| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ankylosing spondylitis (AS) |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002556 |
| E.1.2 | Term | Ankylosing spondylitis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 a day (BID), compared with placebo, in the reduction of signs and symptoms in subjects with active AS at 16 weeks of treatment |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of apremilast 30 mg BID, compared with placebo, in the reduction of signs and symptoms, improvement in physical function and range of motion in subjects with active AS at 24 weeks of treatment.
- To evaluate the efficacy of apremilast 20 mg BID, compared with placebo, in the reduction of signs and symptoms, improvement in physical function and range of motion in subjects with active AS at 24 weeks of treatment.
- To evaluate the efficacy of two doses of apremilast (30 mg BID and 20 mg BID) on AS lesions in the cervical and lumbar spine as assessed by radiographs in subjects with active AS at 104 Weeks and 260 Weeks of treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females, ≥ 18 years of age at the time of signing the informed consent document.
2. 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. Must have a documented diagnosis of ankylosing spondylitis as defined by low back pain and stiffness, which improves with exercise, but is not relieved by rest for more than 3 months prior to screening. At the completion of screening procedures, a documented diagnosis of definite active AS, as defined by the modified New York criteria (1984) whereby both criteria, at least 1 radiographic criterion and at least 1 clinical criterion, must be met:
a.Radiographic criteria (at least 1), documented by the central reader before the subject is randomized
b. Clinical criteria (at least 1), documented in physical examination
5. Must have symptoms of active axial disease at screening and baseline (at time of randomization), as determined by a BASDAI NRS score of ≥ 4 and a total back pain NRS score ≥ 4.
6. Must be receiving treatment on an outpatient basis.
7. Must be in good health (except for AS) as judged by the Investigator, based on medical history, physical examination, 12-lead ECG, chest radiograph, clinical laboratories and urinalysis.
8. Must agree to maintain the same stable dose of medication (or lack of medication) taken for AS prior to randomization through Week 24 of the study as described below. Change in medication may be allowed for safety reasons.
a. Analgesics must be stable for at least 14 days prior to Day 0
b. Disease-modifying anti-rheumatic drugs (DMARDs) must have been taken for at least 16 weeks and must be stable for at least 28 days prior to Day 0
c. Corticosteroids must be stable for at least 28 days prior to Day 0.
9. Must meet the following laboratory criteria at screening:
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/μL (≤ 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). 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%
h. Negative for hepatitis B surface antigen
i. Negative for hepatitis C antibody
10. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. While on investigational product and for at least 28 days after taking the last dose of investigational product, FCBP who engage in activity in which conception is possible must use one of the approved contraception 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 nonlatex 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.
11. 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 |
1. Major surgery (including spinal surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
2. Autoimmune diseases such as, but not limited to: systemic lupus erythematosus, mixed connective tissue disease, multiple sclerosis, or scleroderma.
3. Prior history of, or current, inflammatory joint disease other than AS (eg, rheumatoid arthritis, gout, reactive arthritis, psoriatic arthritis, Lyme disease).
4. Uncontrolled, severe psoriasis (defined as Body Surface Area > 10%) or active inflammatory bowel disease (Crohn’s disease or ulcerative colitis) based on an unequivocal positive calprotectin stool test defined by the local or central lab reference values.
5. Uncontrolled uveitis at the time of randomization. Asymptomatic, concurrently treated and controlled uveitis is acceptable at randomization, as long as the treatment is limited to topical ophthalmic therapy and/or intra-ocular injections of corticosteroids. Subjects are allowed to be initiated with these therapies during screening, continue on them through randomization and tapered off or discontinue these therapies while on study as medically appropriate. Systemic treatment for uveitis is not allowed, and would result in discontinuation from the study.
6. Prior treatment with a TNF blocker or any biologic treatment for AS.
7. If discontinuing treatment of DMARD, then adequate washout is required prior to randomization.
8. Treatment with any investigational agent within four weeks (or five half-lives of the investigational drug, whichever is longer) of screening.
9. Intra-articular or parenteral corticosteroids are not allowed within 6 weeks prior to randomization.
10. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
11. Pregnant women or nursing (breast-feeding) mothers.
12. Evidence of serious, poorly controlled concomitant cardiovascular, nervous system, pulmonary (including severe chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus as defined by HbA1c > 9.0%) or gastrointestinal (GI) disease.
13. Poorly controlled disease states, such as asthma, where flares are commonly treated with oral or parenteral corticosteroids.
14. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, histoplasmosis, coccidiomycosis, but excluding onychomycosis) or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks of screening.
15. History of positive test for, or any clinical suspicion of human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency (eg, common variable immunodeficiency disease).
16. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
17. History of alcohol, drug or chemical abuse within the 6 months prior to screening.
18. Any significant medical condition or laboratory abnormality that in the Investigator’s opinion would cause the subject not to be clinically appropriate for the study.
19. Prior history of suicide attempt at any time in the subject’s life time prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
20. A score of > 0 or a check mark on any column other than “Not at all” on Question 9 of the PHQ-9 questionnaire at screening or prior to randomization.
21. Any chronic pain condition not due to AS (eg, fibromyalgia) that in the Investigator’s opinion would interfere significantly with the efficacy evaluations, including the pain, entheses and joint assessments. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who achieve an ASAS 20. The ASAS is the Assessment of SpondyloArthritis international Society |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24
• Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24
• Proportion of subjects achieving an ASAS 20 at Week 24
• Change from baseline in the physical component score of the Medical Outcome Study Short Form 36-Item Health Survey (SF-36) scale at Week 24
• Change from baseline in Bath Ankylosing Spondylitis Metrology Index –Linear (BASMI-Linear) at Week 24
• Change from baseline in the radiographic score using the modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 (Year 2) and Week 260 (Year 5) by treatment group (20 mg BID, 30 mg BID, Placebo/30 mg BID, 20 mg BID/30 mg BID) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Austria |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| 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
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
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