Inclusion Criteria:
1. Subject ≥18 of age at the screening visit.
2. Subject must be able to understand and willing to adhere to all protocol
requirements and voluntarily sign and date an informed consent, approved by an
Independent Ethics Committee (IEC)/institutional review board (IRB), prior to the
initiation of any screening or study-specific procedures.
3. Diagnosis of axSpA by their treating rheumatologist.
4. Classification of axSpA according to ASAS Classification Criteria. 5. History of at least one acute anterior uveitis event in the 52 week period prior to
baseline, diagnosed by an ophthalmologist.
6. Active disease as defined by a BASDAI value of ≥4 and TBP score of ≥4 (on a 0-10 NRS
scale) at screening and baseline.
7. History of an inadequate response to at least two different NSAIDs over a period of
4 weeks in total at the maximum recommended or tolerated doses, or
intolerance/contraindication (e.g., allergic reaction, gastrointestinal symptoms or
signs, severe arterial hypertension, etc.) for NSAIDs.
8. Subjects must have been treated for ≥3 consecutive months prior to the study entry
with bDMARD therapy and/or for ≥4 weeks of NSAID therapy, in accordance with local
product label for AS or nr-axSpA, but continue to exhibit active SpA, or had to
discontinue previous bDMARD and/or NSAID treatment due to intolerability or
toxicity, irrespective of treatment duration. A total of 50 subjects who are
bDMARD-naïve and 150 subjects who are b-DMARD-IR will be included in the study.
9. For all females of child-bearing potential: must not have a positive serum pregnancy
test at the Screening Visit and must have a negative urine pregnancy test at
Baseline prior to the first dose of study drug (local practices may require serum
pregnancy testing at Baseline). Subjects with a borderline serum pregnancy test at
Screening must have absence of clinical suspicion of pregnancy or other pathological
causes of borderline results and a serum pregnancy test ≥3 days later to document
continued lack of a positive result (unless prohibited by local requirements).
10. Subjects who are regularly taking NSAIDs or analgesics (including low potency
opioids) as part of their axSpA therapy are required to be on a stable dose/dose
regimen for at least 7 days prior to the baseline visit. If entering the study on
concomitant tramadol, combination of acetaminophen/paracetamol and codeine or
combination of acetaminophen/paracetamol and hydrocodone, and/or non-opioid
analgesics, subject must be on stable dose(s) for at least 7 days prior to the
baseline Visit. However, subject must not have used opioid analgesics (except for
combination of acetaminophen/paracetamol and codeine or combination of
acetaminophen/paracetamol and hydrocodone which are allowed) within 7 days prior to
the BL Visit.
11. Subjects taking oral corticosteroids must be on an average daily and stable dose of
≤10mg/day prednisone or equivalent for at least 14 days prior to the baseline visit.
12. Subjects entering the study on the following concomitant csDMARDs must be on a
stable dose as indicated below for at least 28 days prior to the baseline Visit (in
case of Leflunomide washout must be either 11 days with colestyramine or 30 days
with activated charcoal or as per local label). A combination of up to 2 background
csDMARDs is allowed EXCEPT the combination of methotrexate (MTX) and leflunomide. •
MTX (≤ 25 mg/week); or • Sulfasalazine (SSZ) (≤ 3 g/day); or • Hydroxychloroquine (≤
400 mg/day); or • Chloroquine (≤ 250 mg/day); or • Leflunomide (≤ 20 mg/day)
13. If subjects are currently taking bDMARD therapy, they may be recruited after an
appropriate wash-out period of bDMARD prior to the Baseline Visit. Washout periods
are as follows: 4 weeks for Etanercept, 8 weeks for Infliximab, Golimumab, and
Certolizumab, 10 weeks for Adalimumab, and Ixekizumab, 12 weeks for Secukinumab.
However, subjects should not stop their previous successful biological therapy only
to be included in this study. For subjects intolerant to bDMARD and not on such
treatment a washout period may not be necessary.
Exclusion Criteria:
1. Active infection(s) requiring treatment with parenteral anti-infectives within 30
days, or oral antiinfectives within 14 days prior to the baseline Visit; Chronic
recurring infection and/or active viral infection that based on the investigator's
clinical assessment makes the subject an unsuitable candidate for the study.
2. COVID-19: In subjects who tested positive for COVID-19, at least 5 days must have
passed between a COVID-19 positive test result and the Baseline visit of
asymptomatic subjects. Subjects with mild/moderate COVID-19 infection can be
enrolled if fever is resolved without use of antipyretics for 24 hours and other
symptoms improved, or if 5 days have passed since the COVID-19 positive test result
(whichever comes last). Subjects may be rescreened if deemed appropriate by the
investigator based upon the subject's health status. 3. Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known
exposure, or high-risk behavior should undergo molecular (e.g., PCR) testing to rule
out SARS-CoV-2 infection or must be asymptomatic for 5 days from a potential
exposure;
4. History of recurrent (more than one episode) herpes zoster or
disseminated/multi-dermatomal (a single episode) herpes zoster or disseminated (a
single episode) herpes simplex.
5. Primary or secondary immunodeficiency.
6. Subjects with active TB or who meet TB exclusionary parameters (specific
requirements for TB testing are provided in Section 7.0: TB Testing/TB Prophylaxis)
7. Chronic infection with hepatitis B virus. At screening HBsAg and anti-HBc will be
tested. Subjects who are HBsAg positive will be excluded. In case of HBsAg
negativity, but anti-HBc positivity, participation in the study is possible if
HBV-DNA testing is negative and no exclusionary liver function tests.
8. Chronic infection with hepatitis C (HCV) (HCV ribonucleic acid (RNA) detectable in
any subject with anti-HCV antibody (HCV Ab), or Human Immunodeficiency Virus (HIV)
infection confirmed by positive HIV-antibody and antigen test.
9. Female subjects who are breastfeeding, pregnant, or plan to become pregnant during
the study or within 4 weeks following the last dose of study drug.
10. Subjects with chronic inflammatory articular disease (other than axSpA or systemic
autoimmune diseases, e.g., systemic lupus erythematosus, Sjögren´s syndrome, RA,
unequivocal chronic fatigue syndrome, or unequivocal fibromyalgia. Subjects with a
diagnosis of Crohn's disease or ulcerative colitis are allowed as long as they have
no active symptomatic disease within 4 weeks prior to BL.
11. Concomitant treatment with strong inductors or inhibitors of cytochrome P450 3A
(e.g., Ketoconazole, Fluconazole, Rifampicin, Clarithromycin, St-John´s-wort).
12. Prior treatment with upadacitinib or another JAK-inhibitor or TYK2-inhibitor for
axSpA.
13. History of hypersensitivity to any component of upadacitinib tablets.
14. Treatment with intravenous, intramuscular or intraarticular/periarticular, or
intrarectal steroids within 4 weeks prior to baseline Visit; treatment with oral
steroids in a dose of >10 mg prednisolone equivalent per day within 4 weeks prior to
baseline visit.
15. Subject must not have been treated with any investigational drug of chemical or
biologic nature within a minimum of 30 days or five half-lives (whichever is longer)
prior to the first dose of study drug or is currently enrolled in another
interventional clinical study.
16. History of an infected joint prosthesis at any time, with the prosthesis still in
situ.
17. Actual malignancies or history of malignancies with curative treatment within 5
years prior to screening, except successfully treated non-metastatic squamous cell
or basal cell carcinoma of the cutis or carcinoma in situ of the cervix.
18. A subject with any condition possibly affecting oral drug absorption, e.g.,
gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of
bariatric surgery such as gastric bypass. Procedures such as gastric banding, that
simply divides the stomach into separate chambers, are NOT exclusionary.
19. Significant trauma or surgery procedure within 4 weeks prior to baseline.
20. Evidence of other severe uncontrolled gastrointestinal, hepatic (serum albumin <25
mg/l or ChildPugh-Score >10), renal, pulmonary, cardiovascular, nervous or endocrine
disorders.
21. Any history of prior cardiovascular event, including but not limited to
cerebrovascular accident, myocardial infarction, coronary stenting, and
aorto-coronary bypass surgery.
22. History of thrombosis and/or hematological disorder increasing the propensity to
thrombosis.
23. Any subject who has been vaccinated with live or attenuated vaccines within the 4
weeks prior to the first dose of study medication or is to be vaccinated with these
vaccines at any time during treatment or within 4 weeks after the last dose of study
drug.
24. Any of the following lab abnormalities detected at screening: a) Hemoglobin <9 g/dl;
b) Absolute neutrophil count (ANC) <1.2 x 109/L (<1020/mm3) c) Absolute lymphocyte
count (ALC) <0.750 x 109/L (<750/mm3) d) Platelet count <9 g/dL e) Liver function
tests (LFT) >2 x ULN f) Serum apartate transaminase (AST) >2 x ULN g) Serum alanine
transaminase (ALT) >2 x ULN; h) Estimated glomerular filtration rate (GFR) by
simplified 4-variable MDRD formula < 30 mL/min/1.73 m2; i) Total white blood cell
(WBC) count < 2,500/μL
