Concomitant Use of Apremilast for the Treatment of Active RA Despite TNF-Inhibition and Methotrexate- CATARA

The primary objective of this study is to evaluate the efficacy of apremilast when used in
combination with a background DMARD and TNF inhibition in patients with active RA using the
ACR responder index looking for a 20% improvement.

To evaluate the safety and tolerability of apremilast when used in combination with TNF
inhibition in patients with active RA.

To evaluate the clinical outcomes in RA using the individual domains of the ACR responder
index1 .

To evaluate the clinical outcomes of RA using the Disease Activity Score (DAS28)2 To
investigate the effects of apremilast on change in cytokine plasma concentration levels
(from baseline to Week 12) and the achievement of an ACR response

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form

- 18 years of age at the time of signing the informed consent form.

- Able to adhere to the study visit schedule and other protocol requirements

- Must have a diagnosis of RA of at least 6 months duration based on the ACR criteria

- Must have evidence of active disease with DAS-28 > 3.8

- May be on one of the following DMARDs for at least 12 weeks and at a stable dose for
at least 6 weeks:

- Methotrexate 7.5-25mg/week

- Hydroxychloroquine (200-400mg/day)

- Must be on one of the following SQ TNF inhibitors at a stable, label approved dose
for at least 12 weeks:

- adalimumab (Humira®, Abbott Laboratories, North Chicago, IL)

- certolizumab pegol (Cimzia®, UCB, Inc, Smyrna, GA)

- golimumab (Simponi®, Johnson & Johnson, New Brunswick, NJ)

- etanercept (Enbrel®, Amgen, Thousand Oaks, CA and Wyeth Pharmaceuticals,
Philadelphia, PA)

- Concommitant use of non-steroidal anti-inflammatory drugs and/or oral corticosteroids
(prednisone<10mg/day or equivalent) are permitted if doses have been stable for at
least 14 days.

- If taking methotrexate, patient must also be taking folic or folinic acid at at dose
of no less then 5mg/week.

- Must meet the following laboratory criteria:

- Hemoglobin > 9 g/dL

- White blood cell (WBC) count; 3000 /;L (3.0 X 109/L) and 14,000/L (< 14 X 109/L)

- Platelets; 100,000 /L (100 X 109/L)

- Serum creatinine; 1.5 mg/dL (or 133mol/L)

- Total bilirubin; 2.0 mg/dL

- Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and
alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]); 1.5x
upper limit of normal (ULN)

- Females of childbearing potential (FCBP)‡ must have a negative urine pregnancy test
at screening (Visit 1). In addition, sexually active FCBP must agree to use TWO of
the following adequate forms of contraception while on study medication: oral,
injectable, or implantable hormonal contraceptives; tubal ligation; intrauterine
device; barrier contraceptive with spermicide; or vasectomized partner while on
study. A FCBP must agree to have pregnancy tests every 4 weeks while on study
medication and for one month after taking the last dose of study medication.

- Males (including those who have had a vasectomy) must agree to use barrier
contraception (latex condoms) when engaging in reproductive 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

- 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

- Systemic fungal infection

- Active tuberculosis 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) with anteriorposterior
and lateral views at screening. Chest x-rays performed within 3 months prior to start
of study drug are acceptable.

- Use of any investigational medication within 4 weeks prior to start of study drug or
5 pharmacokinetic/pharmacodynamic half-lives (whichever is longer)

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

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

- Hepatitis B surface antigen positive or Hepatitis B core antibody positive at
screening

- History of Human Immunodeficiency Virus (HIV) infection

- Antibodies to Hepatitis C 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)