A Dose Response Study of Dabigatran Etexilate(BIBR 1048) in Pharmacodynamics and Safety in Patients With Non-valvular Atrial Fibrillation in Comparison to Warfarin

Atrial Fibrillation Clinical Trial

Official title:

Open Label, Randomised Exploratory Dose Response Study in Pharmacodynamics and Safety of BIBR 1048 (110 mg Twice Daily (b.i.d.) and 150 mg b.i.d.) for 12 Weeks in Patients With Non-valvular Atrial Fibrillation in Comparison to Warfarin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01136408
• Other study ID #: 1160.49
• Status: Completed
• Phase: Phase 2
• First received: May 19, 2010
• Last updated: February 18, 2014
• Start date: November 2005

Study information

• Verified date: February 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial Summary

The primary objective was to evaluate the safety of dabigatran etexilate(BIBR 1048) administered orally at doses of 110 and 150 mg, twice daily, for 12 weeks in patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent) in comparison with warfarin.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 174
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

Inclusion criteria Inclusion criteria

1. Patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent)

2. Patients who had additional risk factor for thromboembolism; one or more of the following conditions/events:

• Hypertension

• Diabetes mellitus

• Left-side heart failure

• A previous ischemic stroke or transient ischemic attack

• Age 75 years or older

• A history of coronary artery diseases

Exclusion criteria Exclusion criteria

1. Patients diagnosed as having a valvular heart disease by echocardiography, or patients who had a history of prosthetic valve replacement or valve surgery

2. Patients who were to receive electric defibrillation or pharmacological defibrillation during the study period

3. Patients who developed stroke or transient ischemic attack within 30 days before the date of informed consent

4. Patients who developed myocardial infarction or were admitted to hospital due to acute coronary syndrome or for percutaneous transluminal coronary angioplasty within 3 months before the date of informed consent or patients underwent coronary stenting within 6 months before the date of informed consent

5. Patients with atrial myxoma or left ventricular thrombosis

6. Patients with contraindication to anticoagulant therapies

7. Patients scheduled for major surgery or invasive procedure

8. Patients having major bleeding from non-gastrointestinal organs within 6 months before the date of informed consent

9. Patients with uncontrolled hypertension

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Dabigatran etexilate
Dabigatran etexilate 110 mg capsule, twice a day, oral administration
• Dabigatran etexilate
Dabigatran etexilate 150 mg capsule, twice a day, oral administration
• Warfarin
Dose-adjusted warfarin based on target INR values

Locations

Country	Name	City	State
Japan	1160.49.024 Boehringer Ingelheim Investigational Site	Aki-gun, Hiroshima
Japan	1160.49.025 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	1160.49.026 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	1160.49.021 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1160.49.027 Boehringer Ingelheim Investigational Site	Iizuka,Fukuoka
Japan	1160.49.013 Boehringer Ingelheim Investigational Site	Kyoto, Kyoto
Japan	1160.49.011 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1160.49.012 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1160.49.004 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaragi
Japan	1160.49.022 Boehringer Ingelheim Investigational Site	Okayama, Okayama
Japan	1160.49.023 Boehringer Ingelheim Investigational Site	Okayama, Okayama
Japan	1160.49.006 Boehringer Ingelheim Investigational Site	Oota, Tokyo
Japan	1160.49.016 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1160.49.017 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1160.49.018 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1160.49.019 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1160.49.020 Boehringer Ingelheim Investigational Site	Sakai, Osaka
Japan	1160.49.001 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido
Japan	1160.49.028 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido
Japan	1160.49.002 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	1160.49.005 Boehringer Ingelheim Investigational Site	Shinjuku, Tokyo
Japan	1160.49.014 Boehringer Ingelheim Investigational Site	Suita, Osaka
Japan	1160.49.015 Boehringer Ingelheim Investigational Site	Suita, Osaka
Japan	1160.49.007 Boehringer Ingelheim Investigational Site	Tokorozawa, Saitama
Japan	1160.49.009 Boehringer Ingelheim Investigational Site	Toyama, Toyama
Japan	1160.49.003 Boehringer Ingelheim Investigational Site	Tsuchiura, Ibaragi
Japan	1160.49.029 Nagano National Hospital	Ueda, Nagano
Japan	1160.49.008 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency (Occurrence Rates) of Major Bleeding Event	The percentage of patients with major bleeding event.; Major bleeding was defined as any bleed fulfilling one of the following conditions: Fatal or life-threatening; Retroperitoneal, intracranial, intraocular, or intraspinal bleeding (verified by objective testing); Bleeding requiring surgical treatment; Clinically overt bleeding leading to a transfusion (erythrocyte component transfusion or whole blood transfusion) of 4.5 units (equal to 2 units in EU/US) or more; Clinically overt bleeding leading to a fall in haemoglobin of at least 2 g/dL	upto 15 weeks	Yes
Primary	Frequency (Occurrence Rates) of Clinically Relevant Bleeding Event	The percentage of patients with clinically relevant bleeding event.; Any bleed that did not qualify as a major bleed was defined as a minor bleed; minor bleed which fulfilled one of the criteria below was defined as a clinically relevant bleeding event: A skin haematoma of at least 25 sqcm; Spontaneous nose bleed lasting for more than 5 minutes; Macroscopic haematuria (either spontaneous or, if associated with an intervention, lasting more than 24 hours); Spontaneous rectal bleeding (more than spotting on toilet paper); Gingival bleeding lasting for more than 5 minutes; Bleeding leading to hospitalisation; Bleeding leading to blood transfusion (erythrocyte component transfusion or whole blood transfusion) of less than 4.5 units (equal to 2 units in EU/US); Any other bleeding considered clinically relevant by the investigator	upto 15 weeks	Yes
Primary	Frequency (Occurrence Rates) of Nuisance Bleeding Event	The percentage of patients with nuisance bleeding event; Any bleed that did not qualify as a major bleed was defined as a minor bleed; all minor bleeding events not fulfilling one of the criteria below was defined as a nuisance bleeding event: A skin haematoma of at least 25 sqcm; Spontaneous nose bleed lasting for more than 5 minutes; Macroscopic haematuria (either spontaneous or, if associated with an intervention, lasting more than 24 hours); Spontaneous rectal bleeding (more than spotting on toilet paper); Gingival bleeding lasting for more than 5 minutes; Bleeding leading to hospitalisation; Bleeding leading to blood transfusion (erythrocyte component transfusion or whole blood transfusion) of less than 4.5 units (equal to 2 units in EU/US); Any other bleeding considered clinically relevant by the investigator	Upto 15 weeks	Yes
Primary	Incidence and Severity of Adverse Events	Intensity of event is categorised as mild, moderate and severe.	Upto 15 weeks	No
Primary	Discontinuation of the Study Drug Due to Adverse Events	Discontinuation of the study drug due to adverse events.	Upto 15 weeks	No
Primary	Changes in Laboratory Test Values	The number of patients with ALT, AST, alkaline phosphatase, or bilirubin exceeded the upper limit of normal (ULN) range	12 weeks	No
Secondary	Frequency (Occurrence Rates) of a Composite Clinical Endpoint.	Percentage of patients with the composite clinical endpoint (ischemic or haemorrhagic stroke (fatal or non-fatal), transient ischemic attacks, systemic embolism, myocardial infarction (fatal or non-fatal), other major adverse cardiac events, and death)	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Ischemic or Haemorrhagic Stroke (Fatal or Non-fatal)	The percentage of patients with ischemic or haemorrhagic stroke (fatal or non-fatal)	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Transient Ischemic Attack	The percentage of patients with transient ischemic attack	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Systemic Embolism	The percentage of patients with systemic embolism	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Myocardial Infarction (Fatal or Non-fatal)	The percentage of patients with myocardial infarction (fatal or non-fatal)	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Other Major Adverse Cardiac Events	The percentage of patients with other major adverse cardiac events	Upto 15 weeks	No
Secondary	Frequency (Occurrence Rates) of Death	The percentage of patients with death	Upto 15 weeks	No
Secondary	Anticoagulation Effects Trough aPTT (Activated Partial Thromboplastin Time)	The blood coagulation parameter aPTT was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12.	Week 0,1,4 and 12	No
Secondary	Anticoagulation Effects Trough ECT (Ecarin Clotting Time)	The blood coagulation parameter ECT was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12.	Week 0,1,4 and 12	No
Secondary	Anticoagulation Effects Trough INR (International Normalised Ratio)	The blood coagulation parameter INR was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12.	Week 0,1,4 and 12	No
Secondary	Anticoagulation Effects Trough 11-dehydrothromboxane B2	Analysis based on concomitant use of aspirin compared to no aspirin users. 11-dehydrothromboxane B2 is measured in urine of patients.	Week 0 and 12	No
Secondary	Steady-state Pharmacokinetics of Total Dabigatran Trough Plasma Concentration		Week 1,4 and 12	No