The purpose of this study is to investigate the safety and efficacy of multiple dose levels of the investigational product (study drug), IPI-145, in combination with methotrexate compared to methotrexate alone in subjects with active moderate-to-severe Rheumatoid Arthritis.

This Phase 2 study is designed to examine the efficacy and safety of multiple dose levels of IPI-145 in subjects with active moderate-to-severe Rheumatoid Arthritis receiving a background stable dose of methotrexate. The study will employ a randomized, double-blind, placebo-controlled, parallel design.

Approximately 316 adult subjects who meet all eligibility criteria at Screening will be randomized at Baseline in a 1:1:1:1 ratio to one of 4 dose groups.

All treatments will be administered twice a day (BID). After randomization, subjects will enter a 12-week Treatment Period, where study drug (IPI-145 or placebo) will be self-administered BID as an outpatient. During the Treatment Period, subjects will return to the clinic for efficacy and safety assessments every 2 weeks. Following Treatment Period completion at Week 12, subjects will enter a 3-week Follow-up Period which includes one clinic visit approximately 3 weeks after the last dose of study drug.

Inclusion Criteria:

• Documented diagnosis of Rheumatoid Arthritis for at least 6 months
• Active disease, based on Screening clinical and laboratory criteria, despite taking methotrexate for at least 3 months

Exclusion Criteria:

• Pregnant or lactating females
• Previous failure or inadequate response to >2 biologic disease-modifying anti-rheumatic drugs (DMARDs)
• Concurrent DMARD treatment other than methotrexate, sulfasalazine, chloroquine, or hydroxychloroquine
• Treatment with > 10 mg daily prednisone (or equivalent) or more than one non-steroidal anti-inflammatory drug