Efficacy and Safety of CUSA-081 in the Restoration of Central Venous Access Device (CVAD) Functionality

Study Overview
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Brief Summary
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Study to evaluate the efficacy and safety of CUSA-081 in the restoration of central venous access device (CVAD) functionality in participants 18 years and older.

Detailed Description
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This is a phase III, multinational, multicenter, randomized, double-blind, parallel-group, active and placebo-controlled study to examine CUSA-081 versus placebo or alteplase in subjects with dysfunctional non-hemodialysis Central Venous Access Devices (CVADs). During the study, the treatment period will consist of one visit which may take place on the same day as screening or on the following day. After meeting all inclusion criteria, subjects will be randomized in a 9:1:6 ratio of CUSA-081: placebo: alteplase. There will be a follow-up assessment performed on Day 30 (±2 days) after treatment with study drug. Routine blood pressure measurement, heart rate and urine pregnancy test will be performed before enrollment in the study. Safety, including Treatment Emergent AEs (TEAEs), Adverse Drug Reactions (ADRs) and Adverse Events of Special Interest (AESI), will be recorded throughout the study. The end of the trial is defined as the last follow-up contact of the last subject to receive study drug in the trial.

Official Title
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A Phase 3, Randomized, Double-Blind, Active and Placebo-Controlled Study on the Use of CUSA-081 for Dysfunctional Central Venous Access Devices (CVADs)

Conditions
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Catheter Occlusion, Thrombosis

Intervention / Treatment
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* Drug: CUSA-081
* Drug: Placebo
* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inability to have 3mL of blood withdrawn from the selected study catheter; A single or multi-lumen CVAD, implanted ports or peripherally inserted central catheters (PICCs) in place for > 24 hours and documented as previously being patent and functional; Ability to designate one dysfunctional lumen of a multi-lumen catheter to be used throughout the study for both study drug instillation and assessment of CVAD function; Male and non-pregnant female subjects from all racial and ethnic groups 18 years of age and older; Able to have fluids infused at the volume necessary to instill study drug into the CVAD (i.e., up to 2 mL); Informed consent form (ICF) signed and dated indicating that the subject has been informed of and agreed with all pertinent aspects of the study and is willing to comply with all study requirements and procedures. Exclusion Criteria: CVAD (any type) used for hemodialysis; CVAD known to be dysfunctional for more than 48 hours; Reasonable evidence of mechanical or non-thrombotic occlusion in the selected study catheter (e.g., catheter malposition or migration, sutures, kinks, or precipitates causing obstruction), radiographic assessment is not required; Known or suspected catheter related bloodstream infection (CRBSI); Use of any fibrinolytic agent or anticoagulant (e.g., alteplase, tenecteplase, reteplase, urokinase or heparin) within 24 hours prior to the treatment period (first instillation of study drug). Use of subcutaneous LMWH for prophylaxis of thromboembolic events is allowed; Known to be at high risk for bleeding events or embolic complications in the opinion of the Investigator, or has a known condition for which bleeding constitutes a significant hazard (e.g. recent stroke, recent intracranial or intraspinal surgery or serious head trauma, intracranial neoplasm, arteriovenous malformation or aneurysm, known bleeding diathesis); Uncontrolled hypertension (systolic BP ≥160 or diastolic BP ≥110 mmHg) at screening; Clinically unstable in the opinion of the site investigator; Known to be pregnant or breastfeeding at screening; Previously treated in this study (READY 1) or in study READY 2; History of allergic reaction to reteplase, alteplase or vial ingredients (excipients or diluents); Use of any investigational drug or experimental medical device within 28 days prior to treatment; non interventional observational studies participation is allowed. Not mentally, socially, or otherwise able to complete the trial assessment or not likely to survive beyond 30 days.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CUSA-081<br>Participants will receive 1 or 2 doses of CUSA-081, 0.7 milligrams (mg) (0.4 units) per 2 milliliter (mL) directly into the catheter lumen. Participants will receive the first dose at minute (min) 0, and the second dose, if needed, at min 90. | Drug: CUSA-081<br>* Participants will receive 1 or 2 doses of CUSA-081 0.7 mg/2 mL directly into the catheter lumen<br>* Other names: reteplase;|
| Placebo Comparator: Placebo<br>Participants will receive 1 or 2 doses of placebo (normal saline) directly into the catheter lumen. Participants will receive the first dose at min 0, and the second dose, if needed, at min 90. | Drug: Placebo<br>* Participants will receive 1 or 2 doses of placebo (normal saline) directly into the catheter lumen<br>|
| Active Comparator: Alteplase<br>Participants will receive 1 or 2 doses of alteplase, 2 mg/mL, directly into the catheter lumen. Participants will receive the first dose at min 0, and the second dose, if needed, at min 90. | Drug: Alteplase<br>* Participants will receive 1 or 2 doses of alteplase, 2 mg/2 mL, directly into the catheter lumen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Dwell Time Up To 90 Mins | Treatment success is defined as the restoration of CVAD functionality, measured as the ability to withdraw 3 mL of blood and infuse 5 mL of saline. For this assessment, dwell time is up to 90 mins. The percentage will be calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%. | Day 1 (up to 90 mins postdose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Total Dwell Time Up To 30 And 60 Mins | Treatment success is defined as the restoration of CVAD functionality, measured as the ability to withdraw 3 mL of blood and infuse 5 mL of saline. For this assessment, dwell time is up to 60 mins. The percentage will be calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%. | Day 1 (up to 30 and 60 mins postdose) | 
| Percentage Of Participants With Treatment Success After Up To 2 Instillations Of Study Drug With A Total Dwell Time Up To 120, 150, And 180 Mins | Treatment success is defined as the restoration of CVAD functionality, measured as the ability to withdraw 3 mL of blood and infuse 5 mL of saline. For this assessment, dwell time is up to 180 mins. The percentage will be calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%. | Day 1 (up to 120, 150, and 180 mins postdose) | 
| Rate Of Recurrent Catheter Dysfunction Within 30 Days Following Treatment With Study Drug | The rate of recurrent catheter dysfunction is defined as re-occlusion. The rate of recurrent catheter dysfunction will be analyzed using the Kaplan-Meier method. This analysis is based on all participants with treatment success following up to 2 administrations of study drug with a total dwell time up to 180 mins. | Day 1 (postdose) up to Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CVAD, CUSA-081, reteplase, alteplase, occluded catheters, catheter, occlusion, thrombosis, thrombotic occlusion