| 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 | 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 |
| The primary efficacy objective of this study is to confirm the efficacy of R788 100 mg PO bid as determined by ACR20 responder rates at 6 months. |
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| E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives of this study are as follows:
1) To compare response rates for R788 100 mg PO bid and R788 150 mg PO qd as determined by ACR20, ACR50, ACR70, ACRn, DAS28-CRP and DAS28-ESR response rates over 6 months;
2) To assess the rapidity of onset of clinical effect among the R788 100 mg PO bid, R788 150 mg PO qd, and placebo groups as determined by ACR20 response rates at Weeks 1 and 2;
3) To compare changes for R788 100 mg PO bid and R788 150 mg PO qd in the FACIT-fatigue and SF-36 from baseline to 6 months;
4) To assess and compare the safety profiles for R788 100 mg PO bid and R788 150 mg PO qd compared with placebo for effects on liver function tests, clinically significant reductions in peripheral neutrophil counts, G-I side effects and other adverse effects as they may appear.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients must give written informed consent by signing an IRB/EC-approved Informed Consent Form (ICF) prior to admission to this study.
2) Males and females, 18 years of age or older, with active RA for at least 6 months prior to Day 1 dosing (functional class I–III, e.g., not bed or wheelchair-bound).
Active RA is defined as the presence of (a) ≥ 6 swollen joints (28 joint count); AND (b) ≥ 6 tender joints (28 joint count); AND at least one of the following (c) ESR >28 mm/hr or CRP >ULN for the central reference laboratory.
3) Patients must have been receiving weekly MTX doses (7.5–25 mg/week) for a minimum of 3 months prior to Day 1 dosing and must be receiving a stable MTX dose, with no change in route, for the previous 6 weeks prior to Day 1 dosing. If the current MTX dose is < 10 mg/week, the patient's intolerance to ≥ 10 mg dose must be documented in the patient’s medical history.
4) Patients must be receiving a folic or folinic acid supplementation at a stable dose for at least 6 weeks prior to Day 1 dosing.
5) Females of childbearing potential must be fully informed of the potential for R788 to adversely affect the fetus and, if sexually active, must agree to use a well established method of birth control during the study (oral contraceptive, mechanical barrier, long acting hormonal agent). These patients must not be lactating and must have a negative urine pregnancy test at the time of randomization and at each laboratory determination.
6) The patient must otherwise be in good health as determined by the Investigator on the basis of medical history, physical examination, and laboratory screening tests during the screening period. See exclusion criteria for specific exclusions.
7) In the Investigator’s opinion, the patient has the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the Investigator and to participate in, and to comply with, the requirements of the entire protocol.
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| E.4 | Principal exclusion criteria |
1) The patient has a history of, or a concurrent, clinically significant illness, medical condition (other than arthritis) or laboratory abnormality that, in the Investigator’s opinion, could affect the conduct of the study. Specifically, excluded are patients with the following:
a) uncontrolled or poorly controlled hypertension;
b) other autoimmune disease (psoriatic arthritis, lupus, mixed connective disorder) or arthritis syndromes (gout, Lyme disease, Reiter’s syndrome);
c) recent (within past 2 months prior to Day 1 dosing) serious surgery or infectious disease;
d) recent history (past 5 years prior to Day 1 dosing) of, or treatment for, a malignancy other than nonmelanomatous skin cancer, or any history of lymphoma;
e) Hepatitis B surface antigen positive;
f) Hepatitis C antibody positive; may be included if Hepatitis C RIBA negative or HCV RNA negative (qualitative);
g) interstitial pneumonitis or active pulmonary infection on chest x-ray (taken within 1 month prior to screening);
h) Tuberculosis (TB): the TB skin test should be negative (if the patient was never vaccinated, or if vaccinated more than 10 years ago; in this context negative means < 5 mm induration); if the TB skin test is positive (in an unvaccinated patient), an appropriate prophylactic anti-TB regimen must be documented: Patients should have completed anti-TB treatment 1 year prior to Day 1 dosing. For vaccinated patients, if the vaccination was less than 10 years ago and the skin test is positive, an exception may be requested if the induration is < 10mm, the chest x-ray shows no sign of TB as confirmed by a radiologist, or the patient has had a course of Isoniazid (or comparable regimen).
i) known laboratory abnormalities: ALT > 1.2x ULN, creatinine >1.5x ULN, an ANC < 2,500/mm3 or lymphocyte count < 600/mm3, Hgb <9 g/dL, platelet count < 125,000/mm3 are excluded.
2) The patient has a history of substance abuse, drug addiction or alcoholism. Patients may consume up to 4 units of alcohol per week; however, alcohol should be avoided in the 72 hours prior to lab assessments. Patients who cannot reliably comply with this should be excluded. A unit of alcohol is defined as the following: Beer=12 oz or 355 mL; wine = 5 oz or 148 mL; sweet dessert wine=3 oz or 89 mL; 80 proof distilled spirits= 1.5 oz or 44 mL.
3) The patient has been treated previously treated with R788 under a different protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary Efficacy parameter is ACR20 response rate at Month 6 post dosing. A patient will be defined as an ACR responder if he or she shows at least 20% improvement from baseline in both tender and swollen joint counts, and at least 20% improvement in any 3 of the following 5 criteria:
1) Physician global assessment of disease activity (VAS)
2) Patient global assessment of disease activity (VAS)
3) Patient reported pain score (VAS)
4) Health Assessment Questionnaire Disability Index (HAQ-DI)
5) C-reactive protein (CRP) or ESR
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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 | 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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
| |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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