Study of Efficacy, Safety and Tolerability of AIN457 in Patients With Active Overuse Tendinopathy

Study Overview
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Brief Summary
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This was a randomized, double-blind, placebo-controlled, multi-center, Phase II study of s.c. secukinumab 300 mg in 98 randomized patients with overuse rotator-cuff tendinopathy without systemic inflammatory disease.

Detailed Description
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This was a randomized, double-blind, placebo-controlled, multi-center, Phase II study of s.c. secukinumab 300 mg in 98 randomized patients with overuse rotator-cuff tendinopathy without systemic inflammatory disease and refractory to NSAIDs/acetaminophen, physiotherapy or corticosteroids. The study consisted of a 4-week screening period, a 2-week run-in period, a 12-week treatment period and a 12-week follow-up period after last treatment. The population consisted of patients with unilateral overuse (non-systemic inflammatory) shoulder tendinopathy, 18 - 65 years of age. Safety assessments included physical examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse event and serious adverse event monitoring.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase II, 24-week Study Investigating the Efficacy, Safety and Tolerability of AIN457 in Patients With Active Overuse Tendinopathy Refractory to Oral NSAIDs/Acetaminophen, Physiotherapy or Corticosteroid Injections

Conditions
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Tendinopathy

Intervention / Treatment
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* Drug: secukinumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant, non-lactating female patients 18 to 65 years of age at randomization Presence of unilateral rotator cuff tendinopathy with: Symptoms present ≥6 weeks, but <12 months prior to randomization Tendinopathy with no more than a 50% tear as established by ultrasound at screening (historic data acceptable if not older than 3 months) and MRI at baseline: Sein MRI tendinopathy scoring system grade I-III; with no tear or partial tear [maximum 50% tendon thickness (Bauer tendon thickness score maximum 2); AP length maximum 10 mm (Bauer tendon length score max 2)]. Maximum 50% of patients with partial tear Pain in the affected shoulder (at rest or on movement) on at least 3 days out of 7 days in the past week prior to baseline and a score of ≥4 out of 10 on a VAS pain scale Positive Painful Arc Test on examination and/or nightly pain in the affected shoulder on at least 4 out of 7 days in the past week prior to baseline The rotator-cuff tendinopathy must have been refractory to standard treatment, including NSAIDs and physiotherapy Exclusion Criteria: 1. Rheumatologic, inflammatory diseases, including but not limited to: PsA, AS and RA 2. Previous shoulder surgery in affected shoulder 3. History of adhesive capsulitis/frozen shoulder or calcification in the tendon (in affected or contralateral shoulder) confirmed by X-Ray, historic X-Rays can be used if performed within 3 months of baseline 4. Symptomatic osteoarthritis of the shoulder (gleno-humeral, acromioclavicular) (in affected or contralateral shoulder confirmed by X-Ray, historic X-Rays can be used if performed within 3 months of baseline 5. Neck conditions, including but not limited to cervical spine syndrome, which in the opinion of the investigator, may explain the patient's symptoms 6. Previous platelet rich plasma injections within the last 12 months prior to randomization 7. Previous treatment with any cell-depleting therapies including but not limited to anti- CD20, investigational agents (e.g. Campath, anti-CD4, anti-CD5, anti-CD3, anti-CD19) 8. Previous exposure to any biologic immunomodulating agents, including but not limited to TNFalpha inhibitors (including, but not limited to adalimumab, infliximab), or biologics targeting IL-17 (including, but not limited to secukinumab, ixekizumab or brodalumab) or the IL-17 receptor within the last 12 months prior to baseline 9. Any intraarticular/subacromial corticosteroid treatment within 8 weeks prior to randomization and more than 3 injections for the current tendinopathy. Oral, intramuscular or i.v. corticosteroid treatment within the last 12 months prior to randomization -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: secukinumab<br>AIN457 300 mg subcutaneously (s.c.) for 12 weeks | Drug: secukinumab<br>* AIN457 300 mg subcutaneously for 12 weeks<br>* Other names: AIN457;|
| Placebo Comparator: Placebo<br>Placebo subcutaneously for 12 weeks | Other: Placebo<br>* Placebo to match AIN457 subcutaneously for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Western Ontario Rotator Cuff (WORC) Patient Reported Outcome (PRO) Score at Week 14 in All Patients - Statistical Analysis Results of Total WORC Scores at Week 14 | WORC PRO score at week 14. The WORC Index consists of 21 items divided into 5 Domains: Physical Symptoms (6 items), Sport/Recreation (4 items), Work Function (4 items), Lifestyle Function (4 items) and Emotional Function (3 items). The total scores and sub scores used were the percentages of the normal scores with 0 being worst and 100 being best. All Patients - Statistical analysis results of WORC scores at Week 14 | Week 14 (Day 99) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Western Ontario Rotator Cuff (WORC) Patient Reported Outcome (PRO) Scores Over Time in All Patients | WORC score at Days 15, 29, 57, 85, 127, and End of Study (day 169). The scale range for WORC total score is 0-100, 0 being the worst possible outcome (highly symptomatic patient) and 100 being the best possible outcome (asymptomatic patient) | Days 15, 29, 57, 85, 127, and End of Study | 
| Disability of Arm, Shoulder and Hand Questionnaire Score (QuickDASH) Over Time | Patient Reported Outcome: Disability of Arm, Shoulder and Hand (QuickDASH) This questionnaire asks about symptoms as well participant's ability to do certain activities - ranging from 1 (No difficulty) to 5 (Unable). The scale range for QuickDASH total score is 0-100, 0 being the best possible outcome and 100 being the worst possible outcome | Days 15, 29, 57, 85, 99, 127, and End of Study | 
| American Shoulder and Elbow Surgeons (ASES) Score Over Time | Patient Reported Outcome: American Shoulder and Elbow Surgeons Shoulder Evaluation Form (ASES) score is self-administered and has 17 questions in the areas of shoulder symptoms and functions. The ASES total score ranges from 0 to 100 (best). | Days 15, 29, 57, 85, 99, 127, and End of Study | 
| Your Health Today Score Over Time | Patient Reported Outcome: Statistical analysis results of EQ-5D-5L for Your health Today questionnaire, which reflects how good or bad the subjets Health is on a scale from 0 (worst health) to 100 (best health). | Days 15, 29, 57, 85, 99, 127, and End of Study | 
| EQ-5D-5L Index Score Over Time | Patient Reported Outcome: Statistical analysis results of EQ-5D-5L Index score, which contains 5 items to assess Health Status (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression). Overall scores range from 0 to 1 with lower scores representing a higher level of dysfunction. | Days 15, 29, 57, 85, 99, 127 and End of Study | 
| Pain Score Over Time Using a VAS Scale | Pain intensity is assessed by a Visual Analog Scale (VAS) which is measured on a 100mm line that represents a continuum between no pain and worst pain. The scale range for pain score is 0-100, 0 being the best possible outcome (no pain) and 100 being the worst possible outcome (worst pain). | Days 15, 29, 57, 85, 99, 127 and End of Study | 
| Patient Global Assessment (PGA) Score Over Time Using a VAS Scale | The patient's global assessment of disease activity is performed using a 100 mm Visual Analog Scale (VAS) ranging from no activity to most active in the last 24 hours. The scale range for PGA score is 0-100, 0 being the best possible outcome (no disease activity) and 100 being the worst possible outcome (maximal disease activity). | Days 15, 29, 57, 85, 99, 127 and End of Study | 
| Physician Global Assessment (PhGA) Score Using a VAS Scale Over Time | Physician global assessment (PhGA) score using a VAS scale (considering the last 24 hours). The scale range for PhGA score is 0-100, 0 being the best possible outcome (no disease activity) and 100 being the worst possible outcome (maximal disease activity). | Days 15, 29, 57, 85, 99, 127 and End of Study | 
| Pharmacokinetics - Cmin | Mean trough concentrations Cmin is a pharmacokinetics term for the minimum blood plasma concentration reached by a drug prior to administration of a second dose (mass/volume) Serum trough concentrations of secukinumab 300 mg group was measured at Days 1, 29, 85 and EoS | Days 1, 29, 85 and EoS (End of Study) | 
| Immunogenicity Assessment - Treatment Emergent ADAs | Number of Participants with Treatment emergent Anti-secukinumab antibodies | Day 1 and EoS | 
| Number of Participants With Tendinosis Grade Score 1, 2 or 3 Measured by Magnetic Resonance Imaging (MRI) Sein Scores | Assessment of structural changes in the rotator cuff tendinopathy over time The MRI Sein score was used to grade supraspinatus tendinosis using a modified 4-point scale from 0 to 3 and changes in grading over time were captured in the shift table. Grade 0 is normal, grade 1 is mild, Grade 2 is moderate and grade 3 is marked tendinosis. In this Sein score assessment, only data from Day 99 and baseline could be compared, as only those two time points were double read and adjudicated in case the 2 readers had different results. At any other time-points (Day 57 and EOS), images were assessed only by one reader and thus could not be compared to baseline. | Baseline and Day 99 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Overuse tendinopathy, shoulder, rotator cuff, IL-17A-Ab, AIN457X