| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Psoriatic arthritis, an inflammatory arthritis that occurs in 6-39% of
psoriasis patients |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 clinical efficacy of 2 doses of apremilast (20 mg or 30 mg orally twice per day [BID]), compared with placebo, on the signs and symptoms of psoriatic arthritis (PsA) after 16 weeks’ administration |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the following in subjects with active PsA who are treated with apremilast or placebo for up to 24 weeks:
- safety and tolerability
- efficacy
- physical function
- fatigue
- clinical disease activity
To evaluate the following in subjects with active PsA who are treated with apremilast for up to 52 weeks:
- safety and tolerability
- efficacy
- physical function
- fatigue
- clinical disease activity
To evaluate the efficacy, safety, and tolerability of 2 doses of apremilast for up to 5 years' administration to subjects with active PsA |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 PsA (by any criteria) of ≥ 6 months’ duration.
5. Meet the CASPAR criteria for PsA at time of screening.
6. Have ≥ 3 swollen AND ≥ 3 tender joints, despite prior or current treatment with DMARDs (inadequate control by DMARDs applies to therapeutic failure, loss of insurance, intolerance, adverse events, or other reasons for discontinuation).
7. Be receiving treatment on an outpatient basis.
8. If taking methotrexate, leflunomide, or sulfasalazine, must have been treated for at least 16 weeks and on a stable dose (oral or parenteral methotrexate ≤ 25 mg/week; leflunomide ≤ 20 mg/day; sulfasalazine ≤ 2 g/day) for at least 4 weeks prior to screening and through Week 24 of the study. One reduction in DMARD dose will be permitted after Week 24.
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 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 10^9/L) and < 14,000/mm3
(< 14 x 109/L)
- Platelet count ≥100,000/mm3 (≥ 100 x 10^9/L)
- Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
- AST (SGOT) and 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 (male latex condom or any nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on study medication and for a least 28 days after the last dose of study medication.
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 contraception† while on IP and for at least 28 days after taking the last dose of IP with either: 1) one highly effective form (non-oral hormonal, intrauterine device [IUD], tubal ligation, vasectomized partner); or 2) an oral hormonal contraceptive PLUS one additional form of barrier contraception (male or female latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane], diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge with spermicide); or 3) two forms of barrier contraception (male or female latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) PLUS one of the following (diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge with spermicide).
Note: The protocol language regarding contraception has been revised. As this study is fully enrolled, the updated language regarding contraception is included in Section 6.2 (Contraception Education) of this amendment.
† The female subject’s chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at
least 28 days before randomization). |
|
| E.4 | Principal 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 ECG at Screening.
4. Pregnant or breast feeding.
5. History of allergy to any component of the investigational product (IP).
6. Hepatitis B surface antigen positive at screening.
7. Hepatitis C antibody positive at screening.
8. AST (SGOT) and/or ALT (SGPT) > 1.5X ULN and total bilirubin > ULN or albumin < 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 generalized pustular psoriasis at randomization.
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, polymyositis or fibromyalgia.
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. Use of the following systemic therapy(ies) within 4 weeks of randomization, including but not limited to cyclosporine or other calcineurin inhibitors, corticosteroids and small molecule DMARDs (except as noted in inclusion criteria), oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, tacrolimus, azathioprine, fumaric acid esters.
22. Use of phototherapy within 4 weeks of randomization (ie, UVB, PUVA).
23. Use of adalimumab, etanercept, golimumab, infliximab, certolizumab pegol, or tocilizumab within 12 weeks of randomization.
24. Use of alefacept or ustekinumab within 24 weeks of randomization.
25. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20).
26. Treatment with intravenous gamma globulin, plasmapheresis, or Prosorba® column within 6 months of baseline.
27. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
28. Prior treatment with apremilast.
29. Therapeutic failure of > 3 agents for PsA (small molecules or biologics), or > 1 biologic TNF blocker. Subjects who terminated previous treatment with small molecules or biologics due to cost or safety, such as discomfort with the subcutaneous injections, may participate in this study after adequate washout.
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 the American College of Rheumatology criteria for a 20% improvement (ACR 20), compared with baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety of up to 5 years’ administration as defined by:
- Type, frequency, severity, and relationship of adverse events to apremilast
- Number of subjects who prematurely discontinue study medication due to any adverse event
- Frequency of clinically significant changes in physical examination, vital signs, electrocardiogram, and/or laboratory findings
Efficacy at Week 16 (after 16 weeks of treatment):
- Change from baseline in physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI])
- Change from baseline in the physical function domain score of the Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36)
- Proportion of subjects who achieve the modified Psoriatic Arthritis Response Criteria (PsARC)
- Change from baseline in subject’s assessment of pain (VAS)
- Change from baseline in the Maastricht Ankylosing Spondylitis Entheses Score (MASES) in subjects with pre-existing enthesopathy
- Change from baseline in the dactylitis severity score in subjects with pre-existing dactylitis
- Change from baseline in the Clinical Disease Activity Index (CDAI)
- Change from baseline in the Disease Activity Score (DAS28)
- Change from baseline in the Functional Assessment of Chronic Illness Therapy –Fatigue (FACIT-Fatigue) score
- Proportion of subjects with pre-existing enthesopathy whose MASES improves by ≥ 20%
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves by ≥ 1
- Proportion of subjects with a good or moderate European League Against Rheumatism (EULAR) response
- Proportion of subjects who achieve an ACR 50, compared with baseline
- Proportion of subjects who achieve an ACR 70, compared with baseline
- Proportion of subjects with pre-existing enthesopathy whose MASES improves to 0
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves to 0
Efficacy at Week 24 (after 24 weeks of treatment):
- Proportion of subjects who achieve the ACR 20, compared with baseline
- Change from baseline in physical function (HAQ-DI)
- Change from baseline in the physical function domain score of the SF-36
- Proportion of subjects who achieve the modified PsARC
- Change from baseline in subject’s assessment of pain (VAS)
- Change from baseline in the MASES in subjects with pre-existing enthesopathy
- Change from baseline in the dactylitis severity score in subjects with pre-existing dactylitis
- Change from baseline in the CDAI
- Change from baseline in the DAS28
- Change from baseline in the FACIT-Fatigue score
- Proportion of subjects with pre-existing enthesopathy whose MASES improves by ≥ 20%
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves by ≥ 1
- Proportion of subjects with a good or moderate EULAR response
- Proportion of subjects who achieve an ACR 50, compared with baseline
- Proportion of subjects who achieve an ACR 70, compared with baseline
- Proportion of subjects with pre-existing enthesopathy whose MASES improves to 0
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves to 0
Efficacy at Week 52 (after 52 weeks of treatment):
- Proportion of subjects who achieve the ACR 20, compared with baseline
- Change from baseline in physical function (HAQ-DI)
- Change from baseline in the physical function domain score of the SF-36
- Proportion of subjects who achieve the modified PsARC
- Change from baseline in subject’s assessment of pain (VAS)
- Change from baseline in the MASES in subjects with pre-existing enthesopathy
- Change from baseline in the dactylitis severity score subjects with pre-existing dactylitis
- Change from baseline in the CDAI
- Change from baseline in the DAS28
- Change from baseline in the FACIT-Fatigue score
- Proportion of subjects with pre-existing enthesopathy whose MASES improves by ≥ 20%
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves by ≥ 1
- Proportion of subjects with a good or moderate EULAR response
- Proportion of subjects who achieve an ACR 50, compared with baseline
- Proportion of subjects who achieve an ACR 70, compared with baseline
- Proportion of subjects with pre-existing enthesopathy whose MASES improves to 0
- Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves to 0 |
|
| 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 | 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) | 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 | 3 |
| 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 | 52 |
| 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 |
| Belgium |
| Bulgaria |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Taiwan |
| United Kingdom |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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