Phase III Study of Efficacy and Safety of Secukinumab Versus Placebo, in Combination With Glucocorticoid Taper Regimen, in Patients With Giant Cell Arteritis (GCA)

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Patient must be able to understand and communicate with the investigator and complywith the requirements of the study.

3. Male or non-pregnant, non-lactating female patients at least 50 years of age.

4. Diagnosis of GCA based on meeting all of the following criteria:

• Age at onset of disease ≥ 50 years.

• Unequivocal cranial symptoms of GCA (e.g., new-onset localized headache, scalpor temporal artery tenderness, permanent or temporary ischemia-related visionloss, or otherwise unexplained mouth or jaw pain upon mastication), and/orunequivocal symptoms of polymyalgia rheumatica (PMR) (defined as shoulderand/or hip girdle pain associated with inflammatory morning stiffness) and/orsymptoms of limb ischemia (claudication).

• TAB revealing features of GCA and/or cross-sectional imaging study such asultrasound (e.g., cranial or axillary), MRI/MRA, CTA, or PET-CT with evidenceof vasculitis.

5. Active disease as defined by meeting both of the following within 6 weeks of BSL (see Section 8.1 for details)

• Presence of signs or symptoms attributed to active GCA and not related to priordamage (e.g., visual loss that occurred prior to 6 weeks before BSL without newfindings occurring within 6 weeks of BSL)

• Elevated ESR ≥ 30 mm/hr or CRP ≥ 10 mg/L attributed to active GCA or active GCAon TAB or on imaging study.

6. Patients to meet definition of new-onset GCA or relapsing GCA:

• Definition of new-onset GCA*: GCA that is diagnosed within 6 weeks of BSL visit

• Definition relapsing GCA: GCA diagnosed > 6 weeks before BSL visit andfollowing institution of an appropriate treatment course for GCA, participanthas experienced recurrence of active symptoms or signs of disease afterresolution.

• The 6-week timeframe is to be calculated from the date of suspected GCAdiagnosis. Suspected diagnosis is defined as date when GC therapy wasinitiated.

7. Patients' current GCA episode should be treatable with a dose of prednisone (orequivalent) designed to adequately achieve disease control in accordance withinternational guidelines. If this is not possible due to concerns regarding GCtoxicity, the patient should not be enrolled. It must be medically appropriate forthe patient to receive prednisone (or equivalent) 20 mg-60 mg daily (or equivalent)at BSL.

8. Patients taking MTX (≤ 25 mg/week) are allowed to continue their medication providedthey have taken it for at least 2 months and are on a stable dose for at least 4weeks prior to randomization and if they are on stable folic acid treatment beforerandomization.

Exclusion Criteria:

1. Pregnant or nursing (lactating) women where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive human chorionic gonadotropin (hCG) laboratory test.

2. Women of childbearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using effective methods of contraception duringstudy treatment or longer if required by locally approved prescribing information (e.g., in European Union (EU) 20 weeks after treatment discontinuation). Also,contraception should be used in accordance with locally approved prescribinginformation of concomitant medications administered (e.g., Rescue Treatment).Effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Bilateral oophorectomy with or without hysterectomy, total hysterectomy orbilateral salpingectomy at least 6 weeks before taking study treatment. In caseof oophorectomy alone, only when the reproductive status of the woman has beenconfirmed by follow-up hormone level assessment are they not considered to beof child-bearing potential.

• Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks beforetaking study treatment.

• Male sterilization (vasectomy) of male partner(s) of the female participant atleast 6 months prior to screening.

• Barrier methods of contraception: Condom or Occlusive cap (diaphragm orcervical/vault caps). NOTE: for United Kingdom: with spermicidalfoam/gel/film/cream/vaginal suppository.

• Use of oral, (estrogen and progesterone), injected or implanted hormonalmethods of contraception or other forms of hormonal contraception that havecomparable efficacy (failure rate <1%), for example, hormone vaginal ring ortransdermal hormone contraception or placement of an intrauterine device (IUD)or intrauterine system (IUS). In case of use of oral contraception women shouldhave been stable on the same pill for a minimum of 3 months before taking studytreatment.

• Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.,age-appropriate history of vasomotor symptoms). Women participants areconsidered not of child-bearing potential if they are post-menopausal or havehad, surgical bilateral oophorectomy (with or without hysterectomy), totalhysterectomy or bilateral salpingectomy at least six weeks prior to first doseof study treatment in the study . In the case of oophorectomy alone, only whenthe reproductive status of the woman has been confirmed by follow-up hormonelevel assessment is she considered to be not of child-bearing potential. If local regulations are more stringent than the contraception methods listed aboveto prevent pregnancy, local regulations apply and will be described in the InformedConsent Form (ICF).

3. Previous exposure to secukinumab or other biologic drug directly targeting IL-17 orIL-17 receptor.

4. Patients treated with any cell-depleting therapies.

5. Previous participation in a clinical trial where the outcome of treatment with theGCA drug is unknown. This does not include trials where the treatment for GCA wasGCs, MTX, leflunomide or azathioprine

6. Patients who have been treated with inhibitors directly targeting IL-1, or IL-1receptor, IL-12 and IL-23, or abatacept within 4 weeks or within 5 half-lives of thedrug (whichever is longer) prior to BSL.

7. Treatment with tocilizumab, other IL-6/IL6-R inhibitor or JAK inhibitor within 12weeks or within 5 half-lives of the drug (whichever is longer) prior to BSL, or ifthe patient did not respond to or experienced a relapse during treatment any timebefore BSL.

8. Any treatment received for GCA in which patient did not respond to treatment orexperienced a relapse while on that treatment any time before BSL. This alsoincludes patients who were treated in a clinical trial for GCA. Patients who failedon treatment with GCs, MTX, leflunomide and/or azathioprine may be included.

9. Patients treated with i.v. immunoglobulins or plasmapheresis within 8 weeks prior toBSL.

10. Patients treated (i.e. systemic therapy) with cyclophosphamide or hydroxychloroquinewithin 6 months prior to BSL, or tacrolimus, everolimus, cyclosporine A,azathioprine, sulfasalazine, mycophenolate mofetil within 4 weeks prior to BSL.

11. Patients treated with leflunomide within 8 weeks of BSL unless a cholestyraminewashout has been performed in which case the patient must be treated within 4 weeksof BSL.

12. Patients treated with an alkylating agent within 5 years prior to BSL, unlessspecified in other exclusion criteria.

13. Patients requiring or anticipated to require systemic chronic glucocorticoid therapyor pulses of glucocorticoids for reasons other than GCA (e.g., COPD, asthma, plannedsurgery) at screening or randomization.

14. Criterion removed in protocol V01.

15. Patients requiring chronic (i.e., not occasional "prn") high potency opioidanalgesics for pain management.

16. Use of other investigational drugs within 5 half-lives of enrollment or within 30days (e.g. small molecules) or until the expected pharmacodynamic effect hasreturned to BSL (e.g., biologics), whichever is longer; or longer if required bylocal regulations.

17. History of hypersensitivity or contraindication to any of the study treatments orits excipients or to drugs of similar chemical classes.

18. Active IBD or other ongoing inflammatory diseases other than GCA that might confoundthe evaluation of the benefit of secukinumab therapy, including uveitis at screeningor randomization.

19. Major ischemic event (e.g., myocardial infarction, stroke, etc.) or transientischemic attack (TIA) (except ischemia-related vision loss), related or unrelated toGCA, within 12 weeks of screening.

20. Confirmed diagnosis of any primary form of systemic vasculitis, other than GCA.

21. Any other systemic biologics (e.g., denosumab, TNFα inhibitors) within 4 weeks orwithin 5 half-lives of the drug (whichever is longer) prior to BSL, or anticipateduse of a systemic biologic prior to EOS

22. Active ongoing diseases which in the opinion of the investigator immunocompromisesthe patient and/or places the patient at unacceptable risk for treatment withimmunomodulatory therapy.

23. Significant medical problems or diseases, including but not limited to thefollowing: uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (NewYork Heart Association (NYHA) status of class III or IV) and uncontrolled diabetesmellitus.

24. History of clinically significant liver disease or liver injury as indicated byabnormal liver function tests (LFTs) such as Aspartate Aminotransferase (AST),alanine aminotransferase (ALT), alkaline phosphatase (ALP) or serum bilirubin. Theinvestigator should be guided by the following criteria:

• SGOT (AST) and SGPT (ALT) may not exceed 3 × the upper limit of normal (ULN). Asingle parameter elevated up to and including 3 × ULN should be re-checked oncemore as soon as possible, and in all cases, at least prior to randomization, torule-out laboratory error.

• Alkaline phosphatase may not exceed 2 × ULN. An elevation up to and including 2 × ULN should be re-checked once more as soon as possible, and in all cases, atleast prior to randomization, to rule-out laboratory error.

• Total bilirubin may not exceed 2 × ULN. If the total bilirubin concentration isincreased above 2 × ULN, total bilirubin should be differentiated into thedirect and indirect reacting bilirubin.

25. Criterion removed in protocol V01

26. Screening total WBC count < 3,000/μL, or platelets < 100,000/μL or neutrophils < 1,500/μL or Hgb < 8.3 g/dL (83 g/L).

27. Active infections during the last 2 weeks prior to randomization.

28. History of ongoing, chronic or recurrent infectious disease or evidence oftuberculosis infection as defined by a positive QuantiFERON TB-Gold Plus test.Patients with a positive test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patienthas no evidence of active TB. If the test result is indeterminate, the investigatormay repeat the test once or may proceed directly to perform the work-up for TB asper local procedures. If presence of latent TB is established then treatmentaccording to local country guidelines must be initiated prior to randomization.

29. Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C (if not treated and cured) at screening or randomization

30. History of lymphoproliferative disease or any known malignancy or history ofmalignancy of any organ system within the past 5 years (except for basal cellcarcinoma or actinic keratosis that have been treated with no evidence of recurrencein the past 3 months, carcinoma in situ of the cervix or non-invasive malignantcolon polyps that have been removed).

31. Live vaccinations (e.g., monkey pox vaccine, oral polio vaccine, varicella/zostervaccines) within 6 weeks prior to BSL, or planned or anticipated potential need forlive vaccination during study participation until 12 weeks after last studytreatment administration.

32. Current severe progressive or uncontrolled disease, which in the judgment of theclinical investigator renders the patient unsuitable for the trial.

33. Any medical or psychiatric condition, which, in the investigator's opinion, wouldpreclude the patient from adhering to the protocol or completing the study perprotocol.

34. Donation or loss of 400 mL or more of blood within 8 weeks before randomization.

35. History or evidence of ongoing alcohol or drug abuse, within the last 6 monthsbefore randomization.