A Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase III Multicenter Study of Intravenous Secukinumab to Compare Efficacy at 16 Weeks With Placebo and to Assess Safety and Tolerability up to 52 Weeks in Subjects With Active Ankylosing Spondylitis or Non-radiographic Axial SpondyloArthritis
Overview
- Phase
- Phase 3
- Intervention
- Secukinumab
- Conditions
- Ankylosing Spondylitis
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 527
- Locations
- 1
- Primary Endpoint
- Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this global study was to demonstrate the efficacy, safety, and tolerability of an intravenous (i.v.) regimen of secukinumab compared to placebo in participants with active ankylosing spondylitis (AS) or non-radiographic axial spondyloarthritis (nr-axSpA ) at Week 16 despite current or previous non-steroidal anti inflammatory drugs (NSAID), disease-modifying antirheumatic drugs (DMARD) and/or anti Tumor Necrosis Factor (TNF) therapy. In addition, to further support efficacy and safety of an i.v. regimen, data was collected for up to 52 weeks of treatment.
Detailed Description
This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design to study the efficacy, safety, and tolerability of treatment with intravenous secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg administered every four weeks starting at Week 4) in subjects with active axial spondyloarthritis (axSpA). The study population consisted of active of 413 participants with AS and 113 participants with active nr-axSpA. This study consisted of 4 periods totaling up to 70 weeks: the screening period (up to 10 weeks), the treatment period 1 (total duration of 16 weeks), treatment period 2 (total duration of 36 weeks) followed by the safety follow up period of 8 weeks after the end of treatment visit (at Week 60) regardless of whether participant completed the study as planned or discontinued prematurely. At baseline, participants were randomized to one of the two treatment groups and stratified to disease condition (AS or nr-axSPa): * Group 1: secukinumab 6 mg/kg i.v.) at baseline and which was followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52) at clinic visits * Group 2: i.v. placebo at baseline, Weeks 4, 8, and 12 and switched to secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52) at clinic visits Although study treatment was open label secukinumab i.v. starting at Week 16, all subjects and investigators/site staff remained blinded to original treatment assignment to ensure unbiased efficacy and safety assessments for the remainder of the study. This study enrolled participants with active disease despite current or previous NSAIDs, conventional DMARDs and/or TNF inhibitor therapy or intolerance to these therapies. The regular assessment of disease activity ensured that subjects who experienced worsening of disease in any of the treatment groups could exit the study at any time upon their own accord or based on the advice of the investigator. A temporary pause of study recruitment only was implemented from 09-Apr-2020 to 11-May-2020, due to the COVID-19 pandemic, but not for study visits, assessments or other conduct of the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects eligible for inclusion in this study must meet all of the following criteria:
- •Subject must be able to understand and communicate with the investigator, comply with the requirements of the study. and must give written, signed and dated informed consent before any study assessment is performed
- •Male and non-pregnant, non-lactating female patients ≥ 18 years of age
- •Diagnosis of axSpA according to ASAS criteria
- •Inflammatory back pain for at least 6 months
- •Onset before 45 years of age
- •For subjects with AS: Diagnosis of AS with prior documented radiologic evidence (x-ray or radiologist's report) fulfilling the Modified New York criteria for AS
- •For subjects with nr-axSpA:
- •X-ray of SIJ negative (centrally read) for AS by Modified NY criteria AND
- •Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B-27 positive with ≥2 SpA features AND
Exclusion Criteria
- •Subjects meeting any of the following criteria are not eligible for inclusion in this study
- •Subjects with total ankylosis of the spine
- •Chest x-ray or MRI with evidence of ongoing infectious or malignant process obtained within 3 months of screening and evaluated by a qualified physician
- •Subjects taking moderate and high potency opioid analgesics (e.g. methadone, hydromorphone, morphine)
- •Presence of significant medical problems which at investigator's discretion, will prevent the subject from participating in the study, including but not limited to the following: Subjects with severely reduced kidney function (estimated glomerular filtration rate (eGFR) \<29 ml/min/1.73m2), history of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum creatinine level exceeding 1.5 mg/dl (132.6 μmol/L)
- •Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before Randomization
- •Underlying conditions (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy
- •Any medical or psychiatric condition which, in the Investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol
- •Active systemic infections during the last two weeks (exception: common cold) prior to randomization or any infection that reoccurs on a regular basis
- •History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by either a positive purified protein derivative (PPD) skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5 mm or according to local practice/guidelines) or a positive QuantiFERON TB-Gold test as indicated in the assessment schedule in Table 8-
Arms & Interventions
Secukinumab
Secukinumab intravenous (i.v.) regimen
Intervention: Secukinumab
Placebo
Placebo intravenous (i.v.) regimen
Intervention: Placebo
Outcomes
Primary Outcomes
Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria)
Time Frame: Baseline to Week 16
ASAS40 is ≥ 40% and an absolute improvement from baseline of ≥20 units (range 0-100) in ≥ 3 of the following 4 domains: back pain \[10 cm visual analogue scale (VAS)\], patient global assessment of disease activity (10 cm VAS), physical function (BASFI; range 0-100) and inflammation (mean score of items 5 and 6 of the BASDAI; both 10 cm VAS) without any worsening in the remaining domain. ASAS consists of 6 domains (4 main and 2 additional): 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) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
Secondary Outcomes
- Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement(Baseline to Week 16)
- The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)(Baseline to Week 16)
- The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI)(Baseline to Week 16)
- The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS)(Baseline to Week 16)
- Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria)(Baseline to Week 16)
- The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol)(Baseline to Week 16)
- The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP)(Baseline to Week 16)
- Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria)(Baseline to Week 16)
- The Percentage of Participants Achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease.(Baseline to Week 16)
- Percentage of Participants Who Achieved ASAS20 (Assessment of Spondylarthritis International Society Criteria) Partial Remission.(Baseline to Week 16)
- Change From Baseline in Pittsburgh Sleep Quality Index (PSQI)(Baseline to Week 16)