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    EudraCT Number:2017-000431-14
    Sponsor's Protocol Code Number:M16-098
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-04-19
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedCroatia - MIZ
    A.2EudraCT number2017-000431-14
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis
    A.4.1Sponsor's protocol code numberM16-098
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAbbVie Deutschland GmbH & Co. KG
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbbVie Ltd
    B.5.2Functional name of contact pointEU Clinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressAbbVie House, Vanwall Business Park, Vanwall Road
    B.5.3.2Town/ cityMaidenhead, Berkshire
    B.5.3.3Post codeSL6 4UB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441628561090
    B.5.5Fax number441628461153
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameUpadacitinib
    D.3.2Product code ABT-494
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNUpadacitinib
    D.3.9.1CAS number 1310726-60-3
    D.3.9.3Other descriptive nameABT-494
    D.3.9.4EV Substance CodeSUB125895
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Active Ankylosing Spondylitis
    E.1.1.1Medical condition in easily understood language
    Ankylosing Spondylitis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002556
    E.1.2Term Ankylosing spondylitis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 14
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 14

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA52
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Korea, Republic of
    New Zealand
    United States
    E.8.7Trial 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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 161
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 170
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who complete the last visit will have a follow-up visit approximately 30 days after the last dose of oral study drug to obtain information on any new or ongoing AEs and to collect vital signs and clinical laboratory tests.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-02-17
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