A controlled, randomized, parallel, multi-centre, feasibility study of the oral direct thrombin inhibitor AZD0837, given as extended-release formulation, in the prevention of stroke and systemic embolic events in patients with atrial fibrillation, who are appropriate for but unable or unwilling to take Vitamin-K antagonist therapy

• Conditions: 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: 9.1Level: LLTClassification code 10003658Term: Atrial fibrillation

• Registration Number: EUCTR2007-001723-36-DK
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-07-02
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 150

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
aClarification:
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.
bClarification:
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
cHypertensive 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.
dReason must be stated in the hospital records and in the pCRF.
eINR must be <2 at randomization.
fReason must be stated in the pCRF.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

Aged <18 years at randomization

Weight <50 kg at enrolment

Lactation; child-bearing potential, ie, women must be either post-menopausal, permanently sterilised or, if of child-bearing potential, must have a negative pregnancy test prior to initiation of study drug and use a reliable form of contraception before and during participation in the study.
- Post menopausal patients are defined as patients with: natural or induced menopause with last menstruation >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 <30 ml/min)

Known hepatic disease and/or ALAT >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)

Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site)

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified