Study to Evaluate Safety and Efficacy of CCX 354-C in Subjects With Rheumatoid Arthritis

1. Male or female subjects, aged 18-75 years inclusive, with stable RA based on American College of Rheumatology (ACR) criteria (see section 11.3) for at least 3 months (subjects do not need to have active RA for Stage A of the study);
2. Subjects must have been on a stable dose of methotrexate (7.5 to 25 mg/week) taken orally, subcutaneously, or intramuscularly, but not intravenously, for ≥ 8 weeks prior to randomization;
3. If a subject is also taking sulfasalazine or hydroxychloroquine, the subject must have been on a stable dose of these medications for at least 8 weeks prior to randomization;
4. If a subject is on corticosteroid therapy, the dose must not exceed 10 mg prednisone or equivalent and the subject must have been on a stable dose for at least 4 weeks prior to randomization;
5. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol;
6. Negative result of the human immunodeficiency virus (HIV) screen, the hepatitis B screen, and the hepatitis C screen;
7. Judged to be otherwise healthy by the Investigator, based on medical history, physical examination (including electrocardiogram [ECG]), and clinical laboratory assessments;
8. Female subjects of childbearing potential, and male subjects with partners of childbearing potential, may participate if adequate contraception is used during, and for at least the four weeks after, any administration of study medication. Adequate contraception is defined as usage by at least one of the partners of a barrier method of contraception, together with usage by the female partner, commencing at least three months prior to Screening, of a stable regimen of any form of hormonal contraception or an intra-uterine device. Use of abstinence alone is not considered adequate. Use of a barrier method alone is considered adequate only if the male partner was vasectomized at least six months prior to Screening. Use of a double-barrier method of contraception is acceptable.

Exclusion Criteria:

1. Diagnosed with RA prior to 16 years of age;
2. Women who are pregnant, breastfeeding, or have a positive serum pregnancy test at Screening;
3. History within one year prior to randomization of illicit drug use;
4. History of alcohol abuse at any time in the past;
5. Use of infliximab, adalimumab, abatacept, certolizumab, golimumab, or tocilizumab within 8 weeks of randomization;
6. Use of leflunomide within 6 months of randomization;
7. Use of etanercept or anakinra within 4 weeks of randomization;
8. Use of rituximab or ocrelizumab, or cytotoxic agents, such as cyclophosphamide or chlorambucil, within one year of randomization;
9. Currently taking cytochrome P450 inhibitors including protease inhibitors such as ritonavir,indinavir, nelfinavir, or macrolide antibiotics such as erythromycin, telithromycin,clarithromycin, or azole antifungals such as fluconazole, ketoconazole, itraconazole, or cimetidine, nefazodone, bergamottin (constituent of grapefruit juice), quercetin, aprepitant,or verapamil;
10. History or presence of any form of cancer within the 10 years prior to randomization, with the exception of excised basal cell or squamous cell carcinoma of the skin, or cervical carcinoma in situ or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis;
11. Evidence of tuberculosis based on chest X rays, tuberculin skin test, QuantiFERON®-TB Gold test, or T-SPOT®.TB test performed during screening;
12. Presence of Felty's syndrome, psoriatic arthritis, or other auto-immune diseases;
13. Major surgery (including joint surgery) within 12 weeks prior to randomization;
14. Subject's hemoglobin is less than 11 g/dL (6.83 mmol/L) at Screening;
15. Subject has any evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin > 1.5 x the upper limit of normal;
16. Subject has any evidence of renal impairment; serum creatinine > 1.5 x upper limit of normal;
17. The subject had an infection requiring antibiotic treatment within 4 weeks of randomization;
18. History or presence of any medical or psychiatric condition or disease, or laboratory abnormality that, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation and may prevent the subject from completing the study; and
19. Participated in any clinical study of an investigational product within 30 days prior to randomization.