A dose-finding study with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective total knee replacement surgery

2010 ◽  
Vol 104 (12) ◽  
pp. 1150-1157 ◽  
Author(s):  
Charlie Cao ◽  
Bengt I. Eriksson ◽  
William Fisher ◽  
Stuart Kupfer ◽  
Gary Raskob ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Factor Xa ◽  
Study Drug ◽  
Dose Finding ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Open Label ◽  
Finding Study ◽  
Dose Finding Study

SummaryThis multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6–8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12–24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.

Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 307-307 ◽  
Author(s):  
Ajay K. Kakkar ◽  
Benjamin Brenner ◽  
Ola E. Dahl ◽  
Bengt I. Eriksson ◽  
Patrick Mouret ◽  
...  
Keyword(s):  
Total Hip Arthroplasty ◽  
Hip Arthroplasty ◽  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Direct Factor ◽  
Short Term ◽  
Double Blind

Abstract Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy. Short-term s.c. enoxaparin 40 mg od % (n/N) Extended oral rivaroxaban 10 mg od % (n/N) Relative risk reduction (%) P-value for difference DVT, non-fatal PE, and all-cause mortalitya 9.3% (81/869) 2.0% (17/864) 79% P<0.001 Major VTEb 5.1% (49/962) 0.6% (6/961) 88% P<0.001 Major bleedingc 0.1% (1/1229) 0.1% (1/1228) - P=0.980 Non-major bleedingc 5.5% (67/1229) 6.5% (80/1228) - P=0.246

Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 6-6 ◽  
Author(s):  
Bengt I. Eriksson ◽  
Lars C. Borris ◽  
Richard J. Friedman ◽  
Sylvia Haas ◽  
Menno V. Huisman ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Direct Factor ◽  
Mitt Population ◽  
All Cause Mortality ◽  
Subcutaneous Enoxaparin

Abstract Background Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA. Methods Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively. Results A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). Conclusions Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA. Rivaroxaban 10mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction % (95% CI) P-value for difference DVT, non-fatal PE, and all-cause mortality 1.1% (18/1595) 3.7% (58/1558) 70% (49–82%) P<0.001 Major VTE 0.2% (4/1686) 2.0% (33/1678) 88% (66–96%) P<0.001 Major bleeding 0.3% (6/2209) 0.1% (2/2224) - P=0.178 Non-major bleeding 5.8% (128/2209) 5.8% (129/2224) - P=1.000

Correction of Anemia with Hematide™, a Synthetic Peptide-Based Erythropoiesis Stimulating Agent (ESA), in Oncology Patients Receiving Chemotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3666-3666 ◽  
Author(s):  
Lisa M. Pickering ◽  
Karel Cwiertka ◽  
Jacek Jassem ◽  
Jira Petera ◽  
Ruth Pettengell ◽  
...  
Keyword(s):  
Synthetic Peptide ◽  
Study Drug ◽  
Erythropoietin Receptor ◽  
Dose Finding ◽  
Phase 2 ◽  
Open Label ◽  
Efficacy Data ◽  
Pharmacodynamic Analysis ◽  
Finding Study ◽  
Dose Finding Study

Abstract Introduction: Hematide™ a novel, synthetic, PEGylated peptidic compound, binds to and activates the erythropoietin receptor. It is in development for treatment of anemia associated with chronic renal failure and cancer. Objective: To assess the subcutaneous (SC) Hematide™ dose required to increase hemoglobin (Hb) by ≥ 1 g/dL in ≥ 50% of anemic cancer patients (pts) on chemotherapy. Safety, pharmacodynamics and pharmacokinetics were also assessed. Method: In a phase 2, open label, multi-center, dose finding study, up to four doses of Hematide™ were given SC every 3 wks (Q3W) to 4 cohorts of fifteen pts at 0.05, 0.10, 0.15 or 0.2 mg/kg each. Entry criteria included confirmed solid tumor malignancy or lymphoma, &gt;9 weeks of chemotherapy, baseline (BL) H ≥ 8 and &lt;11 g/dL, and adequate iron, folate and B12 stores. Results: Sixty patients were enrolled (45% male). Preliminary data show that across cohorts 0.05, 0.10, 0.15 and 0.20 mg/kg, mean (BL) Hb values were 10.1(±1.07), 10.0(±0.89), 9.8(±0.67), 10.1(±0.69); the % of pts completing the study were approximately 79%, 50%, 60%, and 92%. An increase in mean Hb from BL of ≥ 1g/dL in the pharmacodynamic dataset (forty two pts) at Week 7 occurred in approximately 20%, 70%, 55% and 55% of patients. Three pts withdrew due to AEs and six due to SAEs (none attributed to study drug). Three deaths occurred (two disease progression, one renal insufficiency) none attributed to study drug. One SAE, thrombophlebitis, was considered to be possibly/probably related to study drug. Final safety and efficacy data will be provided at the meeting. Conclusion: In this study, HematideTM dosed SC Q3W resulted in an increase from BL of ≥ 1 g/dL of Hgb in ≥ 50% of patients in the 0.10, 0.15 and 0.20 mg/kg cohorts in the pharmacodynamic analysis. HematideTM appeared to be well tolerated at all doses studied.

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