Safety and Efficacy Study of Apremilast to Treat Psoriatic Arthritis
Condition: Psoriatic Arthritis
MeSH terms: Arthritis; Arthritis, Psoriatic
Intervention: Apremilast 30 mg; Placebo
Intervention description: 30mg of Apremilast will be orally administered twice daily for 104 weeks; Identically appearing Placebo tablets will be orally administered twice daily for up to 24 weeks
Intervention MeSH terms: Apremilast
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 219.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Apremilast, Psoriatic Arthritis, PDE4 inhibitor

Summary:

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

Eligibility criteria:

        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).