| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037160 |
| E.1.2 | Term | Psoriatic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of apremilast 30 mg twice daily (BID) monotherapy, compared with placebo, over 24 weeks of treatment, with the primary analysis at Wk 16, in subjects with active psoriatic arthritis |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the onset of clinical effect of apremilast 30 mg BID monotherapy, compared with placebo, in subjects with active psoriatic arthritis.
To evaluate the impact of treatment with apremilast 30 mg BID monotherapy, compared with placebo, on health related quality of life in subjects with active
To evaluate the effect of apremilast 30 mg BID monotherapy, compared with placebo, on inflammatory biomarkers associated with PsA, in a subset of subjects with active psoriatic arthritis
To evaluate pharmacogenetic (PG) markers associated with clinical response to apremilast 30 mg BID monotherapy, compared with placebo, in a subset of subjects with active psoriatic arthritis
psoriatic arthritis.
To evaluate the safety and tolerability of apremilast 30 mg BID monotherapy, compared with placebo, in subjects with active psoriatic arthritis. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study:
1. Males or females, 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 PsA (by any criteria) of ≥ 3 months’ duration
5. Meet the CASPAR criteria for PsA at the time of Screening.
6. Have ≥ 3 swollen AND ≥ 3 tender joints.
7. Must have hsCRP ≥ 0.2 mg/dL at Screening.
8. Must be receiving treatment on an outpatient basis.
9. Must be TNF blocker and other Biologic naïve for dermatologic and rheumatic conditions
10. Subjects taking DMARDs, with the exception of cyclosporine and leflunomide (see Section 7.3. Exclusion Criteria 20, 21), do not require a washout period, 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 ≤ 10 mg/day or equivalent for at least 30 days prior to the Baseline visit (ie, Day 0)
14. If taking 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:
a. White blood cell count ≥ 3000/mm3 (≥ 3.0 X 109/L) and < 14,000/mm3 (< 14 X 109/L)
b. Platelet count ≥ 100,000/mm3 (≥ 100 X 109/L)
c. Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
d. AST (SGOT) and ALT (SGPT) ≤ 2 X upper limit of normal (ULN). If initial test shows ALT or AST > 2 times the ULN, one repeat test is allowed during the Screening period.
e. Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L) or albumin > LLN. If initial test result is > 2
mg/dL, one repeat test is allowed during the Screening period.
f. Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
g. Hemoglobin A1c ≤ 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. |
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| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a subject from enrollment:
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 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 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 and no new or recurrent infections prior to the Baseline visit.
13. Malignancy or history of malignancy, except for:
a. treated [ie, cured] basal cell or squamous cell in situ skin carcinomas;
b. 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 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 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 or Anti IL-17 agents.
25. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, alemtuzumab, ocrelizumab, 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects in each treatment group who achieve an ACR 20 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety: The following safety parameters will be evaluated throughout the duration of the study:
a. Type, frequency, severity and relationship of adverse events to study medication
b. Number of subjects who discontinue study medication due to any adverse event
c. Frequency of clinically significant changes in physical examination, vital signs,
electrocardiogram, and/or laboratory findings
Efficacy (Double-blind Placebo-controlled Treatment Phase):
a. Change from baseline in physical function (Health Assessment Questionnaire-
Disability Index [HAQ-DI] score) at Week 24
b. Proportion of subjects who achieve an ACR 20 at Week 24
c. Change from baseline in the Disease Activity Score (DAS28) at Week 24
d. Change in SF-36v2 physical functioning domain score at Week 24
e. Change from baseline in duration /severity of morning stiffness at Week 24
f. Change from baseline in HAQ-DI score at Week 16
g. Change from baseline in the DAS28 at Week 16
h. Change in SF-36 v2 physical function domain scores at Week 16
i. Change from baseline in duration/ severity of morning stiffness at Week 16
j. Proportion of subjects who achieve an ACR 20 at Weeks 2, 4, 6, 8, 12, and 20
Efficacy at Week 52 (Active Treatment Phase) and Week 104 (Open-label
Extension Phase):
a. Proportion of subjects who achieve an ACR 20 response at Week 52 and Week 104 Change from baseline in physical function [ (HAQ-DI score) at Week 52 and Week 104
b. Change from baseline in the DAS28 at Week 52 and Week 104
c. Change in SF-36 v2 physical function domain scores at Week 52 and Week 104
d. Change from baseline in duration/ severity of Morning Stiffness, at Week 52 and Week 104
Exploratory Endpoints:
a. Change from baseline in ACR component scores at Weeks 16, 24, 52, 68, 84, and 104
b. Proportion of subjects who achieve an ACR 50 response at Weeks 16, 24, 52, 68, 84, and 104
c. Proportion of subjects who achieve an ACR 70 response at Weeks 16, 24, 52, 68, 84, and 104
d. Change from baseline in duration/severity of Morning Stiffness at Weeks 68 and 84
e. Change from baseline in the Gladman Enthesitis Index (GEI) in subjects with
preexisting enthesopathy at Weeks 16, 24, 52, and 104
f. Change in Work Productivity and Activity Impairment: PsA Questionnaire from
baseline at Weeks 16, 24, 52, and 104
g. Change from baseline in the plasma concentration of inflammatory biomarkers
h. Identification of the pharmacogenetic markers associated with a clinical response to apremilast 30 mg BID versus placebo, as defined by the ACR 20, ACR 50, and ACR 70 response rate at Week 16, in a subset of subjects
i. Change from baseline in SF-36 v2 by visit |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Czech Republic |
| Estonia |
| Hungary |
| New Zealand |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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