principal Investigator: Cindy Gauger, MD
Phone: 904-697-3206
Nemours Children's Clinic At Nemours Children’s Clinic, Jacksonville, we've treated every child as we would...
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2401 Gillham Rd
Kansas City, Missouri 64108
(816) 234-3000
Principal Investigator: Shannon Carpenter, MD
Phone: 816-855-1768
Children's Mercy Hospital Children's Mercy Hospitals and Clinics continues redefining pediatric medicine throughout the Midwest...
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4650 Sunset Blvd
Los Angeles, California 90027
 (323) 660-2450
Principal Investigator: Julie Jaffray, MD
Phone: 323-361-3478
Childrens Hospital Los Angeles Children's Hospital Los Angeles is a 501(c)(3) nonprofit hospital for pediatric...
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231 E Chestnut St
Louisville, Kentucky 40202
(502) 629-6000
Principal Investigator: Kerry McGowan, MD
Phone: 502-629-5604
Kosair Children's Hospital For more than a century, Kosair Children's Hospital and its predecessor hospitals...
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Miami, Florida 33124
(305) 284-2211
Principal Investigator: Fernando Corrales-Medina, MD
Phone: 305-243-6925
University of Miami A private research university with more than 15,000 students from around the...
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1211 Medical Center Dr
Nashville, Tennessee 37232
(615) 322-5000
Principal Investigator: Alexandrea Borst, MD
Vanderbilt Univ Med Ctr Vanderbilt University Medical Center (VUMC) is a comprehensive healthcare facility dedicated...
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601 Children's Lane
Norfolk, Virginia 23507
(757) 668-7000
Principal Investigator: Eric Lowe, MD
Phone: 757-668-7909
Children's Hospital of The King's Daughters Children
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1201 W La Veta Ave
Orange, California 92868
(714) 997-3000
Principal Investigator: Arash Mahajarin, MD
Phone: 714-509-8735
Children's Hospital of Orange County For more than 45 years, CHOC Children’s has been steadfastly...
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Philadelphia, Pennsylvania 19134
Principal Investigator: Deepti Raybagkar, MD
Phone: 215-427-4607
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4200 Fifth Ave
Pittsburgh, Pennsylvania 15260
(412) 624-4141
Principal Investigator: James Cooper, MD
Phone: 412-692-6467
University of Pittsburgh The University of Pittsburgh is a state-related research university, founded as the...
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100 N Mario Capecchi Dr
Salt Lake City, Utah 84132
(801) 662-1000
Principal Investigator: Anupam Verma, MD
Phone: 801-587-7541
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Atlanta, Georgia 30322
Principal Investigator: Gary Woods, MD
Phone: 404-785-9856
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13123 E 16th Ave
Aurora, Colorado 80045
(720) 777-1234
Principal Investigator: Taizo Nakano, MD
Phone: 303-724-6187
Children's Hospital Colorado At Children's Hospital Colorado, we see more, treat more and heal more...
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Baltimore, Maryland 21231
Principal Investigator: Courtney Lawrence, MD
Phone: 410-614-0050
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300 Longwood Ave
Boston, Massachusetts 02115
(617) 355-6000
Principal Investigator: Rachel Grace, MD
Phone: 617-355-8733
Boston Children's Hospital Boston Children's Hospital is a 395-bed comprehensive center for pediatric health care....
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Bronx, New York 10467
Principal Investigator: Jennifer Davila, MD
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171 Ashley Avenue
Charleston, South Carolina 29425
843-792-1414
Principal Investigator: Shayla Bergmann, MD
Phone: 843-876-8652
Medical University of South Carolina The Medical University of South Carolina (MUSC) has grown from...
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Charlottesville, Virginia 22903
Principal Investigator: Colleen Druzgal, MD
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1653 W. Congress Parkway
Chicago, Illinois 60612
(312) 942-5000
Principal Investigator: Mindy Simpson, MD
Phone: 312-942-7902
Rush University Medical Center Rush University Medical Center encompasses a 664-bed hospital serving adults and...
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Chicago, Illinois 60614
Principal Investigator: Rukhmi Bhat, MD
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Columbia, South Carolina 29203
Principal Investigator: Stuart Cramer, MD
Phone: 803-434-3109
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Dallas, Texas 75390
Principal Investigator: Ayesha Zia, MD
Phone: 214-456-8185
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Detroit, Michigan 48201
Principal Investigator: Madhvi Rajpurkar, MD
Phone: 313-966-8393
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East Lansing, Michigan 48824
Principal Investigator: Ajovi Scott Emuakpor, MD
Phone: 517-353-9385
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Grand Rapids, Michigan 49503
Principal Investigator: Deanna Mitchell, MD
Phone: 616-391-5075
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Hershey, Pennsylvania 17033
Principal Investigator: Smita Dandekar, MD
Phone: 717-531-7765
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Houston, Texas 77030
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Indianapolis, Indiana 46260
Principal Investigator: Charles Nakar, MD
Phone: 317-871-0011
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705 Riley Hospital Dr
Indianapolis, Indiana 46202
(317) 944-5000
Principal Investigator: Kerry Hege, MD
Phone: 317-948-3395
Riley Hospital for Children Riley Hospital for Children at IU Health is a place of...
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Iowa City, Iowa 52242
Principal Investigator: Anjali Sharathkumar, MD
Phone: 319-356-1212
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Ithaca, New York 14853
Principal Investigator: Nicole Kucine, MD
Phone: 212-746-4933
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Kalispell, Montana 59901
Principal Investigator: Courtney Lyle, MD
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1 Children's Way
Little Rock, Arkansas 72202
(501) 364-1100
Principal Investigator: Shelley Crary, MD
Arkansas Children's Hospital Arkansas Children's Hospital (ACH) is the only pediatric medical center in Arkansas...
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New Haven, Connecticut 06520
Principal Investigator: Sally Pels, MD
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New Hyde Park, New York 11040
Principal Investigator: Suchitra Acharya, MD
Phone: 718-470-4434
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161 Fort Washington Avenue
New York, New York 10032
Principal Investigator: Cindy Neunert, MD
Phone: 212-342-3853
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201 Lyons Ave
Newark, New Jersey 07112
(973) 926-7000
Principal Investigator: Shalu Narang, MD
Newark Beth Israel Medical Center Newark Beth Israel Medical Center, a regional care, teaching hospital...
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940 NE 13th St
Oklahoma City, Oklahoma 73190
(405) 271-6458
Principal Investigator: Osman Kahn, MD
University of Oklahoma Health Sciences Center The OU Health Sciences Center is composed of seven...
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Palo Alto, California 34304
Principal Investigator: Clara Lo, MD
Phone: 650-723-6992
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Parkville, Victoria 3052
Principal Investigator: Paul Monagle, MD
Phone: 61 3 9936-6330
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1919 E Thomas Rd
Phoenix, Arizona 85006
(602) 933-1000
Principal Investigator: Christine Knoll, MD
Phone: 602-933-0171
Phoenix Children's Hospital Phoenix Children's Hospital has provided hope, healing, and the best healthcare for...
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Portland, Oregon 97227
Principal Investigator: Kristina Haley, MD
Phone: 503-494-7425
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Rochester, New York 14642
Principal Investigator: Criag Mullen, MD
Phone: 585-275-2981
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Sacramento, California 95817
Principal Investigator: Arun Panigrahi, MD
Phone: 916-734-2780
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Saint Petersburg, Florida 33701
Principal Investigator: Marisol Betensky, MD
Phone: 727-767-3213
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San Diego, California 92123
Principal Investigator: Courtney Thornburg, MD
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