Official Title: “A Randomized, Double Blind Comparison of ATI-5923, a Novel Vitamin K Antagonist, With Warfarin in Patients Requiring Chronic Anticoagulation”

The purpose of this research study is to test an experimental drug ATI-5923 vs Coumadin. The study is intended to demonstrate ATI-5923 is superior to Coumadin for keeping INR values in the desired therapeutic range. Patients who require chronic anticoagulation with one or more of the following conditions are eligible for the study: atrial fibrillation or atrial flutter, prosthetic heart valve, venous thromboembolic disease, or history of myocardial infarction or cardiomyopathy will be enrolled.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: June 2009

The primary study objective is to evaluate whether ATI-5923 is superior to adjusted dose warfarin in the quality of anticoagulation as measured by interpolated INR time in therapeutic range. This is a Phase II/III multi-center, randomized, stratified, double blind, parallel group, active control study comparing ATI-5923 with Coumadin in patients who require chronic, oral anticoagulation. Up to 600 patients who successfully complete all screening assessments and meet all eligibility criteria will be enrolled in the study and receive study drug treatment for 6-12 months depending on time of study entry.

Intervention(s) in this Clinical Trial

• Drug: ATI-5923
  • Dose Adjusted based on INR.
• Drug: Coumadin (warfarin)
  • Dose adjusted based on INR.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1. ATI-5923
  • Dose adjusted ATI-5923
• Active Comparator: 2. Coumadin
  • Dose adjusted Coumadin (warfarin)

Primary Measures

• Percent of time INR is in therapeutic range after the exclusion of the first 4 weeks of treatment, using the linear interpolation method of Rosendaal(Rosendaal, 1993).
  • Time Frame: After the first month through end of study.
    Safety Issue?: Yes

Secondary Measures

• The proportion of all study recorded INR values that are within the target range, after the exclusion of the INR values from the first 4 weeks of treatment
  • Time Frame: After the first month through end of study
    Safety Issue?: Yes
• Proportion of time patients have significant deviations from therapeutic INR range.
  • Time Frame: After the first month through end of study
    Safety Issue?: Yes
• A composite of the following clinically important outcome events
  • Time Frame: After the first month through end of study
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Patients with one or more of the following indications for chronic warfarin anticoagulation (the patient may either be a new candidate for anticoagulation or may already be receiving warfarin):
• 1. Atrial fibrillation (paroxysmal, persistent or permanent, not due to a reversible cause, documented by ECG) or atrial flutter.
• 2. A prosthetic heart valve in the aortic or mitral position that requires chronic anticoagulation.
• 3. A history of venous thromboembolic disease (DVT and/or PE) requiring long term anticoagulation (> 6 months).
• 4. A history of myocardial infarction or cardiomyopathy requiring anticoagulation.
• 5. Currently receiving chronic warfarin therapy for another indication not listed, with Sponsor approval.
• 2. Male or female greater than 18 years of age.
• 3. Able and willing to sign IRB approved written informed consent to participate in the study.
• 4. Able and willing to follow instructions, to comply with protocol requirements, and to attend required study visits.

Exclusion Criteria:

• 1. Contraindications to anticoagulation as listed in the warfarin package insert (Appendix D), such as active bleeding or lesions at risk of bleeding such as gastric ulceration, colonic or cerebral AV malformations, cerebral or aortic aneurysms, pericarditis or endocarditis. Patients who have had recent (< 14 days from screening) surgery or invasive procedures or are about to undergo surgery or other invasive procedures, such as lumbar puncture. Patients with blood dyscrasias or inherited disorders of hemostasis. Patients with a history of hemorrhagic tendencies or prior serious hemorrhagic events such as hemorrhage within the cranium, eye, spinal cord, retroperitoneum, or gastrointestinal tract.
• 2. Laboratory evidence at screening of clinically significant active bleeding, such as unexplained positive occult blood in stool, or unexplained positive urinary blood that is more than trace positive for hemoglobin.
• 3. Concomitant use of other anticoagulant or antiplatelet agents that may add to the hemostatic burden such as clopidogrel, ticlopidine, heparin or low molecular weight heparin (LMWH), or regular use of non selective long acting NSAIDs that cannot be discontinued prior to initiating ATI 5923/warfarin dosing (daily use of 81-100 mg aspirin is allowed).
• 4. A life expectancy of < 1 year, end stage renal failure requiring dialysis, end stage pulmonary disease requiring home oxygen, severe heart failure (NYHA class IV).
• 5. Dementia, severe psychiatric disorder, or ongoing alcohol or substance abuse.
• 6. Laboratory screening values indicating severe anemia (Hb < 10 gm/L), thrombocytopenia (platelet count < 90,000/mcL), or active liver disease.
• 7. Patients with conditions that will interfere with determination of the INR using the INRatio device, i.e., hematocrit <30% or >55%. Patients with the antiphospholipid syndrome may have abnormal INR results and should not be enrolled.
• 8. History of non disabling ischemic stroke within the last 3 months, prior major disabling ischemic stroke, or any history of intracranial bleeding.
• 9. Pregnant or nursing women or women of childbearing potential who will not use adequate contraception, such as oral or implantable contraceptives, IUD, or barrier methods (IUD or condom) with spermicide.
• 10. Currently participating in another clinical trial at screening, treatment with an investigational drug within 30 days of the first dose of study medication, or patients who previously participated in an ATI-5923 trial.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: ARYx Therapeutics

Overall Clinical Trial Officials and Contacts

Overall Contact: Eppie Chang 510-585-2200 echang@aryx.com

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00691470

Study ID Number: CLN-505

ClinicalTrials.gov Identifier: NCT00691470

Health Authority: United States: Food and Drug Administration

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