E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Active Ankylosing Spondylitis |
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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] - Immune System Diseases [C20] |
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 |
Period 1:
1. To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and symptoms as measured by proportion of subjects who achieve an Assessment of SpondyloArthritis international Society (ASAS) 40 response at Week 14 in subjects with active ankylosing spondylitis (AS) who have had an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are biologic disease-modifying antirheumatic drug (bDMARD)-naïve.
2. To assess the safety and tolerability of upadacitinib in subjects with active AS who have had an inadequate response to at least two NSAIDs or intolerance to or a contraindication for NSAIDs, and who are bDMARD-naïve.
Period 2:
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of treatment in subjects who have completed Period 1. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of upadacitinib in subjects with active AS who have had an inadequate response to at least two NSAIDs or intolerance to or a contraindication for NSAIDs, and who are bDMARD-naïve.
Period 2:
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of treatment in subjects who have completed Period 1. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age.
2. Subject with a clinical diagnosis of AS and meeting the modified New York Criteria for AS.
3. Subject must have baseline disease activity as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 and a Patient's Assessment of Total Back Pain score ≥ 4 based on a 0 – 10 Numeric Rating Scale (NRS) at the Screening and Baseline Visits.
4. Subject has had an inadequate response to at least two NSAIDs over an at least 4-week period in total at maximum recommended or tolerated doses, or subject has an intolerance to or contraindication for NSAIDs as defined by the Investigator.
5. If entering the study on concomitant MTX, leflunomide, SSZ and/or hydroxychloroquine, subject must be on a stable dose of MTX (≤ 25 mg/week) and/or SSZ (≤ 3 g/day) and/or hydroxychloroquine (≤ 400 mg/day) or leflunomide (≤ 20 mg/day) for at least 28 days prior to the Baseline Visit. A combination of up to two background csDMARDs is allowed EXCEPT the combination of MTX and leflunomide.
6. If entering the study on concomitant oral corticosteroids, subject must be on a stable dose of prednisone (≤ 10 mg/day), or oral corticosteroid equivalents, for at least 14 days prior to the Baseline Visit. Subject must be on stable dose(s) for at least 14 days prior to the Baseline Visit. |
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E.4 | Principal exclusion criteria |
1. Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).
2. Prior exposure to any biologic therapy with a potential therapeutic impact on spondyloarthritis (SpA).
3. Intra-articular joint injections, spinal/paraspinal injection(s), or parenteral administration of corticosteroids within 28 days prior to the Baseline Visit. Inhaled or topical corticosteroids are allowed.
4. Subject on any other DMARDs (other than those allowed), thalidomide, or apremilast within 28 days or five half-lives (whichever is longer) of the drug prior to the Baseline Visit.
5. Subject on opioid analgesics (except for combination acetaminophen/codeine or acetaminophen/hydrocodone which are allowed) or use of inhaled marijuana within 14 days prior to the Baseline Visit.
6. Subject has a history of inflammatory arthritis of different etiology other than axial SpA (including but not limited to rheumatoid arthritis [RA], psoriatic arthritis [PsA], mixed connective tissue disease, systemic lupus erythematosus, reactive arthritis, scleroderma, polymyositis, dermatomyositis, fibromyalgia), or any arthritis with onset prior to 17 years of age.
7. Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug: serum aspartate transaminase (AST) > 2 × ULN; serum alanine transaminase (ALT) > 2 × ULN; estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2; hemoglobin < 10 g/dL; total white blood cell (WBC) count < 2,500/µL; absolute neutrophil count (ANC) < 1,500/µL; absolute lymphocyte count < 800/µL; and platelet count < 100,000/µL. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants with Assessment of SpondyloArthritis international Society (ASAS) 40 response (It is defined as a >= 40% improvement and an absolute improvement of >= 2 units (on a scale of 0 to 10) from Baseline in at least three of the following four domains, with no worsening at all in the remaining domain:
a. Patient's Global Assessment
b. Pain
c. Function
d. Inflammation)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key multiplicity adjusted secondary efficacy endpoints are:
1. Change from Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
2. Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada (SPARCC) score (Spine);
3. Proportion of subjects with BASDAI 50 response;
4. Change from Baseline in Ankylosing Spondylitis Quality of Life (AS QoL);
5. Proportion of subjects with ASAS partial remission (PR);
6. Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI);
7. Change from Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin);
8. Change from Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES);
9. Change from Baseline in Work Productivity and Activity Impairment (WPAI);
10. Change from Baseline in ASAS Health Index (HI);
11. ASAS 20;
12. Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada (SPARCC) score Sacroiliac (SI) joints.
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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 | Yes |
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 | Yes |
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) | Yes |
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 | 3 |
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 |
Australia |
Canada |
Japan |
Korea, Republic of |
New Zealand |
United States |
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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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |