Prolonged Hemodialysis Catheter Survival With Copolymer Coating and Rt-PA

Study Overview
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Brief Summary
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Surface thrombogenicity of standard double lumen catheters (stDLC) and surface modified film-coated domain structured double lumen catheters (fcDLC) consisting of a novel reactive polyurethane copolymer coating showed that in vitro measured surface thrombogenicity was reduced in the modified catheter compared with standard catheter. The clinical investigation revealed that both number of days before catheter removal according to clinical requirements and number of treatments per catheter were significantly higher with the modified catheter as compared with the standard catheter. Recombinant tissue plasminogen activator (rt-PA) has been used primarily to treat catheter thrombosis. The relatively high cost of rt-PA and its theoretical potential to cause bleeding, as well as the morbidity and mortality associated with catheter malfunction and infection, justify the need for more definitive evidence of the efficacy of rt-PA as a locking solution. No study aims to evaluate the impact of rt-PA locking in long-term Hemodialysis (HD) uncuffed catheters survival.

Detailed Description
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The solution instilled into the central venous catheter lumens after each HD session and left in the catheter until the next session (catheter locking solution) is used to prevent thrombosis during the period between HD sessions and may also prevent catheter-related infection. However, evidence supporting the use of various locking solutions to achieve these objectives is limited. Heparin has been the traditional locking solution. Several small studies have assessed whether citrate and heparin are equally efficacious for maintaining catheter patency but the interpretation of the results was limited because the studies had a short follow-up period and included both uncuffed and cuffed central venous catheters. Thrombosis is a major cause of HD catheter dysfunction, and this problem is rectified by the use of thrombolytic agents, invasive procedures for declotting, or catheter replacement. A thrombus at the tip of the catheter or a fibrin sheath around it may resist local thrombolysis if it is not reached by sufficient concentrations of the drug. Urokinase has traditionally been used as the thrombolytic agent for HD vascular access declotting, and success rates for declotting vary from 55% to 85%. However, successful treatment of occluded central venous catheter (non HD) with recombinant tissue plasminogen activator (rt-PA) or alteplase was recently achieved in more than 1,000 patients with success (function restored in 798 patients [75.0%; 95% CI: 72.3 to 77.6%]). Serious adverse events monitored within 30 days was very rare and efficacy was independent of age, sex, body weight, and catheter type.

Official Title
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Prolonged Hemodialysis Catheter Survival With Copolymer Coating and Rt-PA - PROCOPrt-PA Trial

Conditions
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Malfunction; Catheter, Thrombosis, Mechanical Complication of Hemodialysis Catheter

Intervention / Treatment
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* Drug: rt-PA (2mg/2mL) actilysis
* Drug: rt-PA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: End-stage kidney disease patients with newly inserted temporary untunnelled dual-lumen catheter Naive to study but not naive to catheters (both virgin and non-virgin catheters will be included) Expected to use catheter, and to dialyze at study centre, for at least six months Frequency of HD 3 times per week If indication for catheter was replacement for catheter related infection patients will be eligible after the infection has been treated and the patient has been off antibiotics for 3 HD sessions Patient or legal representative able to provide written consent Eighteen years of age or older Baseline INR ≤ 1.3 (no anticoagulation allowed outside the HD session) Baseline platelet count ≥ 60 x 109/L Exclusion Criteria: Use of systemic anticoagulation (if indication for anticoagulation is catheter patency patients may be eligible if the systemic anticoagulation is discontinued and baseline INR is ≤ 1.3) Insertion of a new catheter into the femoral vein Current use of antibiotics for catheter-related bacteraemia (see inclusion criteria above) Major haemorrhage in the prior 4 weeks, defined as bleeding resulting in a drop in haemoglobin of greater than 20 g/L or bleeding requiring transfusion of packed red blood cells with other clinical evidence or suspicion of bleeding History of intra-cranial bleed in the prior 4 weeks Intra-cranial or intra-spinal neoplasm (current) Allergy or intolerance to rt-PA or heparin or its constituents Active pericarditis - defined by the presence of a pericardial rub Weight ≤ 30 kg or > 130 kg Patient pregnant or lactating Child bearing potential (i.e. pre-menopausal woman who is not using a reliable method of contraception) Major surgery in past 48 hours (CABG, organ biopsy, puncture of non-compressible vessels), or scheduled for major surgery during the study period Involvement in another randomized drug trial Presence of a fever as defined by a temperature > 38.2°C

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fmDLC and rt-PA (2mg/2mL actilysis)<br>Surface thrombogenicity of film-coated domain structured double lumen catheters (fmDLC) consisting of a novel reactive polyurethane copolymer coating will be assessed by measurement of thrombin-antithrombin (TAT) III complex in vitro after the use of rt-PA (2mg/2mL) in each lumen of the catheter for 45 minutes. Each lumen of the thrombosed (dysfunctional) catheter will be locked with the exact volume (luminal volume) of rt-PA (rt-PA (2mg/2mL) actilysis) during 45 min. | Drug: rt-PA (2mg/2mL) actilysis<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. All catheters analyzed (fmDLC, polyDLC and siDLC) will be locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions: i.e. fmDLC, polyDLC amd siDLC.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany;Drug: rt-PA<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed in this study (i.e. fmDLC, polyDLC, siDLC) will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany);|
| Active Comparator: polyDLC and rt-PA (2mg/2mL actilysis)<br>The same procedure will be assessed in the polyurethane double lumen catheter (polyDLC)as with the fmDLC. Indeed, surface thrombogenicity of polyDLC will be assessed by measurement of thrombin-antithrombin (TAT) III complex in vitro after the use of rt-PA (2mg/2mL) in each lumen of the catheter for 45 minutes. Each lumen of the thrombosed (dysfunctional) catheter will be locked with the exact volume (luminal volume) of rt-PA (rt-PA (2mg/2mL) actilysis) during 45 min. | Drug: rt-PA (2mg/2mL) actilysis<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. All catheters analyzed (fmDLC, polyDLC and siDLC) will be locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions: i.e. fmDLC, polyDLC amd siDLC.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany;Drug: rt-PA<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed in this study (i.e. fmDLC, polyDLC, siDLC) will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany);|
| Active Comparator: siDLC and rt-PA (2mg/2mL actilysis)<br>Same procedure as the previous catheters. Surface thrombogenicity of silicone double lumen catheter (siDLC) will be assessed by measurement of thrombin-antithrombin (TAT) III complex in vitro after the use of rt-PA (2mg/2mL) in each lumen of the catheter for 45 minutes. Each lumen of the thrombosed (dysfunctional) catheter will be locked with the exact volume (luminal volume) of rt-PA (rt-PA (2mg/2mL) actilysis) during 45 min. | Drug: rt-PA (2mg/2mL) actilysis<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. All catheters analyzed (fmDLC, polyDLC and siDLC) will be locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions: i.e. fmDLC, polyDLC amd siDLC.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany;Drug: rt-PA<br>* At the first catheter dysfunction (Qb < 250 ml/min) due to thrombotic event, the patient will receive rt-PA (2mg/2mL Alteplase vial - Cathflo, Boehringer Ingelheim, Ingelheim, Germany). Each lumen of the thrombosed catheter is locked with the exact volume (luminal volume) of rt-PA during 45 min. Each catheter analyzed in this study (i.e. fmDLC, polyDLC, siDLC) will be filled with rt-PA (2mg/2mL) if they are dysfunctional as described above in Arm/Group Descriptions.<br>* Other names: Cathflo, 2mg/2mL (Boehringer Ingelheim, Ingelheim/Germany);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lifespan patency with the ability to complete HD session in three different UCs using rt-PA locking protocol | The ability to achieve blood flow rates of >= 250 mL/min in three different UCs using rt-PA locking protocol if the UCs present a clotting event (complete or partial thrombosis). | 240 days after patients' enrollement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of catheter-related bacteremia after rt-PA use in case of thrombosed UCs | The solution instilled into the central venous catheter lumens after each HD session and left in the catheter until the next session (catheter locking solution) is used to prevent thrombosis during the period between HD sessions and may also prevent catheter-related infection. | 240 days after patients' enrollement | 
| Economic evaluation of rt-PA in catheter patency after UCs dysfunction | An economic evaluation of rt-PA in catheter patency after dysfunction (partial or complete catheter thrombosis) will be conducted. | 240 days after patients' enrollement | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Temporary hemodialysis catheters, Non-cuffed hemodialysis catheters, Thrombolysis, rt-PA, Thrombosis, Lifespan, Blood flow rate, Catheter related bacteriemia