| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of osteoarthritis (OA) and/or rheumatoid arthritis (RA) in high GI risk patients |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether celecoxib is superior to combined therapy with diclofenac SR and omeprazole for the incidence of clinically significant upper and/or lower GI events (CSULGIEs) in high GI risk subjects with OA and/or RA. |
|
| E.2.2 | Secondary objectives of the trial |
| To determine safety and tolerability of celecoxib in subjects treated with celecoxib compared to treatment with diclofenac SR plus omeprazole in subjects with OA and/or RA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male and female subjects who meet all criteria listed below will be included in the study.
1. Outpatient or inpatient
2. Subjects with a clinical diagnosis of OA or RA*
3. Subjects who are expected to require regular anti-inflammatory therapy for arthritis symptom management
4. Subjects must be aged ≥ 60 years with or without a history of GD ulceration; or be of any age ≥ 18 years and have had documented in clinical notes evidence of GD ulceration 90 days or more prior to the screening visit The following are acceptable as documentation of a previous history of GD ulceration:
investigational site clinical notes/ endoscopy or radiographic report; documentation provided by another institution or the subject’s primary care provider; verbal confirmation by another institution or the subject’s primary care provider. Verbal confirmation by the subject alone without corroboration is not sufficient. History of GD ulceration includes both uncomplicated and complicated events. Subjects who have a history of complicated ulcer disease are most at risk of the development of further serious events. In considering subjects with previous complicated ulcers for inclusion into the trial investigators must carefully weigh the balance of benefit: risk for inclusion of the subject into the trial and discuss this with the subject as per the
informed consent
5. Screening tests are negative for H pylori (serology, 13C or 14C breath test or rapid
urease/histology or fecal antigen). Subjects who test positive on serology must have active
infection excluded using a second methodology (Section 6.1 Screening)
6. Female subjects of childbearing potential must not be pregnant or lactating at screening and must have a negative urine pregnancy test at screening (women post-menopausal for <2 years will also require a urine pregnancy test at screening)
7. Female subjects of childbearing potential must be using effective contraception since the last date of their menses and continue to do so during the study period
8. Written informed consent obtained.
9. If required locally, negative fecal occult blood test (local standard) x 3. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. GI ulcer hemorrhage or active GD ulceration less than 90 days prior to screening visit
2. Current use of anticoagulant agents, lithium, disease modifying anti-rheumatic drugs (DMARDs- unless on stable dose for at least 12 weeks), corticosteroids (dose equivalent of prednisolone/ prednisone ≤10mg daily allowable if on stable dose for at least 12 weeks), NSAIDs, proton pump inhibitors (PPIs – other than use of study medication), sucralfate, misoprostol or regular use of a histamine-2 receptor antagonist (H2RAs; > 3 days/week). Current H2RAs use intermittently (no more than 3 days/week) for dyspepsia is allowed; antacids are allowed. Subjects receiving PPI, COX-2 specific inhibitor or NSAID therapy at the screening visit are allowable into the trial, if these treatments are discontinued at the time of screening and the other inclusion/ exclusion criteria are met.
3. Subjects on iron replacement therapy (or a dose >15mg elemental iron/day) or taking iron supplements for deficiency prevention (a dose ≤15mg elemental iron/day) due to anemia or any other reason will not be included in the study. However, subjects taking a dietary supplement not containing iron can be included.
4. Subjects using aspirin, including low dose aspirin, and subjects not using low dose aspirin but considered by the investigator to be indicated for cardiovascular prophylaxis with low dose aspirin.
5. Subjects using other antiplatelet agents (ticlopidine, clopidogrel, dipyridamole)
6. Subjects with a history of established ischemic heart disease (e.g. myocardial infarction, stable angina, unstable angina), peripheral arterial disease and/or cerebrovascular disease (e.g. ischemic or hemorrhagic stroke, transient ischemic attack), as well as subjects with previous revascularization procedure to coronary, carotid, cerebral, renal, aortic or peripheral arterial vasculature.† The investigator should exclude subjects with ischemic or other electrocardiographic modifications that in his/her opinion are clinically significant.
7. History of gastric or duodenal surgery other than patch repair/ over sew
8. Presence of erosive esophagitis, gastric-outlet obstruction
9. Malignancy or history of malignancy other than surgically removed basal cell carcinoma. Subjects with successfully treated malignancy and no history or evidence of recurrent disease within 5 years prior to enrollment may be included in the study
10. Pregnant or lactating women, or women of childbearing potential including women less than two years post-menopausal not using an acceptable method of contraception
11. Participation in any other studies involving investigational or marketed products,
concomitantly or within 30 days prior to entry in the study
12. Current or history of alcohol and/or any other substance abuse
13. Previous participation in this study (subjects who fail screening due to HP infection may be considered for future enrollment in the trial if in the view of the investigator treatment for HP is deemed appropriate, is successfully eradicated, and at the time of re-screening the subject meets all inclusion/ exclusion criteria) (Section 6.1 Screening)
14. Previous history of intolerance or hypersensitivity to diclofenac, celecoxib, omeprazole, NSAIDs, aspirin and sulfonamides (including but not limited to subjects who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other allergic-type reactions after taking aspirin or NSAIDs)
15. Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol
16. Impaired hepatic function (SGPT (ALT) or SGOT (AST) > 1.5x upper limit of normal) or impaired renal function (serum creatinine >1.2 x upper limit of normal)
17. Any other condition or Baseline finding which, in the investigator’s judgment, might increase the risk to the subject or decrease the chance of obtaining satisfactory data to achieve the objectives of the study
18. Anemia with Hb <11.5g/dl
19. Suspected or clinical diagnosis of inflammatory bowel disease
20. Congestive heart failure (NYHA class II- IV)
21. Subjects considered to have a requirement for continued use of a PPI (for example, severe gastro-esophageal reflux disease or recurrent ulcer complications). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the incidence of clinically significant upper and/or lower
GI events (CSULGIEs). For the purposes of this trial CSULGIEs are considered any event that
in clinical practice would impact the subject in terms of inpatient or outpatient investigation for
GI pathology with blood loss or other serious complication.
CSULGIEs are a composite of any of the following (adjudicated by GI Events Adjudication
Committee):
• Gastroduodenal hemorrhage
• Gastric outlet obstruction
• Gastroduodenal, small bowel or large bowel perforation
• Small bowel hemorrhage
• Large bowel hemorrhage
• Clinically significant anemia of defined GI origin
• Acute GI hemorrhage of unknown origin, including presumed small bowel hemorrhage
• Clinically significant anemia of presumed occult GI origin including possible small
bowel blood loss. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Parallel Group Triple Dummy |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Background drug will be Losec |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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