| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
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| 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 evaluate the clinical efficacy of GW406381versus placebo in the treatment of the signs and symptoms of Rheumatoid Arthirtis. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of GW406381 administered orally to subjects with Rheumatoid Arthirtis.
• To evaluate the optimal therapeutic dose(s) of GW406381 for further clinical investigations in rheumatoid arthritis.
• To explore the effect of GW406381 versus celecoxib on pain intensity and function in subject with Rheumatoid Arthirtis.
• To evaluate health outcomes data generated from subject completed questionnaires.
• To evaluate population pharmacokinetics (PK)/pharmacodynamics (PD) of GW406381 in subjects with Rheumatoid Arthirtis.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subject is a male or female outpatient, at least 18 years of age.
A female is eligible to enter and participate in the study if she is of:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); or,
b. Childbearing potential, has a negative pregnancy test and is not lactating at the Screening Visit and Baseline Visit, and agrees to satisfying one of the requirements listed Appendix 3: Acceptable Methods of Contraception.
2. Subject is able and willing to give written informed consent.
3. Subject is able to read, comprehend and record information required in the protocol, e.g., complete assessments using an electronic device.
4. Onset of RA at >16 years of age and symptom duration for >12 months.
5. Diagnosis of RA as defined by the American Rheumatism Association (ARA) 1987 criteria..
6. ARA Functional Class I, II or III.
7. Required a NSAID or COX-2 inhibitor for the treatment of their RA for at least 5 out of 7 days of each week for the 4 weeks prior to screen.
8. Satisfies all the following definitions of active disease and baseline criteria defined by:
• a minimum of six tender/painful joints with an increase of at least two tender/painful joints (or 20% increase, whichever is greater) at baseline compared to screen,plus
• a minimum of three swollen joints at baseline with an increase of at least two swollen joints (or 20% increase, whichever is greater) at baseline compared to screen,plus
• a patient’s assessment of pain (VAS) of at least 40mm at baseline with an increase of at least 10mm (or 20% increase, whichever is greater) at baseline as compared to screen
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| E.4 | Principal exclusion criteria |
1. Known history of hypersensitivity or intolerance to NSAIDs, aspirin, COX-2 inhibitors, unless subject has subsequently taken at least two separate NSAIDs/COX 2 inhibitors for at least one month without reaction. Intolerance of paracetamol acetominophen. History of aspirin-sensitive asthma or nasal polyps.
2. Any clinical or biological abnormality found at screen (other than those related to the disease under investigation), which, in the opinion of the investigator, is clinically significant and would preclude safe participation in this study.
3. History of gastroduodenal perforations and/or obstructions.
4. History of any gastric or duodenal surgery.
5. Active gastrointestinal ulceration of the upper GI tract within the previous 6 months, bleeding of the upper GI tract within the previous year (including hematemesis).
6. History of lower GI bleeding (excluding hemorrhoids) within the past year.
7. History of inflammatory bowel disease.
8. Use of proton pump inhibitors at any dose for any period longer than 4 consecutive days during the month prior to study start or during the study unless the subject has a history of GI ulceration (≥ 6 months prior to study start).
9. Use of sucralfate and misoprostol
10. Use of potent CYP3A4 inhibitors i.e., ritonavir, ketoconazole, itraconazole, saquinavir, nelfinavir, troleandomycin, azithromycin and erythromycin. Other CYP3A4 inhibitors are permitted.
11. History of coronary artery disease (angina [stable or unstable], myocardial infarction or any coronary artery surgery)
12. History of congestive heart failure or renal artery stenosis
13. History of stroke or transient ischemic attack
14. Uncontrolled hypertension (treated or untreated) at screen (sitting systolic blood pressure >160mmHg and/or sitting diastolic blood pressure >90mmHg).
15. Subjects taking aspirin (including low dose [<325mg per day] for cardiovascular prophylaxis) are excluded; subjects may not discontinue low dose aspirin for the purpose of study participation.
16. Use of a combination of a diuretic with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). Note that subjects taking only a diuretic, or only an ACE/ARB drug, are not excluded.
17. Use of anticoagulants (warfarin, heparin) or anti-platelet aggregation agents (including low-dose aspirin) or a condition associated with decreased haemostasis.
18. Subjects with any one of creatinine, bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (ULN) at screen are excluded. Subjects with two or more of bilirubin, ALT or AST above ULN are excluded.
19. A history of clinically significant drug or alcohol abuse, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.
20. Demonstrated allergic-type reactions to sulphonamides (including celecoxib or valdecoxib).
21. Participation in another investigational drug or device study during the 3 months prior to the Baseline/Randomisation Visit or participation in a study of a marketed NSAID or COX-2 inhibitor, given in accordance with the dosage and administration section of the approved product labelling, during the month prior to the Baseline/Randomisation Visit.
22. Previous participation in an investigational study of GW406381.
23. Initiation or change of dose of a standard disease modifying anti-rheumatic drug (DMARD) within 12 weeks prior to baseline, e.g., penicillamine, sulfasalazine, oral or intramuscular gold salts, azathioprine, antimalarials, with the exception of leflunomide (Arava) <20mg daily within 4 weeks prior to screen.
24. Use of methotrexate at doses of >20mg/week or initiation or change to the dose of methotrexate within 8 weeks prior to baseline.
25. Use at doses or dose intervals outside those specified in the label of biological anti-cytokine directed therapeutics (e.g., anti-tumor necrosis factor [TNF]) and/or given less frequently than weekly (e.g., remicade). These agents may be used without restriction if dosed at least once per week and if stable for 6 months.
26. Use of B-cell targeted therapy (e.g., rituximab) if not stable for 6 months prior to Screen or at doses/schedules outside the label. Appropriate monitoring must have been performed.
27. Use of oral corticosteroids at doses greater than the equivalent of 10 mg/day of prednisolone/prednisone (average daily dose for patients on alternating doses) or initiation of treatment within 4 weeks prior to commencing study drug.
28. Intra-articular injections within 4 weeks prior to commencing study drug or during the study period (or anticipated need during study).
29. Initiation of or change to an established physiotherapy program within 2 weeks prior to or during the study period. An established physiotherapy program may be continued throughout the study period if unchanged in frequency and intensity.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Percentage of American College of Rheumatology (ACR)20 Responders at the end of treatment (Week 12): a clinical response will be defined according to ACR response criteria, i.e., a >20% improvement in 1 and 2 below, coupled with at least a 20% improvement in three of the remaining five parameters.
1. Tender/painful joint count.
2. Swollen joint count.
3. Patient’s pain assessment (Visual Analogue Scale [VAS]).
4. Physician’s global assessment of Rheumatoid Arthritis (VAS).
5. Patient’s global assessment of Rheumatoid Arthritis (VAS).
6. Functional disability index (Health Assessment Questionnaire [HAQ]).
7. C-reactive protein (CRP).
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health-related Quality of Life |
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| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| As described in the protocol |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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