Study of Efficacy and Safety of Secukinumab in Patients With Non-radiographic Axial Spondyloarthritis

Study Overview
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Brief Summary
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The purpose of this study was to demonstrate the clinical efficacy, safety and tolerability of secukinumab compared to placebo in patients with nr-axSpA at Week 16 as well as Week 52 and long term efficacy and safety up to Week 104 (core phase) followed by an optional extension phase consisting of a 16-week randomized dose escalation treatment period and a continuous treatment period for up to Week 208

Detailed Description
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Patients were randomized to one of three treatment groups (1:1:1) in the core phase: Secukinumab 150 mg Load: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-filled syringe (PFS) at baseline, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4 Secukinumab 150 mg No Load: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS at baseline, placebo at Weeks 1, 2, and 3, followed by secukinumab 150 mg PFS administration every four weeks starting at Week 4 Placebo: placebo (1 mL) s.c. PFS at baseline, Weeks 1, 2, 3, followed by administration every four weeks starting at Week 4. All patients received secukinumab 150 mg as open-label treatment from Week 52 up to Week 100, unless they had discontinued study treatment. At Week 104, all patients who finished the core phase according to the protocol were asked to continue in an optional, exploratory extension phase. Patients who achieved ASAS20 response at Week 104 (Core Phase Responders) were randomized to the following treatment groups (blinded) in the extension phase: Core Phase Responder 150 mg: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS and placebo (1 mL) s.c. PFS every four weeks; Core Phase Responder 300 mg: 2 injections with secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS every four weeks. Core Phase Non-Responders (not achieving ASAS20 at Week 104) were escalated to secukinumab 300 mg in an open-label manner. - Core Phase Non-Responder 300 mg: 2 injections with secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS every four weeks open-label. Starting from Week 156 onward, a patient could switch to secukinumab 300 mg open-label based on the clinical judgment of disease activity by the investigator.

Official Title
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A Randomized, Double-blind, Placebo-controlled Multicenter Study of Secukinumab 150 mg in Patients With Active nr- axSpA to Evaluate the Safety,Tolerability and Efficacy up to 2 Yrs, Followed by an Opt Phase of Either 150 mg or 300 mg Randomized Dose Escalation for up to Another 2 Yrs

Conditions
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Non-radiographic Spondyloarthritis

Intervention / Treatment
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* Drug: Secukinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant, non-nursing female patients at least 18 years of age Diagnosis of axial spondyloarthritis according to Ankylosing SpondyloArthritis International Society (ASAS) axial spondyloarthritis criteria objective signs of inflammation (magnetic resonance imaging (MRI) or abnormal C-reactive protein) active axial spondyloarthritis as assessed by total Bath Ankylosing Spondylitis Disease Activity Index >=4 cm Spinal pain as measured by Bath Ankylosing Spondylitis Disease Activity Index question #2 ≥ 4 cm (0-10 cm) at baseline Total back pain as measured by Visual Analogue scale ≥ 40 mm (0-100 mm) at baseline Patients should have been on at least 2 different non-steroidal anti-inflammatory drugs with an inadequate response Patients who have been on a Tumor Necrosis Factor (TNF) α inhibitor (not more than one) must have experienced an inadequate response Exclusion Criteria: Patients with radiographic evidence for sacroiliitis, grade ≥ 2 bilaterally or grade ≥ 3 unilaterally Inability or unwillingness to undergo MRI Chest X-ray or MRI with evidence of ongoing infectious or malignant process Patients taking high potency opioid analgesics Previous exposure to secukinumab or any other biologic drug directly targeting interleukin-17 (IL-17) or IL-17 receptor Pregnant or nursing (lactating) women

Ages Eligible for Study
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Minimum Age: 18 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: This was a randomized, double-blind, placebo-controlled study. Approximately 555 patients were randomized to one of three treatment groups (secukinumab 150 mg Load, secukinumab 150 mg No Load or placebo in a ratio of 1:1:1): Group 1 (secukinumab 150 mg Load): secukinumab 150 mg (1 mL, 150 mg/mL) s.c. prefilled syringe (PFS) at baseline (BSL), Weeks 1, 2 and 3, followed by administration every four weeks starting at Week 4 Group 2 (secukinumab 150 mg No Load): secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS at BSL, placebo at Weeks 1, 2 and 3, followed by secukinumab 150 mg PFS administration every four weeks starting at Week 4 Group 3 (placebo): placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, followed by administration every four weeks starting at Week 4 Based on the clinical judgment of disease activity by the investigator and the patient, background medications, such as NSAIDs and DMARDs, may have been modified or added to treat signs and symptoms of nr-axSpA from Week 16 on.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Secukinumab, 150 mg Load (Core phase)<br>Secukinumab 150 mg s.c., pre-filled syringe (PFS) at baseline, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4, Load, Core phase | Drug: Secukinumab<br>* Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly<br>* Other names: AIN457;|
| Experimental: Secukinumab, 150 mg No Load (Core phase)<br>Secukinumab 150 mg s.c. PFS at baseline, placebo at Weeks 1, 2, and 3, followed by secukinumab 150 mg PFS administration every four weeks starting at Week 4, No Load, Core phase | Drug: Secukinumab<br>* Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly<br>* Other names: AIN457;|
| Placebo Comparator: Placebo (Core phase)<br>Placebo s.c., PFS at baseline, Weeks 1, 2, 3, followed by administration every four weeks starting at Week 4, Core phase | Drug: Placebo<br>* Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly<br>* Other names: AIN457;|
| Experimental: Core Phase Responder 150 mg (Extension phase)<br>Core Phase Responder 150 mg blinded: secukinumab 150 mg s.c. PFS and placebo (1 mL) s.c. PFS every four weeks, in the Extension phase | Drug: Secukinumab<br>* Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly<br>* Other names: AIN457;Drug: Placebo<br>* Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly<br>* Other names: AIN457;|
| Experimental: Core Phase Responder 300 mg (Extension phase)<br>Core Phase Responder 300 mg blinded: 2 injections with secukinumab 150 mg s.c. PFS every four weeks, in the Extension phase | Drug: Secukinumab<br>* Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly<br>* Other names: AIN457;|
| Experimental: Core Phase Non-Responder 300 mg (Extension phase)<br>Core Phase Non-Responder 300 mg: 2 injections with secukinumab 150 mg s.c. PFS every four weeks open-label, in the Extension phase | Drug: Secukinumab<br>* Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly<br>* Other names: AIN457;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number and Percentage of TNF Naive Participants Who Achieved an Assessment of Spondylo Arthritis International Society (ASAS) 40 Response at Week 16 | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain. A higher score on the VAS signifies higher severity. | Week 16 | 
| The Number and Percentage of TNF Naive Participants Who Achieved an Assessment of SpondyloArthritis International Society (ASAS) 40 Response at Week 52 | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain. A higher score on the VAS signifies higher severity. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number and Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society (ASAS) 40 Response | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain. A higher score on the VAS signifies higher severity. | Week 16 and week 52 | 
| The Number and Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society (ASAS) 20 Response | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). ASAS 20 response is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain. A higher score on the VAS signifies higher severity. | Week 16 | 
| The Number and Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society (ASAS) 5/6 Response | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains. A higher score on the VAS signifies higher severity. | Week 16 | 
| The Number and Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society Partial Remission (ASAS PR) | Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 6 domains (4 main and 2 additional assessment domains): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions as measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). The ASAS partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 10. A higher score on the VAS signifies higher severity. | Week 16 | 
| Change in Bath Ankylosing Spondylitis Functional Index (BASFI) | The Bath Ankylosing Spondylitis Functional Index (BASFI) is a set of 10 questions designed to determine the degree of functional limitation in those subjects with AS. The ten questions were chosen with a major input from subjects with AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions assess the subjects' ability to cope with everyday life. A 100 mm visual analog scale (VAS) is used to answer the questions. The mean of the ten questions gives the BASFI score - a value between 0 and 10. (0 being no problem and 10 being the worst problem, captured as a continuous visual analog scale (VAS)). A higher score on the VAS signifies higher severity. | Baseline and Week 16 | 
| The Number and Percentage of Patients to Achieve a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response | The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 5 major symptoms of AS. The BASDAI 50 is defined as an improvement of at least 50% in the BASDAI compared to baseline. A higher score on the VAS signifies higher severity. | Week 16 and 52 | 
| Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a validated assessment tool using 1 through 10 scales (1 indicating no problem and 10 indicating  worst problem), to characterize six clinical domains (fatigue, spinal pain, joint pain/selling, localized tenderness, morning stiffness duration, morning stiffness severity) pertaining to five major symptoms of Ankylosing Spondylitis (AS). The computed final BASDAI score is a value between 0 and 10 with a higher score indicating worse disease. A higher score on the VAS signifies higher severity. | Baseline and Week 16 | 
| Change in Ankylosing Spondylitis Quality of Life (ASQoL) Scores at Week 16 | The Ankylosing Spondylitis Quality of Life scores (ASQoL) is a self-administered questionnaire designed to assess health-related quality of life in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a dichotomous yes/no response option. A single point is assigned for each yes response and no points for each no response resulting in overall scores that range from 0 (least severity) to 18 (highest severity). As such, lower score indicate better quality of life. Items include an assessment of mobility/energy, self-care and mood/emotion. The recall period is at the moment, and the measure requires approximately 6 minutes to complete. | Baseline and Week 16 | 
| Change in Ankylosing Spondylitis Quality of Life (ASQoL) Scores at Week 52 | The Ankylosing Spondylitis Quality of Life scores (ASQoL) is a self-administered questionnaire designed to assess health-related quality of life in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a dichotomous yes/no response option. A single point is assigned for each yes response and no points for each no response resulting in overall scores that range from 0 (least severity) to 18 (highest severity). As such, lower score indicate better quality of life. Items include an assessment of mobility/energy, self-care and mood/emotion. The recall period is at the moment, and the measure requires approximately 6 minutes to complete. Summary statistics are presented for participants (n) without intercurrent events. | Baseline and Week 52 | 
| The Number and Percentage of Patients Who Achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease | Ankylosing Spondylitis Disease Activity Score (ASDAS) - C-reactive protein (CRP) inactive disease criteria are defined as a value below 1.3. Higher score indicates worse symptoms. The formula is: ASDAS-CRP = 0.121 x total back pain + 0.110 x patient global + 0.073 x peripheral pain/swelling + 0.058 x duration of morning stiffness + 0.579 x ln(hsCRP +1) | Week 52 | 
| Change in High Sensitivity C-reactive Protein | High sensitivity C-reactive protein is measured as a marker of inflammation from blood samples during the study. | Baseline and Week 16 | 
| Change in Short Form-36 Physical Component Summary (SF-36 PCS) | The Short Form-36 Physical Component Summary (SF-36 PCS) is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales (domains) that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The eight domains are based on a scale from 0-100 while PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement. | Baseline and Week 16 | 
| Change in Sacroiliac Joint Edema - Week 16 | Magnetic Resonance Images (MRI) of the Sacroiliac Joint (SIJ) were assessed for the presence and severity of SIJ bone marrow edema according to the Berlin Active Inflammatory Lesions Scoring with a maximum score of 24. | Baseline and Week 16 | 
| Change in Sacroiliac Joint Edema - Week 52 | Magnetic Resonance Images (MRI) of the Sacroiliac Joint (SIJ) were assessed for the presence and severity of SIJ bone marrow edema according to the Berlin Active Inflammatory Lesions Scoring with a maximum score of 24. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-radiographic spondyloarthritis, axial spondyloarthritis, Ankylosing Spondylitis