TROPICS 1: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Tenecteplase for Restoration of Function in Central Venous Catheters.

Central venous catheters (CVCs) are vital to the management of many acute and chronic diseases. These catheters facilitate infusion of therapeutic agents and nutritional products, withdrawal of blood and its constituents, and accurate assessment of hemodynamic variables. A common cause of CVC dysfunction is occlusion, most frequently due to thrombosis. In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to occluded CVCs.

A dysfunctional CVC was defined as a catheter from which one could not withdraw 3 mL of blood (1 mL of blood for subjects weighing <10 kg). Eligible adult and pediatric subjects with dysfunctional non-hemodialysis CVCs were stratified by body weight (<30 kg and ≥30 kg) and randomized 1:1 to two treatment arms. In the first arm (TTP), subjects received an initial dose of intraluminal tenecteplase (T) and, if indicated, a second dose of tenecteplase and a third dose, consisting of placebo (P). In the PTT arm, placebo was instilled first followed by up to 2 doses of tenecteplase, if needed for restoration of catheter function. The dose of study drug was 2 mL (2 mg tenecteplase) in subjects weighing ≥30 kg. Subjects weighing <30 kg received a dose equal to 110% of the internal lumen volume of the CVC. Following the administration of each dose, CVC function was assessed at 15, 30, and 120 minutes. Restoration of catheter function was defined as the ability to withdraw at least 3 mL blood or fluid and infuse 5 mL normal saline (1 mL and 3 mL, respectively, for subjects <10 kg). Once catheter function was restored, or at 120 minutes after catheter assessment following the third dose, subjects exited the treatment algorithm. The primary efficacy endpoint was the percentage of subjects with restoration of catheter function within 120 minutes after a single administration of study drug. Secondary endpoints included cumulative rates of restoration of catheter function after up to 2 doses of tenecteplase and the percentage of subjects who maintained catheter patency up to 7 days after drug instillation. Adverse events (AEs) were monitored through 48–96 hours after treatment. Serious AEs judged related to the study drug and targeted AEs (intracranial hemorrhage [ICH], major bleeding, embolic events, thrombosis, catheter-related bloodstream infection [CRBSI], and catheter-related complications) were recorded through 7 days after treatment.

A total of 97 subjects received TTP (n = 50) or PTT (n = 47). The mean age was 39.6 years (range, 1–87 years); 34 subjects (35.1%) were <17 years old. The most common indication for catheter insertion was chemotherapy (n = 81; 83.5%). The majority of subjects had port catheters (n = 62; 63.9%), and 25 subjects (25.8%) had double-lumen catheters. Within 120 minutes of initial study drug instillation, catheter function was restored to 30 subjects (60.0%) in the TTP arm and 11 subjects (23.4%) in the PTT arm, for a treatment difference of 36.6 percentage points (95% CI, 18.4–54.8; P = .0002). Cumulative restoration rates for CVC function increased to 88.0% after a second dose of tenecteplase in the TTP arm, and the overall cumulative restoration rate was 86.6% after the second dose of tenecteplase in both arms combined. Catheter patency was 80.4% among subjects who had treatment success and whose catheters were accessed within 7 days posttreatment. Twenty subjects (20.6%) reported a treatment-emergent AE, with a similar incidence between treatment arms. Two targeted AEs, both deep vein thromboses, were reported, one of which was felt to be study drug related by the investigator. No cases of ICH, major bleeding, embolic events, CRBSIs, or catheter-related complications were reported.

Tenecteplase is safe and effective for restoration of catheter function in pediatric and adult subjects with dysfunctional CVCs.

Off Label Use: Tenecteplase is a thrombolytic agent under study for clearance of dysfunctional central venous catheters . Sandler:Governors Cancer Control and Reserach Advisory Board: Chair; Children's Oncology Group: Voting body steering committee; Wolfson Children's Hospital: Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Membership on an entity's Board of Directors or advisory committees. Charu:Glaxo-Smith-Kline: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anas:Genentech: Honoraria. Blaney:Genentech: Employment, Equity Ownership. Ashby:Genentech: Employment, Equity Ownership. Gillespie:Quintiles: Employment, Quintiles is a contract research organization contracted by Genentech to execute the TROPICS trials. Begelman:Genentech: Employment, Equity Ownership.