BI 655066 (Risankizumab) Proof of Concept Dose Finding Study in Ankylosing Spondylitis (AS)

Study Overview
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Brief Summary
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The overall purpose of the trial is to assess the clinical efficacy of three different subcutaneous doses of BI 655066 (risankizumab) in adult patients with AS, in order to provide clinical proof of concept and to select dose (s) for confirmatory clinical trials.

Official Title
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A 48 Weeks, Phase II, Randomized, Double-blind, Placebo-controlled, Proof of Concept and Dose Finding Study of Three Different Dose Regimens of BI 655066 Administered Subcutaneously in Patients With Ankylosing Spondylitis.

Conditions
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Ankylosing Spondylitis (AS)

Intervention / Treatment
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* Drug: placebo for risankizumab
* Drug: risankizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female patients Age = 18 years and = 70 years Definite AS based on the modified New York criteria (1984) Documented disease duration = 3 months at screening Active disease at screening, defined as: BASDAI score (0-10) = 4, AND Spinal pain level assessed by the 2nd BASDAI question (0-10) = 4 Have either a documented inadequate response for axial symptoms to 30 days of optimal daily doses of at least two non-steroidal anti-inflammatory drugs (NSAIDs), or documented intolerance to NSAIDs Female patients who meet any of the following criteria from screening visit up to the End of Observation visit (EOO): using adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral contraceptives, intrauterine device (IUD) sexually abstinent have a vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) surgically sterilised (including hysterectomy) postmenopausal defined as at least 1 year of spontaneous Amenorrhea Patients (males or females) receiving background MTX or Leflunomide therapy who are following the national regulatory guidelines regarding contraception Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation Exclusion criteria: Radiographic evidence of total ankylosis of the spine at screening or before (spinal XRay examinations at screening visit/ during screening period are not mandatory ¿ see footnote 12 from Flow-Chart 1) Patient previously treated with any biological immunomodulating agent for AS, either licensed or experimental Previous or current participation in a clinical trial testing an investigational drug for AS within 12 weeks prior to randomization (any biological immunomodulating agents are excluded) Usage of any investigational drug within 30 days prior to randomization or the planned use of an investigational drug during the course of the actual study Active uveitis or inflammatory bowel disease at screening Diagnosed psoriatic arthritis at screening, satisfying the modified New York criteria Patients who had received intraarticular injection(s) with corticosteroids within 4 weeks prior to screening visit Patients who must or wish to continue the intake of restricted medications (cf. Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the study Major surgery performed within 8 weeks prior to screening or planned within 12 months after screening (e.g. hip replacement) Chronic or relevant acute infections including HIV, viral hepatitis and tuberculosis (positive tests for HIV, HBV/HCV at screening will be exclusionary) For tuberculosis patients, they are not eligible according to the following screening criteria: Have signs or symptoms suggestive of current active or latent TB upon medical history, physical examination and/or a chest radiograph (both posterior-anterior and lateral views, taken within 3 months prior to the first administration of study drug and read by a qualified radiologist) Have history of latent or active TB prior to screening, except for patients who have documentation of having completed an adequate treatment regimen at least 6 months prior to the first administration of study agent Have positive QuantiFERON-TB Gold In-Tube test within 2 months prior to or during screening, in which active TB has not been ruled out, except for patients with history of latent TB and documentation of having completed an adequate treatment regimen at least 6 months prior to the first administration of study agent Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix Evidence of current or previous clinically significant disease, medical condition other than AS, finding of the medical examination (including vital signs and ECG), or laboratory value at the screening visit outside the reference range that is of clinical relevance, that in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data. This criterion provides an opportunity for the investigator to exclude patients based on clinical judgment, even if other eligibility criteria are satisfied. History of allergy/hypersensitivity to a systemically administered biologic agent or its excipients History of alcohol abuse within last 12 months (intake of more than 30 g/day) History of drug abuse within last 12 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subcutaneous injection of Placebo (solution for injection matching risankizumab, 1 mL pre-filled syringe) administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period. | Drug: placebo for risankizumab<br>* Placebo for risankizumab administered by subcutaneous (SC) injection<br>|
| Experimental: Risankizumab 18 mg<br>Subcutaneous injection of risankizumab 18 mg administered every 8 weeks at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks | Drug: risankizumab<br>* Risankizumab administered by subcutaneous (SC) injection<br>* Other names: SKYRIZI;|
| Experimental: Risankizumab 90 mg<br>Subcutaneous injection of risankizumab 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period | Drug: risankizumab<br>* Risankizumab administered by subcutaneous (SC) injection<br>* Other names: SKYRIZI;|
| Experimental: Risankizumab 180 mg<br>Subcutaneous injection of risankizumab 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period | Drug: risankizumab<br>* Risankizumab administered by subcutaneous (SC) injection<br>* Other names: SKYRIZI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Achieved Assessment of Spondyloarthritis International Society (ASAS) 40 Improvement Criteria at Week 12. | ASAS 40 evaluations are based on the following 4 components (also called domains) that include patient' self-assessments on a numerical rating scale (NRS) from 0 to 10 with higher numbers representing a worse disease status: Global AS disease activity Inflammation based on the mean of Bath AS Disease Activity Index (BASDAI) questions addressing the level of morning stiffness and duration Spinal pain based on the mean of 2 questions Physical function based on the Bath AS Functional Index (BASFI) The ASAS 40 response is defined as an improvement in 3 of 4 components and no worsening in the remaining component; an improvement is defined as a reduction from baseline of ≥40% and an absolute reduction of ≥2 units in each of the 3 components. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Disease Activity Assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS). | This is the key secondary endpoint. ASDAS is a linear function of Back Pain (Question 2 from Bath Ankylosing Spondylitis (AS) Disease Activity Index (BASDAI): range 0-10), Duration of Morning Stiffness (Question 6 from BASDAI: range 0-10), Patient's global assessment of the disease on Numerical rating Scale (NRS) (range 0-10), peripheral joint pain/swelling (Question 3 from BASDAI: range 0-10) and the C-reactive protein (CRP) lab value at the visit. ASDAS-CRP: 0.121*Back pain +0.058*Duration of Morning Stiffness +0.11*Patient Global + 0.073*Peripheral pain/ Swelling + 0.579*Ln (CRP +1). For all of the scales that make up the ASDAS, higher indicates worse disease. | Baseline and Week 12 | 
| Percentage of Patients Who Achieved ASAS 5/6 Improvement Criteria at Week 12 | The ASAS 5/6 evaluation is based on 6 components: Global AS disease activity Inflammation based on the mean of BASDAI questions addressing the level-of morning stiffness and duration Spinal pain Physical function based on the Bath AS Functional Index (BASFI) Spinal mobility assessment (lateral lumbar flexion), corresponding to one out of 5 measurements of Bath Ankylosing Spondylitis Metrology Index (BASMI) Serum CRP levels The ASAS 5/6 response is defined as an improvement in any 5 of the 6 components and no worsening in the remaining component. A reduction from baseline of ≥20% is defined as an improvement according to the ASAS criteria. | Week 12 | 
| Percentage of Patients Who Achieved Partial Remission According to the ASAS Criteria at Week 12 | Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12 is presented | Week 12 | 
| Percentage of Patients Who Achieved ASAS 20 Improvement Criteria at Week 12 | ASAS 20 evaluations are based on the following 4 components (also called domains) that include patient' self-assessments on a numerical rating scale (NRS) from 0 to 10 with higher numbers representing a worse disease status: Global AS disease activity Inflammation based on the mean of Bath AS Disease Activity Index (BASDAI) questions addressing the level of morning stiffness and duration Spinal pain based on the mean of 2 questions Physical function based on the Bath AS Functional Index (BASFI) The ASAS 20 response is defined as an improvement in 3 of 4 components and no worsening in the remaining component; an improvement is defined as a reduction from baseline of ≥20% and an absolute reduction of ≥1 units in each of the 3 components. | Week 12 | 
| Change From Baseline to Week 12 in Disease Activity Assessed by BASDAI | BASDAI assesses the AS disease activity of a patient within the last week based on 6 questions on a NRS (1 to 10) How would you describe the overall level of fatigue/tiredness you have experienced? AS neck, back or hip pain you have had? pain/swelling in joints other than neck, back or hips you have had? discomfort you have had from any areas tender to touch or pressure? morning stiffness you have had from the time you wake up? How long does your morning stiffness last from the time you wake up? A score of 10 means very severe disease activity for each of the BASDAI questions 1, 2, 3, 4 and 5. BASDAI question 6 addresses the stiffness duration. A NRS of 0 means 0 h; a NRS of 10 mean ≥2 h. The BASDAI was computed in the following way: the sum of the values of question 1 to 4 was calculated and the mean of questions 5 and 6 was added. This value was divided by 5. | Baseline and Week 12 | 
| Percentage of Patients Who Achieved ASAS 40 Improvement Criteria at Week 24 | Percentage of patients who achieved ASAS 40 improvement criteria at Week 24 is presented | Week 24 |