E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Chronic inflammatory rheumatic disease affecting spine |
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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 | 13.1 |
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 |
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. |
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E.2.2 | Secondary 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary 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).
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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) |
• 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 12 and week 24 for efficacy measures, week 28 for safety measure |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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. |
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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 | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |