Long-term Safety in Atrial Fibrillation Patients

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00645853
• Collaborator: (none)
• Enrollment: 523
• Arms: 2
• Duration (Months): 19

Study Details

Study Description

Brief Summary

The purpose of this study is to provide safety and tolerability data for AZD0837 during long-term treatment (5 years) in patients with non-valvular atrial fibrillation (AF) and one or more additional risk factors for stroke and systemic embolic events (moderate to high risk patients).

Condition or Disease	Intervention/Treatment	Phase
Persistent or Permanent Nonvalvular Atrial Fibrillation	Drug: AZD0837; Drug: VKA INR 2-3	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 523 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Long-term Treatment With the Oral Direct Thrombin Inhibitor AZD0837, Compared to Vitamin-K Antagonists, as Stroke Prevention in Patients With Non-valvular Atrial Fibrillation and One or More Risk Factors for Stroke and Systemic Embolic Events. A 5-year Follow-up Study
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: AZD0837; Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od and then switching to one general common dose, 300 mg od
Active Comparator: 2	Drug: VKA INR 2-3; Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5; Other Names: warfarin

Outcome Measures

Primary Outcome Measures

1. Bleeding: Number of Patients With Any Bleeding Event, During Treatment Period [154-711 days on treatment]

   Participants

Secondary Outcome Measures

1. Alanine Transaminase (ALAT): Number of Patients With ALAT>=3xULN, Post Baseline [From baseline to Follow up]

   ULN=Upper limit of Normal

2. Bilirubin: Number of Patients With Bilirubin>=2xULN, Post Baseline [From baseline to Follow up]

3. Creatinine: Absolute Change From Baseline, at End of Treatment [Baseline and End of treatment]

4. D-dimer:Median and Quartile Range at End of Treatment [End of treatment]

   Median (Lower Quartile-Upper Quartile ), ng/mL

5. Activated Partial Thromboplastin Time (APTT): Absolute Change From Baseline to End of Treatment [Baseline and End of treatment]

   Median Full range, Seconds

6. Electroconvulsive Therapy (ECT): Absolute Change From Baseline to End of Treatment [Baseline and End of Treatment]

7. AZD0837: Plasma Concentration of AZD0837 at End of Treatment [End of treatment]

8. AR-H067637XX, the Active Major Metabolite of AD0837: Plasma Concentration of AR-H067637XX, at End of Treatment [154-711 days on treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with paroxysmal, persistent or permanent Non Valvular Atrial Fibrillation with one or more additional risk factors for stroke and systemic embolic event

• completing treatment with study drug in D1250C00008.

Exclusion Criteria:

• Atrial Fibrillation secondary to reversible disorders, eg hyperthyroidism

• Presence of a valvular heart disease, mechanical heart valves, active endocarditis, left ventricular aneurysm or thrombus, atrial myxoma or any condition other than Atrial Fibrillation requiring chronic anticoagulation treatment

• Myocardial infarction, heart surgery or percutaneous coronary intervention (PCI) within the previous three months prior to inclusion; Stroke and/or systemic embolism within the previous 30 days prior to inclusion

• Conditions associated with increased risk of major bleeding.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Lars Hvilstedt Rasmussen, MD, PhD, FESC, Head of Cardiology at Heart Centre Aalborg Aarhus University Hospital DK 9100 Aalborg Denmark

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00645853
• Other Study ID Numbers: D1250C00042
• First Posted: Mar 28, 2008
• Last Update Posted: Mar 23, 2012
• Last Verified: Mar 1, 2012

• Additional relevant MeSH terms: Atrial Fibrillation; Warfarin

Study Results

Participant Flow

Recruitment Details	The study population included male and female participants >18 years of age with chronic non-valvular Atrial Fibrillation. The participants were recruited during the time period from 25 October 2007 to 20 May 2008 at medical clinics in Europe.
Pre-assignment Detail	All participants had previously participated in the Prevention of Stroke and Systemic Embolic Events in Patients With Atrial Fibrillation (NCT00684307) study

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Period Title: Overall Study
STARTED	288	235
No of Patients After Dose Switch	209	188
Discontinued Patient No Due to Closure	196	178
AZ Study Closure in Hungary	60	40
COMPLETED	196	178
NOT COMPLETED	92	57

Baseline Characteristics

Arm/Group Title	AZD0837	VKA, INR 2-3	Total
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5	Total of all reporting groups
Overall Participants	288	235	523
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	69.9	68.0	68.95
Sex: Female, Male (Count of Participants)
Female	90 31.3%	73 31.1%	163 31.2%
Male	198 68.8%	162 68.9%	360 68.8%

Outcome Measures

1. Primary Outcome

Title	Bleeding: Number of Patients With Any Bleeding Event, During Treatment Period
Description	Participants
Time Frame	154-711 days on treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Measure Participants	288	235
Number [Participants]	55 19.1%	56 23.8%

2. Secondary Outcome

Title	Alanine Transaminase (ALAT): Number of Patients With ALAT>=3xULN, Post Baseline
Description	ULN=Upper limit of Normal
Time Frame	From baseline to Follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Measure Participants	288	235
Number [Participants]	9 3.1%	6 2.6%

3. Secondary Outcome

Title	Bilirubin: Number of Patients With Bilirubin>=2xULN, Post Baseline
Time Frame	From baseline to Follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Measure Participants	288	235
Number [Participants]	3 1%	3 1.3%

4. Secondary Outcome

Title	Creatinine: Absolute Change From Baseline, at End of Treatment
Time Frame	Baseline and End of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Measure Participants	288	235
Mean (Full Range) [µmol/L]	3.70 (-67.0)	-1.17 (-56.0)

5. Secondary Outcome

Title	D-dimer:Median and Quartile Range at End of Treatment
Description	Median (Lower Quartile-Upper Quartile ), ng/mL
Time Frame	End of treatment

Outcome Measure Data

Analysis Population Description

Only patients who switched to one common dose, 300 mg od, are included in the AZD0837 analysis

Arm/Group Title	AZD0837	VKA, INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.	Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
Measure Participants	193	232
Median (Inter-Quartile Range) [ng/mL]	68.9	54.9

6. Secondary Outcome

Title	Activated Partial Thromboplastin Time (APTT): Absolute Change From Baseline to End of Treatment
Description	Median Full range, Seconds
Time Frame	Baseline and End of treatment

Outcome Measure Data

Analysis Population Description

Only patients who switched to one common dose, 300 mg od, are included in the AZD0837 analysis

Arm/Group Title	AZD0837
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.
Measure Participants	173
Median (Full Range) [sec]	12.9

7. Secondary Outcome

Title	Electroconvulsive Therapy (ECT): Absolute Change From Baseline to End of Treatment
Time Frame	Baseline and End of Treatment

Outcome Measure Data

Analysis Population Description

Only patients who switched to one dose, 300 mg od, are included in the AZD0837 analysis

Arm/Group Title	AZD0837
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.
Measure Participants	129
Median (Full Range) [sec]	49.0

8. Secondary Outcome

Title	AZD0837: Plasma Concentration of AZD0837 at End of Treatment
Time Frame	End of treatment

Outcome Measure Data

Analysis Population Description

Only patients who switched to one dose, 300 mg od, are included in the AZD0837 analysis

Arm/Group Title	AZD0837
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.
Measure Participants	195
Median (Full Range) [nmol/L]	675

9. Secondary Outcome

Title	AR-H067637XX, the Active Major Metabolite of AD0837: Plasma Concentration of AR-H067637XX, at End of Treatment
Time Frame	154-711 days on treatment

Outcome Measure Data

Analysis Population Description

Only patients who switched to one dose, 300 mg od, are included in the AZD0837 analysis

Arm/Group Title	AZD0837
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od, then switching to one general common dose, 300 mg od.
Measure Participants	195
Median (Full Range) [nmol/L]	341

Adverse Events

Time Frame	154-711 days on treatment
Arm/Group Title	AZD0837		VKA INR 2-3
Arm/Group Description	Treatment with AZD0837 starting with 4 different doses, 150 mg od, 300 mg od, 200 mg bid or 450 mg od and then switching to one general common dose, 300 mg od		Vitamin K antagonists (VKA), titrated to an international normalised ratio (INR) of 2.0 to 3.0 with a target value of 2.5
All Cause Mortality
	AZD0837		VKA INR 2-3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD0837		VKA INR 2-3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/288 (25.3%)		61/235 (26%)
Blood and lymphatic system disorders
Neutropenia	1/288 (0.3%)		0/235 (0%)
Cardiac disorders
Cardiac Failure	7/288 (2.4%)		6/235 (2.6%)
Atrial Fibrillation	4/288 (1.4%)		4/235 (1.7%)
Angina Unstable	0/288 (0%)		3/235 (1.3%)
Bradycardia	3/288 (1%)		2/235 (0.9%)
Angina Pectoris	2/288 (0.7%)		1/235 (0.4%)
Sick Sinus Syndrome	2/288 (0.7%)		1/235 (0.4%)
Acute Coronary Syndrome	0/288 (0%)		1/235 (0.4%)
Atrial Flutter	0/288 (0%)		1/235 (0.4%)
Bradyarrhythmia	0/288 (0%)		1/235 (0.4%)
Cardiac Failure Congestive	1/288 (0.3%)		0/235 (0%)
Chordae Tendinae Rupture	0/288 (0%)		1/235 (0.4%)
Coronary Artery Stenosis	1/288 (0.3%)		0/235 (0%)
Heart Valve Incompetence	1/288 (0.3%)		0/235 (0%)
Myocardial Ischaemia	0/288 (0%)		1/235 (0.4%)
Palpitations	0/288 (0%)		1/235 (0.4%)
Tachyarrhythmia	0/288 (0%)		1/235 (0.4%)
Tachycardia	1/288 (0.3%)		1/235 (0.4%)
Ventricular Tachycardia	0/288 (0%)		1/235 (0.4%)
Endocrine disorders
Hyperthyroidism	1/288 (0.3%)		0/235 (0%)
Eye disorders
Cataract	1/288 (0.3%)		2/235 (0.9%)
Eye Haemorrhage	0/288 (0%)		1/235 (0.4%)
Glaucoma	0/288 (0%)		1/235 (0.4%)
Retinal Artery Embolism	1/288 (0.3%)		0/235 (0%)
Gastrointestinal disorders
Gastrointestinal Haemorrhage	0/288 (0%)		3/235 (1.3%)
Gastric Ulcer	0/288 (0%)		2/235 (0.9%)
Abdominal Hernia	1/288 (0.3%)		0/235 (0%)
Abdominal Pain	0/288 (0%)		1/235 (0.4%)
Abdominal Pain Lower	0/288 (0%)		1/235 (0.4%)
Anal Haemorrhage	1/288 (0.3%)		0/235 (0%)
Anal Ulcer	0/288 (0%)		1/235 (0.4%)
Diarrhoea	0/288 (0%)		1/235 (0.4%)
Gastritis	0/288 (0%)		1/235 (0.4%)
Haematemesis	0/288 (0%)		1/235 (0.4%)
Inguinal Hernia	1/288 (0.3%)		1/235 (0.4%)
Melaena	0/288 (0%)		1/235 (0.4%)
Nausea	1/288 (0.3%)		0/235 (0%)
Periodontal Disease	0/288 (0%)		1/235 (0.4%)
General disorders
Death	2/288 (0.7%)		0/235 (0%)
Non-Cardiac Chest Pain	0/288 (0%)		2/235 (0.9%)
Asthenia	1/288 (0.3%)		0/235 (0%)
Hepatobiliary disorders
Cholecystitis Chronic	0/288 (0%)		1/235 (0.4%)
Cholelithiasis	0/288 (0%)		1/235 (0.4%)
Jaundice Cholestatic	0/288 (0%)		1/235 (0.4%)
Immune system disorders
Corneal Graft Rejection	0/288 (0%)		1/235 (0.4%)
Infections and infestations
Bronchitis	2/288 (0.7%)		3/235 (1.3%)
Erysipelas	3/288 (1%)		1/235 (0.4%)
Pneumonia	3/288 (1%)		3/235 (1.3%)
Abscess Limb	1/288 (0.3%)		0/235 (0%)
Endocarditis	0/288 (0%)		1/235 (0.4%)
Gastroenteritis	1/288 (0.3%)		1/235 (0.4%)
Intervertebral Discitis	0/288 (0%)		1/235 (0.4%)
Laryngitis	1/288 (0.3%)		0/235 (0%)
Pyelonephritis	1/288 (0.3%)		0/235 (0%)
Respiratory Tract Infection	1/288 (0.3%)		0/235 (0%)
Sinusitis	1/288 (0.3%)		0/235 (0%)
Urinary Tract Infection	0/288 (0%)		1/235 (0.4%)
Urosepsis	0/288 (0%)		1/235 (0.4%)
Injury, poisoning and procedural complications
Concussion	0/288 (0%)		1/235 (0.4%)
Contusion	0/288 (0%)		1/235 (0.4%)
Foreign Body Trauma	0/288 (0%)		1/235 (0.4%)
Head Injury	0/288 (0%)		1/235 (0.4%)
Joint Dislocation	1/288 (0.3%)		0/235 (0%)
Post Procedural Haemorrhage	0/288 (0%)		1/235 (0.4%)
Subdural Haematoma	0/288 (0%)		1/235 (0.4%)
Tibia Fracture	1/288 (0.3%)		0/235 (0%)
Investigations
Alanine Aminotransferase Increased	2/288 (0.7%)		1/235 (0.4%)
Haemoglobin Decreased	1/288 (0.3%)		2/235 (0.9%)
Blood Alkaline Phosphatase Increased	0/288 (0%)		1/235 (0.4%)
Blood Glucose Increased	0/288 (0%)		1/235 (0.4%)
International Normalised Ratio Increased	0/288 (0%)		1/235 (0.4%)
Metabolism and nutrition disorders
Diabetes Mellitus	2/288 (0.7%)		1/235 (0.4%)
Dehydration	1/288 (0.3%)		1/235 (0.4%)
Hyperkalaemia	1/288 (0.3%)		0/235 (0%)
Hypoglycaemia	1/288 (0.3%)		0/235 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/288 (0%)		2/235 (0.9%)
Osteoarthritis	2/288 (0.7%)		0/235 (0%)
Arthralgia	1/288 (0.3%)		0/235 (0%)
Back Pain	1/288 (0.3%)		1/235 (0.4%)
Bursitis	1/288 (0.3%)		0/235 (0%)
Inguinal Mass	0/288 (0%)		1/235 (0.4%)
Muscle Atrophy	0/288 (0%)		1/235 (0.4%)
Muscular Weakness	1/288 (0.3%)		0/235 (0%)
Myalgia	0/288 (0%)		1/235 (0.4%)
Osteitis	1/288 (0.3%)		0/235 (0%)
Rheumatoid Arthritis	0/288 (0%)		1/235 (0.4%)
Scleroderma	1/288 (0.3%)		0/235 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	3/288 (1%)		0/235 (0%)
Basal Cell Carcinoma	1/288 (0.3%)		0/235 (0%)
Colon Adenoma	0/288 (0%)		1/235 (0.4%)
Colon Cancer Metastatic	0/288 (0%)		1/235 (0.4%)
Metastases To Central Nervous System	1/288 (0.3%)		0/235 (0%)
Nervous system disorders
Syncope	3/288 (1%)		1/235 (0.4%)
Headache	0/288 (0%)		2/235 (0.9%)
Transient Ischaemic Attack	1/288 (0.3%)		2/235 (0.9%)
Cerebral Artery Embolism	0/288 (0%)		1/235 (0.4%)
Cerebrovascular Accident	1/288 (0.3%)		1/235 (0.4%)
Dizziness	1/288 (0.3%)		1/235 (0.4%)
Encephalitis	1/288 (0.3%)		0/235 (0%)
Epilepsy	1/288 (0.3%)		0/235 (0%)
Ischaemic Stroke	1/288 (0.3%)		0/235 (0%)
Status Epilepticus	1/288 (0.3%)		0/235 (0%)
Vascular Encephalopathy	1/288 (0.3%)		0/235 (0%)
Vertebrobasilar Insufficiency	1/288 (0.3%)		0/235 (0%)
Psychiatric disorders
Delusional Disorder, Persecutory Type	1/288 (0.3%)		0/235 (0%)
Dysthymic Disorder	1/288 (0.3%)		0/235 (0%)
Renal and urinary disorders
Haematuria	2/288 (0.7%)		1/235 (0.4%)
Dysuria	1/288 (0.3%)		0/235 (0%)
Renal Failure	1/288 (0.3%)		0/235 (0%)
Urinary Bladder Haemorrhage	0/288 (0%)		1/235 (0.4%)
Reproductive system and breast disorders
Postmenopausal Haemorrhage	1/288 (0.3%)		0/235 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/288 (0.7%)		1/235 (0.4%)
Dyspnoea Exertional	1/288 (0.3%)		0/235 (0%)
Haemoptysis	0/288 (0%)		1/235 (0.4%)
Pleural Effusion	1/288 (0.3%)		1/235 (0.4%)
Skin and subcutaneous tissue disorders
Rash	0/288 (0%)		1/235 (0.4%)
Vascular disorders
Arterial Occlusive Disease	1/288 (0.3%)		0/235 (0%)
Arterial Stenosis Limb	1/288 (0.3%)		0/235 (0%)
Hypertension	1/288 (0.3%)		0/235 (0%)
Orthostatic Hypotension	1/288 (0.3%)		0/235 (0%)
Peripheral Artery Aneurysm	1/288 (0.3%)		0/235 (0%)
Peripheral Embolism	1/288 (0.3%)		0/235 (0%)
Subclavian Vein Thrombosis	1/288 (0.3%)		0/235 (0%)
800003Varicose Vein	1/288 (0.3%)		0/235 (0%)
Other (Not Including Serious) Adverse Events
	AZD0837		VKA INR 2-3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	125/288 (43.4%)		106/235 (45.1%)
Gastrointestinal disorders
Diarrhoea	37/288 (12.8%)		18/235 (7.7%)
Flatulence	20/288 (6.9%)		1/235 (0.4%)
General disorders
Oedema Peripheral	25/288 (8.7%)		20/235 (8.5%)
Fatigue	19/288 (6.6%)		9/235 (3.8%)
Infections and infestations
Nasopharyngitis	35/288 (12.2%)		30/235 (12.8%)
Bronchitis	14/288 (4.9%)		18/235 (7.7%)
Urinary Tract Infection	13/288 (4.5%)		15/235 (6.4%)
Injury, poisoning and procedural complications
Fall	4/288 (1.4%)		12/235 (5.1%)
Musculoskeletal and connective tissue disorders
Back Pain	15/288 (5.2%)		12/235 (5.1%)
Arthralgia	9/288 (3.1%)		13/235 (5.5%)
Nervous system disorders
Dizziness	24/288 (8.3%)		17/235 (7.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.