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

This study has been completed.
Sponsor:
Information provided by:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01136408
First received: May 19, 2010
Last updated: February 18, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation
Drug: Dabigatran etexilate
Drug: Warfarin
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Frequency (Occurrence Rates) of Major Bleeding Event [ Time Frame: upto 15 weeks ] [ Designated as safety issue: Yes ]

    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

  • Frequency (Occurrence Rates) of Clinically Relevant Bleeding Event [ Time Frame: upto 15 weeks ] [ Designated as safety issue: Yes ]

    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

  • Frequency (Occurrence Rates) of Nuisance Bleeding Event [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: Yes ]

    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

  • Incidence and Severity of Adverse Events [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    Intensity of event is categorised as mild, moderate and severe.

  • Discontinuation of the Study Drug Due to Adverse Events [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    Discontinuation of the study drug due to adverse events.

  • Changes in Laboratory Test Values [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    The number of patients with ALT, AST, alkaline phosphatase, or bilirubin exceeded the upper limit of normal (ULN) range


Secondary Outcome Measures:
  • Frequency (Occurrence Rates) of a Composite Clinical Endpoint. [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    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)

  • Frequency (Occurrence Rates) of Ischemic or Haemorrhagic Stroke (Fatal or Non-fatal) [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with ischemic or haemorrhagic stroke (fatal or non-fatal)

  • Frequency (Occurrence Rates) of Transient Ischemic Attack [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with transient ischemic attack

  • Frequency (Occurrence Rates) of Systemic Embolism [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with systemic embolism

  • Frequency (Occurrence Rates) of Myocardial Infarction (Fatal or Non-fatal) [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with myocardial infarction (fatal or non-fatal)

  • Frequency (Occurrence Rates) of Other Major Adverse Cardiac Events [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with other major adverse cardiac events

  • Frequency (Occurrence Rates) of Death [ Time Frame: Upto 15 weeks ] [ Designated as safety issue: No ]
    The percentage of patients with death

  • Anticoagulation Effects Trough aPTT (Activated Partial Thromboplastin Time) [ Time Frame: Week 0,1,4 and 12 ] [ Designated as safety issue: No ]
    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.

  • Anticoagulation Effects Trough ECT (Ecarin Clotting Time) [ Time Frame: Week 0,1,4 and 12 ] [ Designated as safety issue: No ]
    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.

  • Anticoagulation Effects Trough INR (International Normalised Ratio) [ Time Frame: Week 0,1,4 and 12 ] [ Designated as safety issue: No ]
    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.

  • Anticoagulation Effects Trough 11-dehydrothromboxane B2 [ Time Frame: Week 0 and 12 ] [ Designated as safety issue: No ]
    Analysis based on concomitant use of aspirin compared to no aspirin users. 11-dehydrothromboxane B2 is measured in urine of patients.

  • Steady-state Pharmacokinetics of Total Dabigatran Trough Plasma Concentration [ Time Frame: Week 1,4 and 12 ] [ Designated as safety issue: No ]

Enrollment: 174
Study Start Date: November 2005
Primary Completion Date: September 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dabigatran etexilate 220 mg daily
Dabigatran etexilate 110 mg capsule, twice a day, oral administration
Drug: Dabigatran etexilate
Dabigatran etexilate 110 mg capsule, twice a day, oral administration
Experimental: Dabigatran etexilate 300 mg daily
Dabigatran etexilate 150 mg capsule, twice a day, oral administration
Drug: Dabigatran etexilate
Dabigatran etexilate 150 mg capsule, twice a day, oral administration
Active Comparator: Warfarin
Dose-adjusted warfarin based on target INR values
Drug: Warfarin
Dose-adjusted warfarin based on target INR values

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01136408

Locations
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
1160.49.012 Boehringer Ingelheim Investigational Site
Nagoya, Aichi, Japan
1160.49.011 Boehringer Ingelheim Investigational Site
Nagoya, Aichi, Japan
1160.49.004 Boehringer Ingelheim Investigational Site
Naka-gun, Ibaragi, Japan
1160.49.023 Boehringer Ingelheim Investigational Site
Okayama, Okayama, Japan
1160.49.022 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
1160.49.019 Boehringer Ingelheim Investigational Site
Osaka, Osaka, Japan
1160.49.018 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
1160.49.015 Boehringer Ingelheim Investigational Site
Suita, Osaka, Japan
1160.49.014 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, Japan
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01136408     History of Changes
Other Study ID Numbers: 1160.49
Study First Received: May 19, 2010
Results First Received: November 18, 2010
Last Updated: February 18, 2014
Health Authority: Japan: Ministry of Health, Labor and Welfare

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014