Safety and Efficacy Study of Apremilast to Treat Psoriatic Arthritis

A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) Monotherapy in Subjects With Active Psoriatic Arthritis

The purpose of this study is to determine whether apremilast is safe and effective for treating patients with psoriatic arthritis.

This is a Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of apremilast monotherapy in subjects with active psoriatic arthritis.

Approximately 214 subjects will be randomized in a 1:1 ratio to either apremilast 30 mg BID (twice a day) or identically-appearing placebo, with approximately 107 subjects per treatment group.

This is a 113-week study. The subjects will spend 24 weeks in the double-blind, placebo-controlled treatment phase, followed by 28 weeks of active treatment phase (ie, up to Week 52 visit). The original treatment assignments (apremilast 30 mg BID (twice a day) or placebo) will remain blinded until all subjects have completed their Week 52 visit (or have discontinued). After the Week 52 visit, all subjects in the extension phase will continue to receive treatment with apremilast 30 mg BID (twice a day) until the end of the study (ie, up to Week 104 visit) or until early discontinuation from the trial.

The study will consist of 5 phases:

1. Screening Phase - up to 5 weeks
2. Randomized, Placebo-controlled, Double Blind Treatment Phase - Weeks 0 to 24
3. Active Treatment Phase - Week 24 to Week 52
4. Open-label Extension Phase - Week 52 to Week 104
5. Post-treatment Observational Follow-up Phase

Inclusion Criteria:

1. Males or females, 18 years and older 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 (by any criteria) of at least 3 months' duration

5. Meet the classification criteria for psoriatic arthritis (CASPAR) at the time of screening.

6. Have at least 3 swollen AND at least 3 tender joints.

7. Must have high sensitivity C-Reactive Protein (hs-CRP) of at least 0.5 mg/dL at screening and at baseline.

8. Must be receiving treatment on an outpatient basis.

9. Must be tumor necrosis factor (TNF) blocker naive and other Biologic naïve for dermatologic and rheumatic conditions

10. Subjects taking disease modifying anti-rheumatoid drugs (DMARDs), with the exception of cyclosporine and leflunomide (see 7.3. Exclusion Criteria 20, 21), do not require a washout, however, they must discontinue the DMARD treatment at least one day prior to their baseline visit (ie, Visit 2, Day 0)

11. Subjects who have been previously treated with leflunomide will require a 12-week washout or treatment with the cholestyramine, per leflunomide prescribing label (ie. 8 g cholestyramine 3 times daily for 11 days.

12. Subjects who have been previously treated with cyclosporine will require a 4-week washout prior to randomization to participate in the study

13. If taking oral corticosteroids, must be on a stable dose of prednisone less than or equal to 10 mg/day or equivalent for at least 30 days prior to baseline visit (ie, Day 0)

14. If taking nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotic analgesics, must be on stable dose for at least 30 days prior to baseline visit (ie, Day 0) and until they have completed the Week 24 study visit.

15. Must meet the following laboratory criteria:

    • White blood cell count greater than 3000/mm^3 (greater than 3.0 X 10^9/L) and less than 14,000/mm^3 (less than 14 X 10^9/L)
    • Platelet count at least 100,000/mm^3 (at least 100 X 10^9/L)
    • Serum creatinine less than or equal to 1.5 mg/dL (less than or equal to 132.6 μmol/L)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to twice upper limit of normal (ULN). If initial test shows ALT or AST greater than 2 times the ULN, one repeat test is allowed during the screening period.
    • Total bilirubin less than or equal to 2 mg/dL (less than or equal to 34 μmol/L) or Albumin greater than LLN. If initial test result is greater than 2 mg/dL, one repeat test is allowed during the screening period.
    • Hemoglobin at least 9 g/dL (at least 5.6 mmol/L)
    • Hemoglobin A1c less than or equal to 9.0%

16. All females of childbearing potential (FCBP) must use one of the approved contraceptive options as described below while on investigational product and for at least 28 days after administration of the last dose of the investigational product.

    At the time of study entry, and at any time during the study when a female subject of childbearing potential's contraceptive measures or ability to become pregnant changes, the investigator will educate the subject regarding contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy.

    Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. All FCBP subjects who engage in activity in which conception is possible must use one of the approved contraceptive options described below:

    Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or non latex condom NOT made out of natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.

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

Exclusion Criteria:

1. History of clinically significant (as determined by the investigator) cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.

2. 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.

3. Clinically significant abnormality on a 12-lead electrocardiogram (ECG) at Screening.

4. Pregnant or breast feeding.

5. History of allergy to any component of the investigational product.

6. Hepatitis B surface antigen positive at screening.

7. Hepatitis C antibody positive at screening.

8. History of positive human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease).

9. Active tuberculosis or a history of incompletely treated tuberculosis.

10. Clinically significant abnormality based upon chest radiograph with at least posterior-anterior (PA) view (the 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.

11. Active substance abuse or a history of substance abuse within 6 months prior to Screening.

12. 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 and the infection cured, at least 4 weeks prior to Screening.

13. Malignancy or history of malignancy, except for:

    1. treated [ie, cured] basal cell or squamous cell in situ skin carcinomas;
    2. treated [ie, cured] cervical intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years.

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

15. Erythrodermic, guttate, or generalized pustular psoriasis at randomization.

16. Rheumatic autoimmune disease other than PsA, including, but not limited to: systemic lupus erythematosis (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or fibromyalgia.

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

18. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive arthritis, rheumatoid arthritis (RA), ankylosing spondylitis, Lyme disease).

19. Prior treatment with more than one non-biologic DMARD

20. Use of the following systemic therapy(ies) within 4 weeks of randomization: cyclosporine or other calcineurin inhibitors, corticosteroids exceeding 10 mg daily prednisone equivalent, as well as other oral agents such as retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, tacrolimus.

21. Use of leflunomide within 12 weeks of randomization, unless subject has taken cholestyramine, 8g TID (three times a day) x 11 days after stopping leflunomide.

22. Previous treatment with biologic agents for rheumatic diseases such as, but not limited to: adalimumab, abatacept, canakinumab, etanercept, golimumab, infliximab, rilonacept, certolizumab pegol, or tocilizumab.

23. Previous treatment with biologic agents for dermatologic diseases such as alefacept, anti-TNFs (eg etanercept, adalinumab) or ustekinumab.

24. Previous treatment with tofacitinib, Anti IL-17 agents or secukinumab

25. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, alemtuzumab, ocrelizumab, alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20).

26. Treatment with intravenous gamma globulin, plasmapheresis, or Prosorba® column

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

28. Prior treatment with any non-biologic DMARDS other than methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, fumeric acid esters, cyclosporine, or leflunomide

29. Prior treatment with apremilast, or participation in a clinical study, involving apremilast

30. Use of any investigational drug within 4 weeks of randomization, or 5 pharmacokinetic/ pharmacodynamic half lives, if known (whichever is longer).