Clinical Trials Resource Center

Cardiac Surgery

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).

October 24, 2011

The Medicines Company released results from a phase IIa trial of MDCO-2010, under development for the reduction of blood loss during surgery. This randomized, double-blind, placebo-controlled study enrolled 32 subjects undergoing elective, primary coronary artery bypass graft surgery. The subjects received one of five MDCO-2010 doses or placebo infused immediately after heparin bolus until sternal closure. Blood loss was measured by the amount of blood drained via chest tubes at 12 hours postoperatively. The median chest tube drainage in the placebo arm was 900 mL versus 350 mL, 350 mL and 360 mL, respectively in the three highest MDCO-2010 cohorts (p<0.025). The subjects in these arms also had less transfusion requirements as compared to placebo.

September 8, 2008

Allon reported negative results from a phase II trial of AL-208 for the prevention or reduction of mild cognitive impairment (MCI) in subjects undergoing coronary artery bypass graft (CABG) surgery. This study enrolled 234 subjects in the United States and Canada. It consisted of an open label safety stage and a randomized, double-blind, placebo controlled stage. The active group was administered 300 mg of AL-208 as a 15-minute intravenous infusion 30 minutes prior to being placed on the bypass pump. The placebo group received an intravenous infusion of saline under the same conditions. The primary endpoints were a series of executive function and memory tests, as well as executive function and memory composite scores comprised of the individual tests. Approximately two weeks after surgery, subjects in both the treated and placebo groups performed at a level similar to age-matched normal adults on executive function and memory tests, indicating that neither group was significantly impaired, and that the single-dose has no observable effect because no functional deficit was present. Based on the results, Allon plans to re-focus development of AL-208 as a second generation Alzheimer's product.

March 3, 2008

Medicure reported negative results from a phase III trial of MC-1 for the treatment of coronary artery disease. This double-blind, randomized, placebo-controlled trial, dubbed MEND-CABG II, enrolled three thousand subjects undergoing coronary artery bypass graft surgery, at several cardiac surgical centers throughout North America and Europe. Subjects were randomized to receive placebo or MC-1 (250mg) prior to surgery and for thirty days post operatively (POD 30). They were then followed for sixty days after treatment (ninety days post operatively) for additional safety and efficacy analysis. The study failed to meet the primary endpoint, the reduction in the composite of cardiovascular death and non-fatal myocardial infarction up to POD 30. Based on the data, Medicure does not plan on filing for FDA approval of MC-1 for this indication.

August 28, 2006

Neuron reported positive pharmacokinetic results from a phase IIa trial of Glypromate for the prevention of cognitive decline following cardiac surgery. This trial enrolled 33 cardiac surgery subjects, 12 of whom received Glypromate at 3.0 mg/kg/hr, 11 of whom received it at 1.0 mg/kg/hr and 10 subjects received placebo. Pharmacokinetic results revealed a linear dose/exposure relationship; subjects infused at the lower dose achieved blood levels of Glypromate of 960 ng/mL and those infused at the higher dose had a maximal level of 3,508 ng/mL. At both doses Glypromate displayed an elimination half-life of 2 to 3 minutes. Neuren expected to initiate phase III trials before the end of 2006.

August 14, 2006

Inspire Therapeutics reported negative results of a phase II trial of INS50589, a platelet aggregation inhibitor, for the treatment of post-operative bleeding complications following coronary artery bypass surgery. This randomized, double-blind trial enrolled 160 subjects undergoing coronary artery bypass graft surgery. Subjects were to receive three intravenous doses of INS50589, or placebo, at 0.2, 0.5, and 1 mg/kg/hour. Interim analysis obtained from 27 treated subjects revealed that safety endpoints were not achieved, as a range of bleeding complications was observed. Based on this data, an independent Data Monitoring Committee recommended that the trial be terminated at all dose levels. Inspire had no plans to further develop INS50589 at this time.

March 6, 2006

Allon Therapeutics has issued positive results of a phase I trial of AL-208, for the treatment of mild cognitive impairment (MCI) following coronary artery bypass graft surgery (CABG). Trial data yielded a positive overall safety profile, with no serious adverse events reported and good tolerability. This open-label single-ascending-dose study enrolled 64 healthy volunteers in San Antonio, who received one of 6 doses of the drug (10 mcg, 30 mcg, 50 mcg, 100 mcg, 200 mcg or 300 mcg). Based on these results, the company announced plans to initiate both a phase IIa efficacy trial in post-CABG MCI and a phase Ib safety, tolerability and pharmacokinetic trial for the treatment of chronic neurodegenerative conditions.

Avant Immunotherapeutics issued negative preliminary results of a phase IIb trial of TP10, for the treatment of female patients undergoing cardiopulmonary bypass (CPB) surgery. Trial data yielded no significant differences in safety and efficacy measures between drug and placebo groups, confirming results of an earlier phase II trial. This randomized, placebo-controlled study enrolled 297 women, who received a thirty minute infusion of 5 mg/kg TP10 or placebo prior to CPB, with a 28 day follow-up. Based on these results, the company announced plans to continue development of the drug for the treatment of male patients only.

D-Pharm reported positive results of a phase II trial of DP-VPA, for the treatment of epilepsy, in the journal Drugs of the Future. Results yielded a significant reduction in mean (30%) and median (23%) seizure frequency, relative to placebo (p=0.02). In addition, carryover-efficacy was noted in reducing seizure frequency after the treatment period. No serious treatment related adverse events were reported. This double-blind, placebo-controlled cross-over study treated epileptic patients with DP-VPA or placebo for 28 days, in addition to background treatment.

April 11, 2005

ImaRx reported positive results of a phase I/II proof of concept study of SonoLysis, for the treatment of dialysis graft occlusion. The drug proved efficacious in clearing occlusive clots from hemodialysis grafts and in improving blood flow after 30 minutes, the study's primary endpoint. No serious safety or tolerability concerns were raised. This open-label study enrolled 22 subjects with clot-occluded dialysis grafts, who received one of several regimens of Sonolysis (MRX-815 nanobubbles in combination with varying intensities of ultrasound) with or without t-PA (an approved thrombolytic).

April 4, 2005

Corautus Genetics has announced positive results from a planned interim analysis of their phase IIb trial of VEGF-2 gene therapy (naked-plasmid vector) for the treatment of severe angina. Results of the interim analysis, based on data from the first 54 patients enrolled in the study, found no significant safety concerns or reported unexpected serious adverse events. These results were deemed sufficient for the trial’s independent data monitoring committee to recommend continuation of enrollment. This ongoing, randomized, double-blinded, dose-ranging and placebo-controlled clinical trial plans to enroll 404 angina patients across roughly 25 US sites. Subjects were to receive treatment with either the VEGF-2 plasmid or placebo, delivered via injection through Boston Scientific’s Stiletto endocardial direct injection catheter system. Corautus expects enrollment to be completed during Q1 2006.

Corgentech and Bristol-Myers Squibb reported negative top-line results of a phase III trial of edifoligide (E2F Decoy), for the prevention of vein graft failure following coronary artery bypass graft (CABG) surgery. Trial data failed to meet the drug’s primary endpoint, with no significant reduction in the incidence of graft failure, defined as blockage of the graft of 75 percent or greater as measured by quantitative coronary angiography at 12 months, compared to placebo. The trial did demonstrate a generally positive safety and tolerability profile, and the company expected full results in the near future. This multi-center, placebo-controlled, double-blind study enrolled 3,014 subjects undergoing CABG surgery, who were randomized to receive a single-dose of either edifoligide or placebo during surgery. Based on these results, the companies announced the termination of their co-development agreement and the discontinuation of development of edifoligide. The ongoing phase I trial of the drug, for the treatment of arterio-venous grafts, was to be completed as planned.

November 29, 2004

Pharmos has issued results of an exploratory phase IIa trial of dexanabinol, their investigational NMDA-receptor antagonist, for the prevention of post-surgical cognitive impairment following coronary artery bypass graft (CABG). Preliminary results were mixed. Subjects receiving the drug demonstrated significantly superior response in one primary endpoint, diagnostic assessment with the Stroop Color Word test (a standardized measure of executive function, selective attention and interference susceptibility) three months post surgery, compared with placebo (p=0.01). No significant superiority was noted in five other diagnostic assessments focused on other areas of cognition, including memory assessment, nor was significant benefit seen in multiple analysis of variance (MANOVA; p=0.37), which assessed compiled performance on all tests versus placebo at 6 weeks and 3 months post-surgery. Pharmos did note that MANOVA accuracy was limited by a lack of data for 19.3% of patients at 3 months (n=39). Furthermore, no significant benefit was seen with respect to secondary endpoints, including cognitive index and Mini Mental State Examination scores. The double-blind, placebo-controlled trial enrolled 202 patients undergoing CABG at 6 medical centers in Israel. Subjects were randomized to receive a single dose of either 150 mg dexanabinol or placebo just before surgery, with efficacy assessments at 6 weeks and 3 months post-surgery. Based on these results, Pharmos announced plans to refocus their development efforts for dexanabinol on the maintenance of integrative and executive cognitive function.

November 15, 2004

AVI BioPharma reported positive phase II results for Resten-NG (AVI-4126), their third-generation antisense oligonucleotide for the treatment of cardiovascular restenosis. Results indicated that the drug met its primary endpoint, demonstrating significant efficacy in preventing restenosis following balloon angioplasty compared with subjects receiving standard therapy or sub-therapeutic doses of Resten-NG, as confirmed by quantitative angiography and ultrasound imaging. Secondary efficacy was seen in significantly reducing neointimal growth. This multi-center, double-blind, study randomized coronary artery disease patients at risk for restenosis to receive either a therapeutic or sub-therapeutic dose regimen of Resten-NG or standard therapy following balloon angioplasty. AVI announced plans to initiate a phase III clinical trial of the drug in Europe based upon these results.

NitroMed has issued results from a phase III study of BiDil (isosorbide dinitrate/hydralazine), for the treatment of heart failure in African American patients. Trial results demonstrate that the drug met its primary efficacy endpoints, with a 43% improvement in patient survival (p=0.01), a lower sudden death rate (6.2% vs. 10.2%; p=0.02), a 33% reduction in first hospitalization for heart failure (p=0.001), and a significant improvement in quality of life (p=0.02), vs. placebo. This double-blind, placebo-controlled trial enrolled 1,050 African American patients with heart failure across 170 investigative sites, who were randomized to receive either BiDil or placebo in addition to standard therapy for 18 months. NitroMed announced that it had submitted the data from the trial to the FDA, as required to amend their NDA for the treatment of heart failure in African American patients.

October 18, 2004

Critical Therapeutics has issued positive results of a phase I trial of their investigational anti-inflammatory cytokine-synthesis inhibitor CTI-01 (ethyl pyruvate), for the treatment of critical inflammatory conditions. The trial met its primary safety endpoint, with multiple escalating dose regimens of the drug producing no serious adverse events, including doses higher than the anticipated therapeutic range. This double-blind, placebo-controlled study randomized a total of 60 healthy subjects to receive one of eight escalating multi-dose regimens of the drug. The trial followed the successful completion of a single escalating-dose study of the drug, initiated in June 2003. Critical Therapeutics announced plans to initiate a phase II trial of the drug in the prevention of organ damage following cardiopulmonary bypass by the end of Q4 2004, based upon these results.

September 27, 2004

Avant Immunotherapeutics has published the results from a phase II trial of their cardioprotective investigational drug TP10 in the journal Circulation. The trial did not meet its primary endpoint, a significant decrease in mortality or acute myocardial infarction following cardiopulmonary bypass (CPB) during cardiac surgery. However, when data were analyzed for male patients only, the drug was successful in both outcomes, reducing mortality by 36% in all men and by 43% in CABG men. The drug did demonstrate significant pharmacodynamic activity on its target in both men and women. This multi-center, double-blind, placebo-controlled study enrolled a total of 564 high risk men and women undergoing cardiac surgery including CPB. Avant announced that it plans to initiate a second, all-female phase II trial, in addition to phase III testing.

Medicure has announced positive results from a phase I trial of a new IV formulation of their lead compound MC-1, for the treatment of cardiovascular emergencies, including stroke and acute coronary syndrome. The drug was found to be safe and well tolerated in healthy volunteers, and, similar to the effect observed with the drug’s oral formulation, did not produce any significant adverse cardiovascular effects, a common concern with other similar products. This trial and the IV formulation of the drug were designed to expand the clinical potential of MC-1, and permit use of the drug both pre-operatively, as a cardioprotective, and as an intervention therapy in acute cardiovascular events.

June 1, 2004

Alexion Pharmaceuticals and Procter & Gamble Pharmaceuticals reported positive results from a phase III trial investigating pexelizumab, a terminal complement inhibitor for the treatment of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass. Results showed a significant reduction in the Death/MI (myocardial infarction) composite in the intent to treat population and demonstrated a sustained Death/MI reduction through six months. Data showed that the incidence of death or myocardial infarction was significantly reduced compared to placebo in the intent to treat population. The double-blind, placebo-controlled study, called PRIMO-CABG: "Pexelizumab for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft Surgery", enrolled 3,099 subjects undergoing CABG. Results were reported in the May 19th, 2004 issue of the Journal of the American Medical Association. The companies plan to initiate a confirmatory phase III trial with pexelizumab in CABG patients in mid 2004.

November 17, 2003

Alexion Pharmaceuticals and Procter & Gamble reported mixed results from a phase III trial investigating pexelizumab, an anti-inflammatory C5 inhibitor designed to treat patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Results showed that the primary endpoint did not meet statistical significance, however, the drug did achieve significant reductions in the same Death/MI endpoint in each additional secondary analysis. The primary endpoint was the incidence of death or myocardial infarction (Death/MI) at post-operative Day 30. The incidence of Death/MI was reduced by 9.8% with pexelizumab vs. 11.8 with placebo. The study called PRIMO-CABG (Pexelizumab for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft Surgery), enrolled over 3,000 subjects undergoing CABG surgery. Results were presented at the American Heart Association Scientific Sessions in Orlando, Florida.

Esperion Therapeutics reported positive results from a phase II trial investigating ETC-216 (ApoA-I Milano /phospholipid complex) for the treatment atherosclerosis. Results showed the drug rapidly reduced the size of plaque in coronary arteries and reversed atherosclerosis. Data revealed a statistically significant reduction in the percent plaque volume in the combined ETC-216 treatment groups comparing end-of-treatment values to baseline values. Overall adverse event rates were similar in all three treatment groups and ETC-216 was generally well-tolerated. The study enrolled 47 subjects with acute coronary syndromes. Subjects received five weekly intravenous infusions of placebo or ETC-216 (15-45 mg/kg). Results were reported in the November 2003 issue of the Journal of the American Medical Association.

September 22, 2003

Boston Scientific reported positive results from a medical device trial investigating Taxus IV, a drug eluting stent for the treatment of restenosis. Results showed a target lesion revascularization (TLR) rate of 3.0% with Taxus compared with 11.3% in the control group. Data demonstrated an in-segment binary restenosis rate, defined as 50% or greater vessel re-occlusion, of 7.9% with Taxus compared with 26.6% in the control group. The randomized, double blind pivotal trial enrolled 1,326 subjects and was designed to assess the safety and efficacy of a paclitaxel-eluting coronary stent system in reducing. Results were reported at the annual Transcatheter Cardiovascular Therapeutics symposium in Washington, D.C.

February 25, 2002

Avant Immunotherapeutics reported that TP10 failed to meet the primary endpoint in a double-blind, placebo-controlled phase II trial. The trial included 564 adult subjects undergoing high-risk cardiac surgery. Subjects were randomized to receive either a placebo or one of four doses of TP10 as a 30-minute intravenous infusion, and they were followed for 28 days post-surgery. The primary endpoint was the comparison of TP10- and placebo-treated subjects who experienced either death, myocardial infarction, required prolonged intubation or prolonged intra-arterial balloon pump therapy. The results did not show any clinically important differences between the placebo and four dose groups.

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