Study of Apremilast to Evaluate the Safety and Effectiveness for Patients With Rheumatoid Arthritis

Inclusion Criteria:

- Must have a documented diagnosis of Rheumatoid Arthritis (1987 American College of
Rheumatology Criteria) with onset of signs/symptoms of disease ≥ 4 months of duration
from randomization.

- Must be receiving treatment on an outpatient basis.

- Must have active disease despite current methotrexate treatment as defined below:

- ≥ 6 swollen joints (66 swollen joint count) AND

- ≥ 6 tender joints (68 tender joint count)

-. Must meet at least one of the four lab requirements below:

- High Sensitivity C-Reactive Protein (hsCRP) ≥ 10 mg/L

- Erythrocyte Sedimentation Rate (ESR) > 28 mm after the first 1 hour

- Positive for Rheumatoid Factor (RF)

- Positive for Anti-cyclic Citrullinated Peptide (anti-CCP) antibodies

- For participants participating in the Magnetic Resonance Imaging (MRI) assessment:

• Must have Rheumatoid Arthritis joint involvement, as assessed by swollen joint
counts in: 1) at least two Metacarpophalangeal (MCP) swollen joints on the same hand,
or 2) at least one swollen Metacarpophalangeal (MCP) joint and swollen wrist on the
same hand.

- Must have been treated with methotrexate for at least 4 months prior to randomization,
and must be on stable dose. Participants will be required to maintain their stable
dose through Week 52 of the study. Oral folate (folic acid) supplementation is
required with a minimum dose of 5 mg/week, or instead leucovorin may be used up to 10
mg/week orally.

• Non-steroidal anti-inflammatory drugs (NSAIDs) and pain medications are allowed,
however, must be on stable regimen for at least 7 days prior to randomization and
through Week 52 of the study.

- Oral corticosteroids (if taken) are allowed, however, must be on stable dose of
prednisone ≤ 10 mg/day or equivalent for at least 28 days prior to randomization and
through Week 52 of the study.

- Must meet the following laboratory criteria at screening:

- White blood cell count ≥ 3000/mm^3 (≥ 3.0 x 10^9/L) and < 14,000/mm^3 (< 14 x
10^9/L)

- Platelet count (≥ 100,000/μL ((≥ 100 x 10^9/L)

- Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)

- Aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT)
and alanine aminotransferase or serum glutamic-pyruvic transaminase (ALT/ SGPT) ≤
2 x upper limit of normal (ULN). If initial test shows Aspartate aminotransferase
(AST) or alanine aminotransferase (SLT) or 2 times the upper limit of normal
(ULN), one repeat test is allowed during the screening period.

- Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L). If initial test result is > 2 mg/dL, one
repeat test is allowed during the screening period.

- Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)

- Hemoglobin A1c ≤ 9.0%

- Negative for hepatitis B surface antigen

- Negative for hepatitis C antibody

- Males who engage in activity in which conception is possible must use protocol
described barrier contraception while on Investigational Product and for at least 28
days after the last dose of Investigational Product.

- Females of childbearing potential (FCBP) must have a negative pregnancy test at
Screening and Baseline. FCBP who engage in activity in which conception is possible
must use protocol described contraception while on Investigational Product and for at
least 28 days after taking the last dose or Investigational Product.

Exclusion Criteria:

- Major surgery (including joint surgery) within 8 weeks prior to screening or planned
major surgery within 6 months following randomization.

- Rheumatic autoimmune disease other than Rheumatoid Arthritis, including systemic lupus
erythematosus, mixed connective tissue disease, scleroderma, polymyositis or
significant systemic involvement secondary to Rheumatoid Arthritis (eg, vasculitis,
pulmonary fibrosis or Felty syndrome). Sjögren syndrome secondary to Rheumatoid
Arthritis is allowable.

- Functional Class IV as defined by the American College of Rheumatology (ACR)
Classification of Functional Status in Rheumatoid Arthritis.

- Prior history of, or current, inflammatory joint disease other than Rheumatoid
Arthritis (eg, gout, reactive arthritis, psoriatic arthritis, ankylosing spondylitis,
Lyme disease).

- Receiving treatment with Disease-modifying antirheumatic drugs (DMARDs) (other than
methotrexate), including biologic Disease-modifying antirheumatic drugs
(DMARDs)Previous use is only allowed after adequate washout prior to randomization.

- Inadequate response to treatment with an anti-tumor necrosis factor (anti-TNF) agent.
Patients who terminated previous anti-tumor necrosis factor (anti-TNF) treatment due
to cost or safety reason, such as discomfort with the subcutaneous injections, may
participate in this study after adequate washout.

- Treatment with any investigational agent within four weeks (or five half-lives of the
investigational drug, whichever is longer) of screening.

- Previous treatment with any cell depleting therapies, including investigational
agents.

- Treatment with intravenous gamma globulin, plasmapheresis or Prosorba® column within 6
months of baseline.

- Intra-articular or parenteral corticosteroids are not allowed within 6 weeks prior to
randomization.

- Any previous treatment with alkylating agents such as cyclophosphamide or
chlorambucil, or with total lymphoid irradiation.

- Pregnant women or nursing (breast feeding) mothers.

- Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary
(including severe or very severe chronic obstructive pulmonary disease), renal,
hepatic, endocrine (including uncontrolled diabetes mellitus as defined by Hemoglobin
A1c > 9.0%) or gastrointestinal (GI) disease.

- Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease,
where flares are commonly treated with oral or parenteral corticosteroids.

- Known active current or history of recurrent bacterial, viral, fungal, mycobacterial
or other infections (including but not limited to tuberculosis and atypical
mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding
onychomycosis) or any major episode of infection requiring hospitalization or
treatment with IV or oral antibiotics within 4 weeks of screening.

- History of positive Human Immunodeficiency Virus (HIV), or congenital or acquired
immunodeficiency (eg, Common Variable Immunodeficiency Disease).

- History of malignancy, including solid tumors and hematologic malignancies (except
basal cell carcinoma of the skin that has been excised and cured).

- History of alcohol, drug or chemical abuse within the 6 months prior to screening.

- Any significant medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from participating in the study.

- Any condition including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.

- Any condition that in the investigator's opinion would interfere significantly with
the efficacy evaluations, including the pain and joint assessments (eg, fibromyalgia).

For Magnetic Resonance Imaging (MRI) Only:

- Receiving medication(s) or will require medication(s) during the study that impact on
vascular flow (eg, nitrates, calcium channel blockers, ergot containing drugs) on the
day of the Magnetic Resonance Imaging (MRI test and in the investigator's judgement
the subject cannot hold back from taking these medications on the day of the Magnetic
Resonance Imaging (MRI) prior to the Magnetic Resonance Imaging (MRI) test. The
subject can continue taking the medication(s) at any time after the Magnetic Resonance
Imaging (MRI) test is completed, as clinically indicated and scheduled. Exclusions of
antihypertensive and migraine medications can be determined after discussion with the
Sponsor.

- Unable to undergo an Magnetic Resonance Imaging (MRI) examination, including but not
limited to the presence of a pacemaker, defibrillator, or other implanted device such
as anterior interbody cages, aneurysm clip, pedicle screws, or any other metal
contained in the body (eg, such as tattoos that contain metallic pigment, or metal in
the eyes from metal grinding [eg, a metal worker, etc]), or severe claustrophobia, or
any other contraindication to an Magnetic Resonance Imaging (MRI) as per local imaging
center guidelines.

- Allergic or adverse reactions to gadolinium

- Estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2 (based on the
Modification of Diet in Renal Disease [MDRD] formula).