PETRO Stroke Prevention in Patients With AF by Treatment With Dabigatran, With and Without Aspirin, Compared to Warfarin

Dose Exploration in Patients With Atrial Fibrillation

The purpose of this trial is to evaluate the safety of different doses of BIBR 1048, alone or in combination with acetylsalicylic acid (ASA), as determined by the rates of bleeding and other adverse events.

A secondary objective of this trial is to evaluate the anticoagulant effect of different doses of BIBR 1048, based on the reduction of plasma concentrations of D-dimer, a laboratory marker for activated coagulation in patients with atrial fibrillation (AF), and to correlate bleeding and other events with pharmacokinetic (PK) and pharmacodynamic (PD) data.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: dabigatran without ASA; Drug: dabigatran with ASA; Drug: warfarin

• Study Type: Interventional
• Enrollment (Actual): 502
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • 1160.20.45010
  • Aarhus C, Denmark
    • 1160.20.45005 Aarhus Sygehus
  • Brædstrup, Denmark
    • 1160.20.45007 Medicinsk afdeling
  • Esbjerg, Denmark
    • 1160.20.45011 Medicinsk afd.
  • Frederikssund, Denmark
    • 1160.20.45012 Afdeling B3
  • Helsingør, Denmark
    • 1160.20.45003 Forskningscentret plan 3
  • Herlev, Denmark
    • 1160.20.45004 Herlev Hospital
  • Holbæk, Denmark
    • 1160.20.45009 Medicinsk amb. B8
  • Hvidovre, Denmark
    • 1160.20.45002 Kardiologisk afdeling
  • Køge, Denmark
    • 1160.20.45014 Hjertemedicinsk afd.
  • Odense, Denmark
    • 1160.20.45001 Kardiologisk Laboratorium
  • Roskilde, Denmark
    • 1160.20.45013 Kardiologisk afd.
  • Svendborg, Denmark
    • 1160.20.45006 Medicinsk afdeling
• Sweden
  • Eskilstuna, Sweden
    • 1160.20.46013 HIA, Mälarsjukhuset
  • Falun, Sweden
    • 1160.20.46007 Falu Lasarett
  • Jönköping, Sweden
    • 1160.20.46005 Ryhovs Länssjukhus
  • Kalmar, Sweden
    • 1160.20.46010 Länssjukhuset Kalmar
  • Malmö, Sweden
    • 1160.20.46009 Universitetssjukhuset MAS
  • Norrköping, Sweden
    • 1160.20.46008 Vrinnevisjukhuset
  • Stockholm, Sweden
    • 1160.20.46002 Södersjukhuset
  • Stockholm, Sweden
    • 1160.20.46011 Arytmienheten, Med klin
  • Umeå, Sweden
    • 1160.20.46006 Norrlands Universitetssjukhus
  • Västerås, Sweden
    • 1160.20.46003 Centrallasarettet
  • Örebro, Sweden
    • 1160.20.46004 Universitetssjukhuset
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States
      • 1160.20.10010
  • California
    • La Mesa, California, United States
      • 1160.20.10003 La Mesa Cardiac
  • Florida
    • Pensacola, Florida, United States
      • 1160.20.10006 The Ford Research Institute, PA
    • Port Charlotte, Florida, United States
      • 1160.20.10004
    • St. Petersburg, Florida, United States
      • 1160.20.10002
  • Maryland
    • Baltimore, Maryland, United States
      • 1160.20.10015
    • Westminister, Maryland, United States
      • 1160.20.10008
  • Massachusetts
    • Pittsfield, Massachusetts, United States
      • 1160.20.10012
  • Michigan
    • Troy, Michigan, United States
      • 1160.20.10007
  • New York
    • Hawthorne, New York, United States
      • 1160.20.10014
    • New Hyde Park, New York, United States
      • 1160.20.10013
  • North Carolina
    • North Durham, North Carolina, United States
      • 1160.20.10009
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 1160.20.10001
  • Tennessee
    • Germantown, Tennessee, United States
      • 1160.20.10005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

1. Non-rheumatic atrial fibrillation.
2. Coronary artery disease (CAD), documented by previous myocard infarction (MI), angina, positive stress test, previous coronary intervention or bypass surgery, or atherosclerotic lesion(s) diagnosed by coronary angiography) is only considered as one of several possible qualifying risk factors. After recruitment of ca. 30%, a protocol amendment 4 was issued so that CAD was only considered as one of several possible qualifying risk factors, 2. see (3 f) below.

3. An additional risk factor for stroke, i.e. one or more of the following conditions/events:

   1. hypertension (defined as systolic bloodpressure (SBP) > 140 mmHg and/or diastolic bloodpressure (DBP) > 90 mm Hg) requiring antihypertensive medical treatment.
   2. diabetes mellitus (type I and II).
   3. symptomatic heart failure or left ventricular dysfunction (ejection fraction (EF) < 40%).
   4. a previous ischemic stroke or transient ischemic attack.
   5. age greater than 75 years.
   6. history of coronary artery disease (by amendment 4)
4. Treatment with warfarin or other vitamin K dependent anticoagulants for at least 8 weeks prior to inclusion. International normalised ratio (INR) should be within therapeutic range (i.e. INR 2.0 - 3.0) at visit 1 otherwise the visit should be rescheduled.
5. Age > = 18 years at entry.
6. Written, informed consent.

Exclusion criteria

1. Valvular heart disease.
2. Planned cardioversion.
3. Recent (=< 1 month) myocardial infarction, stroke or transient ischemic attack (TIA), or patients who have received a coronary stent within the last 6 months.
4. Intolerance or contraindications to acetylsalicylic acid (ASA).
5. Any contraindication to anticoagulant therapy.
6. Major bleeding within the last 6 months (other than gastrointestinal (GI) hemorrhage).
7. Severe renal impairment (estimated glomerular filtration rate (GFR) =< 30 mL/min).
8. Uncontrolled hypertension (SBP > 180 mmHg and/or DBP > 100 mmHg).
9. Abnormal liver function as defined by aspartat-aminotransferase (AST), alanin-aminotransferase (ALT), serum bilirubin or alkaline phosphatase (AP) above the reference range, or history of liver disease.
10. Women who are pregnant or of childbearing potential who refuses to use a medically acceptable form of contraception throughout the study.
11. Patients who have received an investigational drug within the last 30 days.
12. Patients scheduled for major surgery or invasive procedures which may cause bleeding, or those who have had major surgery or percutaneous coronary intervention (PCI) within 6 weeks.
13. Patients considered unreliable by the investigator.
14. Another indication for anticoagulant treatment.
15. Patients suffering from anemia.
16. Patients suffering from thrombocytopenia.
17. Any other condition which, in the discretion of the investigator, would not allow safe participation in the study.
18. Concomitant treatment with antiplatelet agents other than ASA.
19. Recent malignancy or radiation therapy (=< 6 month).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dabigatran 50 mg twice daily (bid); Dabigatran: one capsule in the morning and 1 capsule in the evening. Twice daily (bis in die = bid).	Drug: dabigatran without ASA; dose comparison
Experimental: dabigatran 50 mg bid + 81 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. Acetylsalicylic acid (ASA) once daily (quaque dies = qd) in the morning.	Drug: dabigatran with ASA; dose comparison in combination
Experimental: dabigatran 50 mg bid + 325 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning	Drug: dabigatran with ASA; dose comparison in combination
Experimental: dabigatran 150 mg bid; Dabigatran: one capsule in the morning and 1 capsule in the evening	Drug: dabigatran without ASA; dose comparison
Experimental: dabigatran 150 mg bid + 81 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning	Drug: dabigatran with ASA; dose comparison in combination
Experimental: dabigatran 150 mg bid + 325 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning	Drug: dabigatran with ASA; dose comparison in combination
Experimental: dabigatran 300 mg bid; Dabigatran: one capsule in the morning and 1 capsule in the evening	Drug: dabigatran without ASA; dose comparison
Experimental: dabigatran 300 mg bid + 81 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning	Drug: dabigatran with ASA; dose comparison in combination
Experimental: dabigatran 300 mg bid + 325 mg ASA qd; Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning	Drug: dabigatran with ASA; dose comparison in combination
Active Comparator: warfarin; once daily, dosed to target International Normalised Ratio (INR) 2.0 to 3.0	Drug: warfarin; comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Fatal or Life-threatening Major Bleeding Events	Retroperitoneal, intracranial, intraocular, or intraspinal bleeding, or requiring surgical treatment, or leading to a transfusion of 2 units or more, or leading to a fall in hemoglobin of 20g/L or more	12 weeks
Number of Participants With Minor/Relevant Bleeding Events	Haematuria, rectal bleeding, gingival bleeding, skin hematoma of 25cm^2 or more, nose bleed of more than 5 minutes duration, bleeding leading to a hospitalization, leading to a transfusion of less than 2 units or any other clinically relevant bleeding	12 weeks
Number of Participants With Minor/Nuisance Bleeding Events	All bleeding events not fulfilling one of the criteria for major bleeding event or minor/relevant bleeding events.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Thromboembolic Events: Composite Endpoint	Combination of ischemic stroke (fatal or non fatal), transient ischemic attack, systemic thromboembolism, myocardial infarction (fatal or non fatal), other major adverse cardiac event and all cause mortality	12 weeks
Number of Participants With Thromboembolic Events: Ischemic Stroke	Occurence of an ischemic stroke (fatal or non-fatal)	12 weeks
Thromboembolic Events: Number of Participants With Transient Ischemic Attack	Occurence of a transient ischemic attack	12 weeks
Thromboembolic Events: Number of Participants With Systemic Thromboembolism	Occurence of a systemic thromboembolism	12 weeks
Thromboembolic Events: Number of Participants With Myocardial Infarction	Occurence of a myocardial infarction	12 weeks
Thromboembolic Events: Number of Participants With Other Major Cardiac Events	Occurence of other major adverse cardiac events	12 weeks
Thromboembolic Events: Number of Participants Who Died	Occurence of death by all causes	12 weeks
D-dimer: Difference From Baseline	Difference in D-dimer from baseline to last available value	baseline and 12 weeks
Soluble Fibrin: Difference From Baseline	Difference from baseline to visit 7	baseline and 12 weeks
11-dehydrothromboxane B2 (TXB2): Difference From Baseline	Difference from baseline to visit 7	baseline and 12 weeks
Ecarin Clotting Time (ECT): Difference From Baseline		baseline and 12 weeks
Activated Partial Thromboplastin Time (aPTT): Difference From Baseline		baseline and 12 weeks
Trough Plasma Concentration of Dabigatran (BIBR 953)	The values of the trough plasma concentration of dabigatran (BIBR 953) are the by-patient geometric means of week 1, 4 and 12.	12 weeks
Number of Participants With Increase of Aspartat-Aminotransferase (AST) to >2*Baseline	Increase of AST to more than two times the baseline value	12 weeks
Number of Participants With Increase of Alkaline Phosphatase (AP) to >2*Baseline	Increase of AP to more than two times the baseline value	12 weeks
Number of Participants With Increase of Bilirubin to >2*Baseline	Increase of Bilirubin to more than two times the baseline value	12 weeks
Number of Participants With Increase of Alanine-Aminotransferase (ALT) to >2*Baseline	Number of Participants with Increase of ALT to more than two times the baseline value	12 weeks
Severity of Adverse Events	Total number of patients with any adverse event of worst intensity 'mild', 'moderate' and 'severe'.	12 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: September 1, 2003
• Primary Completion (Actual): November 1, 2004

Study Registration Dates

• First Submitted: October 22, 2010
• First Submitted That Met QC Criteria: October 22, 2010
• First Posted (Estimate): October 25, 2010

Study Record Updates

• Last Update Posted (Estimate): May 5, 2014
• Last Update Submitted That Met QC Criteria: April 22, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran; Warfarin
• Other Study ID Numbers: 1160.20; PETRO trial (Other Identifier: OTHER)