Study of Efficacy and Safety of Secukinumab in Participants With Moderate-severe Rotator Cuff Tendinopathy

Study Overview
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Brief Summary
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The purpose of the present study is to assess the efficacy of secukinumab 300 mg s.c. (subcutaneous) compared to placebo, each in combination with standard of care, in improving signs, symptoms and physical function in participants with moderate to severe rotator cuff tendinopathy (RCT), using a randomized, double-blind, placebo controlled, parallel group design to minimize bias.

Detailed Description
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The trial is designed as a randomized, double-blind, placebo-controlled Phase III study over 24 weeks in approximately 234 participants with moderate to severe rotator cuff tendinopathy (RCT), refractory to Standard of Care (Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) course as per local standard practice, if not intolerant or contraindicated, and a course of physiotherapy over a period of 8 weeks). The trial comprises the following periods: - Screening / run-in period A screening period of up to maximum of 56 days will be used to assess participant eligibility. During this time, the participant can demonstrate that they are refractory to Standard of Care. During the 2-week run-in period prior to the Baseline visit, the participant will need to have 2 weeks of stable NSAID intake and standardized physiotherapy. This is important in order to ensure the participants are refractory to SoC and to establish compliancy with the stabilized dosing of NSAID treatment and physiotherapy regimen to be maintained throughout the study. MRI will be performed during Screening period to exclude other shoulder pathologies and tears (if present) >50%. Evidence of tendinopathy should be established by a centrally read Magnetic Resonance Imaging (MRI). MRI performed within 3 months from baseline may be accepted if deemed suitable by the central reader. Shoulder x-rays will also be performed in order to rule out other shoulder pathologies. Historic x-rays will be accepted if performed ≤ 3 months prior to Baseline. - Study period 1 (Baseline to Week 16) During Study period 1, double-blinded treatment is administered over 12 weeks, reflecting 16 weeks of total drug exposure. Approximately 234 eligible participants will be randomized at Baseline (BSL) in a 1:1 ratio to one of the following arms: Arm 1 (N=117): secukinumab 300 mg s.c. at Day 1 and Weeks 1, 2, 3, 4, 8, and 12 Arm 2 (N=117): placebo at Day 1 and Weeks 1, 2, 3, 4, 8, and 12 The last dose of study treatment will be administered at Week 12; the primary outcome assessments will be performed at Week 16. Randomization will be stratified by tear status (no tear/partial tear). Participants should continue on stable NSAID pain medication and a standardized physiotherapy regimen. Reduction in NSAID dose is permitted after BSL, but participants must not increase above dose established during run-in. Use of corticosteroid injections is not permitted during this time. - Study period 2 (Follow-up period) A follow-up period of 8 weeks after the end of the treatment period is planned to assess the maintenance of effect and collect follow-up safety data up to Week 24. Investigator, site personnel, persons performing the assessments and participants will remain blinded, but Novartis clinical trial and submission teams will be unblinded after Week 16 readout. Participants should continue on stable NSAID therapy and physiotherapy during this period. Reduction in NSAID dose is permitted after BSL, but participants must not increase above dose established during run-in. Corticosteroid injections are also not permitted after Week 16. - Off-site procedures At the Investigator's discretion, participants may avail of home administration of study drug (self-administered or by a care-giver) at Week 1 and Week 3. Participant and/or caregiver would need to be trained and approved by Investigator for these administrations. Site should have confirmed contact with participant for these home administrations. Tele-visits, i.e., secure videoconferencing, between the Participant and Investigator or designated site staff may also be utilized to support administration of study drug at home. Rescue Medicine Any changes to type of NSAID taken by the participant or any increase in NSAID dosages from stable dose established during run-in period are considered prohibited throughout the duration of the study. If pain or discomfort is intolerable, participants may use non-NSAID medication including, for example, acetaminophen/paracetamol, low-dose opioids and tramadol, as needed. If the participant continues to experience intolerable pain or discomfort, then any increase to the dose of NSAID taken should be kept to an absolute minimum in terms of dosage and duration. Any changes to NSAID type and/or increase in dose will be recorded as a deviation to the protocol but would not result in withdrawal of the participant. Rational for placebo arm The placebo effect in interventional trials in the treatment of RCT is considerable; hence, a placebo control is warranted.

Official Title
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A Randomized, Parallel-group, 24 Week, Double-blind, Placebo-controlled, Multicenter Phase 3 Study to Assess the Efficacy and Safety of Secukinumab Compared to Placebo in Adult Patients With Active Rotator Cuff Tendinopathy

Conditions
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Rotator Cuff Tendinopathy

Intervention / Treatment
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* Drug: Secukinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unilateral rotator cuff tendinopathy with ≥ 6 weeks to ≤ 6 months symptom duration at BSL. Nocturnal pain in shoulder on at least 3 out of 7 nights in the week prior to Baseline or positive painful arc test on examination. Total WORC percentage score ≤ 40 at the Screening and Baseline visits. Average weekly (i.e., the average of the 7 scores taken once a day) numerical rating scale (NRS) pain score of ≥5 during the past 7 days prior to the Baseline visit. Refractory to standard of care: NSAIDs course as per local standard practice (if not intolerant or contraindicated) and a course of physiotherapy over a period of 8 weeks. Participant must agree to remain on stable NSAID dosage regimen (if not intolerant or having contraindications; NSAID dose is permitted to be reduced, but not increased above dose established at run-in) and physiotherapy regimen from run-in period until End of Study (EOS). Presence of tendinopathy in the affected shoulder on a centrally read MRI (Magnetic Resonance Imaging), with the following conditions: with no tear or partial tear (maximum 50% tendon thickness; AP length maximum 10 mm). Exclusion Criteria: Rheumatological and non-rheumatological inflammatory diseases, including but not limited to polymyalgia rheumatica (PMR), psoriatic arthritis (PsA), axial spondyloarthritis (AS: Ankylosing Spondylitis, nr-axSpA: non-radiographic Axial Spondyloarthritis), psoriasis (PsO), and rheumatoid arthritis (RA); fibromyalgia or severe pain disorder unrelated to the target shoulder; gout; and systemic lupus erythematosus. Rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibodies positive at Screening. Oral, intramuscular or intravenous (i.v.) corticosteroid treatment within the last 12 weeks prior to randomization, or presence of any condition that might require intermittent corticosteroid use. Lack of compliance with adhering to NSAID (unless intolerant or contraindicated) and physiotherapy regimen during run-in period. Positive painful arc test result in contralateral shoulder. Inability or unwillingness to undergo MRI of the shoulder (e.g., participants with pacemakers, or metal fragments/foreign objects in the body that are not compatible with performing an MRI) to fulfill eligibility criteria (unless centrally read MRI images acquired within 3 months of Baseline can be provided and the quality of images is deemed sufficient).

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Secukinumab<br>Name and Strength: 2 X Secukinumab 150 mg / 1 mL Pharmaceutical Dosage Form: Solution for subcutaneous (s.c.) injection Randomized in a 1:1 ratio | Drug: Secukinumab<br>* The participants will receive Secukinumab 300 mg s.c. at randomization (Baseline visit), Week 1, 2, 3, 4, 8, and 12<br>* Other names: AIN457;|
| Placebo Comparator: Placebo<br>Name and Strength: 2 X Placebo / 1 mL Pharmaceutical Dosage Form: Solution for subcutaneous (s.c.) injection Randomized in a 1:1 ratio | Drug: Placebo<br>* The participants will receive placebo s.c. at randomization (Baseline visit), Week 1, 2, 3, 4, 8, and 12<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from BSL in in the Western Ontario Rotator Cuff Index (WORC) Physical Symptom Domain (PSD) score | Change in physical shoulder symptoms in participants with moderate to severe RCT at Week 16 The WORC PSD is a sub-domain of the WORC Patient-Reported Outcome (PRO) and comprises 6 questions that capture the key symptoms experienced by participants with RCT relating to pain, weakness, stiffness, and mechanical symptoms. A score of 0 is the best outcome in terms of physical symptoms and a score of 60 is the worst possible score | At Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who achieve an improvement (increase) of at least 40 points from BSL in the WORC PSD | Achieving a clinically meaningful response in improving physical shoulder symptoms in participants with moderate to severe RCT at Week 16 | At Week 16 | 
| Proportion of participants who achieve an improvement (increase) of at least 50 points from BSL in the WORC total score | Improving symptoms caused by RCT and the associated impact on day-to-day functioning in participants with moderate to severe RCT at Week 16 | At Week 16 | 
| Change from BSL in the Patient-Reported Outcomes Measurement Information System (PROMIS) - Short Form (SF) Upper Extremity score | Change in physical function in participants with moderate to severe RCT at Week 16. PROMIS-SF Upper Extremity measures self-reported capability of Physical Function. Participants will be asked a series of 7 questions rating their ability to perform a range of physical activities related to daily life that would be impacted by shoulder function. Each response is scored from 5 (Without any difficulty) to 1 (Unable to do) | At Week 16 | 
| Proportion of participants who achieve an improvement (increase) of at least 40 points from BSL in the WORC PSD. Change from BSL in the WORC PSD score | Improvement of physical symptoms at Week 24 | At Week 24 | 
| Secukinumab serum concentrations | Pharmacokinetic parameters (measures of treatment exposure) will be evaluated in all participants, with moderate to severe RCT, treated with secukinumab 300 mg s.c. The following pharmacokinetic parameter will be determined using the actual recorded sampling times with Phoenix WinNonlin (Version 6.4 or higher): minimal serum concentration per dosing interval (Cmin). Cmin will be reported in microgram per milliliter (µg/mL) and is the minimum serum concentration that secukinumab will achieve after dosing. | Day 1 and Weeks 4 and 16 | 
| Number of participants with adverse events | Evaluate safety and tolerability of 300 mg s.c. secukinumab, in participants with moderate to severe RCT: Adverse Events and Serious Adverse Events (incidence, severity, and relationship with study drug), incidence of clinically significant changes in laboratory parameters and vital signs | Up to Week 24 | 
| Incidence of binding and neutralizing Anti-drug antibodies | Evaluate immunogenicity of 300 mg s.c. secukinumab, in participants with moderate to severe RCT | At Day 1 and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate to Severe Rotator Cuff Tendinopathy, Adult, Unilateral, Refractory to standard of care