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

Primary Purpose

Deep Vein Thrombosis, Post-Thrombotic Syndrome, Venous Thrombosis

Status

Withdrawn

Phase

Phase 3

Locations

Study Type

Interventional

Intervention

Recombinant tissue plasminogen activator (rt-PA)

Standard Anticoagulation Therapy

About this trial

This is an interventional treatment trial for Deep Vein Thrombosis focused on measuring 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

Eligibility Criteria

6 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard Anticoagulation Therapy

Catheter-Directed Thrombolysis

Arm Description

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.

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

Outcomes

Primary Outcome Measures

Development of Post-Thrombotic Syndrome (PTS)

Post-thrombotic syndrome (PTS) as determined by the Manco-Johnson Pediatric PTS Instrument

Secondary Outcome Measures

Change in Quality of Life (PedsQL)

Quality of life (QoL) as determined by the PedsQL(TM)

Change in Quality of Life (Peds-VEINES)

Quality of life (QoL) as determined by the Peds-VEINES-QoL

Assessment of Venous Valvular Reflux

Venous reflux will be assessed in a subset of patients using standard techniques

Severity of Post-Thrombotic Syndrome (PTS)

Severity of PTS as determined by the Manco-Johnson PTS Instrument.

Time to Resolution of presenting Deep Vein Thrombosis (DVT) symptoms

Degree of clot lysis

Full Information

NCT ID

NCT02767232

First Posted

December 16, 2015

Last Updated

August 8, 2018

Sponsor

University of Colorado, Denver

Collaborators

RTI International, Mid America Heart Institute, National Heart, Lung, and Blood Institute (NHLBI), Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02767232

Brief Title

Pediatric High-Risk Deep Venous Thrombosis Lytic Outcomes Trial

Acronym

PHLO

Official Title

Pediatric High-Risk Deep Venous Thrombosis Lytic Outcomes Trial

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Withdrawn

Why Stopped

Did not receive NIH Funding

Study Start Date

July 2018 (Anticipated)

Primary Completion Date

April 2023 (Anticipated)

Study Completion Date

June 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Colorado, Denver

Collaborators

RTI International, Mid America Heart Institute, National Heart, Lung, and Blood Institute (NHLBI), Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Deep Vein Thrombosis, Post-Thrombotic Syndrome, Venous Thrombosis

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard Anticoagulation Therapy

Arm Type

Active Comparator

Arm Description

Arm Title

Catheter-Directed Thrombolysis

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Recombinant tissue plasminogen activator (rt-PA)

Other Intervention Name(s)

rt-PA, recombinant tissue plasminogen activator, Activase, Alteplase

Intervention Description

Catheter-directed thrombolysis, consisting of intrathrombus administration of rt-PA using a catheter/device.

Intervention Type

Drug

Intervention Name(s)

Standard Anticoagulation Therapy

Intervention Description

Standard anticoagulation determined by physician for a period of 3-6 months

Primary Outcome Measure Information:

Title

Development of Post-Thrombotic Syndrome (PTS)

Description

Post-thrombotic syndrome (PTS) as determined by the Manco-Johnson Pediatric PTS Instrument

Time Frame

within 24 months after randomization

Secondary Outcome Measure Information:

Title

Change in Quality of Life (PedsQL)

Description

Quality of life (QoL) as determined by the PedsQL(TM)

Time Frame

within 24 months of randomization

Title

Change in Quality of Life (Peds-VEINES)

Description

Quality of life (QoL) as determined by the Peds-VEINES-QoL

Time Frame

within 24 months of randomization

Title

Assessment of Venous Valvular Reflux

Description

Venous reflux will be assessed in a subset of patients using standard techniques

Time Frame

at 12 months post-diagnosis

Title

Severity of Post-Thrombotic Syndrome (PTS)

Description

Severity of PTS as determined by the Manco-Johnson PTS Instrument.

Time Frame

within 24 months of randomization

Title

Time to Resolution of presenting Deep Vein Thrombosis (DVT) symptoms

Time Frame

within 24 months of randomization

Title

Degree of clot lysis

Time Frame

within 24 months of randomization

Other Pre-specified Outcome Measures:

Title

Development of Major Bleeding

Time Frame

within 7 days and 24 months after randomization

Title

Development of Symptomatic Pulmonary Embolism

Time Frame

within 7 days and 24 months after randomization

Title

Recurrence of Venous Thromboembolism

Time Frame

within 7 days and 24 months after randomization

Title

Death

Time Frame

within 7 days and 24 months after randomization

Title

Cost-Effectiveness

Description

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.

Time Frame

within 24 months after randomization

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marilyn J Manco-Johnson, MD

Organizational Affiliation

University of Colorado Denver Anschutz Medical Campus

Official's Role

Principal Investigator

12. IPD Sharing Statement

Links:

URL

http://patient.info/health/deep-vein-thrombosis-leaflet

Description

Deep Vein Thrombosis

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Pediatric High-Risk Deep Venous Thrombosis Lytic Outcomes Trial

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