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

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.

Study Overview

• Status: Withdrawn
• Conditions: Venous Thrombosis; Deep Vein Thrombosis; Post-Thrombotic Syndrome
• Intervention / Treatment: Drug: Standard Anticoagulation Therapy; Drug: Recombinant tissue plasminogen activator (rt-PA)

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
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: Alteplase; Activase; rt-PA; recombinant tissue plasminogen activator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of Post-Thrombotic Syndrome (PTS)	Post-thrombotic syndrome (PTS) as determined by the Manco-Johnson Pediatric PTS Instrument	within 24 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quality of Life (PedsQL)	Quality of life (QoL) as determined by the PedsQL(TM)	within 24 months of randomization
Change in Quality of Life (Peds-VEINES)	Quality of life (QoL) as determined by the Peds-VEINES-QoL	within 24 months of randomization
Assessment of Venous Valvular Reflux	Venous reflux will be assessed in a subset of patients using standard techniques	at 12 months post-diagnosis
Severity of Post-Thrombotic Syndrome (PTS)	Severity of PTS as determined by the Manco-Johnson PTS Instrument.	within 24 months of randomization
Time to Resolution of presenting Deep Vein Thrombosis (DVT) symptoms		within 24 months of randomization
Degree of clot lysis		within 24 months of randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of Major Bleeding		within 7 days and 24 months after randomization
Development of Symptomatic Pulmonary Embolism		within 7 days and 24 months after randomization
Recurrence of Venous Thromboembolism		within 7 days and 24 months after randomization
Death		within 7 days and 24 months after randomization
Cost-Effectiveness	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.	within 24 months after randomization

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Predictors of the Post Thrombotic Syndrome During Long-Term Treatment of Proximal Deep Vein Thrombosis
• Deep Vein Thrombosis

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2018
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: May 6, 2016
• First Posted (Estimate): May 10, 2016

Study Record Updates

• Last Update Posted (Actual): August 10, 2018
• Last Update Submitted That Met QC Criteria: August 8, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: thrombolysis; Alteplase; deep vein thrombosis; blood clot; deep venous thrombosis; recombinant tissue plasminogen activator; rt-PA; PTS; Activase; post-thrombotic syndrome; PHLO; catheter-directed thrombolysis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Peripheral Vascular Diseases; Venous Insufficiency; Phlebitis; Thrombosis; Venous Thrombosis; Postthrombotic Syndrome; Postphlebitic Syndrome; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: 14-0659; ML29463 (Other Identifier: Genentech, Inc.)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No