Rotator Cuff Tendinopathy
Conditions
Keywords
Moderate to Severe Rotator Cuff Tendinopathy, Adult, Unilateral, Refractory to standard of care
Brief summary
The purpose of the present study was 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
This was a randomized, double-blind, placebo-controlled Phase III study, stratified by tear status (no tear/ partial tear) in participants with moderate to severe rotator cuff tendinopathy (RCT), experiencing active disease from at least 6 weeks to 6 months at baseline, and were refractory to standard of care (non-steroidal anti-inflammatory drug \[NSAIDs\] and course of physiotherapy) over a period of 8 weeks. The study was terminated due to the project being discontinued in order to prioritize other key programs in the portfolio. Due to the early termination and small sample size, the analysis by tear status stratification was not performed. The study duration was up to 32 weeks, consisting of a screening period lasting up to 8 weeks (inclusive of a mandatory 2-week run-in period), a 16-week treatment period with last dose administered at Week 12, and an 8-week safety follow-up period. The primary endpoint assessment was at Week 16, and the safety follow-up data collection was through to Week 24.
Interventions
DRUGSecukinumab
2 X secukinumab 150 mg / 1 mL as solution for subcutaneous (s.c.) injection
DRUGPlacebo
2 X placebo / 1 mL as solution for s.c. injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Investigator, site personnel, persons performing the assessments and participants remained blinded through the Week 24 final database lock. The Novartis clinical trial and submission teams remained blinded to the identity of the treatment from the time of randomization until the Week 16 database lock (for the primary endpoint analysis). The following methods were utilized for blinding: (1) Randomization data were kept strictly confidential until the time of unblinding and were not accessible by anyone else involved in the study with the following exceptions: bioanalyst; (2) the identity of the treatments was concealed by the use of study treatments that were all identical in packaging, labeling, schedule of administration, and appearance.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Unilateral rotator cuff tendinopathy with ≥ 6 weeks to ≤ 6 months symptom duration at baseline. 2. 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. 3. Total WORC percentage score ≤ 40 at the screening and baseline visits. 4. 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. 5. Refractory to standard of care: non-steroidal anti-inflammatory drug (NSAIDs) course as per local standard practice (if not intolerant or contraindicated) and a course of physiotherapy over a period of 8 weeks. 6. Participant agreed to remain on stable NSAID dosage regimen (if not intolerant or having contraindications; NSAID dose was 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). 7. 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; anteroposterior (AP) length maximum 10 mm)
Exclusion criteria
1. 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. 2. Rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibodies positive at screening. 3. 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. 4. Lack of compliance with adhering to NSAID (unless intolerant or contraindicated) and physiotherapy regimen during run-in period. 5. Positive painful arc test result in contralateral shoulder 6. Inability or unwillingness to undergo MRI of the shoulder (e.g., participants with pacemakers, or metal fragments/foreign objects in the body that were not compatible with performing an MRI) to fulfill eligibility criteria (unless centrally read MRI images acquired within 3 months of baseline could be provided and the quality of images was deemed sufficient).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Western Ontario Rotator Cuff Index (WORC) Physical Symptom Domain (PSD) Score at Week 16 | 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) - Short Form (SF) Upper Extremity Score | At Week 16 | PROMIS-SF Upper Extremity measures self-reported capability of physical function. Participants were 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 was scored from 1 (unable to do) to 5 (without any difficulty). The responses for the 7 questions were added to the total raw score ranging from 7 (worst) to 35 (best) and converted to a T-score with a range from 16.3 (worst outcome) to 58.2 (best outcome), which was used for the analysis. Therefore, the theoretical range for the value for change from baseline for converted T-scores was between -41.9 to 41.9. A positive change from baseline indicated a better outcome. |
| Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 16 | 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms. |
| Percentage of Participants Who Achieved an Improvement (Increase) of at Least 50 Points From Baseline in the WORC Total Score | At Week 16 | The WORC is a patient-reported outcome tool, uniquely developed for rotator cuff conditions. The WORC is self-administered and consists of 21 items divided into five domains: physical symptoms, sport/recreation, work function, lifestyle function, and emotional function. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms. |
| Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 24 | At Week 24 | 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms. |
| Change From Baseline in WORC PSD Score at Week 24 | At Week 24 | 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms. |
| Secukinumab Serum Concentrations | Day 1 and Weeks 4 and 16 | Pharmacokinetic parameters (measures of treatment exposure) were evaluated in all participants, with moderate to severe RCT, treated with secukinumab 300 mg s.c. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Up to Week 24 | Severity: Mild - usually transient in nature and generally not interfering with normal activities; Moderate - sufficiently discomforting to interfere with normal activities; Severe - prevents normal activities. |
| Percentage of Participants With Clinically Significant Changes in Laboratory Parameters | Up to Week 24 | Laboratory parameters included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, amylase, calcium, creatinine, bilirubin, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, sodium, urate, and urea nitrogen. |
| Percentage of Participants With Clinically Significant Changes in Vital Signs | Up to Week 24 | Vital signs included sitting systolic blood pressure, sitting diastolic blood pressure, and sitting pulse rate. |
| Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies | At Day 1 and Week 16 | — |
Countries
Argentina, Bulgaria, Canada, Czechia, Malaysia, Portugal, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
166 participants were screened in this study, of which 133 discontinued prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Secukinumab Participants received secukinumab 300 mg at randomization (baseline visit) and Weeks 1, 2, 3, 4, 8, and 12. | 17 |
| Placebo Participants received placebo at randomization (baseline visit) and Weeks 1, 2, 3, 4, 8, and 12. | 16 |
| Total | 33 |
Baseline characteristics
| Characteristic | Placebo | Total | Secukinumab |
|---|---|---|---|
| Age, Continuous | 47.4 years STANDARD_DEVIATION 10.12 | 48.5 years STANDARD_DEVIATION 10.3 | 49.6 years STANDARD_DEVIATION 10.66 |
| Age, Customized 18 - < 25 years | 1 participants | 2 participants | 1 participants |
| Age, Customized 25 - < 45 years | 4 participants | 8 participants | 4 participants |
| Age, Customized 45 - <= 65 years | 11 participants | 23 participants | 12 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized White | 14 participants | 29 participants | 15 participants |
| Sex: Female, Male Female | 10 Participants | 24 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 8 / 17 | 3 / 16 |
| serious Total, serious adverse events | 0 / 17 | 1 / 16 |
Outcome results
Primary
Change From Baseline in the Western Ontario Rotator Cuff Index (WORC) Physical Symptom Domain (PSD) Score 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms.
Time frame: At Week 16
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned. Number analyzed is the number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Secukinumab | Change From Baseline in the Western Ontario Rotator Cuff Index (WORC) Physical Symptom Domain (PSD) Score at Week 16 | 45.89 score on a scale | Standard Deviation 25.49 |
| Placebo | Change From Baseline in the Western Ontario Rotator Cuff Index (WORC) Physical Symptom Domain (PSD) Score at Week 16 | 38.40 score on a scale | Standard Deviation 29.908 |
Secondary
Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) - Short Form (SF) Upper Extremity Score
PROMIS-SF Upper Extremity measures self-reported capability of physical function. Participants were 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 was scored from 1 (unable to do) to 5 (without any difficulty). The responses for the 7 questions were added to the total raw score ranging from 7 (worst) to 35 (best) and converted to a T-score with a range from 16.3 (worst outcome) to 58.2 (best outcome), which was used for the analysis.
Time frame: At Week 16
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Secukinumab | Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) - Short Form (SF) Upper Extremity Score | 13.86 score on a scale | Standard Deviation 10.535 |
| Placebo | Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) - Short Form (SF) Upper Extremity Score | 13.78 score on a scale | Standard Deviation 11.098 |
Secondary
Change From Baseline in WORC PSD Score at Week 24
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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms.
Time frame: At Week 24
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned. Number analyzed is the number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Secukinumab | Change From Baseline in WORC PSD Score at Week 24 | 51.19 score on a scale | Standard Deviation 26.664 |
| Placebo | Change From Baseline in WORC PSD Score at Week 24 | 43.67 score on a scale | Standard Deviation 34.661 |
Secondary
Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score 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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms.
Time frame: At Week 16
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned. Number analyzed is the number of participants with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 16 | 52.9 percentage of participants |
| Placebo | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 16 | 53.3 percentage of participants |
Secondary
Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 24
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 rotator cuff tendinopathy (RCT) relating to pain, weakness, stiffness, and mechanical symptoms. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms.
Time frame: At Week 24
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned. Number analyzed is the number of participants with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 24 | 66.7 percentage of participants |
| Placebo | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 40 Points From Baseline in the WORC PSD Score at Week 24 | 61.5 percentage of participants |
Secondary
Percentage of Participants Who Achieved an Improvement (Increase) of at Least 50 Points From Baseline in the WORC Total Score
The WORC is a patient-reported outcome tool, uniquely developed for rotator cuff conditions. The WORC is self-administered and consists of 21 items divided into five domains: physical symptoms, sport/recreation, work function, lifestyle function, and emotional function. The raw score was converted to a scale of 0 to 100, where 0 represents the most symptomatic score, and 100 represents no symptoms.
Time frame: At Week 16
Population: The full analysis set included all participants from the randomized set to whom study treatment was assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 50 Points From Baseline in the WORC Total Score | 64.7 percentage of participants |
| Placebo | Percentage of Participants Who Achieved an Improvement (Increase) of at Least 50 Points From Baseline in the WORC Total Score | 43.8 percentage of participants |
Secondary
Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies
Time frame: At Day 1 and Week 16
Population: The safety set included all participants who took at least one dose of study treatment during the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Secukinumab | Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies | Day 1 | 0 percentage of participants |
| Secukinumab | Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies | Week 16 | 0 percentage of participants |
| Placebo | Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies | Day 1 | 0 percentage of participants |
| Placebo | Percentage of Participants With Binding and Neutralizing Anti-drug Antibodies | Week 16 | 0 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Changes in Laboratory Parameters
Laboratory parameters included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, amylase, calcium, creatinine, bilirubin, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, sodium, urate, and urea nitrogen.
Time frame: Up to Week 24
Population: The safety set included all participants who took at least one dose of study treatment during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants With Clinically Significant Changes in Laboratory Parameters | 0 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Changes in Laboratory Parameters | 0 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Changes in Vital Signs
Vital signs included sitting systolic blood pressure, sitting diastolic blood pressure, and sitting pulse rate.
Time frame: Up to Week 24
Population: The safety set included all participants who took at least one dose of study treatment during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants With Clinically Significant Changes in Vital Signs | 0 percentage of participants |
| Placebo | Percentage of Participants With Clinically Significant Changes in Vital Signs | 0 percentage of participants |
Secondary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity
Severity: Mild - usually transient in nature and generally not interfering with normal activities; Moderate - sufficiently discomforting to interfere with normal activities; Severe - prevents normal activities.
Time frame: Up to Week 24
Population: The safety set included all participants who took at least one dose of study treatment during the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Secukinumab | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Mild | 29.4 percentage of participants |
| Secukinumab | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Moderate | 17.6 percentage of participants |
| Secukinumab | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Severe | 0 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Mild | 18.8 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Moderate | 0 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), by Maximum Severity | Severe | 6.3 percentage of participants |
Secondary
Secukinumab Serum Concentrations
Pharmacokinetic parameters (measures of treatment exposure) were evaluated in all participants, with moderate to severe RCT, treated with secukinumab 300 mg s.c.
Time frame: Day 1 and Weeks 4 and 16
Population: The safety set included all participants who took at least one dose of study treatment during the treatment period. Number analyzed is the number of participants with available data at that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Secukinumab | Secukinumab Serum Concentrations | Day 1 | 0.00 μg/mL | Standard Deviation 0 |
| Secukinumab | Secukinumab Serum Concentrations | Week 4 | 89.8 μg/mL | Standard Deviation 20.1 |
| Secukinumab | Secukinumab Serum Concentrations | Week 16 | 37.0 μg/mL | Standard Deviation 14.3 |