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Pediatric High-Risk Deep Venous Thrombosis Lytic Outcomes Trial (PHLO)

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ClinicalTrials.gov Identifier: NCT02767232
Recruitment Status : Withdrawn (Did not receive NIH Funding)
First Posted : May 10, 2016
Last Update Posted : August 10, 2018
Sponsor:
Collaborators:
RTI International
Mid America Heart Institute
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
The purpose of this study is to determine if the use of adjunctive catheter-directed thrombolysis (CDT), which includes the intrathrombus administration of rt-PA (Activase/Alteplase), can prevent post-thrombotic syndrome (PTS) in pediatric patients with symptomatic proximal deep vein thrombosis (DVT) as compared with optimal standard anticoagulation alone.

Condition or disease Intervention/treatment Phase
Deep Vein Thrombosis Post-Thrombotic Syndrome Venous Thrombosis Drug: Recombinant tissue plasminogen activator (rt-PA) Drug: Standard Anticoagulation Therapy Phase 3

Detailed Description:

rt-PA, the study drug, is a fibrinolytic drug that is indicated for use in acute myocardial infarction, acute ischemic stroke, and acute massive pulmonary embolism in adults. Previous studies have shown the ability of rt-PA to lyse venous thrombus in patients with deep vein thrombosis (DVT), and suggest that successful rt-PA mediated thrombolysis can prevent post-thrombotic syndrome (PTS).

rt-PA is delivered directly into venous thrombus using a catheter/device which is embedded within the thrombus by a physician under imaging guidance. This method of rt-PA delivery, catheter-directed thrombolysis (CDT), is thought to be safer, more effective, and more efficient than previous methods. The question of whether CDT using rt-PA improves long-term DVT patient outcomes with acceptable risk and cost is currently being studied in the ATTRACT Trial for adults, but has not yet been addressed in the pediatric population.

The rationale for performing the PHLO Trial is based upon:

  • the major burden of PTS on pediatric DVT patients and the U.S. healthcare system
  • the reported association between rapid clot lysis and prevention of PTS
  • the proven ability of rt-PA to dissolve venous thrombus in proximal DVT
  • the recent advances in CDT methods which may lower bleeding risk, but which could, inadvertently, cause more endothelial injury in the smaller caliber vessels of pediatric patients
  • the lack of outcome evidence for either anticoagulation or catheter-directed thrombolysis in children
  • the major clinical controversy on whether CDT should routinely be used for first-line DVT therapy

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pediatric High-Risk Deep Venous Thrombosis Lytic Outcomes Trial
Estimated Study Start Date : July 2018
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Alteplase

Arm Intervention/treatment
Active Comparator: Standard Anticoagulation Therapy
Anticoagulant therapy will be prescribed in accordance with 2012 ACCP Guidelines for children. Initial therapy generally will consist of low molecular weight heparin (LMWH) or unfractionated heparin (UFH), monitored to achieve and maintain a target anti-Xa activity of 0.5-1.0 IU/mL for LMWH and 0.35-0.7 IU/mL for UFH. Long-term therapy generally will consist of warfarin/coumadin, monitored to achieve and maintain a target INR of 2.0-3.0. The use of novel anticoagulants is permitted based on investigator preference.
Drug: Standard Anticoagulation Therapy
Standard anticoagulation determined by physician for a period of 3-6 months

Experimental: Catheter-Directed Thrombolysis
Catheter-Directed Thrombolysis (CDT) with intrathrombus delivery of Recombinant tissue plasminogen activator (rt-PA) (maximum allowable total dose 35 mg/24 hours) into the DVT over a period of up to 24 hours. CDT will be initiated within 72 hours of diagnosis. Two methods of initial rt-PA delivery will be used: 1.) AngioJet Thrombectomy System- maximum first-session rt-PA dose 25 mg; or 2.) Catheter-directed rt-PA infusion for up to 24 hours at 0.01 mg/kg/hr (maximum 1.0 mg/hr) via a multisidehole catheter. Before and after CDT, patients will receive standard DVT therapy as in the standard anticoagulation group
Drug: Recombinant tissue plasminogen activator (rt-PA)
Catheter-directed thrombolysis, consisting of intrathrombus administration of rt-PA using a catheter/device.
Other Names:
  • rt-PA
  • recombinant tissue plasminogen activator
  • Activase
  • Alteplase




Primary Outcome Measures :
  1. Development of Post-Thrombotic Syndrome (PTS) [ Time Frame: within 24 months after randomization ]
    Post-thrombotic syndrome (PTS) as determined by the Manco-Johnson Pediatric PTS Instrument


Secondary Outcome Measures :
  1. Change in Quality of Life (PedsQL) [ Time Frame: within 24 months of randomization ]
    Quality of life (QoL) as determined by the PedsQL(TM)

  2. Change in Quality of Life (Peds-VEINES) [ Time Frame: within 24 months of randomization ]
    Quality of life (QoL) as determined by the Peds-VEINES-QoL

  3. Assessment of Venous Valvular Reflux [ Time Frame: at 12 months post-diagnosis ]
    Venous reflux will be assessed in a subset of patients using standard techniques

  4. Severity of Post-Thrombotic Syndrome (PTS) [ Time Frame: within 24 months of randomization ]
    Severity of PTS as determined by the Manco-Johnson PTS Instrument.

  5. Time to Resolution of presenting Deep Vein Thrombosis (DVT) symptoms [ Time Frame: within 24 months of randomization ]
  6. Degree of clot lysis [ Time Frame: within 24 months of randomization ]

Other Outcome Measures:
  1. Development of Major Bleeding [ Time Frame: within 7 days and 24 months after randomization ]
  2. Development of Symptomatic Pulmonary Embolism [ Time Frame: within 7 days and 24 months after randomization ]
  3. Recurrence of Venous Thromboembolism [ Time Frame: within 7 days and 24 months after randomization ]
  4. Death [ Time Frame: within 7 days and 24 months after randomization ]
  5. Cost-Effectiveness [ Time Frame: within 24 months after randomization ]
    Cost-effectiveness of CDT followed by anticoagulation relative to anticoagulation alone will be measured via hospital bills, UB-04 summary bills, and EQ-5D-Y.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject and/or legal guardian has voluntarily provided signed informed consent.
  • Subject is 6-21 years old with a minimum weight of 20 kg at the time of enrollment.
  • Radiologically-confirmed, symptomatic proximal lower extremity DVT involving the inferior vena cava, iliac vein, and/or common femoral vein; DVT must be occlusive in at least one involved vein
  • Life expectancy greater than or equal to 2 years.

Exclusion Criteria:

  • Symptom duration > 14 days for DVT episode in affected leg
  • Known history of a bleeding disorder
  • Known history of heparin-induced thrombocytopenia (HIT)
  • Prior established diagnosis of PTS in lower extremities
  • Circulatory compromise necessitating surgery
  • Pulmonary embolism with hemodynamic compromise or other acute illness precluding tolerance of catheter-directed therapy
  • Severe hypersensitivity or allergy to Activase(R), iodinated contrast or planned treatment anticoagulant drug, except for mild-moderate contrast allergies for which steroid pre-treatment can be used.
  • Inability to maintain hemoglobin <9.0 mg/dL, INR >1.7, or platelets <100,000/mL, using transfusion as indicated.
  • Active or historic bleeding, vasculopathy, coagulopathy, invasive procedure or medical condition contraindicating thrombolysis or anticoagulation
  • Previous thrombolysis within the last month
  • Pregnant female or within 7 days of uncomplicated delivery
  • Participation in another investigational study within the last month
  • Life expectancy < 2 years or with chronic non-ambulatory status
  • Inability to provide informed consent or to comply with study assessments

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02767232


Sponsors and Collaborators
University of Colorado, Denver
RTI International
Mid America Heart Institute
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Investigators
Principal Investigator: Marilyn J Manco-Johnson, MD University of Colorado Denver Anschutz Medical Campus

Additional Information:
Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT02767232     History of Changes
Other Study ID Numbers: 14-0659
ML29463 ( Other Identifier: Genentech, Inc. )
First Posted: May 10, 2016    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Colorado, Denver:
PHLO
deep vein thrombosis
deep venous thrombosis
blood clot
catheter-directed thrombolysis
thrombolysis
post-thrombotic syndrome
PTS
recombinant tissue plasminogen activator
rt-PA
Activase
Alteplase

Additional relevant MeSH terms:
Thrombosis
Venous Thrombosis
Postthrombotic Syndrome
Postphlebitic Syndrome
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Venous Insufficiency
Phlebitis
Peripheral Vascular Diseases
Plasminogen
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action