Dysfunctional Hemodialysis Catheters
Conditions
Keywords
HD, Hemodialysis, Catheter clearance, TNKase, Renal Insufficiency
Brief summary
This was a Phase III, randomized, double-blind, placebo-controlled study conducted at 37 centers in the United States. 150 subjects ≥ 16 years of age who required hemodialysis (HD) and had a dysfunctional HD catheter were enrolled in the study.
Interventions
DRUGplacebo
For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
DRUGtenecteplase
For the initial treatment, 2 mL of reconstituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinically stable, in the opinion of the investigator * Use of a cuffed, tunneled HD catheter * HD prescribed at a 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
* 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 A laboratory test to confirm the INR must have been performed within 7 days prior to Visit 1. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1 | Visit 1 of HD treatment | Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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. |
| Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Visits 1 and 2 of consecutive HD treatments | Targeted AEs were intracranial hemorrhages (ICHs), major bleeding, embolic events, thrombosis, catheter-related bloodstream infections (CRBSIs), and catheter related complications |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in BFR From Baseline to the End of HD at Visit 1 | Visit 1 of HD treatment | BFR is measured in mL/minute. |
| Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1) | Visit 2 of consecutive HD treatments | Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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. |
| Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2) | Visit 2 of consecutive HD treatments | Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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. |
Participant flow
Pre-assignment details
One participant was randomized but not treated, therefore the modified intent-to-treat (MITT) analysis population was 149.
Participants by arm
| Arm | Count |
|---|---|
| Tenecteplase For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase | 74 |
| Placebo For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase | 75 |
| Total | 149 |
Baseline characteristics
| Characteristic | Total | Placebo | Tenecteplase |
|---|---|---|---|
| Age Continuous | 59.3 years STANDARD_DEVIATION 15.3 | 57.8 years STANDARD_DEVIATION 16.5 | 60.8 years STANDARD_DEVIATION 14.1 |
| Age, Customized < 17 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >= 17 years to < 65 years | 95 participants | 51 participants | 44 participants |
| Age, Customized >= 65 years | 54 participants | 24 participants | 30 participants |
| Sex: Female, Male Female | 75 Participants | 37 Participants | 38 Participants |
| Sex: Female, Male Male | 74 Participants | 38 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 74 | 11 / 75 |
| serious Total, serious adverse events | 1 / 74 | 5 / 75 |
Outcome results
Primary
Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2
Targeted AEs were intracranial hemorrhages (ICHs), major bleeding, embolic events, thrombosis, catheter-related bloodstream infections (CRBSIs), and catheter related complications
Time frame: Visits 1 and 2 of consecutive HD treatments
Population: MITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Intracranial hemorrhage | 0 percentage of participants |
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Major bleeding | 0 percentage of participants |
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Embolic event | 0 percentage of participants |
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Thrombosis | 0 percentage of participants |
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Catheter-related blood stream infection | 0 percentage of participants |
| Tenecteplase | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Catheter-related complication | 0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Catheter-related blood stream infection | 4.0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Intracranial hemorrhage | 0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Thrombosis | 0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Major bleeding | 0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Catheter-related complication | 0 percentage of participants |
| Placebo | Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 | Embolic event | 0 percentage of participants |
Primary
Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1
Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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.
Time frame: Visit 1 of HD treatment
Population: Modified intent to treat (MITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase | Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1 | 21.6 percentage of success |
| Placebo | Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1 | 5.3 percentage of success |
p-value: 0.0044Cochran-Mantel-Haenszel
p-value: 0.0035Chi-squared
Secondary
Change in BFR From Baseline to the End of HD at Visit 1
BFR is measured in mL/minute.
Time frame: Visit 1 of HD treatment
Population: MITT population
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Tenecteplase | Change in BFR From Baseline to the End of HD at Visit 1 | < 0 mL/min | 8.1 percentage of participants | 102.97 |
| Tenecteplase | Change in BFR From Baseline to the End of HD at Visit 1 | 50-99 mL/min | 8.1 percentage of participants | — |
| Tenecteplase | Change in BFR From Baseline to the End of HD at Visit 1 | 25-49 mL/min | 8.1 percentage of participants | — |
| Tenecteplase | Change in BFR From Baseline to the End of HD at Visit 1 | 100-149 mL/min | 5.4 percentage of participants | — |
| Tenecteplase | Change in BFR From Baseline to the End of HD at Visit 1 | 0-24 mL/min | 58.1 percentage of participants | — |
| Placebo | Change in BFR From Baseline to the End of HD at Visit 1 | 100-149 mL/min | 1.3 percentage of participants | — |
| Placebo | Change in BFR From Baseline to the End of HD at Visit 1 | < 0 mL/min | 9.3 percentage of participants | 55.98 |
| Placebo | Change in BFR From Baseline to the End of HD at Visit 1 | 0-24 mL/min | 80.0 percentage of participants | — |
| Placebo | Change in BFR From Baseline to the End of HD at Visit 1 | 25-49 mL/min | 2.7 percentage of participants | — |
| Placebo | Change in BFR From Baseline to the End of HD at Visit 1 | 50-99 mL/min | 4.0 percentage of participants | — |
p-value: 0.0396Cochran-Mantel-Haenszel
Secondary
Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1)
Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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.
Time frame: Visit 2 of consecutive HD treatments
Population: MITT population with extended-dwell tenecteplase at Visit 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase | Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1) | 41.7 percentage of success |
| Placebo | Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1) | 38.5 percentage of success |
Secondary
Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2)
Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min 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.
Time frame: Visit 2 of consecutive HD treatments
Population: MITT population with open-label tenecteplase at Visit 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase | Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2) | 11.5 percentage of success |
| Placebo | Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2) | 34.8 percentage of success |