Psoriatic Arthritis
Conditions
Keywords
Power Doppler Ultrasonography, Psoriatic Arthritis, Enthesitis, Synovitis, Outcome Measures in Rheumatology, Spondyloarthritis Research Consortium of Canada, active psoriatic arthritis, secukinumab, Arthritis, GLOESS, monoclonal antibody, PsA
Brief summary
This study was designed to leverage the sensitivity of ultrasonography available in clinical practice setting to better describe the time course of response to secukinumab (150 mg and 300 mg) on joint synovitis and enthesitis in PsA patients with an inadequate response to non-biologic DMARDs. PDUS changes in joint synovitis will be assessed using the global Outcome Measures in Rheumatology (OMERACT)-European League against Rheumatism (EULAR) synovitis score (GLOESS) and changes in joint enthesitis were assessed using the OMERACT enthesitis score.
Detailed description
This was a 52-week, multicenter, international study consisting of a 2 to 4-week Screening period, a 12-week randomized, placebo-controlled double-blind treatment period (Period 1), a 12-week open-label treatment period (Period 2) and a 6-month open-label extension period (Period 3). Treatment Period 1 is a 12-week placebo-controlled, randomized period primarily designed to demonstrate the early and optimal efficacy of secukinumab vs placebo on joint synovitis using PDUS via the GLOESS and global entheseal score after 12 weeks of treatment. The main aim of Period 2 was to assess the maintenance or increased magnitude of treatment response on joint synovitis for patients from the original secukinumab groups and to assess the time course of response with secukinumab on joint synovitis in the original placebo group switched to secukinumab from Week 12. The main aim of Period 3 (extension period) was to allow patients who respond to secukinumab to extend study treatment up to Week 52 or until commercial drug becomes available, whichever occurs sooner.
Interventions
Is a recombinant monoclonal antibody which neutralizes the activity of IL-17A, and has been shown to be effective in treating patients with moderate-to-severe plaque psoriasis. Secukinumab 150 mg provided in 1 mL pre filled syringes (PFS) for s.c. injection. The 300 mg dose was administered as 2 × PFS injections.
DRUGPlacebo
Secukinumab placebo was provided in a 1 mL PFS for s.c. injection.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient must be able to understand and communicate with the Investigator and comply with the requirements of the study and must provide written, signed and dated informed consent before any study assessment is performed. 2. Male or female patients at least 18 years of age. 3. Diagnosis of PsA as per CASPAR with active PsA for at least 6 months and a TJC ≥ 3 of 78 and SJC ≥ 3 of 76 at Baseline. 4. Patients must have a total synovitis PDUS score ≥ 2 and inflammation related to PD signal ≥ 1 for at least 2 (affected joints as observed via PDUS) of 48 joints at the Screening visit and at the Baseline visit (before infusion). 5. At least 1 clinically-involved enthesitis site at Screening and at the Baseline visit (before infusion) defined by SPARCC index different from 0.
Exclusion criteria
1. Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process obtained within 3 months prior to Screening and evaluated by a qualified physician. 2. Previous exposure to secukinumab or other biologic drug directly targeting IL-17 or IL-17 receptor. 3. Any change in the dose of oral corticosteroids in the last 4 weeks prior to the Baseline visit or use of i.v. intramuscular or intra-articular corticosteroid during the last 4 weeks prior to the enrollment visit. 4. Patients who have previously been treated with TNFα inhibitors (investigational or approved). 5. History of hypersensitivity to the study drug or its excipients or to drugs of similar classes. 6. 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). 7. Prohibited psoriasis treatments/medications with topical corticosteroids in the last 4 weeks prior to randomization. 8. Pregnant or nursing (lactating) women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference Between Secukinumab and Placebo in Terms of Joint Synovitis as Measured by the Power Doppler Ultrasonography (PDUS) Global OMERACT-EULAR Synovitis Score (GLOESS) | 12 weeks | Mixed model repeated measures (MMRM) analysis of change in Global OMERACT-EULAR Synovitis Score (GLOESS) score at Week 12 (observed data) to compare treatments The range for the GLOESS score is 0 to 144. GLOESS is the ultrasound scoring system measured for 24 pairs of joints. The scoring is from 0 to 3 for each joint; so the minimum score can be 0 and maximum can be 144. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With American College of Rheumatology (ACR)-20 Response | Week 12 | ACR 20 responder has ≥ 20% improvement in TJC and SJC and \>20% improvement in 3 of the following 5 domains: patient's assessment of disease activity, physician's assessment of disease activity, patient's |
| Proportion of Participants With American College of Rheumatology (ACR)-50 Response | Week 12 | ACR 50 responder has ≥ 50% improvement in TJC and SJC and \>25% improvement in 3 of the following 5 domains: patient's assessment of disease activity, physician's assessment of disease activity, patient's assessment of PsA pain, HAQ-DI, or hsCRP. |
| Spondyloarthritis Research Consortium of Canada (SPARCC) | Baseline to Week 12 | Repeated measures mixed effect (MMRM) analysis of SPARCC total score change from baseline to Week 12 between the 2 treatment groups. SPARCC index ranges from 0 to 16. |
Countries
Argentina, Austria, Belgium, Canada, Colombia, Czechia, France, Germany, Hungary, Ireland, Italy, Mexico, Netherlands, Norway, Spain, United Kingdom, United States
Participant flow
Recruitment details
166 participants enrolled in 17 countries
Pre-assignment details
83 partcipants were randomized to each group
Participants by arm
| Arm | Count |
|---|---|
| Group 1 - Secukinumab (150 mg + 300 mg) In Treatment Period-1:
Patients in this group were administered secukinumab with 12 weeks of treatment from baseline.
In Treatment Period-2:
Patients continued to receive the same active dose of secukinumab every 4 weeks until Week 24 (although primary outcome was to week 12 only)
In Treatment Period 3 (extension period):
the extension period allowed responder patients the possibility to continue open-label secukinumab treatment up to Week 52 | 83 |
| Group 2 - Placebo/Secukinumab (150 mg + 300 mg) In Treatment Period-1:
Patients received placebo at baseline and same time points as secukinumab until Week 8.
In Treatment Period-2:
Patients commenced open-label secukinumab 150 or 300 mg every 4 weeks from Week 12, as follows, based on their severity of skin disease at Week 12
In Treatment Period-3:
Open-label secukinumab continued to be assigned to patients | 83 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 2 |
| Treatment Period 1 | Physician Decision | 1 | 0 |
| Treatment Period 1 | Protocol Violation | 0 | 1 |
| Treatment Period 1 | Withdrawal by Subject | 0 | 1 |
| Treatment Period 2 | Lack of Efficacy | 0 | 1 |
| Treatment Period 2 | Lost to Follow-up | 1 | 0 |
| Treatment Period 3 (Extension Period) | Adverse Event | 1 | 1 |
| Treatment Period 3 (Extension Period) | Death | 0 | 1 |
| Treatment Period 3 (Extension Period) | Lack of Efficacy | 0 | 1 |
| Treatment Period 3 (Extension Period) | Withdrawal by Subject | 1 | 2 |
| Treatment Period 3 (Extension Period) | Withdrew before entering period | 4 | 4 |
Baseline characteristics
| Characteristic | Group 1 - Secukinumab (150 mg + 300 mg) | Group 2 - Placebo/Secukinumab (150 mg + 300 mg) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 4 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 79 Participants | 155 Participants |
| Age, Continuous | 46.7 years STANDARD_DEVIATION 12.35 | 46.7 years STANDARD_DEVIATION 12.08 | 46.7 years STANDARD_DEVIATION 12.18 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 75 Participants | 75 Participants | 150 Participants |
| Race/Ethnicity, Customized Native American | 4 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 45 Participants | 46 Participants | 91 Participants |
| Sex: Female, Male Male | 38 Participants | 37 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 161 | 0 / 83 |
| other Total, other adverse events | 79 / 161 | 27 / 83 |
| serious Total, serious adverse events | 9 / 161 | 2 / 83 |
Outcome results
Primary
Difference Between Secukinumab and Placebo in Terms of Joint Synovitis as Measured by the Power Doppler Ultrasonography (PDUS) Global OMERACT-EULAR Synovitis Score (GLOESS)
Mixed model repeated measures (MMRM) analysis of change in Global OMERACT-EULAR Synovitis Score (GLOESS) score at Week 12 (observed data) to compare treatments The range for the GLOESS score is 0 to 144. GLOESS is the ultrasound scoring system measured for 24 pairs of joints. The scoring is from 0 to 3 for each joint; so the minimum score can be 0 and maximum can be 144.
Time frame: 12 weeks
Population: Full analysis set (FAS): The FAS comprised all patients from the Randomized set to whom study treatment had been assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Secukinumab (150 mg + 300 mg) | Difference Between Secukinumab and Placebo in Terms of Joint Synovitis as Measured by the Power Doppler Ultrasonography (PDUS) Global OMERACT-EULAR Synovitis Score (GLOESS) | -9.05 Adjusted Mean Change in scores | Standard Error 0.94 |
| Group 2 - Placebo/Secukinumab | Difference Between Secukinumab and Placebo in Terms of Joint Synovitis as Measured by the Power Doppler Ultrasonography (PDUS) Global OMERACT-EULAR Synovitis Score (GLOESS) | -5.86 Adjusted Mean Change in scores | Standard Error 0.93 |
Comparison: GLOESS scoresp-value: 0.00495% CI: [-5.52, -0.85]Mixed Models Analysis
Secondary
Proportion of Participants With American College of Rheumatology (ACR)-20 Response
ACR 20 responder has ≥ 20% improvement in TJC and SJC and \>20% improvement in 3 of the following 5 domains: patient's assessment of disease activity, physician's assessment of disease activity, patient's
Time frame: Week 12
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Secukinumab (150 mg + 300 mg) | Proportion of Participants With American College of Rheumatology (ACR)-20 Response | 56 Participants |
| Group 2 - Placebo/Secukinumab | Proportion of Participants With American College of Rheumatology (ACR)-20 Response | 26 Participants |
Comparison: Proportion of patients with ACR 20 response at Week 12 (FAS)p-value: <0.000195% CI: [2.38, 8.89]Regression, Logistic
Secondary
Proportion of Participants With American College of Rheumatology (ACR)-50 Response
ACR 50 responder has ≥ 50% improvement in TJC and SJC and \>25% improvement in 3 of the following 5 domains: patient's assessment of disease activity, physician's assessment of disease activity, patient's assessment of PsA pain, HAQ-DI, or hsCRP.
Time frame: Week 12
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Secukinumab (150 mg + 300 mg) | Proportion of Participants With American College of Rheumatology (ACR)-50 Response | 38 Participants |
| Group 2 - Placebo/Secukinumab | Proportion of Participants With American College of Rheumatology (ACR)-50 Response | 7 Participants |
Comparison: Proportion of patients with ACR 50 response at Week 12 (FAS)p-value: <0.000195% CI: [3.92, 23.75]Regression, Logistic
Secondary
Spondyloarthritis Research Consortium of Canada (SPARCC)
Repeated measures mixed effect (MMRM) analysis of SPARCC total score change from baseline to Week 12 between the 2 treatment groups. SPARCC index ranges from 0 to 16.
Time frame: Baseline to Week 12
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Secukinumab (150 mg + 300 mg) | Spondyloarthritis Research Consortium of Canada (SPARCC) | -2.23 Adjusted mean change in scores | Standard Error 0.29 |
| Group 2 - Placebo/Secukinumab | Spondyloarthritis Research Consortium of Canada (SPARCC) | -1.57 Adjusted mean change in scores | Standard Error 0.29 |
Comparison: SPARCCp-value: 0.032795% CI: [-1.374, 0.043]Regression, Logistic