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    EudraCT Number:2011-000844-56
    Sponsor's Protocol Code Number:TOPAS2011
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-06-09
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2011-000844-56
    A.3Full title of the trial
    UsTekinumab for the treatment Of Patients with active Ankylosing Spondylitis (TOPAS) – a 28-week, prospective, open-label, proof-of-concept study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    UsTekinumab for the treatment Of Patients with active Ankylosing Spondylitis
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberTOPAS2011
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01330901
    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 SponsorCharité Universitätsmedizin Berlin
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen-Cilag
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité Universitätsmedizin Berlin
    B.5.2Functional name of contact pointTrial Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressHindenburgdamm 30
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code12203
    B.5.4Telephone number493084454414
    B.5.5Fax number493084454149
    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 Yes
    D. name Stelara
    D. of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameUstekinumab
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ankylosing spondylitis
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory rheumatic disease affecting spine
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    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
    Evaluation of efficacy and safety of ustekinumab 90 mg administered subcutaneosly at week 0, week 4 and week 16 in patients with active AS (the Bath Ancylosing Spondylitis Disease Activity Index – BASDAI ≥4) fulfilling the modified New York criteria who have had an inadequate response to ≥2 NSAIDs or do not tolerate or have a contraindication for NSAIDs.
    E.2.2Secondary objectives of the trial
    • Course of change of active and chronic inflammatory lesions in MRI over 24 weeks
    • Change in the cytokine production by T-cells and monocytes over 24 weeks

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age of ≥18 years.
    2. Definite diagnosis of AS according to the modified New York criteria.
    3. History of an inadequate response to ≥2 NSAIDs taken for at least 2 weeks each or NSAIDs intolerance/contraindication.
    4. Active disease as defined by a BASDAI value of ≥4 at screening despite concomitant treatment with an NSAID or without NSAIDs in case of intolerance/contraindication.
    5. Able and willing to give a written informed consent and comply with the requirements of the study protocol.
    6. If female: either not of child-bearing potential (menopausal since 1 year or surgically sterile) or is willing and able to practice a reliable method of contraception throughout the study and 150 days after the last drug injection. Reliable methods of contraception are: condoms and other barrier methods, intrauterine devices, oral, parenteral or intravaginal contraceptives initiated at least 90 prior to screening, a vasectomised partner.
    7. If male: either not of child-bearing potential (surgically sterilized, e.g. vasectomy) or is willing and able to practice a reliable method of contraception throughout the study and 150 days after the last drug injection.
    8. If on NSAIDs: the dose must be stable for at least 2 weeks prior to baseline.
    9. If on oral steroids: the dose must not exceed 10 mg (prednisolone equivalent) per day and must be stable for at least 4 weeks prior to baseline.
    10. If on methotrexate: the dose must not exceed 25 mg per week and must be stable for at least 4 weeks prior to baseline, must be stable for 4 weeks prior to baseline.
    11. If on analgesics: the dose must be stable for at least 2 weeks prior to baseline.
    E.4Principal exclusion criteria
    1. The female subject is pregnant or lactating.
    2. Patients with other chronic inflammatory articular disease or systemic autoimmune disease, e.g. systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, chronic fatigue syndrome (other manifestations of spondyloarthritis such as psoriasis, inflammatory bowel disease, arthritis, uveitis are not regarded as exclusion criteria).
    3. History of inadequate response to previous anti-TNF α therapy. Patients who discontinued previous anti-TNF α therapy due to intolerability/side effects may participate in the study. This therapy must have been terminated at least 4 weeks prior to baseline if etanercept was used and at least 8 weeks if infliximab, adalimumab, or golimumab were used.
    4. Previous treatment with biologics other than TNF α blockers.
    5. Treatment with any other investigational drug within 4 weeks of 5 half-life of the drug (whichever is longer) prior to baseline.
    6. Treatments with disease modifying anti-rheumatic drugs (DMARDs) other than methotrexate within 4 weeks prior to screening (8 weeks for leflunomide or 4 weeks with a standard cholestyramine wash-out).
    7. Treatment with intravenous, intramuscular or intraarticular/periarticular steroids within 4 weeks prior to screening.
    8. Any active current infection, a history of recurrent clinically significant infection, infections requiring treatment with antibiotics within 4 weeks prior to baseline.
    9. Current clinical signs and symptoms suggestive for tuberculosis.
    10. Positive QuantiFERON®-TB test at screening and/or abnormal chest x-ray (performed at screening or within 3 months prior to screening) suggestive for past or present tuberculosis (positive x-ray). Patients with a positive QuantiFERON®-TB test but negative chest x-ray and without clinical symptoms suggestive for tuberculosis may participate in the study after initiation of standard prophylactic antimycobacterial treatment.
    11. Chronic infection with hepatitis B or C, history of HIV infection.
    12. Primary or secondary immunodeficiency.
    13. 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 or carcinoma in situ of the cervix.
    14. Evidence of severe uncontrolled gastrointestinal, hepatic, renal, pulmonary, cardiovascular, nervous or endocrine disorders.
    15. Any other conditions making the patient unsuitable in the opinion of the investigator for the participation in the current study.
    16. Patients with a history of a severe psychiatric illness, which might interfere with the patient's ability to understand the requirements of the study and assessment.
    17. Diagnosis of fibromyalgia.
    18. Alcohol abuse or illegal drug consume in the last 12 months.
    19. Vaccination with a live vaccine within 12 weeks prior to baseline.
    20. Known hypersensitivity to any component of the study medication.
    21. Any of the following laboratory abnormalities as detected at screening:
    o Haemoglobin < 8.5 g/dl
    o Neutrophil counts < 2.000 / µl
    o Platelet count < 125.000 / µl
    o Serum creatinine > 1.4 mg/dl for women or 1.6 mg/dl for men.
    o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (AP) or gamma-glutamyl-transpeptidase (GGT) >3 times upper limit of normal
    E.5 End points
    E.5.1Primary end point(s)
    The Assessment of Spondyloarthritis International Society (ASAS)40 response at week 24 defined as an improvement of ≥40% and ≥2 points in at least 3 out of 4 following domains (and no worsening in remaining domain) :
    - Patient global
    - Pain
    - Function (BASFI)
    - Inflammation (mean of the BASDAI question 5 and 6).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    • ASAS40 response at week 12
    • ASAS20 response at weeks 12 and 24
    • ASAS5/6 response at weeks 12 and 24
    • ASAS partial remission at weeks 12 and 24
    • BASDAI 20%, 50%, 70% improvement at weeks 12 and 24
    • Improvement in the Ankylosing Spondylitis Disease Activity Score (ASDAS)
    • Percentage of patients reaching the ASDAS clinically important improvement (≥1.1) and major improvement (≥2.0) at weeks 12 and 24
    • Improvement of function (BASFI)
    • Improvement of physician’s global, patient’s global, general pain, nocturnal pain on the numeric rating scale (NRS)
    • Improvement of quality of life and disability measurements (SF-36, EQ-5D, ASQol)
    • Achievement of the patient acceptable symptom state (PASS)
    • Achievement of the physician acceptable symptom state
    • Improvement of axial mobility (the Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion)
    • Improvement in acute phase reactants (C-reactive protein (CRP), ESR)
    • Improvement of swollen joint count
    • Improvement of enthesitis enthesitis (as assessed by the Maastricht Ankylosing Spondylitis Enthesitis Score – MASES, and the Spondylitis Research Consortium of Canada (SPARCC) enthesitis index)
    • Course of change of active and chronic inflammatory lesions in MRI over 24 weeks
    • Change in the cytokine production by T-cells and monocytes
    • Change of the bone and cartilage biomarkers serum levels
    • Percentage of patients experienced adverse events and number of adverse events over 28 weeks
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12 and week 24 for efficacy measures, week 28 for safety measure
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    Both the sponsor and the investigator reserve the right to terminate the study at any time. Should this be necessary, both parties will arrange the procedures on an individual study basis after review and consultation. The study can be terminated in case of negative benefit/risk assessment due to new information.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months18
    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: 20
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    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)
    Not different from the expected normal treatment of ankylosing spondylitis.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-07-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-05-07
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