Evaluating PN 400 (VIMOVO) in Reducing Gastric Ulcers Compared to Non-steroidal Antiinflammatory Drug (NSAID) Naproxen

6-Month, Phase 3, Randomized, Double-blind, Parallel-group, Controlled, Multi-center Study Evaluate Gastric Ulcer Incidence Following Administration of PN400 or Naproxen in Subjects Who Are at Risk for Developing NSAID-associated Ulcers

This study uses a randomized, double-blind, controlled design to demonstrate that PN400 (esomeprazole and naproxen) is more effective in reducing the occurrence of gastroduodenal ulcers, dyspepsia, and heartburn in subjects at risk for developing NSAID-associated gastric ulcers compared to naproxen alone.

Objectives:

Primary: To demonstrate that PN400 is effective in reducing the risk of gastric ulcers in subjects at risk for developing NSAID-associated gastric ulcers.

Secondary:

• To determine if PN400 is effective in reducing the risk of duodenal ulcers in subjects at risk for developing NSAID-associated ulcers
• To compare upper gastrointestinal symptoms in subjects treated with PN400 versus naproxen as measured by scores on the Severity of Dyspepsia Assessment (SODA) instrument and the Overall Treatment Evaluation - Dyspepsia (OTE-DP)
• To compare heartburn symptoms in subjects treated with PN400 versus naproxen
• To evaluate the safety and tolerability of PN400 and naproxen

Inclusion Criteria

A subject was eligible for inclusion in this study if all of the following criteria applied:

1. Male or non-pregnant, non-breastfeeding female subjects with a history of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis or other medical conditions expected to require daily NSAID therapy for at least 6 months, who were

   • 18-49 years of age and had a history of a documented, uncomplicated gastric or duodenal ulcer (a mucosal break of at least 3 mm in diameter with depth, without any concurrent bleeding, clot or perforation) within the past 5 years OR, who were
   • 50 years of age and older (These subjects did not require a history of a documented, uncomplicated gastric or duodenal ulcer within the past 5 years.)

2. Female subjects were eligible for participation in the study if they were of

   • non-childbearing potential (i.e., physiologically incapable of becoming pregnant);
   • childbearing potential, had a negative pregnancy test at Screening, and at least 1 of the following applied or was agreed to by the subject:
   • Female sterilization or sterilization of male partner
   • Hormonal contraception by oral route, implant, injectable, vaginal ring
   • Any intrauterine device with published data showing that the lowest expected failure rate is < 1% per year
   • Double barrier method (2 physical barriers or 1 physical barrier plus spermicide)
   • Any other method with published data showing that the lowest expected failure rate is < 1% per year

3. Each subject was required to understand and comply with study procedures required of a subject and was able and willing to provide written informed consent prior to any study procedures being performed.

Exclusion Criteria

A subject was not eligible for this study if any 1 or more of the following criteria applied:

1. History of hypersensitivity to esomeprazole or to another PPI
2. History of allergic reaction or intolerance to any NSAID (including aspirin) and/or a history of NSAID-induced symptoms of asthma, rhinitis, and/or nasal polyps
3. Participation in any study of an investigational treatment in the 4 weeks before Screening
4. Presence of uncontrolled acute or chronic medical illness, e.g., GI disorder, hypertension, diabetes, thyroid disorder, depression and/or infection that would have endangered a subject if they were to have participated in the study
5. GI disorder or surgery leading to impaired drug absorption
6. Evidence of uncontrolled, or unstable cardio- or cerebrovascular disorder, which in the investigator's opinion would have endangered a subject if they were to have participated in the study
7. Schizophrenia or bipolar disorder
8. Use of any excluded concomitant medication (see Section 9.4.8)
9. A recent history (in the past 3 months) suggestive of alcohol or drug abuse or dependence, including overuse/abuse of narcotics for management of pain
10. Serious blood coagulation disorder, including use of systemic anticoagulants
11. Positive test result for H. pylori at Screening
12. Screening endoscopy showing any gastric or duodenal ulcer at least 3 mm in diameter with depth
13. Screening laboratory alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 2 times the upper limit of normal
14. Estimated creatinine clearance < 30 ml/min
15. Other than noted specifically, any screening laboratory value that was clinically significant in the investigator's opinion and would have endangered a subject if they were to have participated in the study
16. History of malignancy, treated or untreated, within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin