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/…
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Source
Brief title
Condition
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PRIMARY EFFICACY:
Risk of symptomatic recurrent VTE within 1 year
PRIMARY SAFETY:
Risk of clinically-relevant (i.e., major plus clinically-relevant non-major
[CRNM]) bleeding within 3 months (maximum randomized duration of
anticoagulation) plus 10 days
Based upon ISTH standardized definitions for pediatric trials [Mitchell et al.,
2011], *Major bleeding* will be characterized by bleeding satisfying any one of
the following criteria: 1) fatal; 2) clinically overt and associated with a
decrease in hemoglobin of at least 2 g/dL in a 24 hour period; 3) clinically
overt and for which blood product is administered; 4) retroperitoneal,
pulmonary, or involving the central nervous system; 5) requiring surgical
intervention in an operating suite. *CRNM bleeding* definition includes any
bleeding that does not fulfill the above criteria but fulfills one of the
following: 1) Bleeding requiring medical or surgical intervention to restore
hemostasis; 2) Bleeding for which medical attention is sought.
Secondary outcome
SECONDARY SAFETY:
1) Major bleeding episode (defined as above)
2) Minor bleeding episode (defined as all clinically-evident bleeding episodes
not meeting criteria for Major or CRNM bleeding, above) within the therapy
period. Nosebleeds lasting * 15 minutes, bleeding from superficial lacerations,
and bruising at points of minor trauma are all considered as expected events on
anticoagulation, and accordingly will not be collected.
SECONDARY EFFICACY:
1) Risk of symptomatic recurrent VTE at 2 years
2) Risks of PTS at 1 year and 2 years
Background summary
The incidence of pediatric thrombosis is rising due to advancements in
diagnostic modalities for thrombosis, the rise in intensive approaches toward
the support of critically ill children, and the heightened survival of children
with chronic illnesses. Over 90% of VTE in children are classified as
*provoked* (non-spontaneous), meaning that they have been provoked by the
presence or insertion of a central venous catheter, recent hospitalization,
surgery, trauma, immobility, infection, dehydration, flare of autoimmune
condition, oral contraceptive use, etc.
In both children and adults, the current standard of care, is for
anticoagulation of 3-6 months duration for a first-episode VTE in individuals
with few and/or transient pro-thrombotic risk factors, based upon adult trials.
A prolonged duration of anticoagulation is indicated in VTE patients with
chronic potent prothrombotic conditions, in those with unprovoked events (i.e.,
spontaneous; no clinical risk factors identified), and in antiphospholipid
antibody (APA) syndrome, given an increased risk of recurrent VTE in these
groups.
In both children and adults, either unfractionated heparin or LMWH may be used
during the initial (i.e., acute) therapy phase, while either LMWH or vitamin K
antagonists may be used during the extended (i.e., subacute) therapy phase.
The question as to whether outcomes for 6 week vs. 6 month anticoagulation in
adult VTE may be equivalent has not been definitively answered in adults. In
children shortening of the duration of anticoagulation would lessen frequent
invasive monitoring by venipuncture in patients treated with VKA, decrease the
number of invasive twicedaily subcutaneous injections in patients treated with
LMWH and decrease bleeding risk. Nevertheless, the desire to decrease cost and
bleeding risks by shortening the duration of anticoagulant therapy must be
balanced by the need to minimize risk of recurrent thrombosis. Unfortunately,
the relative risk of recurrent VTE for shortened anticoagulation in the
pediatric setting is unknown. Since the rate of recurrent VTE in children
treated with standard duration anticoagulation appears to be quite lower than
that for adults treated similarly, it is expected that the absolute increase in
risk of recurrent VTE (if any) engendered by shortened anticoagulation will be
smaller than that in adults.
No large prospective, randomized, controlled trials on the optimal duration of
anticoagulation for first episode VTE have been performed to date in children.
The Kids-DOTT study will provide key evidence for the optimal duration of
anticoagulant therapy for thrombosis in children.
Study objective
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
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.
Specific Aim #3: 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 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).
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.
Study design
If the patients fulfills the in- and exclusioncriteria, the patient can be
included into the study. This means that after 6 weeks the radiological tests
will be repeated.
If thrombosis is still there or the lupus anticoagulans remains positive, the
patient stays on anticoagulant treatment for at least 6 weeks.
If radiological investigation does not show thrombosis anymore after 6 weeks
and lupus anticoagulans is negative, the patient can be randomized to group A (
stop anticoagulation) or group B (standard of care: totally 3 months of
anticoagulation).
Parents and/or patients may give permission to take blood 6 weeks and 3 months
after diagnosis for biobank.
Intervention
If radiological investigation does not show thrombosis anymore after 6 weeks
and lupus anticoagulans is negative, the patient can be randomized to group A (
stop anticoagulation) or group B (standard of care: totally 3 months of
anticoagulation).
Study burden and risks
The shortened-duration anticoagulation (6 week arm) may incur an increased risk
of recurrent VTE, but this risk is likely minimized by randomization to this
arm only among patients who have no evidence of completely-occlusive thrombosis
after 6 weeks of initial therapy. Furthermore, if an increased risk of
recurrent VTE indeed exists in this carefully defined patient group, such risk
may be offset by a decreased risk of bleeding potentially offered by
abbreviated anticoagulation.
6th Ave S 501
St Petersburg FL 33701
US
6th Ave S 501
St Petersburg FL 33701
US
Listed location countries
Age
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) presence or history of cancer;;(3) systemic lupus erythematosus;(4) known pulmonary embolism (PE), except when limited to peripheral cavitary lesions representing septic emboli; (N.B. imaging for PE should only have been based upon clinical signs/symptoms, and is not a study procedure or requirement);(5) Use of, or intent to use, thrombolytic therapy;(6) Patients with congenital cardiac disease involving a single or hypoplastic ventricle or otherwise requiring aintracardiac shunt;(7) Moderate/severe anticoagulant deficiency as defined by any one of the following:;a. 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;;b. 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;;c. protein S (free antigen or activity) <20 IU/dL.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-001776-21-NL |
| ClinicalTrials.gov | NCT00687882 |
| CCMO | NL56060.078.17 |