Gastric Ulcer
Conditions
Keywords
PA32540 is proposed for the secondary prevention of cardio- and cerebrovascular events in patients at risk for developing aspirin-associated gastric ulcers.
Brief summary
Primary: To demonstrate that PA32540 causes fewer gastric ulcers in subjects at risk for developing aspirin-associated gastric ulcers compared to enteric coated (EC) aspirin 325 mg.
Interventions
DRUGPA32540
PA32540 tablets contain 325 mg enteric coated (EC) aspirin and 40 mg immediate-release omeprazole
DRUGEC-Aspirin 325 mg
The comparator aspirin 325 mg enteric coated tablet (PA32540 minus omeprazole)
Sponsors
POZEN
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. A. Male or non-pregnant, non-breastfeeding females who have been on daily aspirin 325 mg for at least three months and who are expected to use daily aspirin 325 mg for at least six months (Daily is defined as at least 5 days per week): AND, who are * 55 years of age and older; or * 18 - 54 years of age and have a history of a documented gastric or duodenal ulcer within the past five years. 2. A. Aspirin use should be for the secondary prevention of cardiovascular or cerebrovascular events as defined as follows: Have been diagnosed with or have had a history of * MI (myocardial infarction that has been confirmed or suspected) * Ischemic stroke * TIA (transient ischemic attack) Or have established, clinically significant coronary and other atherosclerotic vascular disease (meaning at high risk for surgical intervention or for MI, TIA, stroke, if left untreated), including: * Angina (stable or unstable) * Peripheral arterial disease * Atherosclerotic aortic disease * Carotid artery disease Or have had * CABG (coronary artery bypass graft) * PCI (percutaneous coronary intervention with or without stent) * Carotid endarterectomy 3. A. If female, subjects are eligible if they are of 1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or, 2. childbearing potential, have a negative pregnancy test at screening, and at least one of the following applies or is agreed to by the subject: * Female sterilization or sterilization of male partner * Hormonal contraception by oral route, implant, injectable, vaginal ring * Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 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 less than 1% per year 4. Able to understand and comply with study procedures required and able and willing to provide written informed consent prior to any study procedures being performed
Exclusion criteria
1. Baseline endoscopy showing any gastric, esophageal or duodenal ulcer at least 3 mm in diameter with depth 2. Positive test result for H. pylori at screening 3A. Have had a revascularization procedure (i.e., Coronary Artery Bypass Graft, Percutaneous Transluminal Coronary Angioplasty, or carotid endarterectomy) less than six months prior to screening 4\. Unstable hypertension as judged by the Investigator 5. Uncontrolled diabetes mellitus as judged by the Investigator 6. Unstable cardio- or cerebrovascular disease such that it would endanger the subject if they participated in the trial 7. Clinically significant valvular disease 8. Congestive heart failure or other cardiovascular symptoms according to New York Heart Association (NYHA) Functional Classification III or IV (Appendix 3) 9. History of hypersensitivity to omeprazole or to another proton pump inhibitor 10. History of allergic reaction or intolerance to aspirin and/or a history of aspirin-induced symptoms of asthma, rhinitis, and/or nasal polyps 11. History of serious UGI event, such as bleeding, perforation, or obstruction 12. Gastrointestinal disorder or surgery leading to impaired drug absorption 13. Presence of chronic or uncontrolled acute medical illness, e.g. gastrointestinal disorder (esophageal stricture, severe esophagitis, long-segment Barrett's esophagus, signs and symptoms of gastric outlet obstruction), thyroid disorder and/or infection that would endanger a subject if they were to participate in the study 14. Schizophrenia, uncontrolled bipolar disorder, or severe depression 15. History of alcoholism or drug addiction within a year prior to enrollment in the study 16. Severe hepatic dysfunction (i.e. cirrhosis or portal hypertension) 17. Blood coagulation disorder, including use of systemic anticoagulants such as warfarin or other vitamin K antagonists 18. Any condition that, in the opinion of the Investigator, may either put the subject at risk or influence the results of the study 19. Use of any excluded concomitant medication (see Section 9.2) 20. Screening laboratory ALT or AST value \> two times the upper limit of normal 21A. History of renal insufficiency 22. Other than noted specifically, any screening laboratory value that is clinically significant in the Investigator's opinion and would endanger a subject if the subject was to participate in the study 23. Use of an investigational treatment in the 4 weeks before screening 24. History of malignancy, treated or untreated, within the past five years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin 25. Previous participation in another PA32540 clinical research study 26. Subjects, who are employees of the research facility, immediately related to the Principal Investigator, or are in some way under the supervision of the Principal Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Gastric Ulcer Confirmed by Endoscopy | 6 months | The primary efficacy endpoint was the number of subjects with gastric ulcers at any time throughout 6 months of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter (measured by close application of open endoscopic biopsy forceps) with unequivocal crater depth. A subject is considered to have completed the study if all scheduled assessments up through the 6 month visit have been performed or if the endpoint of gastric ulcer confirmed by endoscopy has been reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Gastric and/or Duodenal Ulcers | 6 months | The Number of Participants with Gastric and/or Duodenal Ulcers throughout 6 months of treatment. |
| The Number of Subjects With Treatment Success | 6 months | Those Subjects Without Gastric Ulcers and Without Upper Gastrointestinal (UGI) Adverse Events leading to discontinuation. |
| The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events | 6 months | The Number of Participants Discontinuing from the Study Due to non-steroidal anti-inflammatory drug (NSAID)-Associated Upper GI Adverse Events during the treatment period |
| The Number of Participants With Heartburn Resolution at 6 Months, i.e. no Heartburn Symptoms During the Last 7 Days Prior to the Visit | 6 months | Subjects were asked whether heartburn symptoms within the 7 days prior to the visit were: * none: no symptoms * mild: awareness of symptom, but easily tolerated * moderate: discomforting symptom sufficient to cause interference with normal activities (including sleep) * severe: incapacitating symptom, with inability to perform normal activities (including sleep) Heartburn was defined as a burning feeling rising from the stomach or lower part of the chest towards the neck. |
Countries
United States
Participant flow
Recruitment details
A multi-center US study in which 75 sites recruited subjects between October 2009 and July 2011
Pre-assignment details
Screening for eligibility and wash-out of restricted medications
Participants by arm
| Arm | Count |
|---|---|
| PA32540 PA32540 tablets contain 325 mg enteric coated (EC) aspirin and 40 mg immediate-release omeprazole dosed once daily (QD) | 259 |
| EC-Aspirin 325 mg EC-Aspirin 325 mg enteric coated tablet (PA32540 minus omeprazole) dosed once daily (QD) | 260 |
| Total | 519 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 26 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Misc | 19 | 18 |
| Overall Study | Withdrawal by Subject | 16 | 14 |
Baseline characteristics
| Characteristic | PA32540 | EC-Aspirin 325 mg | Total |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 7.8 | 65.6 years STANDARD_DEVIATION 7.2 | 65.9 years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 72 Participants | 76 Participants | 148 Participants |
| Sex: Female, Male Male | 187 Participants | 184 Participants | 371 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 175 / 257 | 209 / 259 |
| serious Total, serious adverse events | 23 / 257 | 17 / 259 |
Outcome results
Primary
Number of Participants With Gastric Ulcer Confirmed by Endoscopy
The primary efficacy endpoint was the number of subjects with gastric ulcers at any time throughout 6 months of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter (measured by close application of open endoscopic biopsy forceps) with unequivocal crater depth. A subject is considered to have completed the study if all scheduled assessments up through the 6 month visit have been performed or if the endpoint of gastric ulcer confirmed by endoscopy has been reached.
Time frame: 6 months
Population: Intent to Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA32540 | Number of Participants With Gastric Ulcer Confirmed by Endoscopy | 7 participants |
| EC-Aspirin 325 mg | Number of Participants With Gastric Ulcer Confirmed by Endoscopy | 22 participants |
Comparison: The primary efficacy endpoint was the proportion of subjects with gastric ulcers throughout 6 months of treatment. The primary endpoint was analyzed with the CMH test stratified by NSAID use (COX-2/Other NSAID/No) at randomization. A sample size of 250 subjects/treatment would provide 86% power to detect the difference of 8% between EC aspirin 325 mg (13%) and PA32540 (5%) with a 2-sided significance of 5%; and, provides adequate power to test the key secondary endpoints in sequential order.p-value: 0.00595% CI: [1.1, 5.5]Cochran-Mantel-Haenszel
Secondary
The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events
The Number of Participants Discontinuing from the Study Due to non-steroidal anti-inflammatory drug (NSAID)-Associated Upper GI Adverse Events during the treatment period
Time frame: 6 months
Population: Intent to Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA32540 | The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events | 2 participants |
| EC-Aspirin 325 mg | The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events | 21 participants |
Comparison: The cumulative proportion of subjects discontinuing from the study due to NSAID-associated upper GI adverse events was analyzed using the CMH test stratified by NSAID use=COX-2, other NSAID, or NSAID use=NO at randomization.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
The Number of Participants With Gastric and/or Duodenal Ulcers
The Number of Participants with Gastric and/or Duodenal Ulcers throughout 6 months of treatment.
Time frame: 6 months
Population: Intent to Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA32540 | The Number of Participants With Gastric and/or Duodenal Ulcers | 7 participants |
| EC-Aspirin 325 mg | The Number of Participants With Gastric and/or Duodenal Ulcers | 30 participants |
Comparison: The cumulative proportion of subjects developing gastric ulcers and/or duodenal ulcers at 6 months was analyzed using the CMH test stratified by NSAID use=COX-2, other NSAID, or NSAID use=NO at randomization.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
The Number of Participants With Heartburn Resolution at 6 Months, i.e. no Heartburn Symptoms During the Last 7 Days Prior to the Visit
Subjects were asked whether heartburn symptoms within the 7 days prior to the visit were: * none: no symptoms * mild: awareness of symptom, but easily tolerated * moderate: discomforting symptom sufficient to cause interference with normal activities (including sleep) * severe: incapacitating symptom, with inability to perform normal activities (including sleep) Heartburn was defined as a burning feeling rising from the stomach or lower part of the chest towards the neck.
Time frame: 6 months
Population: Intent to Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA32540 | The Number of Participants With Heartburn Resolution at 6 Months, i.e. no Heartburn Symptoms During the Last 7 Days Prior to the Visit | 200 participants |
| EC-Aspirin 325 mg | The Number of Participants With Heartburn Resolution at 6 Months, i.e. no Heartburn Symptoms During the Last 7 Days Prior to the Visit | 152 participants |
Comparison: The proportion of subjects who had no heartburn at 6 months (regardless of the presence or absence of heartburn at baseline) was analyzed using the CMH test stratified by NSAID use=COX-2, other NSAID, or NSAID use=NO at randomization.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
The Number of Subjects With Treatment Success
Those Subjects Without Gastric Ulcers and Without Upper Gastrointestinal (UGI) Adverse Events leading to discontinuation.
Time frame: 6 months
Population: Intent to Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA32540 | The Number of Subjects With Treatment Success | 250 participants |
| EC-Aspirin 325 mg | The Number of Subjects With Treatment Success | 217 participants |
Comparison: The cumulative proportion of subjects with Treatment Success was analyzed using the CMH test stratified by NSAID use=COX-2, other NSAID, or NSAID use=NO at randomization.p-value: <0.001Cochran-Mantel-Haenszel