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

Phase 2

Completed

Conditions: Tendinopathy

Interventions: Other: Placebo
Drug: secukinumab

Registration Number: NCT03344640

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 96

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:
1. Symptoms present ≥6 weeks, but <12 months prior to randomization
2. 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
3. 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
4. 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

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo subcutaneously for 12 weeks
secukinumab	secukinumab	AIN457 300 mg subcutaneously (s.c.) for 12 weeks

Primary Outcome Measures

Name	Time	Method
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	Week 14 (Day 99)	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

Secondary Outcome Measures

Name	Time	Method
The Western Ontario Rotator Cuff (WORC) Patient Reported Outcome (PRO) Scores Over Time in All Patients	Days 15, 29, 57, 85, 127, and End of Study	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)
Disability of Arm, Shoulder and Hand Questionnaire Score (QuickDASH) Over Time	Days 15, 29, 57, 85, 99, 127, and End of Study	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
American Shoulder and Elbow Surgeons (ASES) Score Over Time	Days 15, 29, 57, 85, 99, 127, and End of Study	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).
Your Health Today Score Over Time	Days 15, 29, 57, 85, 99, 127, and End of Study	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).
EQ-5D-5L Index Score Over Time	Days 15, 29, 57, 85, 99, 127 and End of Study	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.
Patient Global Assessment (PGA) Score Over Time Using a VAS Scale	Days 15, 29, 57, 85, 99, 127 and End of Study	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).
Number of Participants With Tendinosis Grade Score 1, 2 or 3 Measured by Magnetic Resonance Imaging (MRI) Sein Scores	Baseline and Day 99	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.
Pain Score Over Time Using a VAS Scale	Days 15, 29, 57, 85, 99, 127 and End of Study	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).
Physician Global Assessment (PhGA) Score Using a VAS Scale Over Time	Days 15, 29, 57, 85, 99, 127 and End of Study	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).
Pharmacokinetics - Cmin	Days 1, 29, 85 and EoS (End of Study)	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
Immunogenicity Assessment - Treatment Emergent ADAs	Day 1 and EoS	Number of Participants with Treatment emergent Anti-secukinumab antibodies