| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | The patients entering the trial have rheumatoid arthritis although treatment of the disease itself is not under investigation in this study. | |
| MedDRA Classification |
| 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 | | Evaluate the influence of repeated oral dosing of GW406381 on the plasma pharmacokinetics of methotrexate in rheumatoid arthritis patients. | |
| E.2.2 | Secondary objectives of the trial | Evaluate the influence of repeated oral dosing of GW406381 on the plasma pharmacokinetics of 7-hydroxymethotrexate if methotrexate PK data indicates.
Evaluate the influence of repeated oral dosing of GW406381 on the urinary excretion of methotrexate and 7-hydroxymethotrexate if methotrexate PK data indicates.
Assess safety and tolerability of GW406381 in rheumatoid arthritis patients receiving stabilised treatment with methotrexate.
Evaluate the steady state GW406381 pharmacokinetics when co-administered with methotrexate in rheumatoid arthritis patients.
| |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female patients aged 18 years to 65 years.
2. Body mass index (BMI) between 19 and 30 kg/m2.
3. A female is eligible to participate in this study if she is of: a) non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal (>1 year since last menstrual cycle), had a tubal ligation or is surgical sterilised); or, b) child-bearing potential, has a negative pregnancy test (blood) at screen, is non-lactating, and agrees to one of the following:
Female subjects of child-bearing potential will be eligible to participate if they comply with the following:
One of the following methods is acceptable as the sole method of contraception if there is indisputable data that it is >99% effective otherwise it should be used with a barrier method (condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal foam/gel film/cream/suppository):
Abstinence: The lifestyle of the female should be such that there is complete abstinence from intercourse from at least the commencement of their last normal period prior to the first dose of study medication and to continue until the first normal period (defined as normal for the woman, both in terms of duration and quantity of menses) after treatment or five half lives of the study medication, whichever is the longest.
Documented tubal ligation.
Documented placement of an intrauterine device (IUD) or intrauterine system (IUS).
Male partner sterilization (vasectomy) prior to the female subject's entry into the study and is the sole partner for that female subject.
Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
Female patients must use a non-hormonal contraceptive method during the study, which excludes the use of IUDs with hormones.
Male patients must not father a child during the period from the time of the first dose of study medication until 84 days following administration of the last dose of study medication.
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 1987 criteria.
6. The patient must be on a stable single dose of methotrexate (2.5 – 20 mg/week) for at least eight weeks prior to DAy 1 and which will not be changed during the course of this study.
7. Screening: creatinine clearance (estimated with Cystatin C method [Larsson, 2004]) at least 50 mL/min, ALT and AST < 1.5 × upper limit of normal.
8. The patient must be on stable folate supplements determined by the physician with normal red cell folate levels at screening.
9. Able and willing to give written informed consent.
| |
| E.4 | Principal exclusion criteria | A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Known history of hypersensitivity or intolerance to NSAIDs, aspirin, COX-2 inhibitors or acetaminophen. History of asthma, urticaria or allergic reaction after taking aspirin or NSAIDs or evidence of intolerance to celecoxib or acetaminophen/paracetamol.
2. Demonstrated allergic-type reactions to sulfonamides (including celecoxib or valdecoxib).
3. History of any seizure disorders.
4. The patient has significant cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions that, in the opinion of the investigator and/or GSK medical monitor, places the patient at an unacceptable risk as a participant in this trial.
5. Any concurrent illness or disability that may affect the correct study participation or the interpretation of results. In particular, any ongoing signs or symptoms that are suspected of being adverse reactions to methotrexate.
6. History of gastroduodenal perforations and/or obstructions.
7. History of any gastric or duodenal surgery.
8. Active GI ulceration of the upper GI tract within the previous 6 months, bleeding of the upper GI tract within the previous year (including hematemesis).
9. History of lower GI bleeding (excluding hemorrhoids) within the past year.
10. History of inflammatory bowel disease.
11. History of a condition associated with decreased hemostasis (e.g., hemophilia).
12. Use of gastro-protective agents (i.e., misoprostol, sucralfate) within 4 weeks prior to study entry; use of proton pump inhibitors (i.e., omeprazole, lansoprazole), H2-blockers (cimetidine, ranitidine, famotidine, nizatidine) or antacids for the treatment of active gastrointestinal ulcers for any period longer than 4 consecutive days during the month prior to Day 1. NOTE: the use of antacids or H2-blockers at over the counter doses is permitted.
13. Use of digitalis preparations, anticoagulants (warfarin, heparin) or anti-platelet aggregation agents (except low-dose aspirin not to exceed 325 mg/day).
14. Incapability to discontinue NSAID treatment for a period corresponding to 5x half-life (in hours) prior to Day 1.
15. Use of any analgesic, other than protocol defined analgesics, within 5x half-life (in hours) prior to the first dosing day.
16. Treatment, within 12 weeks prior to Day 1, with: gold, penicillamine, chloroquine, antimetabolites or immunosuppressant (Cyclosporin), biological anti-cytokine directed therapeutics (e.g., Anti-TNF) with the exception of stable doses (within 12 weeks prior to screen and during the study) of the following:• etanercept (Enbrel, others) when given subcutaneously twice a week at a stable dose of no more than 25 mg;• anakinra (Kineret) given subcutaneously daily at a stable dose of no more than 100 mg, hydroxychloroquine or sulfasalazine.
17. Use of methotrexate at doses of >20 mg/week or initiation or change to the dose of methotrexate within 8 weeks prior to Day 1.
18. Use of oral/injectable corticosteroids at doses greater than the equivalent of 10 mg/day of prednisolone/prednisone or initiation of treatment within 4 weeks prior to commencing study drug. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary endpoints will be AUC(0-24) and Cmax for plasma methotrexate without and in the presence of GW406381. | |
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | | Completion of the final study assessment by the last subject. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
