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

Phase 3

Terminated

• Conditions: Catheter Occlusion; Thrombosis
• Interventions: Drug: Placebo; Drug: CUSA-081; Drug: Alteplase

• Registration Number: NCT03594175
• Lead Sponsor: Chiesi Farmaceutici S.p.A.

Brief Summary

To evaluate the efficacy and safety of CUSA-081 (diluted reteplase) in the restoration of central venous access device (CVAD) functionality in participants 18 years and older.

Detailed Description

This was a phase III, multinational, multicenter, randomized, double-blind, parallel-group, active and placebo-controlled study to examine CUSA-081 (diluted reteplase) versus placebo or alteplase in subjects with dysfunctional non-hemodialysis Central Venous Access Devices (CVADs).

During the study, the treatment period consisted of 1 visit that may have taken place on the same day as screening or on the following day. After complying with all inclusion criteria, subjects were randomized in a 9:1:6 ratio to CUSA-081 : placebo : alteplase treatment group. A follow-up assessment was performed on Day 30 (±2 days) after treatment with study drug. The end of the study was defined as the last follow-up contact of the last subject to receive study drug in the study.

Routine blood pressure measurement, heart rate and urine pregnancy test were performed before enrolment in the study. Throughout the study, safety assessment included evaluation of treatment emergent adverse events (TEAEs), adverse drug reactions (ADRs), and adverse events (AE) of Special Interest (AESI).

CUSA-081 (reteplase) is a recombinant tissue plasminogen activator (tPA), currently approved in the USA (trade name: RETAVASE®) for treatment of acute ST-elevation myocardial infarction (STEMI) to reduce the risk of death and heart failure.

Alteplase, a biosynthetic form of human tPA, Food and Drug Administration (FDA)-approved under the brand name ACTIVASE® for the treatment of acute ischemic stroke, acute myocardial infarction (AMI) to reduce mortality and incidence of heart failure, and acute massive pulmonary embolism for lysis.

Study Timeline

• Study First Submitted: 2018-07-10
• Study First Submitted QC: 2018-07-10
• Study First Posted: 2018-07-20
• Study Start: 2020-02-12
• Primary Completion: 2023-06-08
• Study Completion: 2023-07-10
• Results First Submitted: 2024-06-10
• Status Verified: 2024-08
• Results First Submitted QC: 2024-08-21
• Last Update Submitted: 2024-08-21
• Results First Posted: 2024-08-23
• Last Update Posted: 2024-08-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 462

Inclusion Criteria

1. Inability to have 3 mL of blood withdrawn from the selected study catheter;
2. 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;
3. 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;
4. Male and non-pregnant female subjects from all racial and ethnic groups 18 years of age and older;
5. Able to have fluids infused at the volume necessary to instil study drug into the CVAD (i.e., up to 2 mL);
6. 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

1. CVAD (any type) used for hemodialysis;
2. CVAD known to be dysfunctional for more than 48 hours;
3. 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;
4. Known or suspected catheter related bloodstream infection (CRBSI);
5. 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 low molecular weight heparin (LMWH) for prophylaxis of thromboembolic events is allowed;
6. 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);
7. Uncontrolled hypertension (systolic BP ≥160 or diastolic BP ≥110 mmHg) at screening;
8. Clinically unstable in the opinion of the site investigator;
9. Known to be pregnant or breastfeeding at screening;
10. Previously treated in this study (READY 1) or in study READY 2;
11. History of allergic reaction to reteplase, alteplase or vial ingredients (excipients or diluents);
12. Use of any investigational drug or experimental medical device within 28 days prior to treatment; non interventional observational studies participation is allowed.
13. Not mentally, socially, or otherwise able to complete the trial assessment or not likely to survive beyond 30 days.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received 1 or 2 doses of placebo (normal saline) directly into the catheter lumen. Participants received the first dose at min 0, and the second dose (if needed) at min 90.
CUSA-081	CUSA-081	Participants received 1 or 2 doses of CUSA-081, 0.7 milligrams (mg) (0.4 units) per 2 milliliter (mL) directly into the catheter lumen. Participants received the first dose at minute (min) 0, and the second dose (if needed) at min 90.
Alteplase	Alteplase	Participants received 1 or 2 doses of alteplase, 2 mg/mL, directly into the catheter lumen. Participants received the first dose at min 0, and the second dose (if needed) at min 90.

Primary Outcome Measures

Name	Time	Method
Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Dwell Time Up To 90 Min -- CUSA-081 vs Placebo -- Full Analysis Set (FAS)	Day 1 (up to 90 mins post dose)	CUSA-081 vs Placebo -- Single instillation of study drug -- Dwell Time Up To 90 Min -- Full Analysis Set (FAS); Treatment success was 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 was up to 90 mins, after a single instillation of study drug. The percentage was calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%.

Secondary Outcome Measures

Name	Time	Method
Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Dwell Time Up To 60 Min -- CUSA-081 vs Placebo -- Full Analysis Set (FAS)	Day 1 (up to 60 min post dose)	CUSA-081 vs Placebo -- Single instillation of study drug -- Dwell Time Up To 60 Min -- Full Analysis set (FAS); Treatment success was 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 was up to 60 mins, after a single instillation of study drug.; The percentage was calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%.
Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Dwell Time Up To 90 Min -- CUSA-081 vs Alteplase -- Full Analysis Set (FAS)	Day 1 (up to 90 min post dose)	CUSA-081 vs Alteplase -- Single instillation of study drug -- Dwell Time Up To 90 Min -- Full Analysis set (FAS); Treatment success was 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, after a single instillation of study drug. The percentage was calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%.
Percentage Of Participants With Treatment Success Following A Single Instillation Of Study Drug With A Dwell Time Up To 90 Min -- CUSA-081 vs Alteplase -- Per Protocol Set (PP)	Day 1 (up to 90 min post dose)	CUSA-081 vs Alteplase -- Single instillation of study drug -- Dwell Time Up To 90 Min -- Per Protocol set (PP); Treatment success was 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 was up to 90 mins, after a single instillation of study drug. The percentage was calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%.; The PP set was used for sensitivity analysis when testing for non-inferiority.
Percentage Of Participants With Treatment Success Following 2 Instillations Of Study Drug With A Dwell Time Up To 180 Min -- CUSA-081 vs Placebo -- Full Analysis Set (FAS)	Day 1 (up to 180 min post dose)	CUSA-081 vs Placebo -- 2 Instillations of study drug -- Dwell Time Up To 180 Min -- Full Analysis set (FAS); Treatment success was 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 was up to 180 mins, following 2 installations of the study drug. The percentage was calculated as the number of participants with treatment success divided by the total number of participants in the group, multiplied by 100%.; Subjects received the first instillation of study drug (CUSA-081, placebo, or alteplase). If patency was not restored after 90 minutes following the first instillation, a second dose of study drug (the same drug as at first instillation) was administered.
Rate Of Recurrent Catheter Dysfunction Within 30 Days Following Treatment With Study Drug	Day 1 (post dose) up to Day 30	The rate of recurrent catheter dysfunction is defined as re-occlusion. The rate of recurrent catheter dysfunction within 30 days following treatment and the results of the Kaplan-Meier and Cox proportional hazards analyses of the time to first re-occlusion are presented in the FAS.; 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 min.; Subjects received the first instillation of study drug (CUSA-081, placebo, or alteplase). If patency was not restored after 90 minutes following the first instillation, a second dose of study drug (the same drug as at first instillation) was administered.
Percentage of Participants With Treatment-emergent Adverse Events (AEs) Leading to Study Discontinuation	Day 1 (start of treatment) and until the end of the treatment period (up to 180 min post dose).	Treatment-emergent AEs leading to study discontinuation were evaluated and the percentage of participants with at least one event reported.; For all subjects who discontinued the study, the AE was 'Device breakage'.
Percentage of Participants With Treatment-emergent Adverse Events (AEs) of Special Interest (AESI)	Day 1 (start of treatment) and until the end of the treatment period (up to 180 min post dose).	Treatment-emergent AEs of special interest (AESI) were monitored. These included major bleeding (defined as severe blood loss \[\>5 mL/kg\] or blood loss requiring transfusion or causing hypotension requiring use of inotropic agents), embolism, thrombosis, and catheter-related blood stream infection. An adverse event was considered as treatment-emergent if it started on or after the first dose of study drug intake up to the end of the 180-minute treatment period.

Trial Locations

Locations (3)

Chiesi Invesitgational Site; 🇷🇴 Cluj-Napoca, Romania

Einspahr; 🇺🇸 Topeka, Kansas, United States

Chiesi Investigational Site; 🇪🇸 Sevilla, Spain