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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.
Full 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):
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.
Enrollment
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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
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
Active axial SpA assessed by BASDAI ≥4 cm (0-10 cm) at Baseline
Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline
Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline
Subjects should have had inadequate response or failure to respond to at least 2 NSAIDs at an approved dose for a minimum of 4 weeks in total and a minimum of 2 weeks for each NSAID prior to randomization, or less than 4 weeks if therapy had to be withdrawn due to intolerance, toxicity or contraindications
Subjects who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part of their AS or nr-axSpA therapy are required to be on a stable dose for at least 2 weeks before randomization
Subjects who are intolerant or have been inadequate responders to a TNF inhibitor (not more than one) will be allowed to enter into the study (not more than 20% per group). They must have experienced an inadequate response to previous or current treatment at an approved dose for at least 3 months prior to randomization, or have been intolerant to at least one administration of an anti-TNF agent. These subjects will undergo an appropriate wash-out period prior to randomization, if required
Subjects taking methotrexate (MTX) (≤ 25 mg/week ) or sulfasalazine (≤ 3 g/day) are allowed to continue their medication and must have taken it for at least 3 months and have to be on a stable dose for at least 4 weeks prior to randomization. Subjects on MTX must be on folic acid supplementation before randomization
Subjects who are on a conventional DMARD other than MTX or sulfasalazine must discontinue the DMARD 4 weeks prior to randomization, except for leflunomide, which must be be discontinued 8 weeks prior to randomization, unless a cholestyramine washout has been performed
Subjects taking systemic corticosteroids must be on a stable dose of ≤10 mg/day prednisone or equivalent for at least 2 weeks before randomization
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 8-1. Subjects with a positive test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the subject has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then treatment according to local country guidelines must have been initiated
Past medical history of infection with HIV or hepatitis B prior to randomization or active infection or on treatment for Hepatitis C at randomization
History of lymphoproliferative disease or any known malignancy, or history of malignancy of any organ system treated or untreated within the past 5 years, regardless of whether there is evidence of local recurrence or metastases (except for skin Bowen's disease, or basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed)
Use or planned use of prohibited concomitant medication (see Section 6.2.2)
Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor tolerability or lack of access to veins)
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
History or evidence of ongoing alcohol or drug abuse, within the last six months before randomization
Screening total WBC count <3,000/μl, or platelets <100,000/μl or neutrophils <1,500/μl or hemoglobin <8.5 g/dl (85 g/L)
History of clinically significant liver disease or liver injury indicated by abnormal liver function tests, such as SGOT (AST), SGPT (ALT), alkaline phosphatase and serum bilirubin. The investigator should be guided by the following criteria:
Significant medical problems or diseases, including but not limited to the following:
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV), uncontrolled diabetes, or very poor functional status precluding ability to perform self-care
Plans for administration of live vaccines during the study period or within 6 weeks prior to randomization
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during the entire study or longer if required by locally approved prescribing information (e.g., 20 weeks in EU). Effective contraception methods include:
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.
Active ongoing inflammatory diseases other than axSpA that might confound the evaluation of the benefits of secukinumab therapy, including inflammatory bowel disease or uveitis
Current severe progressive or uncontrolled disease which in the judgment of the clinical investigator renders the subject unsuitable for the trial
Use of other investigational drugs at the time of enrollment, or within 5 half- lives of enrollment, or within 4 weeks until the expected pharmacodynamic effect has returned to baseline, whichever is longer; or longer if required by local regulations
History of hypersensitivity to any of the study drug constituents
Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting IL-17 or the IL-17 receptor
Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19)
Primary purpose
Allocation
Interventional model
Masking
527 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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