Clinical Trials Resource Center

New Medical Therapies™

Thrombosis

September 30, 2013

The Medicines Company reported results of a phase III trial of intravenous (IV) antiplatelet cangrelor. The trial compared IV cangrelor to either oral clopidogrel or placebo for prevention of thrombotic (clotting) complications during and after percutaneous coronary intervention (PCI) in 25,000 patients. Evidence demonstrates that cangrelor significantly reduced the odds of the primary composite endpoint of death, myocardial infarction (MI), ischemia-driven revascularization (IDR) or stent thrombosis (ST) at 48 hours after randomization by 19% (3.8% for cangrelor v. 4.7% for control; or 0.81, 95% CI 0.71-0.91, p=0.0007) and stent thrombosis by 41% (0.5% v. 0.8%, or 0.59, 95% CI 0.43-0.80, p=0.0008). Angiographic complications during the procedure were significantly reduced by cangrelor with a marked reduction in new or suspected thrombus, in acute stent thrombosis and in the need for bailout glycoprotein IIb/IIIa inhibitor. The pooled analysis also showed the incidence of clinically important major bleeding as measured by GUSTO and TIMI bleeding scales was not increased with cangrelor. An FDA filing is in progress and filing plans in Europe are expected for Q4 2013.

February 13, 2012

Merck released results from a clinical trial of vorapaxar, under development for the prevention of thrombosis and the reduction of cardiovascular events. TRA-2P (Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events) was a secondary prevention study in 26,449 subjects with a heart attack, an ischemic stroke, or documented peripheral vascular disease. The subjects received vorapaxar plus standard of care or standard of care alone. The addition of vorapaxar to standard of care significantly reduced the risk of the primary endpoint of the composite of cardiovascular death, heart attack, stroke or urgent coronary revascularization compared to standard of care. There was a significant increase in bleeding, including intracranial hemorrhage, among subjects taking vorapaxar in addition to standard of care.

January 23, 2012

The Medicines Company issued results from a phase III trial of cangrelor, an intravenous antiplatelet therapy. The prospective, randomized, double-blind, placebo-controlled multicenter trial, BRIDGE, enrolled 210 subjects with an acute coronary syndrome or treated with a coronary stent who were awaiting coronary artery bypass graft (CABG) surgery. The subjects received cangrelor (0.75 g/kg per minute) or placebo for at least 48 hours, which was discontinued one to six hours before CABG surgery. The primary efficacy endpoint was platelet reactivity, measured in P2Y12 reaction units (PRUs), assessed daily. A greater proportion of subjects treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (PRU<240; 98.8% versus 19.0%; p<.001). The main safety endpoint was also reached. Excessive CABG surgery-related bleeding occurred in 11.8% versus 10.4% of the cangrelor and placebo groups, respectively (p≡.763).

December 19, 2011

Isis Pharmaceuticals issued results from a phase I trial of ISIS-FXIRx, under development for the reduction in the risk of thrombosis. This double blind, randomized, placebo-controlled, dose-escalation study enrolled healthy subjects who received single and multiple doses ranging from 50 mg per week up to 300 mg per week. Data showed sustained reductions of up to 78% and 85% in Factor XI protein levels and sustained, reductions of up to 71% and 78% in Factor XI activity in the 200 mg and 300 mg dose cohorts, respectively, (p<0.0001). Reductions in activity were accompanied by a partial thromboplastin time (PTT) prolongation. ISIS-FXIRx demonstrated a good safety profile and was well tolerated.

September 6, 2010

Portola Pharmaceuticals reported positive results from a phase II trial of elinogrel for the prevention of thrombosis during non-urgent percutaneous coronary interventions. This randomized, double-blind trial enrolled 650 subjects and was designed to evaluate intravenous (iv) and oral elinogrel compared with clopidogrel in addition to standard of care. The subjects received 80 or 120 mg administered iv, followed by either a 100 mg or 150 mg oral dose during a 60-120 day treatment period. Elinogrel demonstrated a more rapid and greater antiplatelet effect than loading doses of clopidogrel (300-600 mg), Statistical significance was reached within 15 to 30 minutes (150 mg, p≡0.007; 100 mg, p≡0.015) and at 20 hours (150 mg, p≡0.016; 100 mg, p≡0.025) following drug administration. Antiplatelet activity of elinogrel was sustained during the iv to oral transition and greater antiplatelet effect was achieved versus clopidogrel during oral chronic administration. There were no TIMI major bleeding events in the acute 24 hour phase in either the clopidogrel or the 150 mg and 100 mg elinogrel treated arms. In the chronic phase between 24 hours and 120 days, bleeding events were low with no TIMI major bleeding events in the clopidogrel-treated arm and two TIMI major events in both the elinogrel 150 mg and 100 mg arms.

August 9, 2010

Bayer and Johnson and Johnson released positive results from a phase III trial of rivaroxaban for the treatment of deep vein thrombosis (DVT). This randomized, open-label, assessor-blind, non-inferiority study, EINSTEIN-DVT, enrolled 3,400 subjects with acute symptomatic DVT, but without any symptoms of pulmonary embolism (PE). The subjects received either oral rivaroxaban (15 mg twice-daily for the first three weeks, followed by 20 mg once-daily) or standard therapy of enoxaparin followed a vitamin K antagonist, for three, six or 12 months. The primary efficacy outcome was non-inferiority in the cumulative incidence of symptomatic recurrent VTE and non-fatal or fatal PE between the two treatment arms. This primary endpoint was reached. Rivaroxaban was well tolerated and the safety endpoints were similar to the standard therapy.

July 19, 2010

Daiichi Sankyo reported positive results from a phase III trial of edoxaban for the prevention of venous thromboembolic events following surgery. This multicenter, double-blind, double dummy, randomized trial, STARS E-3 (Studying Thrombosis After Replacement Surgery), enrolled 716 subjects undergoing total knee replacement in Japan and Taiwan. The subjects received either 30 mg once-daily oral dose of edoxaban or subcutaneous injection of 20 mg enoxaparin (standard of care) twice-daily for 11 to 14 days. The primary endpoint was the incidence of symptomatic pulmonary embolism (PE) and symptomatic and asymptomatic deep vein thrombosis (DVT). DVT occurred in 7.4% of the edoxaban arm compared with 13.9% of the enoxaparin arm (relative risk reduction of 46.8 percent; p≡0.01). There were no PE events observed in either treatment group. There was no statistically significant difference in major and clinically relevant non-major bleeding (p=0.13). Both treatment arms were well tolerated.

September 8, 2008

Daiichi Sankyo issued positive results from a phase II trial of DU-176b for the prevention of venous thromboembolism (VTE). This randomized, double-blind comparative study enrolled 903 subjects in Europe and North America undergoing total hip replacement surgery. The subjects received four doses of DU-176b (15, 30, 60 and 90 mg once daily) or the low molecular weight heparin, dalteparin. Data showed a statistically significant dose response in efficacy. Statistical significance in the percentage of VTE incidences following DU-176b treatment occurred in the 30, 60 and 90 mg arms (21.2%, 15.2% and 10.6%; respectively) versus 43.8% in the dalteparin arm (p<0.001). In addition, the observed bleeding rates were low across the groups. Based on the results, Daiichi Sankyo plans to commence phase III studies for DU-176b in atrial fibrillation before the end of 2008.

September 1, 2008

Bristol-Myers Squibb and Pfizer reported negative preliminary results from a phase III trial of apixaban for the prevention of venous thromboembolism (VTE). This study, dubbed ADVANCE-1, enrolled 3,000 subjects undergoing knee replacement surgery. The subjects received apixaban, 2.5 mg given twice daily, or enoxaparin, 30 mg given twice daily. The primary efficacy outcome, a composite of symptomatic or asymptomatic deep vein thrombosis, pulmonary embolism, and death by any cause, was not reached. The rate of the primary efficacy endpoint on apixaban was similar to that observed with enoxaparin (9.0% versus 8.9%, p=.064), but did not meet the statistical criteria for non-inferiority compared to enoxaparin. There were no unexpected adverse events. The major bleeding event rate for apixaban was lower, but was not significantly lower, than enoxaparin (0.7% versus 1.4%, p=.053). In addition, the composite rate of clinically relevant non-major bleeding and major bleeding was significantly less in subjects who received apixaban than those who received enoxaparin (2.9% versus 4.3%, p =.034). Several additional phase III trials of apixaban are currently underway.

July 16, 2007

Portola issued positive results from a phase II trial of PRT054021 for the prevention of venous thromboembolic events (VTE). This randomized, active-control study enrolled 215 subjects undergoing total knee replacement surgery. Subjects received 15 or 40 mg of PRT054021 orally twice a day or 30 mg of Lovenox (enoxaparin) subcutaneously twice a day, for 10-14 days. The primary efficacy endpoint was incidence of VTE through day 10-14 measured by venography. The primary safety endpoint was the incidence of major and clinically significant non-major bleeds through the day after venography. The incidence of VTE was 20% (95% Confidence Interval 12%-32%), 15% (8%-27%) and 10% (3%-23%) in the low dose PRT054021 group, the high dose group of PRT054021, and in the enoxaparin group, respectively. No major bleeds were seen in the PRT054021 and one major bleed was seen in the enoxaparin group. No significant non-major bleeds were identified in the PRT054021 low dose group and two were identified in the PRT054021 high dose group. Two significant non-major bleeds in the enoxaparin group were also observed. Based on the results, Portola plans to initiate phase III trials in the first half of 2008.

December 4, 2006

Epix released positive results from a phase IIa trial of EP-2104R, a fibrin-binding imaging agent for the magnetic resonance imaging (MRI) detection of thrombi. This open-label trial enrolled 52 subjects across six cohorts, all of who were diagnosed with the presence of thrombus, or a strong likelihood of the presence of thrombus. Subjects received a 4 micromol/kg bolus dose of EP-2104R and contrast imaging was performed immediately. A second round of imaging was performed two to five hours following drug administration and some of the subjects underwent a third imaging session 24 hours after receiving the compound. Clots were visualized from 2 to 24 hours following administration of EP-2104R. Results revealed that, across all six cohorts, EP-2104R was able to detect blood clots not previously seen on MRI and enhanced the images of clots that were previously seen on MRI. In addition, EP-2104R detected previously unseen pathologies in some of the subjects. Based on the results, Epix plans to move forward in the development of EP-2104R.

May 24, 2004

TransTech Pharma reported positive results from a phase I trial investigating TTP889, a selective inhibitor of the intrinsic coagulation pathway, as an anticoagulant for the treatment of thromboembolic disorders. Results showed that the drug was safe at all single and multiple doses and demonstrated a predictable PK profile with an oral half-life of approximately 20 hours. The study was administered to healthy subjects at the Clinical Research Unit of MDS Pharma Services, in Nebraska. The company plans to initiate phase II trials of TTP889 in September of 2004. The study will enroll 200 subjects at 25 sites in six European countries. The end-point will be the reduction in incidence of deep vein thrombosis versus placebo.

January 5, 2004

AstraZeneca reported results of its phase III, EXULT B trial comparing the anticoagulant, Exanta (ximelagatran), to warfarin for the prevention of venous thormboembolism (VTE) in subjects undergoing total knee replacement (TKR) surgery. Of evaluable subjects, 22.5% of subjects receiving Exanta experienced VTE or death, compared to 31.9% of subjects treated with dose-adjusted warfarin. There was no statistically significant difference between the two treatment groups in the incidence of bleeding events, pulmonary embolism or death. This phase III, randomized, double-blind, double-dummy, international trial involved 2,303 subjects who, for 7 – 12 days, were treated with either Exanta 36 mg twice daily or warfarin. Incidence of VTE was measured by mandatory bilateral venography or by objective means, if VTE was symptomatic. The EXULT B study followed a first phase III study, EXULT A, which compared Exanta to warfarin in reducing blood clots following TKR surgery.

Esperion Therapeutics reported positive results from a second phase I study investigating ETC-642 (RLT Peptide), a complex of a 22-amino acid peptide and phospholipids for the treatment of cardiovascular disease. Results demonstrated the drug was safe and well tolerated. Data showed evidence of asymptomatic elevations of liver function tests in a one subject at the highest dose level (30 mg/kg). The randomized, double-blind, placebo-controlled study enrolled 20 subjects with cardiovascular disease. The study was designed to determine the maximum tolerated dose for single intravenous infusions of ETC-642. Subjects received one of three dose levels (10, 20 or 30 mg/kg) of ETC-642 or placebo.

July 21, 2003

Alteon reported negative results from a phase IIb trial investigating ALT-711, a crosslink breaker for the treatment of uncontrolled systolic hypertension. Results showed that ALT-711 did not demonstrate statistical significance as compared to placebo in the primary endpoint, the reduction of systolic blood pressure by ‘office cuff pressure’ measurement. The data showed a 6-10 mm Hg drop in systolic blood pressures in all groups during the first two weeks. The dose ranging, double-blind, placebo-controlled trials, called SAPPHIRE (Systolic And Pulse Pressure Hemodynamic Improvement by Restoring Elasticity) and SILVER (Systolic Hypertension Interaction with Left VEntricular Remodeling), enrolled 768 subjects having elevated systolic blood pressure at over 60 sites nationwide. Subjects were maintained on background hypertension medication during treatment.

EPIX Medical reported positive results from two phase III trials investigating MS-324, a blood pool contrasting agent for the use with magnetic resonance angiographs (MRA). The two trials were conducted on subjects with suspected vascular disease in the renal and pedal arteries. Results demonstrated that both studies met their primary clinical endpoint, demonstrating statistically significant improvement in accuracy for detecting renal and pedal vascular disease with MS-325 compared with non-contrast MRA. The renal study enrolled 145 subjects with suspected disease in the renal arteries and administered each a 0.03 mmol/kg dose of MS-325. Data showed that three individual MRA readers achieved an accuracy of 73%, 79% and 79%, with MS-324 enhancement compared with 45%, 56% and 51% for non-contrast MRAs. The pedal study enrolled 96 subjects with suspected pedal artery stenosis and administered each a 0.03 mmol/kg dose of MS-325. The three readers showed improved specificity of 21%, 34% and 34% with MS-325-enhanced MRA compared to non-contrast MRA. Results were announced at the 11th annual meeting of the International Society of Magnetic Resonance in Medicine (ISMRM) in Toronto.

Sanofi-Synthelabo reported positive results from a general surgery study investigating Arixtra (fondaparinux), a selective factor X inhibitor for the treatment of venous thromboembolism (VTE). Results showed that Arixtra was at least as effective and as safe as the low molecular weight heparin (LMWH) dalteparin for the prevention of VTE following major abdominal surgery. In abdominal cancer surgery subjects, fondaparinux was significantly more effective than the low molecular weight heparin. The randomized, double blind study, called PEGASUS (The PEntasaccharide in GenerAl SUrgery Study) enrolled 2,927 subjects who had undergone major abdominal surgery. Results were presented at the 19th Congress of the International Society on Thrombosis and Haemostasis.

February 10, 2003

Pharmacia reported positive results from a large post-marketing study investigating Fragmin (dalteparin sodium injection), a low molecular weight heparin for the treatment of venous thromboembolisms. Results showed that Fragmin produced a 45% relative risk protection from deep vein thrombosis and pulmonary embolisms. Data also showed that benefits of the drug were maintained for 90 days following treatment. Compression ultrasonography was used to diagnose proximal deep vein thrombosis in all subjects. The randomized, double blind, placebo-controlled trial enrolled 3,700 acute care subjects who had extended hospital stays. Over 220 sites worldwide participated in the study. Subjects were administered either subcutaneous Fragmin (5,000 IU) or placebo once daily for 14 days.

November 18, 2002

AstraZeneca reported positive results from a phase III trial of Exanta (ximelagatran) versus enoxaparin, a low-molecular-weight heparin for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Data showed Exanta significantly reduced the risk of proximal DVT and PE by 6.3% compared to 2.3% with enoxaparin. The randomized, double blind, double-dummy study included nearly 2,800 subjects worldwide, undergoing either total knee replacement or total hip replacement surgery. In the study, 1,377 subjects received Exanta and 1,387 received enoxaparin. There were no fatal or critical-site bleeding events in either group. However, excessive bleeding at the operative site, as judged by the investigator was more common in the group receiving Exanta (3 % vs. 1.2 %).

September 9, 2002

Results of the Penthifra Plus study involving 656 subjects undergoing surgery for hip fracture showed that Arixtra (fondaparinux) administered for four weeks significantly reduces the incidence of deep venous thrombosis (DVT), compared to Arixtra administered for one week. In the double-blind, placebo-controlled study, subjects were all given 2.5 mg Arixtra for seven days following surgery for hip fracture. On day seven, subjects were randomized into two groups, and for the remaining 21 days of treatment they either continued being given the study drug or were given placebo. At the end of the treatment period, the incidence of thromboembolic complications was 1.4% for the Arixtra group compared to 35% for the placebo group. This study of Arixtra was sponsored by Sanofi-Synthelabo and NV Organon.

May 20, 2002

Initial results from a phase III trial show that Emisphere Technologies' oral heparin did not demonstrate superior efficacy compared to Aventis' Lovenox (enoxaparin) in preventing deep vein thrombosis (DVT). The PROTECT trial included 2,288 subjects undergoing total hip replacement surgery. The goal of the trial was to demonstrate superior efficacy and comparable safety for oral heparin dosed postoperatively in a 30-day treatment regimen compared to injectable Lovenox dosed for a 10-day regimen. Total DVTs were determined by bilateral venography at 30 days following surgery. The company plans to re-evaluate their oral heparin program based on these results.

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