A Study of Tenecteplase for Restoration of Function in Dysfunctional Hemodialysis (HD) Catheters

Study Overview
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Brief Summary
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This was a Phase III, open-label study conducted at 44 centers in the United States, Canada, and Puerto Rico. 223 subjects who required hemodialysis (HD) and had a dysfunctional HD catheter were enrolled in the study.

Detailed Description
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The study consisted of four visits that corresponded to consecutive HD sessions for each patient, as well as one follow-up visit. Patients could receive up to three treatments with open-label tenecteplase during the study: one or two treatments during an initial treatment course, and eligible patients whose catheter became dysfunctional again within 21 days of the first visit received an additional treatment as part of a retreatment (RT) course. At Visit 1, patients eligible at the beginning of HD had 2 mL (2 mg) of tenecteplase instilled into each of the two lumens of the HD catheter. After a dwell time of 1 hour, study drug was withdrawn and all subjects underwent HD. The duration of the HD session was not fixed by the study protocol, but rather by the site's HD practice, physician orders, and individual patient response during the session. Patients who did not experience treatment success at the end of Visit 1 had 2 mL (2 mg) of tenecteplase instilled into each lumen of their catheter as part of the initial treatment course. The treatment was left to dwell for an extended time, until the second HD session at Visit 2 (up to 72 hours later). Patients who received extended-dwell tenecteplase had the treatment withdrawn from their catheter at the beginning of Visit 2. Patients underwent HD as prescribed or to the extent possible. Patients who had treatment success at Visit 1 or Visit 2 and had a recurrence of catheter dysfunction within 21 days of Visit 1 and met the re-treatment eligibility criteria had 2 mL (2 mg) of tenecteplase instilled into each lumen, followed by a 1-hour dwell time at re-treatment Visit 1.

Official Title
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A Phase III, Open-Label Study of Tenecteplase for Restoration of Function in Dysfunctional Hemodialysis (HD) Catheters

Conditions
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Dysfunctional Hemodialysis Catheters

Intervention / Treatment
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* Drug: Tenecteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: for the Study Clinically stable, in the opinion of the investigator Use of a cuffed, tunneled HD catheter HD prescribed at a blood flow rate (BFR) of ≥300 mL/min Baseline BFR (at any time during the first 60 minutes of HD) of <300 mL/min at an associated pre-pump negative arterial pressure in the range between and including -240 mmHg and -280 mmHg Baseline BFR (at any time during the first 60 minutes of HD) at least 25 mL/min below the prescribed BFR Demonstrated BFR of ≥300 mL/min (using catheter lines in the customary direction) at an arterial pressure in the range of 0 to -280 mmHg in at least one HD session in the 14 days prior to Visit 1 Anticipated use of the same catheter for at least four consecutive HD sessions, on the same type and model of HD apparatus Able to have fluids infused at the volume necessary to instill study drug into the HD catheter Exclusion Criteria: for the Study HD catheter with sustainable BFR of ≥300 mL/min following subject repositioning HD catheter inserted <2 days prior to screening Evidence of a mechanical, non-thrombotic cause of HD catheter dysfunction (e.g., kink in the catheter or suture constricting the catheter) or dysfunction caused by known fibrin sheath Use of an implantable port HD catheter that is internally coated with any therapeutic agent (e.g., the Decathlon™ Gold catheter) Anticipated use of catheter for any other type of diagnostic or therapeutic procedure (i.e., other than HD) during study drug treatment Previously treated in this study or any tenecteplase catheter clearance trial Use of any investigational drug or therapy (defined as any drug or therapy that is not FDA approved) within 28 days prior to screening Use of a fibrinolytic agent (e.g. alteplase, tenecteplase, reteplase, or urokinase) within 7 days prior to Visit 1 Known to be pregnant or breastfeeding at screening or at Visit 1 Known bacteremia or known or suspected infection in the HD catheter Known history of any of the following: intracranial hemorrhage (within the previous 3 years), intracranial aneurysm, or arteriovenous malformation Use of heparin (unfractionated or low molecular weight) or other anticoagulants (e.g., for the treatment of heparin-induced thrombocytopenia) within 24 hours prior to Visit 1, except for heparin used only during HD or for prophylaxis (e.g., heparin lock or deep vein thrombosis prophylaxis) Subjects treated with warfarin only: international normalized ratio (INR) >3.0 within 7 days prior to Visit 1, or a target INR range that allows for an INR >3.0 Initiation of or increase in dose of Plavix® (clopidogrel bisulfate) within 7 days prior to Visit 1 Hemoglobin ≥12.0 g/dL if on an erythropoiesis-stimulating agent (e.g., darbepoetin or erythropoietin) and the dose of the erythropoiesis-stimulating agent has not been held or reduced per institutional policy At high risk for bleeding events or embolic complications (i.e., recent pulmonary embolus, deep vein thrombosis, endarterectomy, or clinically significant right-to-left shunt) in the opinion of the investigator, or with known condition for which bleeding constitutes a significant hazard BFR of <300 mL/min because of symptomatic hypotension Uncontrolled hypertension in the opinion of the investigator Known hypersensitivity to tenecteplase or any component of the formulation
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenecteplase<br>At each treatment, subjects had 2 mL (2 mg) of tenecteplase instilled into each lumen of their HD catheter. Subjects could receive up to three treatments with tenecteplase, the first two as part of the initial treatment course and one additional treatment as part of the retreatment (RT) course. The first treatment, followed by a 1-hour dwell time, was given to all subjects at Visit 1. At the end of hemodialysis at Visit 1, eligible subjects had a second treatment instilled for an extended dwell time until the start of Visit 2 (up to 72 hours). | Drug: Tenecteplase<br>* 2 mL (2 mg) of reconstituted lyophilized tenecteplase instilled into each lumen of the HD catheter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1 | Treatment success is defined as Blood Flow Rate (BFR) ≥ 300 mL/min and an increase of ≥ 25 mL/min from baseline BFR (without reversal of lines), at an associated arterial pressure in the range of 0 to -280 mmHg, 30 (± 10) minutes prior to the end of hemodialysis and at the end of hemodialysis. | Visit 1 (the first hemodialysis session in which treatment was administered). BFR was measured at the beginning of hemodialysis (Baseline measurement) and at 30 minutes prior to the end of hemodialysis and at the end of hemodialysis. | 
| Targeted Adverse Events From the Initial Study Drug Administration Through the Start of Visit 2 or Until Instillation of Extended-Dwell Tenecteplase | The primary outcome measure was the number of targeted adverse events, occurring from initial study drug administration through the end of Visit 1 (prior to administration of open-label, extended-dwell tenecteplase) or, for subjects who did not receive open-label, extended-dwell tenecteplase, from initial study administration through the start of Visit 2. Targeted adverse events were defined as intracranial hemorrhage, major bleeding and embolic events, thrombosis, Catheter-related blood stream infection (CRBSIs), and catheter-related complications. | From initial study drug administration to the end of Visit 1 (prior to administration of open-label, extended-dwell tenecteplase) or, for patients who did not receive extended-dwell tenecteplase, from initial study administration to the start of Visit 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Maintained Catheter Function at Visits 2 and 3 | For patients with treatment success at Visit 1 or Visit 2, maintenance of catheter function at subsequent visits was defined as a BFR ≥ 300 mL/min and an increase of ≥ 25 mL/min from baseline BFR (without reversal of lines), at an associated target arterial pressure in the range of 0 to -280 mmHg at the beginning of that HD session (within the first 30 minutes). | Maintenance BFR measurements were taken at the beginning of HD at Visit 2 (2nd consecutive HD session, within 72 hours of Visit 1) and Visit 3 (3rd consecutive HD session, within 72 hours of Visit 2). | 
| Percentage of Participants With Urea Reduction Ratio ≥ 65% at Visit 1 | The urea reduction ratio (URR) was calculated from measurements of blood urea nitrogen (BUN) as follows: (Pre-treatment BUN) - (Post-HD BUN) * 100% / (Pre-treatment BUN) Pre-treatment URR was assessed within 30-60 minutes after the initiation of HD and does not represent a true baseline value. | At Visit 1 (first hemodialysis session in which treatment was administered) samples for blood urea nitrogen measurements were taken at the beginning of HD (prior to treatment administration) and after HD was completed. | 
| Percentage of Participants With Urea Reduction Ratio ≥ 65% at Visit 2 | The urea reduction ratio (URR) at Visit 2 was calculated for those participants who did not receive extended-dwell tenecteplase at Visit 1 from measurements of blood urea nitrogen (BUN) as follows: (Pre-HD BUN) - (Post-HD BUN) * 100% / (Pre-HD BUN) | At Visit 2 (2nd consecutive HD session, within 72 hours of Visit 1) samples for blood urea nitrogen measurements were taken prior to HD and after HD was completed. | 
| Change in Blood Flow Rate From Baseline to the End of Hemodialysis at Visit 1 | Change in Blood flow rate (BFR) is the BFR at the end of HD for Visit 1 - BFR at Baseline. | Baseline (beginning of HD at Visit 1) to the end of HD at Visit 1. | 
| Percentage of Participants Who Failed Treatment at Visit 1 With Treatment Success at Visit 2 | Patients who failed treatment at Visit 1 and were treated with extended-dwell tenecteplase were analyzed for Treatment Success at Visit 2. Treatment success at Visit 2 was defined as a BFR ≥ 300 mL/min, without line reversal, and increase of ≥ 25 mL/min from baseline BFR, at an associated target arterial pressure in the range of 0 to -280 mmHg, 30 (± 10) minutes prior to the end of HD and at the end of HD. | BFR was measured 30 minutes before the end of HD and at the end of HD at Visit 2 (2nd consecutive HD session, within 72 hours of Visit 1). Baseline BFR was measured at the beginning of HD at Visit 1. | 
| Percentage of Participants Who Failed Treatment at Visit 1 With a Urea Reduction Ratio ≥ 65% at Visits 2 and 3 | Patients who experienced treatment failure at the end of Visit 1 and were eligible for and treated with extended-dwell tenecteplase at Visit 1 were assessed for Urea Reduction Ratio (URR) at Visits 2 and 3. URR was calculated from blood urea nitrogen (BUN) measurements according to the following: (Pre-HD BUN) - (Post-HD BUN) * 100% / (Pre-HD BUN) | Blood urea nitrogen measurements were taken prior to HD and at the end of HD at Visits 2 (2nd HD session, within 72 hours after visit 1) and 3 (3rd HD session, within 72 hours of Visit 2) | 
| Change in Blood Flow Rate From Baseline to the End of HD at Visit 2 | Change in Blood flow rate (BFR) is the BFR at the end of HD for Visit 2 - BFR at Baseline. | Baseline (beginning of HD at Visit 1) to the end of HD at Visit 2 (2nd consecutive HD session, within 72 hours of Visit 1). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HD, TNKase, Hemodialysis, Catheter clearance