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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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PN400 | Experimental | Naproxen 500 mg/Immediate-Release Esomeprazole 20 mg dosed twice daily |
|
| Naproxen | Active Comparator | Naproxen 500 mg dosed twice daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PN400 (VIMOVO) | Drug | PN400 tablets (Naproxen 500 mg and Esomeprazole 20 mg) twice daily (bid) taken orally. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Participants With Pre-Specified NSAID-Associated Upper GI Adverse Events or Duodenal Ulcers | The Number of Participants with Pre-Specified non-steroidal antiinflammatory drug (NSAID)-Associated Upper Gastrointestinal (UGI) Adverse Events or Duodenal Ulcers after 6 months of treatment. Pre-specified UGI adverse events typically associated with NSAID use include dyspepsia, abdominal pain, gastritis, erosive esophagitis, duodenitis, abdominal discomfort |
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Inclusion Criteria
A subject was eligible for inclusion in this study if all of the following criteria applied:
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
Female subjects were eligible for participation in the study if they were of
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:
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| Name | Affiliation | Role |
|---|---|---|
| Everardus Orlemans, PhD | POZEN | Study Chair |
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Screening for eligibility and wash-out of restricted medications
A multi-center US study in which 70 sites recruited subjects between September 2007 and September 2008
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| ID | Title | Description |
|---|---|---|
| FG000 | PN400 (VIMOVO) | Naproxen 500 mg/Immediate-Release Esomeprazole 20 mg dosed twice daily (bid) |
| FG001 | Naproxen | Naproxen 500 mg dosed twice daily (bid) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | PN400 (VIMOVO) | Naproxen 500 mg/Immediate-Release Esomeprazole 20 mg dosed twice daily (bid) |
| BG001 | Naproxen | Naproxen 500 mg dosed twice daily (bid) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Intent to Treat (ITT) Population | Posted | Number | Participants | 6 months |
|
Randomization through 6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PN400 (VIMOVO) | Naproxen 500 mg/Immediate-Release Esomeprazole 20 mg dosed twice daily (bid) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial flutter | Cardiac disorders | MedDRA (10.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspepsia | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Clinical Research | POZEN | 919-913-1030 | eorlemans@pozen.com |
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| ID | Term |
|---|---|
| D013276 | Stomach Ulcer |
| ID | Term |
|---|---|
| D010437 | Peptic Ulcer |
| D004378 | Duodenal Diseases |
| D007410 | Intestinal Diseases |
| D005767 | Gastrointestinal Diseases |
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| ID | Term |
|---|---|
| D009288 | Naproxen |
| ID | Term |
|---|---|
| D009280 | Naphthaleneacetic Acids |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| Naproxen | Drug | Naproxen 500 mg dosed twice daily (bid) orally |
|
|
| 6 months |
| The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events or to Duodenal Ulcer | The Number of Participants Discontinuing from the Study Due to non-steroidal antiinflammatory drug (NSAID)-Associated Upper GI Adverse Events or to Duodenal Ulcer during the treatment period | 6 Months |
| The Number of Participants Developing Duodenal Ulcers Throughout 6 Months of Treatment | The Number of Participants Developing Duodenal Ulcers at any time during the 6 Months of the treatment period | 6 months |
| Heartburn Symptom Resolution, ie 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:
| 6 months |
| Improvement From Baseline in Upper Abdominal Pain and Discomfort Scores at 6 Months, Based on the Overall Treatment Evaluation for Dyspepsia Questionnaire | Improvement from baseline in Upper Abdominal Pain and Discomfort scores at 6 months, based on the overall Treatment Evaluation for Dyspepsia Questionnaire. Subjects were asked: "since treatment started, has there been any change in your upper abdominal pain and/or discomfort?" Answers would be better/about the same/worse. Participants with the response "better" (instead of "about the same" or "worse"), are tabulated by treatment group. | change from baseline at 6 Months |
| Mean Change From Baseline on Pain Intensity of the Severity of Dyspepsia Assessment (SODA) Subscales | Mean Change from Baseline on Pain Intensity of the Severity of Dyspepsia Assessment (SODA) Subscales. There are 6 questions about abdominal pain during the past 7 days: q 1-5 on average: 1. rate with a number between 0 (no pain) and 100 (pain as bad as it could be), 2. rate with a number between 0 (no discomfort) and 10 (discomfort as bad as it can be), 3. on a scale of 5 (from none to excriciating), 4. on 100 mm VAS, 5. on a scale of 4 and 6. worst abdominal pain scale 0 (no discomfort) and 10 (discomfort as bad as it can be). Total composite possible range for "pain intensity" is: 2-47 | Baseline to 6 Months |
| Mean Change From Baseline on Non-Pain Symptoms of the Severity of Dyspepsia Assessment (SODA) Subscales | Change from Baseline of Non-Pain Symptoms on the SODA Assessment. There are 7 categories about the non-pain symptoms: burping/beching, heartburn, bloating, passing gas, sour taste, nausea and bad breath. For each of these categories, subjects were to rate during the past seven days, on average, the severity on a 5 point scale ranging from no problem to very severe problem. The scores are combined into a single composite score. The total possible range of the non-pain symptoms subscale is: 7-35. | baseline to 6 Months |
| Mean Change From Baseline on Satisfaction of the Severity of Dyspepsia Assessment (SODA) Subscales | Mean Change in Satisfaction on SODA Assessment. Questions/statements to rate about satisfaction/dissatisfaction with their present level of abdominal discomfort. Question 1: 4-point scale range 0 (extremely unhappy) to 4 (extremely happy), statement 2 (I feel satisfied with my health with regard to abdominal discomfort) & statement 3 (I am pleased because my abdominal discomfort seems under control) on a 5 point scale (definitely true to definitely false) & question 4 rated how pleased subjects were with abdominal discomfort on a 10 point scale. Total satisfaction composite range: 2-23 | baseline to 6 Months |
| Lost to Follow-up |
|
| Duodenal Ulcer |
|
| misc |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Naproxen |
Naproxen 500 mg dosed twice daily (bid) |
|
|
|
| Secondary | The Number of Participants With Pre-Specified NSAID-Associated Upper GI Adverse Events or Duodenal Ulcers | The Number of Participants with Pre-Specified non-steroidal antiinflammatory drug (NSAID)-Associated Upper Gastrointestinal (UGI) Adverse Events or Duodenal Ulcers after 6 months of treatment. Pre-specified UGI adverse events typically associated with NSAID use include dyspepsia, abdominal pain, gastritis, erosive esophagitis, duodenitis, abdominal discomfort | Intent to Treat (ITT) Population | Posted | Number | Participants | 6 months |
|
|
|
|
| Secondary | The Number of Participants Discontinuing From the Study Due to NSAID-Associated Upper GI Adverse Events or to Duodenal Ulcer | The Number of Participants Discontinuing from the Study Due to non-steroidal antiinflammatory drug (NSAID)-Associated Upper GI Adverse Events or to Duodenal Ulcer during the treatment period | Intent to Treat (ITT) Population | Posted | Number | Participants | 6 Months |
|
|
|
|
| Secondary | The Number of Participants Developing Duodenal Ulcers Throughout 6 Months of Treatment | The Number of Participants Developing Duodenal Ulcers at any time during the 6 Months of the treatment period | Intent to treat (ITT) population | Posted | Number | Participants | 6 months |
|
|
|
|
| Secondary | Heartburn Symptom Resolution, ie 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:
| Intent to Treat (ITT) Population | Posted | Number | participants | 6 months |
|
|
|
|
| Secondary | Improvement From Baseline in Upper Abdominal Pain and Discomfort Scores at 6 Months, Based on the Overall Treatment Evaluation for Dyspepsia Questionnaire | Improvement from baseline in Upper Abdominal Pain and Discomfort scores at 6 months, based on the overall Treatment Evaluation for Dyspepsia Questionnaire. Subjects were asked: "since treatment started, has there been any change in your upper abdominal pain and/or discomfort?" Answers would be better/about the same/worse. Participants with the response "better" (instead of "about the same" or "worse"), are tabulated by treatment group. | Intent to Treat Population | Posted | Number | Participants | change from baseline at 6 Months |
|
|
|
| Secondary | Mean Change From Baseline on Pain Intensity of the Severity of Dyspepsia Assessment (SODA) Subscales | Mean Change from Baseline on Pain Intensity of the Severity of Dyspepsia Assessment (SODA) Subscales. There are 6 questions about abdominal pain during the past 7 days: q 1-5 on average: 1. rate with a number between 0 (no pain) and 100 (pain as bad as it could be), 2. rate with a number between 0 (no discomfort) and 10 (discomfort as bad as it can be), 3. on a scale of 5 (from none to excriciating), 4. on 100 mm VAS, 5. on a scale of 4 and 6. worst abdominal pain scale 0 (no discomfort) and 10 (discomfort as bad as it can be). Total composite possible range for "pain intensity" is: 2-47 | Intent to Treat (ITT) Population | Posted | Least Squares Mean | Standard Error | Units on SODA Subscale | Baseline to 6 Months |
|
|
|
| Secondary | Mean Change From Baseline on Non-Pain Symptoms of the Severity of Dyspepsia Assessment (SODA) Subscales | Change from Baseline of Non-Pain Symptoms on the SODA Assessment. There are 7 categories about the non-pain symptoms: burping/beching, heartburn, bloating, passing gas, sour taste, nausea and bad breath. For each of these categories, subjects were to rate during the past seven days, on average, the severity on a 5 point scale ranging from no problem to very severe problem. The scores are combined into a single composite score. The total possible range of the non-pain symptoms subscale is: 7-35. | Intent to Treat (ITT) Population | Posted | Least Squares Mean | Standard Error | Units on SODA Subscale | baseline to 6 Months |
|
|
|
| Secondary | Mean Change From Baseline on Satisfaction of the Severity of Dyspepsia Assessment (SODA) Subscales | Mean Change in Satisfaction on SODA Assessment. Questions/statements to rate about satisfaction/dissatisfaction with their present level of abdominal discomfort. Question 1: 4-point scale range 0 (extremely unhappy) to 4 (extremely happy), statement 2 (I feel satisfied with my health with regard to abdominal discomfort) & statement 3 (I am pleased because my abdominal discomfort seems under control) on a 5 point scale (definitely true to definitely false) & question 4 rated how pleased subjects were with abdominal discomfort on a 10 point scale. Total satisfaction composite range: 2-23 | Intent to Treat (ITT) Population | Posted | Least Squares Mean | Standard Error | Units on SODA Subscale | baseline to 6 Months |
|
|
|
| 5 |
| 210 |
| 160 |
| 210 |
| EG001 | Naproxen | Naproxen 500 mg dosed twice daily (bid) | 7 | 210 | 174 | 210 |
| Palpitations | Cardiac disorders | MedDRA (10.1) | Systematic Assessment |
|
| Post-procedural hemorrhage | Injury, poisoning and procedural complications | MedDRA (10.1) | Systematic Assessment |
|
| Concussion | Injury, poisoning and procedural complications | MedDRA (10.1) | Systematic Assessment |
|
| Fracture | Injury, poisoning and procedural complications | MedDRA (10.1) | Systematic Assessment |
|
| Upper limb fracture | Injury, poisoning and procedural complications | MedDRA (10.1) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (10.1) | Systematic Assessment |
|
| Suicide attempt | Psychiatric disorders | MedDRA (10.1) | Systematic Assessment |
|
| Mastectomy | Surgical and medical procedures | MedDRA (10.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Diabetic ulcer | Skin and subcutaneous tissue disorders | MedDRA (10.1) | Systematic Assessment |
|
| Gastritis erosive | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Hiatus hernia | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Oesophagitis | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Erosive duodenitis | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Abdominal pain lower | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Duodenitis | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Erosive oesophagitis | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Gastritis haemorrhagic | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (10.1) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (10.1) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (10.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (10.1) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.1) | Systematic Assessment |
|
PI agrees that the first publication will be a multi-center publication of the study results. Following this multi-center publication, PI can publish, present or use any non-confidential study results following Sponsor review and comment.
| D004066 |
| Digestive System Diseases |
| D013272 | Stomach Diseases |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |