INTRODUCTION

Central venous access devices (CVADs), also known as central venous catheters, are inserted to provide durable and reliable intravenous access in a wide array of patients. CVADs are placed to facilitate frequent venous blood sampling for laboratory testing and the continuous or periodic infusion of parenteral therapy such as chemotherapy, antibiotics, nutritional support, antiemetics, analgesics, and blood products. Catheter dysfunction, most commonly as a result of thrombotic occlusion, often necessitates the removal or exchange of the catheter and delay of therapy. Although the most commonly implanted CVADs are manufactured of materials that have been shown to have minimal thrombogenicity, the need for catheter removal due to thrombotic occlusion has been reported in as many as 25% of cases.^1,2 Rapid restoration of catheter function is necessary to ensure timely delivery of vital therapy and efficient patient case management, primarily in the outpatient setting.

Alfimeprase (Nuvelo, San Carlos, CA) is a recombinantly produced, truncated form of fibrolase, a directly fibrinolytic zinc metalloproteinase that was first isolated from the venom of the Southern copperhead snake (Agkistrodon contortrix contortrix).³ Alfimeprase has direct proteolytic activity against the fibrin Aα chain (to a lesser extent the Bβ chain) and directly degrades thrombi.⁴ Unlike thrombolytic agents such as urokinase, alteplase (tissue-type plasminogen activator), and tissue-type plasminogen activator variants, the mechanism of action of alfimeprase is independent of plasminogen activation, is not inhibited by plasminogen activator inhibitors, and is the basis for predicted faster activity. Alfimeprase can be bound covalently and neutralized irreversibly by plasma alpha₂-macroglobulin, a prevalent mammalian serum protease inhibitor.⁵ Preclinical in vitro and in vivo pharmacology studies have shown that fibrin degradation with alfimeprase is up to six times more rapid than with select plasminogen activators.⁶ Completed phase I and II studies in patients with peripheral arterial occlusion support the fact that catheter-directed alfimeprase has the potential to be a fast and effective fibrinolytic without generation of a systemic lytic state.^7,8

This study was designed to compare the safety and efficacy of three intraluminal fixed doses of alfimeprase with the US Food and Drug Administration–approved dose of alteplase (CathfloActivase; Genentech, South San Francisco, CA) in re-establishing function to occluded CVADs in adult patients.

PATIENTS AND METHODS

This phase II, randomized, double-blind, active-controlled, multicenter dose-ranging study was conducted at 20 sites in the United States. The protocol was approved by the institutional review board/independent ethics committee at each study site and all patients, or their legal guardians, provided written informed consent before study enrollment.

RESULTS

Fifty-five patients with CVAD withdrawal occlusion presumed to be caused by a fibrin clot were enrolled and randomly assigned to treatment between May 2003 and August 2004. Each patient received at least one instillation of study drug. Study patient and catheter characteristics are described in Table 1. No statistically significant differences among treatment groups for baseline characteristics were revealed by analysis of variance, except for height (P = .0312). No statistically significant differences in catheter insertion site or catheter type among treatment groups were observed.

Alfimeprase was generally well tolerated. No ICH, major hemorrhagic events, or embolic events were reported for any patients during this study. Fifteen (27%) patients experienced at least one adverse event: four (25%) of 16 in the 0.3-mg alfimeprase group, five (31%) of 16 in the 1.0-mg alfimeprase group, three (30%) of 10 in the 3.0-mg alfimeprase group, and three (23%) of 13 in the alteplase group. The majority of events were mild or moderate in severity. Seven (13%) patients had at least one adverse event that was considered by an investigator to be possibly or probably related to study drug ( Table 2). No type of adverse event was experienced by more than one patient except for generalized pruritus, which was reported for two patients. There was no obvious pattern of adverse events for any treatment group.

Five study patients experienced a total of 10 adverse events that were classified by an investigator as severe in nature: one patient each in the 0.3- and 3.0-mg alfimeprase groups and 2.0-mg alteplase group, and two patients in the 1.0-mg alfimeprase group. The events reported as severe were coagulopathy, lymphadenopathy, catheter-related infection, fungemia, Pseudomonas infection, hypercalcemia, metastatic ovarian cancer, depressed level of consciousness, renal failure, and gangrene. The one serious adverse event that was fatal (metastatic ovarian cancer) was considered not related to administration of alfimeprase. Two serious adverse events (depressed level of consciousness and renal failure), which occurred in one patient, were considered by an investigator to be possibly related to study drug. The one patient who developed renal failure and a depressed level of consciousness did so 15 and 18 days, respectively, after alfimeprase exposure. It is believed by the sponsor that the renal failure was most likely the result of sepsis and dehydration, and that the depressed level of consciousness was related to uremic encephalopathy.

There were no notable changes apparent in vital signs, ECG data, and clinical laboratory test results in any treatment group. One study patient had an elevated lactate dehydrogenase (LDH) level after dosing with 0.3 mg of alfimeprase. This patient had a baseline LDH of 216 U/L, a value of 251 U/L (upper limit of normal, 250 U/L) after dose 1, and a value of 763 U/L after dose 2. The AST, ALT, and total bilirubin levels were normal at all three time points in this patient. The one patient with an elevated LDH after exposure to alfimeprase had a history of renal insufficiency and the event was considered by the investigator to be an event of moderate severity and not related to alfimeprase administration.

Efficacy data are summarized in Table 3 and dose 1 efficacy data are presented graphically in Figure 1. Statistically significant differences in restoration of catheter patency between the 1.0-mg alfimeprase and the 2.0-mg alteplase groups (44% v 0%; P = .0084) and between the 3.0 mg alfimeprase and the 2.0-mg alteplase groups (50% v 0%; P = .0075) were observed 15 minutes after the administration of the first dose of study drug. Catheter patency was restored successfully within 120 minutes of the first instillation of study drug in six patients (60%) in the 3.0-mg alfimeprase group, nine patients (56%) in the 1.0-mg alfimeprase group, six patients (38%) in the 0.3-mg alfimeprase group, and six patients (46%) in the 2.0-mg alteplase group. Restoration of CVAD function was greatest in the 3.0-mg alfimeprase group (80%) followed by the 2.0-mg alteplase (62%), 1.0-mg alfimeprase (56%), and 0.3-mg alfimeprase (44%) groups at 120 minutes after up to a maximum of two doses of study drug (P = .3469).

DISCUSSION

This phase II clinical trial demonstrated that the direct fibrin degradation agent, alfimeprase, can restore CVAD function in up to 60% of treated patients in less than 30 minutes, with the majority of these successes occurring in 15 minutes or less when initial treatment is with 3 mg of alfimeprase. This rapid activity was associated with an acceptable and favorable safety profile. Treatment with alfimeprase was well tolerated, with no ICH, major hemorrhagic events, or embolic events reported for any study patient and no pattern of adverse events that suggested a safety concern.

The active comparator trial design facilitated the first comparison of alfimeprase with a plasminogen activator in humans. Unlike alteplase, alfimeprase is not a plasminogen activator. Alfimeprase directly degrades fibrin and thus intravascular and CVAD-associated thrombi by a plasminogen-independent mechanism. The distinct mechanism of action of alfimeprase is reflected by the rapid time course of cumulative study drug efficacy, as represented in Figure 1. The majority of alfimeprase activity was observed in the first 15 minutes after a single drug instillation.

Restoration of CVAD function in a matter of minutes is important because it may facilitate timely delivery of prescribed therapies. In addition, early identification of CVAD obstructions that are resistant to pharmacologic therapy may facilitate timely patient referral for more invasive means of catheter function restoration. The ability to either rapidly restore catheter function or facilitate prompt catheter replacement may foster a reduction in patient anxiety related to missed or delayed treatment and improve treatment center efficiency.

Adverse event rates were low in all treatment groups. This is not surprising considering the relatively small total doses of study drug and the fact that much, if not all, of the instilled drug may remain within the treated catheter lumen. In addition, the safety profile of alfimeprase is uniquely supported by its mechanism of inactivation by alpha₂-macroglobulin. Any alfimeprase that may enter a patient's systemic circulation would be expected to bind rapidly and irreversibly to available alpha₂-macroglobulin and remain functionally neutralized until cleared by the liver.⁹

A major limitation of this clinical trial was the relatively modest sample size. Comparative statistics should be interpreted carefully. Despite the limited sample size, the independent data and safety monitoring board reported no safety concerns and recommended additional study of the 3.0-mg alfimeprase dose. It should also be noted that the point estimate of patency restoration rates reported for alteplase in this head-to-head comparison were lower than those reported in past larger trials for the 30- and 120-minute time points.^10,11 In this randomized, double-blind trial, intraluminal alteplase resulted in a 23% (95% CI, 5% to 54%) patency restoration rate at 30 minutes in contrast to a rate of 52% in the single-arm, open-label, safety Cardiovascular Thrombolytic to Open Occluded Lines 2 trial.¹¹ The apparent difference may reflect differences in patient populations and differences in the nature of the catheter occlusions. This is the first and only reported assessment of alteplase for catheter occlusion treatment at the 5- and 15-minute time points after a single dose of drug. There are no data to our knowledge that demonstrate anything other than the greater rate of activity observed for alfimeprase compared with alteplase at these early time points.

The efficacy findings in this study suggest that alfimeprase may provide more rapid lysis of thrombi and faster restoration of CVAD function than currently available therapy. Efficacy and safety results of this study support the evaluation of a 3-mg dose of alfimeprase in phase III clinical trials involving adult patients with occluded CVAD.

Appendix

The following investigators and sites participated in the study: Luigi Bertoli, MD, Southern Hematology & Oncology, Birmingham, AL; Donald Chamberlain, MD, Chattanooga GYN Oncology, Chattanooga, TN; Neal Christiansen, MD, South Carolina Oncology Associates, Columbia, SC; Kerry Cleveland, MD, Methodist Healthcare, Memphis, TN; Steven R. Deitcher, MD, The Cleveland Clinic, Cleveland, OH; James De Maio, MD, Northwest Medical Specialties, Tacoma, WA; Mark Fesen, MD, Hutchinson Clinic, Hutchinson, KS; Don Hall, MD, Baptist Hospital of East Tennessee, Knoxville, TN; Howard Homesly, MD, Brody School of Medicine of East Carolina University, Greenville, NC; David Irwin, MD, Alta Bates Comprehensive Cancer Center, Berkeley, CA; Jan Jansen, MD, St Francis Hospital, Beech Grove, IN; Peter Kenyon, MD, Corvallis Clinic, Corvallis, OR; Paul Kiproff, MD, Allegheny Hospital, Pittsburgh, PA; Stephan Moll, MD, University of North Carolina School of Medicine, Chapel Hill, NC; Peter Morris, MD, North Carolina Baptist Hospital, Winston-Salem, NC; Ravi Patel, MD, Comprehensive Blood and Cancer Center, Bakersfield, CA; Jose Prieto, MD, University Community Hospital, Tampa, FL; Ayman Saleh, MD, Forum Health/Western Reserve Care System, Youngstown, OH; Earl Schuman, MD, Emanuel Hospital, Portland, OR; and Peter Swischuk, MD, Horizon Institute for Clinical Research, Hollywood, FL.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Author Contributions