Safety and Efficacy of Alfimeprase for Restoring Function in Occluded Central Venous Catheters: Interim Results of a Phase 2, Multicenter, Randomized, Double-Blind Study (NuCath).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1768-1768 ◽  
Author(s):  
Steven R. Deitcher ◽  
Stephan Moll ◽  
Howard D. Homesley ◽  
Luigi Bertoli ◽  
Peter Kenyon ◽  
...  
Keyword(s):  
Patency Rate ◽  
Central Venous Access ◽  
Study Drug ◽  
Venous Access ◽  
Double Blind Study ◽  
Phase 2 ◽  
Central Venous ◽  
Bleeding Events ◽  
Double Blind ◽  
Safety And Efficacy

Abstract Alfimeprase, a recombinantly produced 22.6 kilodalton metalloproteinase, is a genetically modified variant of fibrolase. Alfimeprase, like fibrolase, proteolytically cleaves both the alpha and beta chains of fibrin(ogen) independent of plasminogen activation to plasmin and directly dissolves thrombi. Readily abundant alpha-2 macroglobulin acts as an endogenous circulating alfimeprase inactivator, forming a covalent, irreversible bond with alfimeprase which results in an inactive complex. Based on the direct thrombolytic effect of alfimeprase, rapid activity was hypothesized. We performed a Phase 2, randomized, double-blind, controlled, dose-ranging study to compare the safety and efficacy of one or two instillations of three intraluminal doses of alfimeprase (0.3 mg; 1.0 mg; and 3.0 mg) and Cathflo® Activase® (Genentech) 2.0 mg in reestablishing patency to occluded central venous access devices (CVADs). This report describes an interim analysis of 48 patients with CVAD withdrawal occlusion who were enrolled and randomized to treatment. Catheter patency was assessed at 5, 15, 30, and 120 minutes after each dose of study drug. Adverse events including bleeding events were assessed for a 30-day period after exposure to study drug. Cumulative patency rates are shown in the table. All study arms had similar patency rates at 120 minutes after the first dose. The alfimeprase 3.0 mg dose produced the highest patency rate at 120 minutes after the second dose. All three alfimeprase doses were more effective than Cathflo® Activase® during the first 30 minutes of treatment. The alfimeprase 1.0 mg and 3.0 mg doses resulted in ≥ 50% patency restoration rates at 15 minutes compared to 0% for Cathflo® Activase®. No intracranial hemorrhage, major hemorrhagic, or embolic events were reported in any treated patients at 5 days. Efficacy and safety results of this study support further evaluation of alfimeprase doses ranging from 1.0 mg to 3.0 mg for treatment of occluded CVADs. Cumulative Patency Rate (%) Alfimeprase 0.3 Alfimeprase 1 Alfimeprase 3 Cathflo Activase N=13 N=14 N=9 N=12 D=dose; min=minutes after dose Baseline 0 0 0 0 D 1; 5 min 15 14 44 0 D 1; 15 min 15 50 57 0 D 1; 30 min 30 50 57 25 D 1; 120 min 46 50 57 50 D 2; 5 min 46 50 57 58 D 2; 15 min 46 50 57 67 D 2; 30 min 46 50 57 67 D 2; 120 min 46 50 78 67

scholarly journals 1477. A Randomized Phase 2 Study of Cefepime Combined with the Novel Extended Spectrum β-Lactamase Inhibitor Enmetazobactam in Hospitalized Adults with Complicated Urinary Tract Infections (cUTI) Including Acute Pyelonephritis (AP)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S539-S539
Author(s):  
Yehuda Carmeli ◽  
Philipp Knechtle ◽  
Jeff Hardenberg ◽  
Mathias Knecht
Keyword(s):  
Study Drug ◽  
Generation Cephalosporin ◽  
Double Blind Study ◽  
The Novel ◽  
Phase 2 ◽  
Double Blind ◽  
Extended Spectrum ◽  
Phase 2 Study ◽  
Dosing Regimens ◽  
Tract Infections

Abstract Background Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae has been classified as critical priority pathogens. The novel extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (formerly AAI101; EMT) in combination with cefepime (FEP) is currently being developed as a carbapenem-sparing treatment of serious Gram-negative infections in settings with a high prevalence of 3GC-resistant Enterobacteriaceae. We report here the results from a phase 2 study that assessed safety, tolerability, and pharmacokinetics of FEP-EMT in patients with cUTI/AP. Methods Forty-five patients were enrolled in a randomized, multicenter, double-blind study of hospitalized adults with cUTI/AP. Patients received dosing regimens of FEP or FEP-EMT IV therapy q8h by 2 hours infusion (table) for 7 to 10 days with a 28-day follow-up. Efficacy was evaluated in the microbiological-modified ITT (µMITT) population. Safety was monitored in patients who received at least 1 dose of study drug. Clinical cure was designated as the resolution of cUTI symptoms present at study entry. Plasma and urine PK were determined from all patients. Results The study drugs were well tolerated in each cohort, with similar % adverse events and no new or unexpected safety concerns (table). Two discontinuations were due to allergic dermatitis. The microbiological- and clinical responses at test-of-cure for the combined FEP-EMT group were 83.3% (20/24) and 95.8% (23/24) compared with responses in the combined FEP group of 73.3% (11/15) and 93.3% (14/15), respectively (table). The most common baseline pathogens were Escherichia coli (66.7%) and Klebsiella pneumoniae (23.1%): 28.2% of isolates produced ESBLs with eradication rates for the combined FEP-EMT group of 85.7% (6/7) and for the combined FEP group of 75.0% (3/4). FEP and EMT PK were best described by a 2-compartment, linear PK model. Both agents exhibited half-lives of 2.3 hours. Creatinine clearance had a significant covariate effect on FEP and EMT, consistent with predominant renal excretion of both agents. Conclusion Results from this phase 2 study justify advancement to phase 3 studies to evaluate the safety and efficacy of FEP-EMT in patients with cUTI/AP. Disclosures All authors: No reported disclosures.

Phase II Trial of Alfimeprase, a Novel-Acting Fibrin Degradation Agent, for Occluded Central Venous Access Devices

2006 ◽  
Vol 24 (19) ◽  
pp. 3056-3060 ◽  
Author(s):  
Stephan Moll ◽  
Peter Kenyon ◽  
Luigi Bertoli ◽  
James De Maio ◽  
Howard Homesley ◽  
...  
Keyword(s):  
Phase Ii ◽  
Central Venous Access ◽  
Venous Access ◽  
Plasminogen Activation ◽  
Central Venous ◽  
Double Blind ◽  
Dose Ranging ◽  
The Difference ◽  
Degradation Effect ◽  
Venous Access Devices

Purpose Alfimeprase is a recombinantly produced, genetically modified variant of the metalloproteinase, fibrolase. Alfimeprase proteolytically cleaves fibrin, independent of plasminogen activation to plasmin, and directly dissolves thrombi. Based on the direct fibrin degradation effect of alfimeprase, rapid activity in patients with occluded central venous access devices (CVADs) was hypothesized. Patients and Methods We performed a phase II, randomized, double-blind, active-control, multicenter, dose-ranging study to compare the safety and efficacy of one or two instillations of three intraluminal doses of alfimeprase (0.3, 1.0, and 3.0 mg) and alteplase 2.0 mg in re-establishing patency to occluded CVADs in 55 adult patients. Results All three alfimeprase doses were more successful than alteplase during the first 15 and 30 minutes of treatment. The alfimeprase 3.0-mg dose resulted in 40%, 50%, and 60% patency restoration rates at 5, 15, and 30 minutes, respectively, compared with 0%, 0%, and 23% for alteplase. The difference at 15 minutes was highly significant (P = .0075). Alfimeprase 3.0 mg produced the highest patency rate at 120 minutes after the first (60%) and second (80%) doses. No major hemorrhagic or embolic events were reported. Conclusion A single 1- or 3-mg dose of alfimeprase has the potential to restore function to occluded CVADs rapidly and safely, and to facilitate on-time infusion of vital therapies.

The safety and efficacy of aeromedical central venous access

2005 ◽  
Vol 24 (5) ◽  
pp. 212-213
Author(s):  
D. Davis ◽  
P. Ramanujam ◽  
C. Buono
Keyword(s):  
Central Venous Access ◽  
Venous Access ◽  
Central Venous ◽  
Safety And Efficacy

Safe and Cost Effective Use of Alteplase for the Clearance of Occluded Central Venous Access Devices

2002 ◽  
Vol 20 (7) ◽  
pp. 1918-1922 ◽  
Author(s):  
J. P. Timoney ◽  
M. G. Malkin ◽  
D. M. Leone ◽  
J. S. Groeger ◽  
M. L. Heaney ◽  
...  
Keyword(s):  
Thrombolytic Agent ◽  
Central Venous Access ◽  
Cost Effective ◽  
Venous Access ◽  
Central Venous ◽  
Safety And Efficacy ◽  
Reasonable Alternative ◽  
Effective Use ◽  
Assessment Initiative ◽  
Venous Access Devices

PURPOSE: To determine whether cryopreserved solutions of the thrombolytic agent alteplase could be used as a safe, effective, and economically reasonable alternative to urokinase in patients presenting with occluded central venous access devices (CVADs). MATERIALS AND METHODS: Alteplase has been reported as an efficacious alternative to urokinase for treatment of occluded CVADs. However, the practicality of using alteplase as the thrombolytic of choice for this indication remained conjectural. To make this approach economically feasible, alteplase was diluted to 1 mg/mL and 2.5-mL aliquots were stored at −20°C until use. A need to confirm that the cryopreserving and thawing of the reconstituted solution did not compromise the safety and efficacy reported from prior trials was recognized. A quality assessment initiative was undertaken to concurrently monitor the safety and efficacy of this approach. Patients presenting with occluded CVADs received a sufficient volume of the thawed alteplase solution to fill the occluded catheter(s). Data, including efficacy, adverse reactions, dwell time, and catheter type, were collected over a 5-month period. RESULTS: One hundred twenty-one patients accounting for 168 attempted clearances were assessable for safety and efficacy. One hundred thirty-six (81%) of the 168 catheter clearance attempts resulted in successful catheter clearance (95% confidence interval, 74% to 86%). No adverse events were reported. CONCLUSION: Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVADs when stored at −20°C for 30 days. The ability to cryopreserve alteplase aliquots makes it an economically reasonable alternative to urokinase in the setting of CVAD occlusion.

Evolution of Antithrombin (AT) and Fibrinogen (Fg) Levels during Induction Chemotherapy with L-Asparaginase (Asp) in Adult Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL). Clinical Outcomes and Use of Coagulation Supportive Treatments: The CAPELAL Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4486-4486
Author(s):  
Mathilde Hunault-Berger ◽  
Yves Gruel ◽  
Jean-Luc Harousseau ◽  
Martine Delain ◽  
Abdallah Maakaroun ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Central Venous Access ◽  
Venous Access ◽  
Fresh Frozen Plasma ◽  
Adult Patients ◽  
Cerebral Vein ◽  
Central Venous ◽  
Bleeding Events ◽  
Vein Thrombosis ◽  
Chromogenic Assay

Abstract The incidence of AT and Fg deficiency and of thrombotic and bleeding events after Asp has been well evaluated in children with ALL, but little is known in adults. In this study, the incidence of these events and the use of coagulation supportive treatments was evaluated in 214 adult patients with ALL (n= 191) or LBL (n=23) included in the GOELAL02 trial (Blood 2004, in press). The induction therapy included steroids (40 mg/m2/d d1-21), vincristine (2 mg d1, 8, 15, 22), idarubicine (5 mg/m2 d1, 8,15, 22) and Asp (7500 UI/m2 d10, 13, 16, 19, 22, 25) delivered through a central venous access. Fresh frozen plasma (FFP), Fg (Clottagen®) and AT (Aclotine®) concentrates were recommended to maintain their levels > 1 g/l and 60%, respectively. If no transfusion, Asp infusion was delayed for 48 hours. Platelets were transfused when < 20 x 109/l. Heparin prophylaxis was left to institutional guidelines. Symptomatic thromboses and significant bleedings were systematically recorded. Active DIC was present in 10.3% of patients on d1. Fg and AT levels were measured 4098 times (20/patient, von Clauss assay) and 1718 times (8/patient, chromogenic assay) respectively, and evolved between d1 and d35 as shown below (mean ± sd). AT nadir was < 60% in 71% of patients with values < 40% in 26% of cases. Fg levels were < 1g/l in 73% of patients with values < 0.5g/l in 9%.Twenty-one thromboses occurred two to 35d after the first Asp infusion (median = 14d) in 20 patients (9.3%), with cerebral vein thrombosis (5), pulmonary embolism (3), upper (5) or lower (8) limb deep vein thrombosis. At the time of event, the median AT level was 48% (mean 60.7) with 12 of 21 thromboses (57%) occurring with AT < 60%. Fourty-two bleedings occurred one to 45d after the first Asp infusion (median = 8d) in 31 patients, with CNS hemorrhage (1), epistaxis (24), central venous access bleeding (8), GI bleeding (1), and large ecchymoses (8). At the time of event, median Fg level was 1.3 g/l. Asp infusions were reduced or delayed in 64% of all patients due to low Fg and/or AT levels. FFP, AT and Fg were infused in 31%, 41% and 52% of patients at mean doses of 5.3 ml/kg/infusion, 31UI/kg/infusion and 7.9 g respectively. AT level increased from 58%±16 (n=79) to 86%±23.2 (n=57) after the first AT infusion but was unchanged after FFP. Fg level increased from 0.9g/l ± 0.3 (n=85) to 1.4g/l ±0.5 (n=69) after Fg infusion but was unmodified after FFP. In conclusion, Fg and AT levels are frequently decreased in adults treated by Asp, with often a less than optimal chemotherapy. Bleeding events were not associated with severe Fg deficiency, but thrombotic events could be favored in some patients by acquired AT deficiency. The benefit of AT concentrates to prevent thrombosis and to reduce delay in Asp infusions could therefore be prospectively assessed in adults treated by Asp. d1 (n) d10-Asp 1 (n) d13-Asp2 (n) d19-Asp 4 (n) d25-Asp 6 (n) AT % - 121±16 (79) 83±16 (125) 65±20 (111) 65±22 (77) Fg g/l 3.2±1.7 (142) 1.9±1.0 (159) 1.4±0.7 (195) 1.1±0.4 (169) 1.4±0.6 (118)

Safety and Efficacy of Alfimeprase in Subjects with Occluded Central Venous Access Devices: The SONOMA-2 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1866-1866
Author(s):  
Stephan Moll ◽  
Nashat Gabrail ◽  
Jim Buchanan ◽  
Mohammad Hirmand ◽  
Michael Levy ◽  
...  
Keyword(s):  
Adverse Events ◽  
Central Venous Access ◽  
Study Drug ◽  
Venous Access ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Central Venous ◽  
Treatment Groups ◽  
Venous Access Devices ◽  
Catheter Function

Abstract Introduction: The infusion of chemotherapy and blood products is facilitated by central venous access devices (CVAD), and the occurrence of thrombotic CVAD occlusion results in delays in these crucial therapies. Alfimeprase is a direct-acting thrombolytic agent with the potential to rapidly re-establish catheter function. Methods: SONOMA-2 was a multicenter, multinational, randomized, double blind, placebo-controlled phase 3 study evaluating the efficacy and safety of alfimeprase in subjects with occluded CVADs. Subjects were randomized in a 2:1 ratio to receive either intra-luminal alfimeprase (A) at a dose of 3.0 mg or placebo (P). Study drug was delivered in a total volume of 2 mL. If re-establishment of catheter function was not established within 30 minutes, a second dose of the same study drug was instilled and allowed to dwell for an additional 30 minutes. Re-establishment of catheter function was assessed by an attempt to withdraw 3 mL of blood and infuse 5 mL of saline. The primary efficacy endpoint was re-establishment of a functional CVAD at 15 minutes post first infusion. The primary efficacy analysis prespecified a significance level of ≤ 0.00125. Results: A total of 303 patients (201 (A), 102 (P)) were randomized into the study. Treatment groups were well balanced at baseline with respect to overall demographics, catheter insertion site, and median days since last failed infusion or blood draw. The primary efficacy endpoint, re-establishment of a functional CVAD at 15 minutes post first infusion, was achieved in 34.3% (A) versus 21.6% (P) of subjects (p = 0.022). The cumulative proportion of subjects with re-establishment of a functional CVAD at 30 minutes post first or second infusions was 52.7% (A) versus 30.4% (P) (p = 0.0002). Rates of adverse events (65.8% (A), 59.4% (P)), serious adverse events (15.5% (A), 16.8% (P)), and hemorrhagic adverse events (3.6% (A), 10.9% (P)) were comparable between treatment groups. No intracranial hemorrhages were observed. Conclusions: Alfimeprase restored CVAD function in a numerically greater fraction of subjects than did placebo; however, the study did not achieve statistical significance for the primary endpoint at the prespecified p-value of ≤ 0.00125 necessary for demonstrating efficacy with a single pivotal study. Alfimeprase was well tolerated. Further clinical studies are underway that evaluate a higher and more concentrated alfimeprase dose which preclinical studies predict will result in greater efficacy. Alfimeprase remains a promising potential candidate for use in patients with CVAD occlusion.

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