This is a phase II study to evaluate the feasibility of conducting a study in patients with AF who are appropriate for, but unable or unwilling to take VKA therapy. The intended indication for the product under development is the prevention of stroke and other thromboembolic complicationds associated with atrial fibrillation (AF) MedDRA version: 9.1 Level: LLT Classification code 10003658 Term: Atrial fibrillation
Conditions
Interventions
Product Name: AZD0837
Pharmaceutical Form: Prolonged-release tablet
CAS Number: 631916-97-7
Current Sponsor code: AZD0837 besylate
Other
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Signed informed consent given by the patient before any study-specific procedures are initiated Paroxysmal, persistent or permanent NVAF verified by at least 2 ECGsa in the last year separated by at least one weekb; for: - Newly diagnosed patients: the second ECG should be carried out within the 2 weeks prior to randomization - Other patients: the second ECG should be carried out within the 12 weeks prior to randomization a Clarification: ECG verification can be done by 12 lead ECG, 24 hour Holter monitoring or event recording of good quality, but not via pacemaker. Thus, paroxysmal AF can be defined by 2 or more episodes of AF (lasting >30 seconds) on a single 24 hour Holter performed within 3 months of randomisation. b Clarification: In 'high risk' AF patients not on VKA treatment, the one week gap between the 1st and 2nd ECGs [which should still be on separate days] is not mandatory, if local clinical practice requires initiation of antithrombotic therapy as soon as possible. The second ECG should still be carried out within the 2 weeks prior to randomisation. In addition to AF the patient must have the following risk factors Either one of the following risk factors is sufficient for inclusion (high risk patient): - Previous cerebral ischaemic attack (stroke or transient ischaemic attack (TIA), >30 days prior to randomization) - Previous systemic embolism or at least one of the following risk factors are needed for inclusion (1 risk factor = moderate risk patient, 2 or more risk factors = high risk patient): - Age =75 years - Symptomatic congestive heart failure - Impaired left ventricular systolic function - Diabetes mellitus - Hypertension requiring anti-hypertensive treatmentc c Hypertensive patients who are enrolled and randomized into the study should be well controlled and have antihypertensive treatment aiming for a blood pressure <160/100 mmHg. In addition to AF the patient must be appropriate for but unable or unwilling to take VKA therapy by fulfilling at least one of the following criteria - In hospital records, documented inability to keep International normalized ration (INR) levels within 2.0 to 3.0 during a continuous and recent period of at least 3 months, leading to the conclusion that VKA therapy does not offer an adequate level of benefit vs. risk, in the specific patientd, e. - Permanent cessation or refusalf by the patient to take VKA therapy due to reasons specified in hospital records present, recorded no later than one month before start of the study. - Refusal to participate in study D1250C00008 due to the possibility of being randomized to VKA treatmentd. For VKA naïve patients this must have been stated in the hospital records at least 1 week in advance of enrolment in the study. - Treating physician’s assessment that VKA is inappropriate for this patient recorded no later than one month before start of this studyd. - Allergic reactions to VKA as documented in hospital recordsf. d Reason must be stated in the hospital records and in the pCRF. e INR must be <2 at randomization.
Exclusion criteria
Exclusion criteria: Aged 1 year ago or bilateral oophorectomy. - Reliable form of contraception is defined as: oral contraceptive, implant, long term injectable contraceptive, intrauterine device or tubal ligation. However, female patients using hormonal anti conception method (oral, transdermal, vaginal ring or combination injectables) must agree to use an additional barrier method for contraception (condom or diaphragm). Atrial fibrillation secondary to reversible disorders, eg, hyperthyroidism, drugs and pulmonary embolism Presence of a clinically significant valvular heart disease, as well as mechanical heart valves, active endocarditis, left ventricular aneurysm or thrombus, atrial myxoma or any condition other than AF requiring chronic anticoagulation treatment Myocardial infarction, heart surgery (eg, coronary artery bypass graft) or percutaneous transluminal coronary angioplasty within the previous 3 months prior to randomization Stroke or TIA and/or systemic embolism within the previous 30 days prior to randomization Conditions associated with increased risk of major bleeding for example: - High risk of falling accident - High bleeding risk, exceeding possible benefit of the antithrombotic treatment - History of intracranial bleeding - History of bleeding gastrointestinal disorder and/or endoscopically verified ulcer disease within the last year prior to randomization - Major surgical procedure or trauma 2 weeks prior to randomization Diastolic blood pressure >100 mmHg or systolic blood pressure >180 mmHg with or without antihypertensive treatment Renal impairment (calculated creatinine clearance 3 x ULN History or presence of infectious hepatitis (including known HbSAg positive or antibodies against Hepatitis C) or human immunodeficiency virus (HIV) Known Gilbert’s syndrome Anemia (Hb<100g/L = 6.2 mmol/L) Platelet count <100 x109/L Treatment with antiplatelet other than ASA or fibrinolytic agents within 10 days before randomization Planned cardioversion or surgery during the study Other serious disease that gives a calculated survival less than 12 months or any condition making a patient too frail to participate in the study Known drug addiction or alcohol abuse Inability to complete the study according to the protocol Previous enrolment or randomization of treatment in the present study. Participating in any other clinical study within 4 weeks (in UK within 12 weeks) prior to enrolment Treatment with AZD0837 in previous or ongoing AZD0837 study(ies) I
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to assess feasibility of conducting a study in patients with atrial fibrillation (AF), who are appropriate for but unable or unwilling to take Vitamin-K antagonist (VKA) therapy, by evaluation of drop-out rate and compliance with treatment and study procedures.; Secondary Objective: To provide information on recruitment rate, expressed as number of randomised patients, in this patient population, with focus on the participating countries To provide dose-guiding information through evaluation of safety and tolerability of 2 dosing regimens of AZD0837 in relation to “standard therapy” according to local clinical practice (acetylsalicylic acid (ASA), clopidogrel or no therapy) in patients with AF, who are appropriate for but unable or unwilling to take VKA therapy To evaluate the pharmacokinetics of AZD0837, the intermediary metabolite (AR H069927XX) and the active form (AR H067637XX) with special regard to the variability in this patient population and the relationship between systemic plasma exposure of AR H067637XX and bleeding events by evaluation of pharmacokinetic variables of AZD0837, AR-H069927XX and AR H067637XX To evaluate the pharmacodynamic properties of AZD0837 in patients with AF who are appropriate for but unable or unwilling to take VKA therapy ; Primary end point(s): Not applicable The primary variables in this study are: Drop Out, - defined as premature discontinuation of study drug, due to any reason - defined as premature discontinuation of study, due to any reason Compliance, - for AZD0837 patients: with regards to study drug, defined as how large percentage of the amount of study drug specified by the protocol that a patient has actually taken - for all patients: with regards to study visi | — |
Countries
Denmark, Sweden, United Kingdom
Outcome results
None listed