| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Psoriatic arthritis is a form of arthritis that affects some people who have psoriasis (scaly skin). Joint pain, stiffness and swelling are the main symptoms of psoriatic arthritis. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037160 |
| E.1.2 | Term | Psoriatic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 |
| The primary objective of the study is to evaluate the efficacy of apremilast 30 mg twice a day (BID) on inflammation indices, assessed by magnetic resonance imaging (MRI) of the hand. |
|
| E.2.2 | Secondary objectives of the trial |
- The efficacy of apremilast 30 mg BID on imaging outcomes associated with structural progression,
assessed by MRI of the hand.
- The efficacy of apremilast 30 mg BID on disease activity and functionality, assessed by clinical outcomes
- The efficacy of apremilast 30 mg BID on inflammation indices of peripheral arthritis and enthesitis, total (sum of arthritis and enthesitis) and separately, assessed by whole-body MRI (WB-MRI)
- The efficacy of apremilast 30 mg BID on The European League Against Rheumatism Psoriatic Arthritis Impact of Disease 12 domains (PsAID-12)
- The safety and tolerability of apremilast 30 mg BID |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females, aged ≥ 18 years at time of consent
2. For all regions, the local Regulatory Label for treatment with apremilast must be followed. For example, subjects in the EU must have had inadequate response or intolerance to a prior csDMARD.
3. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted
4. Able to adhere to the study visit schedule and other protocol requirements
5. Have a documented diagnosis of PsA of ≥ 3 months AND ≤ 5 years in duration, meeting the CASPAR criteria for PsA (Appendix B, Taylor, 2006) at the time of Screening Visit
6. Have ≥ 3 swollen AND ≥ 3 tender joints, with hand involvement (defined as ≥ 1 swollen joint or dactylitis [each clinically active joint of a dactylitic digit is counted as one joint]).
7. Have at least 1 active enthesitis site (one of the SPARCC or LEI sites)
8. Must not have been treated previously with a TNF blocker or other biologic drug for PsA treatment
9. Must not have been treated with more than 2 csDMARDs
10. Subjects taking csDMARDs, with the exception of MTX, cyclosporine, or LEF (see Section 4.4, Exclusion Criterion 18, 19 and 20), do not require a washout period. However, they must discontinue the csDMARD treatment at least one day prior to their Baseline Visit (ie, Visit 2, Day 1)
11. Subjects who have been previously treated with MTX for < 6 months and who are not on stable doses for at least 3 months will require a 28-day washout prior to the Baseline Visit (ie, Visit 2, Day 1) to participate in the study
12. Subjects who have been previously treated with LEF will require a 12-week washout prior to the Baseline Visit (ie, Visit 2, Day 1), or treatment with cholestyramine, per LEF
prescribing label (ie, 8 g cholestyramine 3 times daily for 11 days)
13. Subjects who have been previously treated with cyclosporine will require a 28-day washout prior to the Baseline Visit (ie, Visit 2, Day 1) to participate in the study
14. If taking MTX (≤ 25 mg/week), continuity of treatment will be allowed if duration of treatment is ≥ 6 months and on a stable dose for at least 3 months prior to the Baseline Visit (ie, Visit 2, Day 1)
15. If taking oral glucocorticoids, must be on a stable dose of prednisone ≤ 10 mg/day or equivalent for at least 4 weeks prior to the Baseline Visit (ie, Visit 2, Day 1)
16. If taking NSAIDs or narcotic analgesics, must be on stable dose for at least 4 weeks prior to Baseline Visit (ie, Visit 2, Day 1)
17. A female of childbearing potential (FCBP)† must have a negative pregnancy test at screening and baseline. While on IP and for at least 28 days after taking the last dose of IP, a FCBP who engages 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; 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.
Note: Option 2 may not be acceptable as a highly effective contraception option in all countries , per local guidelines/ recommendations.
† An FCBP is defined as a sexually mature female who 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24
consecutive months).
§ The female subject’s chosen form of contraception must be effective by the time the female subject is screened into the study (for example, hormonal contraception should be initiated at least 28 days before screening).
18. Must be in general good health (except for PsA) as judged by the investigator, based on medical history, physical examination, and clinical laboratories. (Note: The definition of good health means a subject does not have uncontrolled significant comorbid conditions). |
|
| E.4 | Principal exclusion criteria |
1. Contraindication to MRI examination including, but not limited to, intracranial metal clips, heart pacemakers, insulin pumps, implanted hearing aids, neurostimulators, metal hip replacements, profound claustrophobia or inability to lie in the MRI machine in an appropriate position to obtain quality images, history of hypersensitivity to gadolinium contrast agent.
2. Severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft–Gault equation), which would prevent the use of gadolinium enhancement
3. History of clinically significant (as determined by the investigator) cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease
4. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
5. Prior history of suicide attempt at any time in the subject’s lifetime prior to signing the informed consent, or major psychiatric illness requiring hospitalization within the last 3 years prior to signing the informed consent.
6. Pregnant or breast feeding
7. Active substance abuse or a history of substance abuse within 6 months prior to screening
8. History of allergy or hypersensitivity to any component of the IP
9. History of are hereditary problems of galactose intolerance, lapp lactose deficiency or glucose malabsorption
10. History of positive human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease)
11. Active tuberculosis or a history of incompletely treated tuberculosis
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 or myeloproliferative or lymphoproliferative disease within the past 3 years, except for treated (ie, cured) basal cell or squamous cell in situ skin carcinomas;
14. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following Baseline Visit
15. Rheumatic autoimmune disease other than PsA, including, but not limited to: systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or fibromyalgia
16. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive arthritis, RA, ankylosing spondylitis, Lyme disease), which confounds the ability to interpret data from the study
17. Prior treatment with any biologic DMARD
18. Prior treatment with more than 2 csDMARDs
19. Use of the following systemic therapy(ies) within 28 days of the Baseline Visit (ie, Visit 2, Day 1): cyclosporine or other calcineurin inhibitors, glucocorticoids exceeding 10 mg daily prednisone equivalent, as well as mycophenolate.
20. Use of MTX within 4 weeks of the Baseline Visit (ie, Visit 2, Day 1), unless subject is on stable doses for at least 3 months and total treatment duration with MTX is ≥ 6 months
21. Use of LEF within 12 weeks of the Baseline Visit (ie, Visit 2, Day 1), unless subject has taken cholestyramine, 8 g three times daily X 11 days after stopping LEF
22. Previous treatment with a JAK inhibitor (including tyk2 inhibitor)
23. Prior treatment with apremilast, or participation in a clinical study involving apremilast
24. Use of intra-articular (IA) glucocorticoid injection within 8 weeks before the Baseline Visit (ie, Visit 2, Day 1).
25. Use of any investigational drug within 4 weeks of the Baseline Visit, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) Inflammation Score of bone marrow edema [BME] + synovitis + tenosynovitis |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
EFFICACY ENDPOINTS
1. PsAMRIS Inflammation Score of BME + Synovitis + Tenosynovitis
2. PsAMRIS BME + Synovitis
3. PsAMRIS Total Inflammation Score (BME + Synovitis + Tenosynovitis + Periarticular Inflammation)
4. PsAMRIS BME
5. PsAMRIS Synovitis
6. PsAMRIS Tenosynovitis
7. PsAMRIS Periarticular Inflammation
8. PsAMRIS Total Damage Score (erosion + bone proliferation)
9. PsAMRIS Erosion
10. PsAMRIS Bone Proliferation
11. Swollen Joint Count (SJC)
12. Tender Joint Count (TJC)
13. Clinical Disease Activity Index for Psoriatic Arthritis (c-DAPSA)
14. Spondyloarthritis Research Consortium of Canada (SPARCC)
15. Leeds Enthesitis Index (LEI)
16. Enthesitis improvement to 0
17. Leeds Dactylitis Index (LDI)
18. Dactylitis improvement to 0
19. Psoriatic Arthritis Disease Activity Score (PASDAS)
20. Evaluator’s Global Assessment of Disease Activity
21. Subject’s Global Assessment of Disease Activity
22. Subject's Assessment of Pain
23. Health Assessment Questionnaire-Disability Index (HAQ-DI)
24. WB-MRI Peripheral Enthesitis Inflammation Index
25. WB-MRI Peripheral Joints Inflammation Index
26. WB-MRI Total Peripheral Inflammation Index
27. BASDAI
28. The European League Against Rheumatism Psoriatic Arthritis Impact of Disease 12 domains (PsAID-12)
SAFETY ENDPOINTS
29. Adverse events (AEs)
30. Discontinuation due to AEs
31. Clinically significant changes in physical examination, vital signs, and/or laboratory findings |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
#1: Week 48.
#2 - #28: Week 24 & 48
#29 - #31: throughout the study |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Germany |
| Italy |
| Russian Federation |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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