A Multicenter, Double-blind, Randomized, Parallel, Placebo-controlled Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of 2 Oral Doses, 25 mg Twice Daily and 100 mg Twice Daily, of PG 760564 in Adult Patients with Rheumatoid Arthritis Receiving Methotrexate

Patients who meet all of the following criteria are eligible for participation in the study:
a. Men and women, 18 to 70 years of age, inclusive, at screening;
b. Who meet ACR criteria for RA, with a documented diagnosis of RA for at least 6 months;
c. Whose functional capacity is class I, II, or III according to the revised criteria of the ACR (Appendix 6);12
d. Who have active disease despite treatment with MTX before washout of any DMARDs other than MTX. Active disease for this study will be defined as follows:
• At least 6 swollen joints and 6 tender joints; AND,
• At least one of the following 3 criteria must be present:
* ESR of at least 28 mm/hour
* Elevated CRP
* Morning stiffness lasting at least 45 minutes;
e. Who have been treated with MTX for at least 24 weeks. The dose of MTX must be stable for at least 8 weeks, at 15-20 mg/week, or at 10 mg/week if that is the maximal tolerated dose, before starting study medication;
f. If female, must be (as documented in the patient notes):
• Post menopausal (>= age 50 and at least 1 year without spontaneous menses), or
• Surgically sterile (if by tubal ligation, must have been performed at least 3 months before entry into the study), or
• Using acceptable contraception (e.g., oral, intramuscular, or implanted hormonal contraception, intra-uterine device) for at least 3 months prior to randomization and for the duration of the study including the follow-up period, in conjunction with a barrier method (e.g., condom and spermicide, diaphragm and spermicide) for the duration of the study and during the follow-up period; NOTE: All contraception precautions for MTX must be followed.
g. If sexually-active male, must be surgically sterile (e.g., non-reversed vasectomy with confirmed azoospermia) or use condom during the study and during the
(PG-760564) follow-up period;
NOTE: All contraception precautions for MTX must be followed.
h. Who are willing and able to participate in the study and provide signed informed consent.

Patients with any of the following will not be entered into the study:
a. Active or latent tuberculous infection as defined below:
1. History of tuberculosis (TB), or
2. Chest X-ray suggestive of former or current tuberculous infection, or
3. Positive tuberculin skin test with purified protein derivative of tuberculin (PPD) >=5 mm in a patient without history of vaccination with bacillus Calmette-Guérin (BCG), or
4. In Europe, vaccination with BCG and positive PPD >8 mm, or
5. In Europe, vaccination with BCG and positive PPD >=5 mm but <=8 mm and any of the following risk factors:
i. silicosis
ii. residents and employees of high-risk congregate settings
iii. weight loss >10% of ideal body weight
iv. gastrectomy
v. jejunoileal bypass, or
6. In US, vaccination with BCG and positive PPD >=5 mm;
b. Active listeriosis;
c. History of episode of infection requiring hospitalization within 30 days before screening or episode of infection requiring intravenous (IV) antibiotics within 30 days before screening or current active infection;
d. History of chronic or recurrent infections, or immunodeficiency;
e. Indwelling catheters;
f. Bronchiectasis;
g. History of uveitis or other inflammatory eye disease;
h. Autoimmune diseases other than RA [mixed connective tissue disease (MCTD), seronegative spondyloarthropathy, systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD), psoriatic arthritis, sarcoidosis, etc.], except Sjogren*s syndrome secondary to RA;
i. Chronic liver diseases, serologic evidence for infection with hepatitis B or hepatitis C [positive hepatitis B surface antigen (HepBsAg) or hepatitis C antibody (HepCAb)];
j. History of alcohol or drug abuse;
k. Abnormal hepatic and renal functions (LFTs and serum creatinine values elevated above the Central laboratory normal reference range on screening or baseline visits); patients with known elevations of transaminases greater than 1.2 times the upper limit of normal (ULN) on 2 or more occasions in the 6 months before screening will be excluded.
l. Platelets <100 x 109/L;
m. Abnormal WBC and/or significant abnormalities in other complete blood count (CBC) values. Hemoglobin (Hgb) <10 mg/dL;
n. Joint surgery within 2 months of screening;
o. History of lymphoma, leukemia, or lymphoproliferative disorders;
(PG-760564)
p. History of other malignancies other than treated basal cell carcinoma of the skin;
q. History of demyelinating diseases;
r. History of heart failure, New York Heart Association (NYHA) class III or IV (Appendix 7);
s. Pregnant or lactating women, or women who plan to become pregnant;
t. Personal or family history of prolonged QT syndromes. Family history of sudden cardiac death due to arrhythmia or unknown cardiac problems (presumed QT problems);
u. Other risk factors for torsade de pointes (TdP), e.g., history of significant arrhythmias including history of ventricular tachycardia or fibrillation [unless patient has implantable cardiac defibrillator (ICD)]; atrial fibrillation or flutter; history of sick sinus syndrome or significant heart blocks (unless patient has pacemaker); ECGs showing prolongation of QTc interval (>440 msec);
v. Hypokalemia, hypomagnesemia, or hypocalcemia;
w. Drugs known to cause prolongation of QT interval (must be off for at least 5 half-lives to be enrolled) (see list in Appendix 8);
x. Demonstrated likelihood not to comply with protocol requirements ;
y. Current participation in another clinical trial involving active intervention;
z. Known allergy to components of the study medication;
aa. History of efficacy failure with etanercept, infliximab, adalimumab, anakinra, and abatacept;
bb. History of treatment with B-cell depleting therapies (rituximab) and immunoadsorption (Prosorba Column);
cc. History of treatment with p-38 MAP kinase inhibitors;
dd. History of treatment with cyclosporine, cyclophosphamide, or other alkylating agents;
ee. Other diseases requiring immunosuppressive therapy;
ff. Treatment with leflunomide within 6 months prior to study entry;
gg. Intra-articular or intramuscular steroids within 4 weeks before screening;
hh. Change in non-steroidal anti-inflammatory drug (NSAID) and/or corticosteroid doses within 30 days prior to entry into the study (Day 1 of the washout period);
ii. Treatment with any experimental/investigational therapy within the last 2 months for chemical and 6 months (from screening date) for biologic drugs;
jj. Use of the following inducers of CYP 3A4 (carbamazepine, phenobarbital, phenytoin, St John's Wort and troglitazone) or inhibitors of CYP 3A4 (diltiazem, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, mibefradil, nefazodone, troleandomycin, cimetidine, and verapamil); the washout period for these drugs will be 5 days except for phenobarbital for which it will be 21 days;
kk. Patients not treated with folic or folinic acid.
Any other conditions, including important concurrent illnesses (e.g., hypothyroidism) that, in the opinion of the Investigator would jeopardize the study. The Investigator should call the Medical Monitor should there be any questions.