E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
subjects with rheumatoid arthritis (RA) who are on background therapy with methotrexate (MTX) |
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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 |
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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 assess the clinical efficacy of BMS-582949 at a dose of 300 mg once a day (qd) compared to placebo at 12 weeks as measured by ACR 20 in subjects with RA who are on background therapy with MTX. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of BMS-582949 in subjects with RA • To assess the proportion of subjects who achieve an ACR 50 or ACR 70 response in each treatment group • To assess the reduction in disease activity over time as measured by the DAS28 and ACR-N over 16 weeks • To assess the proportion of subjects achieving a 20 percent change in the assessment of pain, disease activity and fatigue using the American College of Rheumatology (ACR) Disease Activity Visual Assessment Scales (VAS) • To assess the percent change in physical function as measured by the disability index of the Health Assessment Questionnaire (HAQ) over 16 weeks of treatment in each treatment group. • To determine the trough plasma concentrations of BMS-582949 (Cmin). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics Blood Sample Amendment (version 1.0, dated 19-Dec-2007): The objective of this Amendment is to permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research studies. BMS will use DNA obtained from the blood sample and health information collected from the main clinical trial, IM119015 case report form, to study the association between genetic variation and drug response. BMS may also use the DNA to study the causes and further progression of Rheumatoid Arthritis. Samples from this and other clinical studies may also be used in conjunction to accomplish this objective. |
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E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent a) Subjects must be able to provide informed, written consent. 2) Target Population a) Subjects must meet the criteria of the American Rheumatism Association (1987) for the diagnosis of RA (Arnett et al, 1988) (Appendix 3). The disease must have been diagnosed for ≥ 6 months prior to screening. b) Subjects must have been taking MTX for at least 3 months at a weekly dose of 7.5 to 30 mg, inclusive, and at a stable dose for 28 days prior to treatment (Day 1). Use of parenteral MTX is acceptable as clinically indicated if subjects cannot tolerate or absorb oral MTX. c) Subjects must be MTX inadequate responders defined as currently having 6 or more swollen joints and 8 or more tender joints at the screening visit (refer to Inclusion number 5, disease activity) 3) Age and Sex a) Men and women at least 18 years of age. Men and women of childbearing potential are eligible if they are practicing effective contraceptive measures. Because subjects are taking background therapy such as methotrexate for treatment of RA, which has potential risks associated with its use in pregnancy, subjects will be re-advised on the use of reliable contraceptive methods and on the potential risks to a pregnancy. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. 4) Concomitant Medication (Anti-rheumatic Treatment) a) MTX alone: Subjects who are treated only with methotrexate will not require washout. b) MTX plus DMARDs other than sulfasalazine or anti-malarials (eg hydoxychloroquine, chloroquine): Subjects who are treated with MTX in combination with another anti-rheumatic treatment (DMARD) will require washout of the other DMARDs. c) Drug stabilization requirements i) If subjects are taking sulfasalazine and/or anti-malarials, which are allowed as concomitant therapy in this study, they must be on a stable dose for 25 out of 28 days prior to treatment (Day 1). ii) All DMARDs (except MTX, sulfasalazine and anti-malarials) must be discontinued at least 28 days prior to treatment (Day 1). In the case of leflunamide, the subject can be washed out with cholestyramine according to manufacturers recommendations. iii) Oral corticosteroid treatment must have been reduced to ≤ 10 mg prednisone or equivalent per day for at least 14 days and stabilized for at least 11 out of 14 days prior treatment (Day 1). iv) Subjects who have had previous treatment with any biologic/immunosuppresant therapy for RA require wash-out for a period of at least 28 days or 5 half lives whichever is longer or a minimum of 3 months for any biologic agent with an unknown half life, prior to treatment (Day 1). v) Subjects requiring NSAIDs must be on a stable dose for at least 14 days prior to Day 1 dose. d) Prior treatment with up to two anti-TNFα inhibitors will be allowed. 5) Disease Activity a) For subjects receiving MTX alone or MTX plus sulfasalizine and/or antimalarials: At the screening visit, subjects must have the following disease activity: i) 6 or more swollen joints (66 joint count) and ii) 8 or more tender joints (68 joint count) and iii) C-reactive protein (CRP) > ULN or erythrocyte sedimentation rate (ESR) (Westergren Method) > 28 mm/hr (Both tests are required. Results will be used from the screening visit to qualify for the study.) b) For subjects receiving MTX plus other DMARDs that require washout: At the screening visit, subjects must have the following disease activity: i) 6 or more swollen joints (66 joint count) and ii) 8 or more tender joints (68 joint count) and iii) No restriction on CRP or ESR (Both tests are required) IN ADDITION All subjects who are receiving other DMARDs plus MTX therapy at the screening visit must undergo washout of their other DMARD (other than MTX, sulfasalazine, and anti-malarials). After washout and within 7 days before randomization on Day 1, subjects must have: iv) CRP > ULN or ESR (Westergren Method) > 28 mm/hr (Both tests are required). Results from this visit will be used to qualify for the study. |
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of investigational product. b) Women who are pregnant or breastfeeding c) Women with a positive pregnancy test on enrollment or prior to investigational product administration. d) Men who are unwilling or unable to use an acceptable method of birth control for the entire study period. 2) Medical History and Concurrent Diseases a) Any clinically significant acute or chronic illness other than RA that is severe, progressive or uncontrolled at the time of screening. This includes any current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, musculoskeletal, genitourinary, or thyroid disease. b) Any major surgery within 4 weeks of screening or planned/scheduled surgery requiring hospitalization during the time of the study. c) Blood transfusion within 4 weeks of screening. d) Donation of blood or plasma to a blood bank or in a clinical study within 4 weeks of screening. e) Any condition that could impact upon the absorption of study drug. (ie, gastric ulcer requiring therapy, gastric stapling, duodenal surgery, malabsorption syndrome). f) Subjects (currently or within 3 months) requiring chronic or intermittent medical therapy or surgical intervention for gastrointestinal disease including gastrointestinal ulceration, chronic heartburn, esophageal reflux, gastric or duodenal ulcer and/or gastritis. g) Any infection requiring systemic anti-microbial treatment that completed within 4 weeks of enrollment. h) Major infection requiring hospitalization or receipt of intravenous antibiotics within 2 months prior to enrollment. i) Subjects at risk for tuberculosis (TB). j) Have a history of opportunistic infection and/or evidence of active infection including but not limited to HIV, Hepatitis B or C viruses. k) History of lymphoproliferative disease, including lymphoma, or signs suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size, location, or clinically significant splenomegaly. l) Any known malignancy or history of malignancy within 5 years including carcinoma in situ prior to enrollment, with the exception of basal cell or squamous cell carcinoma of the skin that has been excised with no evidence of recurrence (squamous cell carcinoma of other location is exclusionary). m) Subjects who have received treatment with any investigational drug within the previous 30 days or 5 half-lives of the Day 1 dose, whichever is greater. n) Subjects who have received a live vaccine within 3 months of Day 1 dosing. 3) Physical and Laboratory Test Findings a) Subjects at screening with PT and/or aPTT and/or INR values ≥ 1.05 X ULN. b) Subjects at screening with ALT or AST elevations ≥ 1.5 X ULN or with a history of frequent or recent ALT or AST elevations are excluded. c) Subjects at screening with CK elevations ≥ 2 X ULN or with a history of frequent or recent CK elevations are excluded. d) Any clinically significant (as determined by the investigator) vital signs and/or physical examination finding. e) Positive blood screen for hepatitis B surface Ag and hepatitis C antibody. f) Chest radiograph at screening showing evidence of chronic infection, malignancy or inflammation. g) Screening ECG showing clinically significant abnormalities. 4) Prohibited Treatments and/or Therapies a) Subjects who have received more than two anti-TNF therapies are excluded. b) Subjects who require chronic use of proton pump inhibitors (eg omeprazole), H2 blockers (eg ranitidine, famotidine), based on the medical history, are excluded. Proton pump inhibitors and H2 blockers are prohibited within 5 days of Day 1 (randomization). Antacids are prohibited 3 hours before and after taking study drug. c) Use of cyclosporin, mycophenolate mofetil or any other immunosuppresants (except for MTX, sulfasalazine and anti-malarials). d) Use of warfarin or similar agents that would effect coagulation are prohibited. e) Use of herbal supplements and dietary over the counter medications (excluding MVI). 5) Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated. b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. c) Subjects with any medical or laboratory abnormality, which in the opinion of the investigator in consultation with the BMS Medical Monitor could affect subject safety, preclude evaluation of response, or render it unlikely that the subject would complete the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint will be the percent of subjects who achieve an ACR 20 response following 12 weeks of treatment and to determine the difference in ACR 20 response between BMS-582949 compared to placebo following 12 weeks of treatment. |
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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 | Yes |
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 | 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) | 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 | 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) | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | 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
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |