Efficacy and Safety Study of Apremilast to Treat Active Psoriatic Arthritis (PsA)

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy and Safety Study of Two Doses of Apremilast (CC-10004) in Subjects With Active Psoriatic Arthritis Who Have Not Been Previously Treated With Disease-modifying Antirheumatic Drugs

The purpose of this study is to determine whether apremilast is safe and effective in the treatment of patients with psoriatic arthritis who have not been previously treated with DMARDs.

Apremilast is proposed to improve signs and symptoms of psoriatic arthritis (tender and swollen joints, pain, physical function) in treated patients.

Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in 6-39% of psoriasis patients. The immunopathogenesis of PsA, which mirrors but is not identical to that seen in psoriatic plaques, reflects a complex interaction among resident dendritic, fibroblastic and endothelial cells, and inflammatory cells attracted to the synovium by cytokines and chemokines. Apremilast (CC-10004) is a novel oral agent that modulates multiple inflammatory pathways through targeted phosphodiesterase type 4 (PDE4) enzyme inhibition. Therefore, apremilast has the potential to be effective in the treatment of PsA.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Male or female, aged ≥ 18 years at time of consent.

2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Have a documented diagnosis of Psoriatic Arthritis (PsA, by any criteria) of ≥ 3 months duration.

5. Meet the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA at time of screening.

6. Have ≥ 3 swollen AND ≥ 3 tender joints.

7. Have not been previously treated with disease-modifying antirheumatic drugs (DMARDS) (small molecules or biologics)

8. Be receiving treatment on an outpatient basis.

9. If taking oral corticosteroids, must be on a stable dose of prednisone ≤ 10 mg/day or equivalent for at least 1 month prior to screening.

10. If taking nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotic analgesics, must be on stable dose for at least 2 weeks prior to screening and until they have completed the Week 24 study visit.

11. Low potency topical corticosteroids (Appendix M or locally available equivalent) will be allowed as background therapy for treatment of psoriasis on the face, axillae and groin in accordance with the manufacturers' suggested usage during the course of the study. Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. A non-medicated skin emollient (eg, Eucerin cream) will also be permitted for body lesions only. Subjects must not use these treatments within 24 hours prior to the clinic visit.

12. Meet the following laboratory criteria:

    • White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (< 14 x 109/L)
    • Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
    • Serum creatinine ≤ 1.5 mg/dL(≤ 132.6 μmol/L)
    • Aspartate aminotransferase/Serum glutamic oxaloacetic transaminase (AST/SGOT) and Alanine aminotransferase/Serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2 x upper limit of normal (ULN)
    • Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L)
    • Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
    • Hemoglobin A1c ≤ 9.0%

13. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex condom or any nonlatex condom NOT made out of natural [animal] membrane [eg, polyurethane]) while on IP and for at least 28 days after the last dose of IP.

14. 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 2 forms of contraception while on investigational product (IP) and for at least 28 days after the last dose of IP: one highly effective form (ie, hormonal, intrauterine device [IUD], tubal ligation, vasectomized partner) and one additional form (latex condom or any nonlatex condom NOT made out of natural [animal] membrane [eg, polyurethane], diaphragm, sponge). If one highly effective form of contraception cannot be used, then 2 forms of barrier contraception must be used, ie, latex condom or any nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane) with either of the following: sponge with spermicide or diaphragm with spermicide.

Exclusion Criteria:

1. History of clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.
2. Any condition, including the presence of laboratory abnormalities that 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.
3. Clinically significant abnormality on 12-lead electrocardiography (ECG) at Screening.
4. Pregnant or breast feeding.
5. History of allergy to any component of the IP.
6. Hepatitis B surface antigen positive at screening.
7. Hepatitis C antibody positive at screening.
8. AST/SGOT and/or ALT/SGPT > 1.5 x ULN and total bilirubin > ULN or albumin < lower limit of normal (LLN).
9. History of positive Human Immunodeficiency Virus (HIV), or congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease).
10. Active tuberculosis or a history of incompletely treated tuberculosis.
11. Clinically significant abnormality based upon chest radiograph with at least PA view (radiograph must be taken within 12 weeks prior to Screening or during the Screening visit). An additional lateral view is strongly recommended but not required.
12. Active substance abuse or a history of substance abuse within 6 months prior to Screening.
13. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections must have been completed at least 4 weeks prior to Screening.
14. Malignancy or history of malignancy (except for treated [ie, cured] basal cell or squamous cell in situ skin carcinomas and treated [ie, cured] cervical intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix).
15. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
16. Erythrodermic, guttate, or pustular psoriasis.
17. Topical therapy for psoriasis, except as noted in the Inclusion Criteria, within 2 weeks of randomization (including but not limited to topical corticosteroids, topical retinoids or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin).
18. Rheumatic autoimmune disease other than PsA, including systemic lupus erythematosis (SLE), mixed connective tissue disease (MCTD), scleroderma, or polymyositis.
19. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis (Appendix Q).
20. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive arthritis, RA, ankylosing spondylitis, Lyme disease).
21. Prior use of disease modifying antirheumatic drugs (DMARDS; small molecules or biologics).
22. Use of the following systemic therapy(ies) within 4 weeks of randomization, including but not limited to corticosteroids (except as noted in inclusion criteria), oral retinoids and fumaric acid esters.
23. Use of phototherapy within 4 weeks of randomization (ie, UVB, PUVA).
24. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20).
25. Treatment with intravenous gamma globulin, plasmapheresis, or Prosorba® column within 6 months of baseline.
26. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
27. Prior treatment with apremilast.
28. Use of any investigational drug within 4 weeks of randomization, or 5 pharmacokinetic/ pharmacodynamic half lives, if known (whichever is longer).