Study to Demonstrate the Efficacy, Safety and Tolerability of an Intravenous Regimen of Secukinumab Compared to Placebo in Subjects With Active axSpA
Condition: Ankylosing Spondylitis
MeSH terms: Spondylitis; Spondylarthritis; Spondylitis, Ankylosing; Axial Spondyloarthritis
Intervention: Secukinumab; Placebo
Intervention description: The subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), 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); The subjects will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: This is a double-blind, randomized treatment trial. Subjects, investigators, investigator staff and persons performing the assessments, will remain blind to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) Randomization data are kept strictly confidential until the time of unblinding and will not be accessible by anyone else involved in the study with the exception of the bioanalyst, (2) the identity of the treatments will be concealed by the use of study treatment in form of vials, filled with secukinumab or placebo that are identical in appearance.
Enrollment: 527.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Active axSpA; Axial spondyloarthritis; non-radiographic-axSpA; nr-axSpA; ankylosing spondylitis; AS; inflammatory back pain; sacroiliitis

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.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects eligible for inclusion in this study must meet all of the following criteria:

          1. 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

          2. Male and non-pregnant, non-lactating female patients ≥ 18 years of age

          3. Diagnosis of axSpA according to ASAS criteria

               1. Inflammatory back pain for at least 6 months

               2. Onset before 45 years of age

          4. 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

          5. For subjects with nr-axSpA:

             X-ray of SIJ negative (centrally read) for AS by Modified NY criteria AND

               1. Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B-27 positive
                  with ≥2 SpA features AND

               2. Objective signs of inflammation at screening, evident by either MRI with SIJ
                  inflammation (centrally read) AND / OR hsCRP > ULN (as defined by the central
                  lab)

          6. Active axial SpA assessed by BASDAI ≥4 cm (0-10 cm) at Baseline

          7. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline

          8. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline

          9. 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

         10. 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

         11. 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

               1. 4 weeks for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours

               2. 8 weeks for Remicade® (infliximab) - with a terminal half-life of 8.0-9.5 days

               3. 10 weeks for Humira® (adalimumab) - with a terminal half-life of 10-20 days
                  (average 2 weeks)

               4. 10 weeks for Simponi® (golimumab) - with a terminal half-life of 11-14 days

               5. 10 weeks for Cimzia® (certolizumab) - with a terminal half-life of 14 days

         12. 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

         13. 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

         14. 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

          1. Subjects with total ankylosis of the spine

          2. 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

          3. Subjects taking moderate and high potency opioid analgesics (e.g. methadone,
             hydromorphone, morphine)

          4. 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)

          5. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before
             Randomization

          6. 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

          7. 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

          8. Active systemic infections during the last two weeks (exception: common cold) prior to
             randomization or any infection that reoccurs on a regular basis

          9. 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

         10. Past medical history of infection with HIV or hepatitis B prior to randomization or
             active infection or on treatment for Hepatitis C at randomization

         11. 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)

         12. Use or planned use of prohibited concomitant medication (see Section 6.2.2)

         13. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor
             tolerability or lack of access to veins)

         14. 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

         15. History or evidence of ongoing alcohol or drug abuse, within the last six months
             before randomization

         16. 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)

         17. 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:

               -  Any single parameter may not exceed 2 x the upper limit of normal (ULN). A single
                  parameter elevated up to and including 2 x ULN should be re-checked once more as
                  soon as possible, and in all cases, at least prior to randomization, to rule-out
                  laboratory error.

               -  If the total bilirubin concentration is increased above 2 x ULN, total bilirubin
                  should be differentiated into the direct and indirect reacting bilirubin. In any
                  case, serum bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L)

         18. 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

         19. Plans for administration of live vaccines during the study period or within 6 weeks
             prior to randomization

         20. 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:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). For female subjects on
                  the study, the vasectomized male partner should be the sole partner for that
                  subject

               -  Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                  cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal
                  suppository

               -  Use of oral, injected or implanted hormonal methods of contraception or other
                  forms of hormonal contraception that have comparable efficacy (failure rate <1%),
                  for example hormone vaginal ring or transdermal hormone contraception

               -  Placement of an intrauterine device or intrauterine system In case of use of oral
                  contraception women should have been stable on the same pill for a minimum of 3
                  months before taking study treatment.

             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.

         21. Active ongoing inflammatory diseases other than axSpA that might confound the
             evaluation of the benefits of secukinumab therapy, including inflammatory bowel
             disease or uveitis

         22. Current severe progressive or uncontrolled disease which in the judgment of the
             clinical investigator renders the subject unsuitable for the trial

         23. 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

         24. History of hypersensitivity to any of the study drug constituents

         25. Previous exposure to secukinumab (AIN457) or any other biologic drug directly
             targeting IL-17 or the IL-17 receptor

         26. 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)