The Controlled Trial of Apremilast for Rheumatoid Arthritis Treatment (CARAT)

Many manifestations associated with RA result from, or are significantly influenced by, the
effects of pro-inflammatory cytokines (e.g., TNF, IL-1, IL-6). Specific inhibition of these
cytokines with newer, parenterally administered biologic agents has revolutionized the
treatment of RA. Apremilast is a novel, orally administered drug which approaches the
reduction of pro-inflammatory cytokines via inhibition of phosphodiesterase type 4 (PDE4).

Apremilast, Acetamide, N-[2-[ (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)
ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl] is a phosphodiesterase type 4 (PDE4) inhibitor
under development for use in the treatment of inflammatory conditions.

PDE4 is one of the major phosphodiesterases expressed in leukocytes. Inhibitors of PDE4 cause
accumulation of intracellular cyclic adenosine monophosphate (cAMP), which in turn activates
protein kinase A and other downstream effectors, resulting in inhibition of pro-inflammatory
cytokine transcription and other cellular responses such as neutrophil degranulation,
chemotaxis, and adhesion to endothelial cells.

In human cellular models, apremilast inhibited production of inflammatory mediators such as
TNF-α, IL-12, IL-2, IFN-γ, IL-5, IL-8, leukotriene B4 (LTB4), and the adhesion molecule
CD18/CD11b (Mac-1).

Apremilast has also been shown to be a potent anti-inflammatory agent in several animal
models of inflammation.

Inclusion Criteria:

- Must be able to adhere to the study visit schedule and other protocol requirements

- documented rheumatoid arthritis (RA) diagnosis by the 1987 American College of
Rheumatology (ACR) criteria for at least 6 months

- disease duration 6 or more months (from symptom onset)

- failed 1 or more DMARD

- active RA despite current DMARD therapy; active disease defined as 4 or more tender
and 4 or more swollen joints (out of 28 joints examined) and any one of the following:

- ESR 28 or higher mm/hr;

- CRP 1.0 or more mg/dl;

- Morning stiffness 45 or more minutes.

- Patients receiving DMARD or biologic therapy must undergo a drug washout.

- Patients receiving a nonsteroidal anti-inflammatory drug (NSAID) and/or prednisone (10
or less mg day) must be on stable doses of these agents for more than 2 weeks.

- Must meet laboratory criteria as specified in the protocol

- Females of childbearing potential (FCBP) must have a negative urine pregnancy test at
screening and must adhere to adequate forms of contraception as defined in the
protocol. Must agree to pregnancy tests every 28 days while on study medication.

- Males (including those who have had a vasectomy) must agree to use barrier
contraception (latex condoms) when engaging in sexual activity with FCBP while on
study medication and for 28 days after taking the last dose of study medication

Exclusion Criteria:

- Inability to provide voluntary consent

- History of any clinically significant cardiac, endocrinologic, pulmonary, neurologic,
psychiatric, hepatic, renal, hematologic, neurologic, gastrointestinal, immunologic,
or other major diseases

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study

- Pregnant or breastfeeding female

- Systemic fungal infection

- Active tuberculosis (TB) or a history of incompletely treated tuberculosis.

- History of recurrent bacterial infection (at least 3 major infections resulting in
hospitalization and/or requiring intravenous antibiotic treatment within the past 2
years)

- Clinically significant abnormality on the chest x-ray (CXR) at screening. Chest x-rays
performed within 3 months prior to start of study drug are acceptable.

- Use of any investigational medication within 28 days prior to randomization or 5
half-lives if known (whichever is longer)

- Any clinically significant abnormality on 12-lead ECG at screening

- History of congenital or acquired immunodeficiency (eg, Common Variable
Immunodeficiency [CVID])

- History of Human Immunodeficiency Virus (HIV) infection

- Presence of hepatitis B surface antigens (HBsAg) or Hepatitis core antibody positive
at screening.

- Antibodies to Hepatitis C virus at screening

- History of malignancy within 5 years prior to the screening visit (except for treated
[i.e. cured] basal cell skin carcinomas and treated [i.e. cured] carcinoma in situ of
the cervix)

- currently on DMARD therapy

- currently taking biologics

- treated with rituximab in the last 6 months

- Recent hospitalization (last 3 months)

- Planned pregnancy or major surgery