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• W1543184109 abstract "SummaryBackground: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg−1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg−1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg−1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg−1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg−1. Background: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg−1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg−1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg−1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg−1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg−1. Currently available anticoagulant therapies for the prevention of venous thromboembolism (VTE) after major orthopedic surgery such as knee and hip replacement include low‐molecular‐weight heparins (LMWH), a pentasaccharide (fondaparinux) and vitamin K antagonists (VKA), all of which have inherent limitations such as daily subcutaneous administrations for LMWH and fondaparinux and the need for International Normalized Ratio (INR) monitoring and dose adjustments for VKA [1Geerts W.H. Bergqvist D. Pineo G.F. Heit J.A. Samama C.M. Lassen M.R. Colwell C.W. Prevention of venous thromboembolism: American college of chest physicians evidence‐based clinical practice guidelines (8th Edition).Chest. 2008; 133: 381S-453SAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Recently, a direct thrombin inhibitor (dabigatran etexilate) and a factor (F)Xa inhibitor (rivaroxaban) were approved in the EU and in other countries, offering improvement in terms of daily oral administration without the need for INR monitoring and dose adjustments [2Weitz J.I. Hirsh J. Samama M.M. New antithrombotic drugs: American college of chest physicians evidence‐based clinical practice guidelines (8th Edition).Chest. 2008; 133: 234S-56SAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Further improvement in this clinical setting may be achieved with a drug that provides a stable, long‐acting antithrombotic effect with a single dose. TB‐402 is a human IgG4 antibody that in vitro exerts a plateau inhibition of factor (F)VIII activity even when TB‐402 is in large excess over FVIII [3Jacquemin M. Radcliffe C.M. Lavend’homme R. Wormald M.R. VanderElst L. Wallays G. Dewaele J. Collen D. Vermylen J. Dwek R.A. Saint‐Remy J.M. Rudd P.M. Dewerchin M. Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibody.J Thromb Haemost. 2006; 4: 1047-55Crossref PubMed Scopus (36) Google Scholar]. In vivo, increasing the dose prolongs its pharmacodynamic effect. As a result of its long half‐life of approximately 3 weeks [4Verhamme P. Pakola S. Jensen T.J. Berggren K. Sonesson E. Saint‐Remy J.M. Balchen T. Belmans A. Cahillane G. Stassen J.M. Peerlinck K. Glazer S. Jacquemin M. Tolerability and pharmacokinetics of TB‐402 in healthy male volunteers.Clin Ther. 2010; 32: 1205-20Abstract Full Text PDF PubMed Scopus (0) Google Scholar], TB‐402 may provide a prolonged antithrombotic effect after a single dose. The antithrombotic efficacy of TB‐402 has been evaluated in a thrombotic priapism model in mice with type II heparin‐binding site antithrombin deficiency [3Jacquemin M. Radcliffe C.M. Lavend’homme R. Wormald M.R. VanderElst L. Wallays G. Dewaele J. Collen D. Vermylen J. Dwek R.A. Saint‐Remy J.M. Rudd P.M. Dewerchin M. Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibody.J Thromb Haemost. 2006; 4: 1047-55Crossref PubMed Scopus (36) Google Scholar]. TB‐402 prevented the development of microscopic and macroscopic thrombus in all mice tested. TB‐402 also significantly reduced thrombus development in a male baboon arteriovenous shunt thrombosis model [5Jacquemin M. Stassen J.M. Saint‐Remy J.M. Verhamme P. Lavend’homme R. VanderElst L. Meiring M. Pieters H. Lamprecht S. Roodt J. Badenhorst P. A human monoclonal antibody inhibiting partially factor VIII activity reduces thrombus growth in baboons.J Thromb Haemost. 2009; 7: 429-37Crossref PubMed Scopus (0) Google Scholar]. Thrombus formation was reduced to a similar extent when the thrombosis challenge was performed 1, 24 h or 7 days after a single administration of TB‐402, suggesting that there was a long duration of effect. In the first phase I dose‐ascending study in healthy male volunteers, TB‐402 was associated with a reduction in FVIII:C over a period of approximately 48 h in doses ranging from 37.5 to 1860 μg kg−1 [4Verhamme P. Pakola S. Jensen T.J. Berggren K. Sonesson E. Saint‐Remy J.M. Balchen T. Belmans A. Cahillane G. Stassen J.M. Peerlinck K. Glazer S. Jacquemin M. Tolerability and pharmacokinetics of TB‐402 in healthy male volunteers.Clin Ther. 2010; 32: 1205-20Abstract Full Text PDF PubMed Scopus (0) Google Scholar]. TB‐402 was associated with a prolongation of the activated partial thromboplastin time (APTT) at doses ≥ 2.5 μg kg−1 (approximately 1.1 to 1.2‐fold predose APTT). The administration of a higher dose of TB‐402 was associated with an extended duration of the APTT prolongation, in the absence of any further increase in its magnitude. The pharmacokinetic and pharmacodynamic profile of the drug was similar in younger and in older subjects. A novel antithrombotic agent requires the demonstration of both efficacy and safety in relevant populations. Phase II studies are frequently performed in patients undergoing total hip replacement or total knee replacement (TKR) because of the well‐documented high incidence of deep vein thrombosis (DVT) in the absence of adequate thromboprophylaxis, as well as the increased risk of bleeding after recent surgery [6Eriksson B.I. Ogren M. Eriksson U.G. Kalebo P. Ahnfelt L. Bjorkstrom S. Sjostedt A. Folestad A. Arfwidsson A.C. Elvander C.S. Frison L. Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies.Thromb Res. 2002; 105: 371-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Quinlan D.J. Eikelboom J.W. Dahl O.E. Eriksson B.I. Sidhu P.S. Hirsh J. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery.J Thromb Haemost. 2007; 5: 1438-43Crossref PubMed Scopus (0) Google Scholar]. In this phase II study, we assessed the safety and efficacy of a single dose of TB‐402 in the prevention of VTE in patients undergoing TKR, relative to standard prophylaxis with LMWH. Prior to study initiation, the Ethics Committees for each participating center approved the study protocol and informed consent form. All patients provided written informed consent. The study was registered as NCT00793234. This was a phase II, dose‐escalating, multicenter, randomized, active‐controlled, open‐label trial. In the 2 weeks before the planned TKR, patients were screened for enrollment. In the evening preoperatively, all patients received enoxaparin 40 mg subcutaneously. After surgery (± 4 h after wound closure), eligible patients were randomized to TB‐402 or enoxaparin in a 3:1 ratio (75 patients TB‐402 and 25 patients enoxaparin per cohort). Randomization was done centrally through an interactive voice response system with computer‐generated blocked sequences. Patients were enrolled into the cohorts in a sequential dose‐escalating fashion. The trial investigated four treatment arms (0.3, 0.6, 1.2 mg kg−1 TB‐402 and enoxaparin 40 mg per day). TB‐402 was supplied in glass vials containing 15 mL of a 10 mg mL−1 solution. Before infusion, TB‐402 was diluted to the appropriate concentration, according to the dose and the patients weight. Patients allocated to TB‐402 were administered a single intravenous (i.v.) infusion of TB‐402 over approximately 15 min in the morning after surgery (at least 18 h and no later than 24 h after wound closure). For the patients assigned to the enoxaparin treatment group, prophylaxis with enoxaparin (Sanofi‐Aventis, Paris, France) was administered 6–8 h after surgery according to current standards and once daily thereafter for at least 10 days. The concomitant use of anticoagulants and platelet inhibitors other than low‐dose aspirin was prohibited. If nonsteroidal anti‐inflammatory drugs (NSAIDs) were needed, NSAIDs with a short half‐life (< 20 h) were recommended. Mandatory bilateral venography to detect DVT was done before discharge between Days 7 and 11. Follow‐up visits were scheduled at 35 (± 7) and 90 (± 10) days after infusion of TB‐402. Men and women aged ≥ 18 and ≤ 80 years undergoing primary elective TKR and willing and able to comply with the study procedures were included. The main exclusion criteria were: premenopausal women, VTE within the past year, increased risk of bleeding, anemia, thrombocytopenia, prolonged APTT or prothrombin time (PT), excessive peri‐operative bleeding and/or active significant postoperative wound bleeding as per the investigator’s judgement, anticipated use of an indwelling intrathecal or epidural catheter for more than 4 h after surgery, antithrombotic therapy within 7 days before surgery or long‐term anticoagulant treatment for a comorbid condition, contraindication or hypersensitivity to enoxaparin, creatinine clearance < 30 mL min−1, hypersensitivity to contrast media, active hepatic disease or active malignant disease. The primary efficacy outcome was the composite of the occurrence of asymptomatic DVT as detected by bilateral venography and symptomatic VTE, i.e. DVT or a fatal or non‐fatal pulmonary embolism (PE) or death that could not be attributed to a documented cause and for which PE/DVT could not be ruled out up to day 7 to 11. Secondary outcomes included major VTE (proximal DVT, PE and VTE‐related death) at hospital discharge, and objectively confirmed VTE until the end of the study. Patients were assessed daily for signs and symptoms of DVT and PE while hospitalized. Evaluable venograms required the visualization of all of the deep veins except for the muscular, anterior tibial and deep femoral veins. A diagnosis of DVT was made if an intraluminal filling defect was observed on at least two images. Diagnosis by ultrasound or venography was required for suspected symptomatic DVT. Suspected PE was evaluated by a radionuclide lung (V/Q) scan, computed tomography (CT) pulmonary angiography or conventional angiography. The principal safety outcome was the composite of the occurrence of major or clinically relevant non‐major bleeding events from randomization until the end of the study, 90 days post‐operatively. The other safety outcomes were the incidence of major bleeding events, clinically relevant non‐major bleeding events, minor bleeding events, all‐cause mortality, (serious) adverse events and changes in safety parameters over time (vital signs, laboratory parameters, antibodies towards TB‐402). Major bleeding was defined as acute clinically overt bleeding associated with a fall in hemoglobin of 2 g dL−1 or more, or as bleeding leading to a transfusion of two or more units of packed red blood cells or whole blood, or as bleeding in a critical site (intracranial, intraspinal, intraocular, pericardial, intra‐articular, intramuscular with compartment syndrome and retroperitoneal), or as bleeding leading to surgical intervention, or as fatal bleeding. Clinically relevant non‐major bleeding was defined as acute clinically overt bleeding not meeting the criteria for major bleeding but associated with excessive wound hematoma or excessive wound bleeding, or a medical intervention or the need for unscheduled contact (visit or telephone call) with a physician, or temporary cessation of a study drug, or resulting in discomfort for the patient such as pain or impairment of activities of daily life. All other acute clinically overt bleeding episodes not meeting the criteria for either major or clinically relevant non‐major bleeding were classified as minor. An independent External Adjudication Committee (EAC) blinded to treatment allocation evaluated all efficacy data and suspected bleeding events. Blood samples for detecting antibodies towards TB‐402 were taken at screening, day 35 and day 90. The immunogenicity assay was performed in three steps: screening, confirmation and titration; using a bridging ELISA format with a cut‐off point representing 5% of false–positive samples. Liver function tests were assessed at screening, at 1 month and at 3 months. Blood samples for PT, APTT and FVIII were analyzed at screening, day 1, day 2, day 7–11, day 35 and day 90. For the patients randomized to TB‐402, one sample pre‐infusion and one sample at 2 ± 1 h after the end of infusion was required on day 1. A PK/PD sub‐study was performed at selected sites; PK/PD blood samples were to be collected in at least 15 patients per treatment arm at screening, day 1, postinfusion day 2, day 7–11, day 35 and day 90. The TB‐402 concentration was determined in an ELISA assay in which binding of TB‐402 to immobilized FVIII was detected with biotinylated polyclonal goat anti‐TB‐402 antibodies. Recombinant human factor VIII (rhFVIII) 70 U kg−1 could be administered as a potential strategy to counteract the pharmacodynamic effect of TB‐402 in case of major bleeding or if the patient was to undergo an invasive procedure with a high bleeding risk. rhFVIII was available at all sites and a 24/24 h 7/7 days medical support line was on stand‐by. The study was conducted under the supervision of an Efficacy Safety Monitoring Board (ESMB), responsible for the ongoing safety oversight with regard to bleeding events, VTE and drug‐related serious adverse events (SAEs) for each dose level. All patients who received at least one dose of the study drug after randomization were included in the safety analysis. The efficacy analysis was first done in a per‐protocol population, comprising all patients on study treatment, with evaluable venograms and without major protocol deviations. We report the subsequent analysis in a modified intention‐to‐treat (ITT) population of patients who received at least one dose of the study medication and who had an evaluable venogram. The incidences of the primary and the secondary efficacy and safety outcome measures were calculated with the corresponding 95% confidence intervals (CI). Although this was an exploratory phase II study, the sample size had been calculated to support a preliminary efficacy analysis. The primary analysis aimed at comparing the pooled second and third cohort of TB‐402 (0.6 and 1.2 mg kg−1) to the enoxaparin treatment group with respect to the primary efficacy outcome in the per‐protocol population. Assuming a primary efficacy outcome event rate of 30% in the enoxaparin cohort and of 29% in the second and third TB‐402 cohort, 112 evaluable patients in the pooled second and third cohort of TB‐402 and 56 evaluable patients in the enoxaparin group (pooled across all three cohorts) would allow detection of a one‐sided 90% CI below the predefined non‐inferiority margin of 15% with 80% power. Taking into account 25% non‐evaluable primary efficacy outcomes, 100 patients would be needed per dose cohort. In case this primary efficacy outcome was met, a superiority analysis was planned in the modified ITT population using Fisher’s exact test for calculating relative risk reductions with corresponding 95% CI. These analyses were repeated for the pooled 3 TB‐402 treatment arms compared with the enoxaparin arm. Differences between the four treatment arms were explored by comparing multiple proportions (Fisher’s exact test) with Bonferroni’s correction for multiple testing. Plasma concentrations and pharmacodynamic parameters were summarized by descriptive statistics. Between February and October 2009, 352 patients were screened, 316 of which were randomized (Fig. 1). The reasons for non‐eligibility were exclusion criteria (12 patients), no informed consent (nine patients) and end of randomization (two patients) or other (13 patients). All but one patient received at least one dose of study drug after randomization (safety analysis population). One randomized patient did not receive TB‐402 (1.2 mg kg−1) because of postoperative bleeding. Of the 316 randomized patients, 20 (6.3%) did not have an evaluable bilateral venography, in 12 patients because the venography was not done, and in eight patients because the venogram was judged to be non‐evaluable by the EAC. Overall, 93% (295/316) of patients qualified for the modified ITT analysis of primary efficacy outcome, and 290 patients were included in the per‐protocol primary efficacy analysis. The five major protocol violations that led to exclusion from the per‐protocol analysis were not meeting in‐/exclusion criteria (n = 2), non‐compliance with study drug administration (n = 2) and venography at day 18 (n = 1). Nine patients did not complete the study: six patients were lost to follow‐up, two patients withdrew their consent and one patient was withdrawn owing to an adverse event. The study included predominantly women (78%). The mean age was 65 years (range 38–81 years). Demographic and baseline characteristics were comparable among the groups (Table 1).Table 1Baseline characteristicsCharacteristicTB‐402 0.3 mg kg−1 n = 75TB‐402 0.6 mg kg−1 n = 74TB‐402 1.2 mg kg−1 n = 87Enoxaparin n = 79Age (range)65 (50–78)65 (46–80)66 (39–81)64 (42–80)Female59 (79%)48 (65%)72 (83%)67 (85%)Mean weight (SD)83 (12)82 (12)80 (12)80 (12)Mean BMI (SD)31.1 (4.4)29.9 (4.2)30.5 (4.8)30.1 (4.8)BMI, body mass index. Open table in a new tab BMI, body mass index. The median duration of enoxaparin treatment after surgery was 11 days (range 7–61 days). The primary efficacy outcome (total VTE, i.e. asymptomatic DVT as detected by bilateral venography and symptomatic VTE until day 7 to 11) for the modified ITT population is summarized in Table 2. The proportion of patients experiencing an asymptomatic DVT or symptomatic VTE was 16.7%, 23.9%, 24.1% and 39.0% for the increasing TB‐402 dose groups and the enoxaparin group, respectively. The primary efficacy analysis in the per‐protocol population demonstrated non‐inferiority of the pooled TB‐402 0.6 and 1.2 mg kg−1 group compared with the enoxaparin group with an upper one‐sided 90% CI of the risk difference of –6.3%. The incidence of the primary efficacy outcome in all TB‐402 groups combined was 21.6% (95% CI 16.6–27.5), an absolute risk reduction of 17.4% (95% CI 5.5–29.6) compared with the enoxaparin group. For the exploratory pairwise comparison of each TB‐402 dose group with the combined enoxaparin group, only the lowest TB‐402 dose group (0.3 mg kg−1) demonstrated a statistically significant lower incidence of total VTE up to day 7 to 11 compared with the enoxaparin group (P = 0.003) at the 1.67% level (Bonferroni‘s adjustment).Table 2The primary and secondary efficacy outcome measures and the individual componentsPrimary efficacy outcome measure and individual componentsTB‐402 cohort 1 (0.3 mg kg−1) N = 72TB‐402 cohort 2 (0.6 mg kg−1) N = 67TB‐402 cohort 3 (1.2 mg kg−1) N = 79Combined enoxaparin cohorts N = 77Asymptomatic DVT or symptomatic VTE (%, 95% CI)12 (16.7, 9.8–26.9)16 (23.9, 15.3–35.3)19 (24.1, 16.0–34.5)30 (39.0, 28.8–50.1)Asymptomatic DVT (%)12 (16.7)16 (23.9)18 (22.8)30 (39.0)Symptomatic VTE or VTE related death (%)001 (1.3)*0Secondary efficacy outcome measuresMajor VTE to hospital discharge (%, 95% CI)1 (1.4, 0.2–7.5)†0 (0, 0.0–6.5)1 (1.3, 0.2–6.8)*3 (3.9, 1.3–10.8)†Major VTE to end of study (%, 95% CI)1 (1.4, 0.2–7.5)†0 (0, 0.0–6.5)1 (1.3, 0.2–6.8)*4 (5.2, 2.0–12.6)‡Venography detected or clinically detected DVT to end of study (%, 95% CI)12 (16.7, 9.8–26.9)16 (23.9, 15.3–35.3)19 (24.1, 16.0–34.5)31 (40.3, 30.0–51.4)*Symptomatic proximal DVT; †Asymptomatic proximal DVTs; ‡3 asymptomatic proximal DVTs and 1 symptomatic proximal DVT at day 60.VTE, venous thromboembolism; DVT, deep vein thrombosis. Open table in a new tab *Symptomatic proximal DVT; †Asymptomatic proximal DVTs; ‡3 asymptomatic proximal DVTs and 1 symptomatic proximal DVT at day 60. VTE, venous thromboembolism; DVT, deep vein thrombosis. Most events were asymptomatic distal DVTs. Until day 7 to 11, five proximal DVTs were observed, two with TB‐402, one of which symptomatic and three asymptomatic proximal DVTs with enoxaparin. In the last group one additional symptomatic DVT occurred at day 60. There was no diagnosis of symptomatic PE, and there was no VTE‐related death. Seven or fewer patients in any treatment group had a bleeding event from randomization to the end of study that was adjudicated to be a major or clinically relevant non‐major bleeding (Table 3). Seven bleeding events were observed in the TB‐402 1.2 mg kg−1 dose group, resulting in the highest bleeding rate of 8.0%. There were four major or clinically relevant non‐major bleedings in the TB‐402 0.6 mg kg−1 (5.4%) and three in both the TB‐402 0.3 mg kg−1 group and the enoxaparin group, resulting in comparable rates of 4.0% and 3.8%, respectively. As a result of the low number of major or clinically relevant non‐major bleeding events, there was no statistically significant difference in the proportions of patients with bleeding events between each of the TB‐402 dose groups and the combined enoxaparin group. The incidence of major and non‐major clinically relevant bleeding was similar in all four treatment groups from commencement of treatment until day 7 to 11; with 3/75, 4/74, 3/87 and 3/79 for TB‐402 0.3, 0.6, 1.2 mg kg−1 and enoxaparin, respectively. Four additional patients had a major or clinically relevant non‐major bleeding in the TB‐402 1.2 mg kg−1 group after day 7 to 11 until the end of the study, but none in any other group. All bleedings in the enoxaparin group and most bleedings in the TB‐402 groups were postoperative complications. There were two gastro‐intestinal bleedings (gastric and duodenal ulcer) that caused major bleeding in the same patient treated with TB‐402 1.2 mg kg−1 (only the first bleeding was counted in the analysis) and there was an epistaxis adjudicated as clinically relevant non‐major bleeding in a patient treated with TB‐402 0.3 mg kg−1. Only two bleedings were adjudicated as minor.Table 3Bleeding events from randomization to the end of the study, safety populationBleeding outcome eventTB‐402 0.3 mg kg−1 n = 75TB‐402 0.6 mg kg−1 n = 74TB‐402 1.2 mg kg−1 n = 87Enoxaparin n = 79Major and CRNM bleeding (%, 95% CI)3 (4.0, 1.4–11.1)4 (5.4, 2.1–13.1)7 (8.0, 4.0–15.7)3 (3.8, 1.3–10.6)Major bleeding0140CRNM bleeding3333Minor bleeding1001CRNM, clinically relevant non‐major. Open table in a new tab CRNM, clinically relevant non‐major. A total of 20 SAEs (excluding bleeding events) were reported in 15 patients over the course of the study; all were treatment emergent. Twelve patients (5.1%) experienced SAEs in the combined TB‐402 group (17 events). Three patients (3.8%) reported one SAE, each in the combined enoxaparin group, all of which were treatment emergent. There were no patients with a treatment emergent AE that led to the discontinuation of study medication or to withdrawal from the study. Two patients died during the study, both were TB‐402‐treated patients in cohort 1 (0.3 mg kg−1). One patient suffered acute cardiac failure and the other a myocardial infarction; while both deaths were treatment emergent, neither death was considered to be related to the study medication. None of the reported SAEs were considered to be related to the study drug. There were no signs of changes in renal or hepatic function over the course of the study as measured by serum creatinine, creatinine clearance, total bilirubin, AST, ALT and GGT. One patient treated with TB‐402 0.6 mg kg−1 had a clear positive antibody titer above the cut‐off point at 3 months. A single i.v. dose of TB‐402 caused FVIII levels to decrease transiently. The mean decrease 2 h after infusion was 40%, 36% and 23% with 0.3, 0.6 and 1.2 mg kg−1, respectively. Levels returned to baseline after approximately 48 h (Fig. 2). Mean APTT at 2 h after infusion was significantly prolonged by 20%, 12% and 20% compared with predose APTT in the 0.3‐, 0.6‐ and 1.2‐mg kg−1 dose groups, respectively (Fig. 2). There was no significant difference between treatments at this time point. The APTT remained mildly prolonged until 35 days with all doses of TB‐402. Levels of functional TB‐402 were measurable until day 7 to 11 for the 0.3‐mg kg−1 dose group and until day 35 for 0.6 and 1.2 mg kg−1 (Fig. 3). In the present study, we assessed for the first time the tolerability and efficacy of TB‐402 as a novel antithrombotic strategy for the prevention of VTE in patients undergoing TKR surgery. As a result of the long half‐life of TB‐402, increasing the dose prolongs the pharmacodynamic effect. Based on pharmacokinetic and pharmacodynamic data [4], an anticoagulant effect for at least 11 days was predicted for the two highest dose groups, but was uncertain for the lowest dose of 0.3 mg kg−1 in patients undergoing TKR. Therefore, the primary efficacy analysis was first done with the two highest dose groups combined, followed by a comparison of all TB‐402 groups with enoxaparin. The findings demonstrate that TB‐402 has antithrombotic activity at the doses tested with overall lower VTE rates than in the enoxaparin comparator arm, a contemporary standard for efficacy and safety. Although total VTE rates differ considerably among studies, the total VTE rate of 39% in the enoxaparin group was similar to the average in recent venographic studies [7Quinlan D.J. Eikelboom J.W. Dahl O.E. Eriksson B.I. Sidhu P.S. Hirsh J. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery.J Thromb Haemost. 2007; 5: 1438-43Crossref PubMed Scopus (0) Google Scholar, 8Eriksson B.I. Dahl O.E. Rosencher N. Kurth A.A. van Dijk C.N. Frostick S.P. Kalebo P. Christiansen A.V. Hantel S. Hettiarachchi R. Schnee J. Buller H.R. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial.J Thromb Haemost. 2007; 5: 2178-85Crossref PubMed Scopus (0) Google Scholar]. The pairwise, exploratory comparison of the different TB‐402 groups suggested that the lowest dose of 0.3 mg kg−1 had a significantly lower VTE rate (16.7%) compared with enoxaparin (39%), thus, we did not identify an ineffective dose of TB‐402 for this duration of thromboprophylaxis. Given the overlapping 95% CI of the VTE rates of the TB‐402 groups, the point estimate of effect of the lowest dose is in the same range as the effect of the other doses. The incidence of major VTE until ho" @default.
• W1543184109 created "2016-06-24" @default.
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• W1543184109 date "2011-04-01" @default.
• W1543184109 modified "2023-10-16" @default.
• W1543184109 title "Single intravenous administration of TB‐402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose‐escalating, randomized, controlled trial" @default.
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