| 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 | 8.1 |
| 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 safety and tolerability of RWJ-445380 at doses of 100, 200, or 300 mg/day for up to 12 weeks in patients with active Rheumatoid Arthritis (RA) despite methotrexate (MTX) therapy. |
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| E.2.2 | Secondary objectives of the trial |
·To evaluate the efficacy of RWJ-445380 in patients with active RA despite methotrexate therapy receiving doses of 100, 200, or 300 mg/day.
·To assess the effect of RWJ-445380 on various biomarkers associated with RA.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have provided written consent to participate in the study prior to any study procedures and understand that they are free to withdraw from the study at any time.
2. Patients must be able to read and understand the consent form, complete the study-related procedures, and communicate with the study staff.
3. Patients may be men or women and must be 18 years or older. (For potential patients > 70 years of age, the investigator must confer with the Medical Monitor during screening to determine the patient’s medical suitability prior to enrollment.)
4. Patient must have a diagnosis of Rheumatoid Arthritis Functional Class I-III according to the American College of Rheumatology (ACR) criteria for at least 6 months prior to Screening. (See Appendix 3).
5. Patients must have active RA at the time of Screening and at baseline, as defined by eight or more swollen joints and eight or more tender joints.
6. Patients must have started oral or parenteral MTX treatment, at least 10 mg/week, for a minimum of 6 months prior to Screening and must have a stable MTX dose for a minimum of 8 weeks prior to the first study drug dose.
7. Patients must be on a stable dose of folic acid (1 to 5 mg) for at least 4 weeks prior to the first study drug dose.
8. If using oral corticosteroids, patients must be on a stable dose equivalent to £ 10 mg of prednisone/day for at least 4 weeks prior to the first study dose. If currently not using corticosteroids, patients must have not received oral corticosteroids for at least 4 weeks prior to the first study dose.
9. If using non-steroidal anti-inflammatory drugs (NSAIDs), patients must be on a stable dose for at least 4 weeks prior to the first study dose. If currently not using NSAIDs, the patient must not have received NSAIDs for at least 4 weeks prior to the first study dose.
10. Patients must have Screening laboratory test result as follows:
· Hemoglobin ³ 9.0 g/dL (International System of Units [SI]: ³ 90 g/L)
· White blood cells (WBC) ³ 3.0 x 103 cells/μL (SI: ³ 3.0 x109 cells/L)
· Neutrophils ³ 1.5 x 103 cells/mL (SI: ³ 1.5 x109 cells/L)
· Platelets ³ 100 x 103 cells/mL (SI: ³ 100 x109 cells/L)
· Transaminase level not exceeding 1.5 times the upper limit of normal (ULN) for the central laboratory conducting the test
· Bilirubin level not exceeding 1.5 times the upper limit of normal (ULN) for the central laboratory conducting the test
· Serum creatinine not exceeding 1.5 mg/dL (SI: £ 125 mmol/L)
11. Patients must have a negative intradermal tuberculin skin test at Screening or within 1 month prior to study treatment initiation. Specific guidelines for administering and interpreting the TB skin test are provided in Appendix 10, along with provisions for enrolling patients with positive TB skin tests because of prior vaccination with BCG. For the purposes of this study, the criterion for PPD positivity generally applied for immunocompromised patients (induration > 5 mm) will be used.
12. Patients must satisfy the following Screening criteria for TB:
· No history of active or latent TB prior to Screening
· Have no signs or symptoms suggestive of active TB upon medical history and/or
physical examination
· Have had no recent close contact with a person with active TB (if contact has
occurred, has been referred to a physician for evaluation; evaluation should be
documented and discussed with sponsor medical monitor, as appropriate).
13. Patients must consent to utilize a medically acceptable and highly effective (< 1% failure rate) method of contraception throughout the entire study period from Screening through study termination.
14. Are willing and able to adhere to the study visit schedule, and understand and comply with other protocol requirements.
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| E.4 | Principal exclusion criteria |
1. Patients who are pregnant, nursing, or planning a pregnancy (both men and women) within 6 months of enrollment.
2. Patients who have other inflammatory diseases that might confound the evaluations from RWJ-445380 therapy (including but not limited to ankylosing spondylitis, systemic lupus erythematosus, Lyme disease).
3. Patients who have received disease-modifying anti-rheumatic drugs ([DMARDs] other than MTX (e.g., D penicillamine, hydroxychloroquine, chloroquine, oral or parenteral gold, azathioprine or sulphasalazine) or interleukin [IL]-1 receptor antagonist [anakinra] within 4 weeks prior to the first study dose, or leflunomide within 3 months of the first study dose.
4. Patients who have been previously treated with more than one therapeutic agent targeted at reducing TNFa (including but not limited to infliximab, etanercept, adalimumab, CDP870 or thalidomide).
5. Patients who have received prior anti-TNF treatment within 4 weeks prior to first study dose or received the anti-TNF infliximab within 3 months prior to the first study dose.
6. Patients who have been treated with any p38 MAP kinase inhibitor, abatacept or rituximab.
7. Patient who have used cytotoxic drugs, including chlorambucil, cyclophos-phamide, nitrogen mustard, or other alkylating agents.
8. Patients who have previously received treatment with a Prosorba® column.
9. Patients who have been treated with any anti-CD4 antibody.
10. Patients who have received intra-articular, intramuscular, or IV cortico-steroids, including intramuscular adrenocorticotrophic hormone during the 4 weeks prior to the first study dose.
11. Patients who have taken any investigational drug within the previous 30 days or within a period of 5 half-lives, whichever is greater, prior to first study dose.
12. Patients who have received, or who are expected to receive, live virus or bacterial vaccinations within 1 month before first study drug dose, during the trial, or up to 1 month after the last study drug dose.
13. Patients who have a history of infected joint prosthesis or have received antibiotics for a suspected infection of a joint prosthesis if that prosthesis has not been removed or replaced.
14. Patients who have, or have had, a serious infection during the previous 2 months prior to first study treatment (including but not limited to hepatitis, pneumonia, or pyelonephritis, or have been hospitalized or received IV antibiotics for an infection.
15. Patients who have a history of, ongoing chronic, or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), sinusitis, recurrent urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis), an open, draining, or infected skin wound, or ulcer.
16. Patients who have, or have history of an opportunistic infection (eg, herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, mycobacteria other than TB, or granulomatous infection).
17. Patients with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
18.Patients with current signs or symptoms of clinically significant, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral disease.
19. Patients with medical conditions associated with pruritus (dermatological or drug induced), current or within 6 months of screening.
20. Patients with a resting heart rate less than 45 or greater than 100 beats per minute.
21. Patients with sitting systolic blood pressure >160 mmHg or <90 mmHg, and/or a sitting diastolic blood pressure of >100 mmHg or <50 mmHg at screening.
22. Patients with confirmed screening QTc interval > 450 msec or a history of additional risk factors for torsades de point (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.
23. Patients who have a history of lymphoproliferative disease, including lymphoma, or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location, or clinically significant splenomegaly.
24. Patients who have any known malignancy or have a history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence).
25. Patients who have a transplanted organ (with exception of a corneal transplant >3 months prior to Screening).
26. Patients who have, or have history of a substance abuse (drug or alcohol) problem within the previous 3 years.
27. Patients who are unable to undergo multiple venipunctures because of poor tolerability or lack of easy access.
28. Patients who are participating in another investigational drug trial during participation in this trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is response to ACR20, but responses to ACR50 and ACR70 will also be evaluated. ACR(%) is a composite efficacy measure comprised of: swollen joint count, tender joint count, patient asseessment of pain (VAS), patient's global assessment of disease activity (VAS), evaluator's global assessment of disease activity (VAS), patients's assessment of physical function as measured by the HAQ and CRP. |
|
| 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 | Yes |
| 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 | Yes |
| 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 | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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
|
| The study is considered complete with the last visit of the last patient. |
|
| 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 | 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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