A Prospective, Open Label Study Evaluating Two Management Strategies on Gastrointestinal Symptoms in Patients Newly on Treatment With Pradaxa for the Prevention of Stroke and Systemic Embolism With Non-valvular Atrial Fibrillation

Study Overview
=================
Brief Summary
-----------------
This is a prospective and open label study that aims to enroll approximately 1200 patients with non-valvular atrial fibrillation (NVAF) not previously treated with Pradaxa® and free of gastrointestinal symptoms (GIS) for at least 2 weeks prior to enrolment. Approximately 125 sites in North America will be recruited. Patients who report GIS during the 3 month treatment period will be randomized to one of two management strategies, and data documenting the intensity and duration of the GIS will be collected.

Official Title
-----------------
A Prospective, Open Label Study Evaluating the Efficacy of Two Management Strategies (Pantoprazole 40 mg q.a.m. and Taking Pradaxa® With Food (Within 30 Minutes After a Meal) on Gastrointestinal Symptoms (GIS) in Patients Newly on Treatment With Pradaxa® 150 mg b.i.d., 110 mg b.i.d. or 75 mg b.i.d. for the Prevention of Stroke and Systemic Embolism in Patients With Non-valvular Atrial Fibrillation (NVAF)

Conditions
-----------------
Atrial Fibrillation

Intervention / Treatment
-----------------
* Drug: pantoprazole
* Drug: Pradaxa (dabigatran etexilate)
* Drug: Pradaxa, within 30 minutes after a meal
* Drug: Pradaxa (dabigatran etexilate)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Documented non-valvular atrial fibrillation (NVAF) for whom Pradaxa® (dabigatran etexilate) is indicated per the current local label, but who have not received treatment with Pradaxa® (dabigatran etexilate), or who have not been started on Pradaxa® (dabigatran etexilate) more than 7 days prior to potential enrolment in the study. NVAF may be documented by 12-lead electrocardiogram, rhythm strip, pacemaker/ implantable cardioverter defibrillator (ICD) electrograms or Holter monitoring Male and female patients, age greater than or equal to 18 years at entry Written, informed consent Exclusion criteria: History within 2 weeks of any of the following gastrointestinal (GI) disorders: heartburn, indigestion, gastritis, upper abdominal pain or discomfort, or gastroesophageal reflux requiring the use of proton pump inhibitors, histamine-2 receptor blockers or antacids. Patients with nausea and/or vomiting within the 2 weeks are not excluded if the symptoms were clearly associated with a self-limited acute or febrile illness. Short-term use of PPIs, as prophylaxis, in a hospital setting for the prevention of stress ulcers is acceptable. Calcium carbonate supplements for calcium replacement is not exclusionary (as long as these products are being used as calcium supplementation/replacement and are not being used to treat or relieve GIS.) GI bleeding within one year or any history of symptomatic or endoscopically documented gastroduodenal ulcer or diverticulitis, unless the cause has been permanently eliminated by medical therapy or by surgery(e.g., patients with peptic ulcer disease with endoscopically proven cure after therapy or lower GI bleeding due to diverticulosis cured by segmental colectomy are not excluded.) not applicable Contraindication to pantoprazole or other proton pump inhibitors, e.g. omeprazole, lansoprazole, rabeprazole, atnoprazole, esomeprazole Contraindication to Pradaxa® (dabigatran etexilate) or known hypersensitivity to Pradaxa® (dabigatran etexilate) or its excipients Hemorrhagic disorder, bleeding diathesis or active pathological bleeding Need for anticoagulant treatment for disorders other than atrial fibrillation Current treatment with rifampin Creatinine clearance <15ml/min (in Canada, <30ml/min), or patients on renal replacement therapy (dialysis) Pre-menopausal women (last menstruation less than or equal to 1 year prior to informed consent) who: are nursing or pregnant, or are of child bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study. Acceptable methods of birth control include abstinence, tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral implantable or injectable contraceptives, double barrier method and vasectomized partner. Patients who have received an investigational drug in the past 30 days or are participating in another drug study Patients considered unreliable by the investigator concerning the requirements for follow-up during the study Any condition the investigator believes would not allow safe participation in the study Contraindication in patients with mechanical heart valves. The use of Pradaxa in the setting of other forms of valvular heart disease, including the presence of a bio-prosthetic valve, is not recommended.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Pradaxa (dabigaran etexilate)<br>Patients with non valvular atrial fibrillation for whom Pradaxa is indicated in accordance with the current local label, not previously treated with Pradaxa, will be provided 3 months of treatment for the prevention of stroke and systemic embolism. Patients who report gastrointestinal symptoms (GIS) will be randomized to one of two management strategies, and data documenting the intensity and duration of the GIS will be collected. | Drug: Pradaxa (dabigatran etexilate)<br>* 150 mg or 75 mg b.i.d. (150 mg or 110 mg b.i.d. in Canada)<br>|
| Active Comparator: Pradaxa and pantoprazole<br>Patients that develop gastrointestinal symptoms (GIS) will be randomized 1:1 to either pantoprazole 40 mg q.a.m., p.o., or taking Pradaxa (dabigatran etexilate) within 30 minutes after a meal | Drug: pantoprazole<br>* 40 mg q.a.m, p.o.<br>Drug: Pradaxa (dabigatran etexilate)<br>* 150 mg or 75 mg b.i.d. (150 mg or 110 mg b.i.d. in Canada)<br>|
| Active Comparator: Pradaxa, 30 minutes after a meal<br>Patients that develop gastrointestinal symptoms (GIS) will be randomized 1:1 to either pantoprazole 40 mg q.a.m., p.o., or taking Pradaxa (dabigatran etexilate) within 30 minutes after a meal | Drug: Pradaxa, within 30 minutes after a meal<br>* Patients randomized to this intervention would be instructed to take their dabigatran 30 minutes after a meal<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Complete Effectiveness of Initial GIS Management Strategy | The percentage of patients experiencing complete relief of gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) vs. administration of Pradaxa® (dabigatran etexilate) within 30 minutes after a meal at 4 weeks. Complete effectiveness is defined as at the time of evaluation, both primary GIS and secondary GIS are all resolved. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Partial Effectiveness of Initial GIS Management Strategies | The percentage of patients experiencing partial relief of gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) and patients taking Pradaxa® (dabigatran etexilate) within 30 minutes after a meal at 4 weeks. Partial effectiveness is defined as at the time of evaluation, either primary GIS is improved; or primary GIS is resolved, but there were still un-resolved secondary GIS. | Week 4 | 
| Combined Rate of Complete or Partial Effectiveness of Initial GIS Management Strategies | The percentage of patients experiencing complete or partial effectiveness of gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) vs. administration of Pradaxa ® (dabigatran etexilate) within 30 minutes after a meal at 4 weeks. Complete effectiveness is defined as at the time of evaluation, both primary GIS and secondary GIS are all resolved. Partial effectiveness is defined as at the time of evaluation, either primary GIS is improved; or primary GIS is resolved, but there were still un-resolved secondary GIS. | Week 4 | 
| Rate of Complete Effectiveness of Combined GIS Management Strategies | The percentage of patients experiencing complete relief of combined gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) vs. administration of Pradaxa ® (dabigatran etexilate) within 30 minutes after a meal. Complete effectiveness is defined as at the time of evaluation, both primary GIS and secondary GIS are all resolved. | Week 8 | 
| Rate of Partial Effectiveness of Combined GIS Management Strategies | The percentage of patients experiencing partial relief of gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) vs. administration of Pradaxa ® (dabigatran etexilate) within 30 minutes after a meal at 4 weeks. Partial effectiveness is defined as at the time of evaluation, either primary GIS is improved; or primary GIS is resolved, but there were still un-resolved secondary GIS. | Week 8 | 
| Combined Rate of Complete or Partial Effectiveness of Combined GIS Management Strategies | The percentage of patients experiencing combined of complete or partial relief of gastrointestinal symptoms (GIS) when taking pantoprazole 40 mg once daily in the morning (q.a.m.) vs. administration of Pradaxa ® (dabigatran etexilate) within 30 minutes after a meal. Complete effectiveness is defined as at the time of evaluation, both primary GIS and secondary GIS are all resolved. Partial effectiveness is defined as at the time of evaluation, either primary GIS is improved; or primary GIS is resolved, but there were still un-resolved secondary GIS. | Week 8 | 
| Rates of Complete Effectiveness of GIS at Each Visit. | The percentage of patients experiencing complete effectiveness of gastrointestinal symptoms (GIS) at each visit by management strategy. Evaluation of GIS was based on Last observation carried forward (LOCF) data up to the last observed time or up to adding the second management strategy. | Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 & Week 8 | 
| Rates of Partial Effectiveness of GIS at Each Visit. | The percentage of patients experiencing partial effectiveness of gastrointestinal symptoms (GIS) at each visit by management strategy. Evaluation of GIS was based on Last observation carried forward (LOCF) data up to the last observed time or up to adding the second management strategy. | Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 & Week 8 | 
| Rates of Complete or Partial Effectiveness of GIS at Each Visit. | The percentage of patients experiencing complete or partial effectiveness of gastrointestinal symptoms (GIS) at each visit by management strategy. Evaluation of GIS was based on Last observation carried forward (LOCF) data up to the last observed time or up to adding the second management strategy. | Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 & Week 8 | 
| Time Between Symptom Onset and First Observed Complete or Partial Effectiveness and Between Symptom Onset and Last Observed Symptom | Time between symptom onset and first observed complete or partial effectiveness and between symptom onset and last observed symptom by management strategy. | Week 8 |