Boehringer Ingelheim Planning to Initiate Two New Global Clinical Trials of Pradaxa® (dabigatran etexilate mesylate)

RIDGEFIELD, Conn., Nov. 19, 2013 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. plans to initiate two new global clinical trials of PRADAXA. One of the new trials, RE-DUAL PCI™ ("Randomized Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy Strategy with Warfarin in Patients with NVAF that have undergone PCI with Stenting"), is designed to evaluate the efficacy and safety of PRADAXA in patients with non-valvular atrial fibrillation (NVAF) who have undergone percutaneous coronary intervention (PCI), also known as angioplasty, with stent placement. The second of the new trials, RE-SPECT ESUS™ ("Randomized Evaluation in Secondary stroke Prevention Comparing the Thrombin inhibitor dabigatran etexilate versus ASA in Embolic Stroke of Undetermined Source"), is designed to evaluate the efficacy and safety of PRADAXA as a secondary stroke prevention therapy in patients who have suffered an embolic stroke of undetermined source (ESUS). Embolic strokes occur when a blood clot forms somewhere in the body and travels through the bloodstream to the brain.

Both trials would become part of the extensive RE-VOLUTION clinical trial program for PRADAXA, which includes 10 completed phase III clinical trials involving approximately 40,000 patients in more than 44 countries globally, and are planning to begin enrollment in 2014 and 2015, respectively.

"Despite current management options, many patients, including those who have already had a stroke and those with NVAF who are about to undergo PCI, continue to face a high stroke risk," said John Smith, M.D., Ph.D., senior vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim. "BI is committed to advancing innovation and research in cardiovascular disease. We are hopeful that the results of the trials will provide greater understanding of PRADAXA's potential to reduce stroke risk in these patient populations."

RE-DUAL PCI is planned to be run cooperatively with Harvard Clinical Research Institute (HCRI) and led by Christopher Cannon, M.D., cardiologist at Brigham and Women's Hospital in Boston and Professor of Medicine at Harvard Medical School. This event-driven trial will evaluate PRADAXA (150 mg or 110 mg twice daily) plus single antiplatelet therapy compared to the current standard of care which includes warfarin and two antiplatelet agents, to assess key outcomes of clinically relevant bleeding and thrombotic events (defined as the combined rate of death, myocardial infarction and stroke) following PCI. Research shows that patients with atrial fibrillation undergoing PCI with stent placement are at high risk of stroke and other major adverse cardiac events, which can be reduced by anticoagulation therapy. Currently, about one in every 20 patients undergoing PCI with stent placement requires anticoagulant therapy to reduce their risk of stroke due to either atrial fibrillation or another condition.

RE-SPECT ESUS is planned to be run by Professor Hans-Christoph Diener, Professor of Neurology and Chairman of the Department of Neurology, University of Essen, Germany. The trial plans to include approximately 6,000 patients who had an ESUS within three months prior to enrollment. The trial will evaluate two doses of PRADAXA compared to acetylsalicylic acid 100 mg once daily for secondary stroke prevention. Patients who are 75 years old or younger and who have normal kidney function will receive PRADAXA 150 mg twice daily. Patients older than 75 or who have reduced renal function will receive PRADAXA 110 mg twice daily. The treatment duration is planned to be six months to three years, with outcomes assessed up until 30 days after the end of treatment. According to the American Heart Association, approximately 795,000 Americans each year suffer a stroke, with nearly one in four patients having already suffered a prior stroke. It is estimated that up to 14 percent of people who have a stroke will have another within one year.

"PRADAXA was approved in the U.S. in 2010 to reduce the risk of stroke and systemic embolism in patients with NVAF, making it the first oral anticoagulant approved since warfarin was launched for this use more than 50 years ago," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim. "These planned new trials reflect our confidence in the future of PRADAXA and our belief in its potential to benefit different patient populations."

About Pradaxa^® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS 
PRADAXA is contraindicated in patients with:

• active pathological bleeding;
• known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA;
• mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS
Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

Risk of Bleeding

• PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
  
• Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment.
  
• A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial.  RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin.  Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.  P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran.  Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

• For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
• For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events.

• PRADAXA 150 mg resulted in higher rates of major GI bleeds and any GI bleeds compared to warfarin.
• In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
• Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions.
• These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer).  Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Please see full Prescribing Information including Boxed WARNING, and Medication Guide.

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About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim has a demonstrated commitment to corporate social responsibility. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about $19.1 billion (14.7 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

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PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

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