First clinical application of an actively reversible direct factor IXa inhibitor as an anticoagulation strategy in patients undergoing percutaneous coronary intervention.

BACKGROUND: The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007. METHODS AND RESULTS: This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal. CONCLUSIONS: This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

The effect of aspirin on endothelial progenitor cell biology: preliminary investigation of novel properties.

UNLABELLED: Atherosclerosis develops in an environment of endothelial injury and inflammation. Circulating endothelial progenitor cells (EPCs) are required for vascular repair and restoration of normal endothelial function. We tested the hypothesis that the nonselective cyclooxygenase (COX) inhibitor aspirin (ASA) exerts an effect on circulating EPCs. METHODS: As part of a larger study evaluating the effect of aspirin dose in primary and secondary prevention, subjects (n=32) were assigned randomly to either 81 mg or 325 mg aspirin daily for two months, and circulating mononuclear cells were enumerated at the beginning of the study and after 2 months using fluorescent antibodies against CD34 and CD133 as well as based on aldehyde dehydrogenase (ALDH) activity. Brachial artery endothelial function via flow-mediated dilation (BAFMD) and light transmittance platelet aggregometry in response to physiologic agonists was also determined. RESULTS: Subjects taking aspirin at the time of study entry had a lower numbers of CD133+/34+ cells compared to those not previously exposed (0.01% vs. 0.05% of MNCs, P<0.03). After 2 months, subjects randomized to 81 vs. 325 mg of ASA had no significant differences in the median numbers of EPCs, although mean numbers trended lower in the high dose group. Patients on chronic ASA therapy continued to have lower numbers of EPCs. Similar effects were observed in CD34 and CD 133 single-positive cells, as well as ALDH(br) cells. BAFMD did not differ nor change significantly over time between aspirin dose groups. All patients had decreased ex vivo platelet aggregation in response to arachidonic acid and ADP stimulation. CONCLUSIONS: Our preliminary studies suggest that aspirin exerts a time-dependent effect on circulating EPCs. Short-term exposure to differing doses of ASA had indeterminate effects on EPCs levels, suggesting that time of ASA exposure may play a more important role than dose. Determining the responsible mechanism(s) and the overall clinical relevance of these findings will require further investigation.

Design and rationale of the Evaluation of M118 IN pErcutaNeous Coronary intErvention (EMINENCE) trial.

BACKGROUND: Currently recommended anticoagulant agents used in the setting of percutaneous coronary intervention (PCI) inhibit, with varying degrees of intensity, 2 critical targets (factor Xa and/or IIa) of the coagulation cascade, yet they carry significant limitations. M118-a novel, rationally engineered heparin-provides consistent anti-Xa and anti-IIa activity with a constant anti-Xa:anti-IIa ratio over time. M118 also combines the desired anticoagulant effects of unfractionated heparin with the beneficial attributes of low-molecular-weight heparin, and may represent the next generation of heparin therapy in patients diagnosed with acute coronary syndrome. STUDY DESIGN: The EMINENCE trial is a prospective, randomized, open-label, multicenter phase 2 study that will evaluate the safety and feasibility of M118 as an anticoagulant versus unfractionated heparin in subjects with stable coronary artery disease undergoing PCI. The primary end point of the study will be the combined incidence of clinical events defined as the composite of 30-day death, myocardial infarction, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, and major or minor bleeding. CONCLUSION: The EMINENCE trial will assess the safety and feasibility of M118 as an anticoagulant in the setting of PCI and will provide important information to determine the appropriate therapeutic range of activated clotting time for M118 and the appropriate dose or doses to be explored in a phase 3 clinical trial.

Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.

BACKGROUND: Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity. METHODS AND RESULTS: We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred. CONCLUSIONS: This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity.

BACKGROUND: Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study. METHODS AND RESULTS: Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline. CONCLUSIONS: These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

Improved surgeon performance in clinical trials: an analysis of quality assurance audits from the American College of Surgeons Oncology Group.

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) represents an organized effort by surgeons to participate in clinical trials research. To assess the quality of trial conduct by surgeons on a national level and the feasibility of improvement through education, this study examined the findings of the Quality Assurance Audit Program of the ACOSOG over time. STUDY DESIGN: Outcomes of 249 routine audits conducted from 2001 to 2004 were reviewed for major and minor deficiencies and overall performance (acceptable versus unacceptable) in compliance with regulatory requirements (REG) and patient case review (PCR). RESULTS: From 2001 to 2004, active trials have increased. Major deficiencies in REG fell from 31% to 20% for IRB documentation (p = 0.002) and from 31% to 9% for informed consent (p < 0.001). The major deficiency rates in PCR decreased from 21% to 6% (patient consent), 16% to 7% (eligibility), 13% to 7% (treatment), 34% to 6% (outcomes), 6% to 1% (toxicity), and 16% to 3% (data). During 2001 to 2004, the overall acceptable performance rates were 82%, 72%, 84%, and 92%, respectively, in REG (p = 0.093), and significantly improved in PCR (47%, 55%, 77%, 94%, respectively; p < 0.001). No difference was detected in acceptable rates between academic versus community sites, for either REG (86% versus 76%, respectively; odds ratio: 1.91; 95% CI: 0.87 to 4.19) or PCR (63% versus 68%, respectively; odds ratio: 0.81; 95% CI: 0.42 to 1.53). CONCLUSIONS: Despite initial deficiencies, surgical trials are now conducted with high standards nationwide. In response to educational programs, surgeon performance in clinical trials has measurably improved. Quality assurance audits have served both surveillance and educational roles.