Ustekinumab for the Treatment of Patients With Active Ankylosing Spondylitis

Study Overview
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Brief Summary
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This study is aimed at investigation of efficacy and safety of ustekinumab (monoclonal antibody against interleukin 12 and 23) treatment in patients with active ankylosing spondylitis (AS) fulfilling the modified New York criteria who have had an inadequate response to standard therapy with non-steroidal anti-inflammatory drugs (NSAIDs) or do not tolerate or have a contraindication for NSAIDs.

Detailed Description
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This study is a prospective, open-label, proof-of-concept clinical trial that will be conducted in a referral center for patients with AS in Berlin. Eligible patients will be treated with ustekinumab 90 mg given subcutaneously at weeks 0, 4, and 16. The entire study period accounts 28 weeks. Assessment of the primary outcome parameter will be performed at week 24. The patients will be closely monitored throughout the study on a total of 9 visits.

Official Title
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UsTekinumab for the Treatment Of Patients With Active Ankylosing Spondylitis (TOPAS) - a 28-week, Prospective, Open-label, Proof-of-concept Study

Conditions
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Ankylosing Spondylitis

Intervention / Treatment
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* Drug: Ustekinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of ≥18 years. Definite diagnosis of AS according to the modified New York criteria. History of an inadequate response to ≥2 NSAIDs taken for at least 2 weeks each or NSAIDs intolerance/contraindication. 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. Able and willing to give a written informed consent and comply with the requirements of the study protocol. 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. 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. If on NSAIDs: the dose must be stable for at least 2 weeks prior to baseline. 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. 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. If on analgesics: the dose must be stable for at least 2 weeks prior to baseline. Exclusion Criteria: The female subject is pregnant or lactating. Patients with other chronic inflammatory articular disease or systemic autoimmune disease. History of inadequate response to previous anti-tumor necrosis factor (TNF) α therapy. Previous treatment with biologics other than TNF α blockers. Treatment with any other investigational drug within 4 weeks of 5 half-life of the drug (whichever is longer) prior to baseline. 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). Treatment with intravenous, intramuscular or intraarticular/periarticular steroids within 4 weeks prior to screening. Any active current infection, a history of recurrent clinically significant infection, infections requiring treatment with antibiotics within 4 weeks prior to baseline. Current clinical signs and symptoms suggestive for tuberculosis. Positive interferon gamma release assay (IGRA) 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 IGRA 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. Chronic infection with hepatitis B or C, history of human immunodeficiency virus infection. Primary or secondary immunodeficiency. 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. Evidence of severe uncontrolled gastrointestinal, hepatic, renal, pulmonary, cardiovascular, nervous or endocrine disorders. Any other conditions making the patient unsuitable in the opinion of the investigator for the participation in the current study. 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. Diagnosis of fibromyalgia. Alcohol abuse or illegal drug consume in the last 12 months. Vaccination with a live vaccine within 12 weeks prior to baseline. Known hypersensitivity to any component of the study medication. Clinically significant laboratory abnormalities Patients who are institutionalised due to regulatory or juridical order. Patients with contraindications for the magnetic resonance imaging (MRI)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ustekinumab<br>Ustekinumab 90 mg subcutaneously at week 0, 4 and 16 | Drug: Ustekinumab<br>* Ustekinumab 90 mg given subcutaneously at weeks 0, 4, and 16<br>* Other names: Stelara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Assessment of Spondyloarthritis International Society (ASAS)40 response | The percentage of patients who achieved ASAS40 response defined as an improvement of ≥40% and ≥2 points in at least 3 out of four following domains (and no worsening in remaining domain): Patient global Pain Function (as measured by the Bath Ankylosing Spondylitis Functional Index - BASFI) Inflammation (mean of the Bath Ankylosing Spondylitis Disease Activity Index - BASDAI question 5 and 6) | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Assessment of Spondyloarthritis International Society (ASAS)20 response at week 24 | The percentage of patients who achieved ASAS20 response defined as an improvement of ≥20% and ≥1 points in at least 3 out of four following domains (and no worsening of ≥20% and ≥1 points in remaining domain): Patient global Pain Function (as measured by the Bath Ankylosing Spondylitis Functional Index - BASFI) Inflammation (mean of the Bath Ankylosing Spondylitis Disease Activity Index - BASDAI question 5 and 6) | Week 24 | 
| The Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement | The percentage of patients who achieved the ASDAS clinically important improvement (≥1.1) at week 24 | Week 24 | 
| The Assessment of Spondyloarthritis International Society (ASAS) partial remission | The percentage of patients who achieved partial remission according to the ASAS definition at week 24 | Week 24 | 
| The Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement | The percentage of patients who achieved the ASDAS major improvement (≥2.0) at week 24 | Week 24 | 
| Number of participants with adverse events as a measure of safety and tolerability | Number of participants with adverse events as a measure of safety and tolerability up to week 28 | Week 28 |