Phase 3 Study to Evaluate Ianalumab on Top of Standard-of-care Therapy in Patients With Systemic Lupus Erythematosus (SIRIUS-SLE 2)

Study Overview
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Brief Summary
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The trial will evaluate efficacy, safety and tolerability of ianalumab compared to placebo, given as monthly subcutaneous (s.c.) injection on top of standard-of-care (SoC) treatment in participants with active systemic lupus erythematosus (SLE).

Detailed Description
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A randomized, double-blind, placebo-controlled multicenter phase 3 study to evaluate efficacy, safety and tolerability of ianalumab on top of standard-of-care therapy in patients with systemic lupus erythematosus (SIRIUS-SLE 2)

Official Title
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A Randomized, Double-blind, Placebo-controlled Multicenter Phase 3 Study to Evaluate Efficacy, Safety and Tolerability of Ianalumab on Top of Standard-of-care Therapy in Patients With Systemic Lupus Erythematosus (SIRIUS-SLE 2)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: ianalumab
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants aged 12 years or older at the time of screening, or limited to 18 years or older in European Economic Area countries and other countries where inclusion of participants below 18 years is not allowed. Diagnosis of systemic lupus erythematosus meeting the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria at least 6 months prior to screening. Elevated serum titers at screening of anti-nuclear antibodies ≥ 1:80 as determined by a central laboratory with a SLE-typical fluorescence pattern. Currently receiving CS and/or anti-malarial treatment and/or another disease-modifying antirheumatic drug (DMARD) as specified in the protocol. SLEDAI-2K criteria at screening: SLEDAI-2K score ≥ 6 points, excluding points attributed to fever, lupus headache, alopecia, and organic brain syndrome BILAG-2004 disease activity level at screening of at least 1 of the following: BILAG-2004 level 'A' disease in ≥ 1 organ system, Or BILAG-2004 level 'B' disease in ≥ 2 organ systems Weigh at least 35 kg at screening Exclusion Criteria: Prior treatment with ianalumab History of receiving following treatment I) high dose CS, calcineurin inhibitors, JAK or other kinase inhibitors or other DMARD (except as listed in inclusion criteria) administered within 12 weeks prior to screening II) cyclophosphamide or biologics such as immunoglobulins (intravenous or s.c.), plasmapheresis, anti-type I interferon receptor biologic agents, anti-CD40 agents, CTLA4-Fc Ig or B-cell activating factor (BAFF)-targeting agents administered within 24 weeks prior to screening; belimumab administered within 12 weeks prior to screening. III) any B cell-depleting therapies, other than ianalumab administered within 36 weeks prior to randomization or as long as B cell count is less than the lower limit of normal or baseline value prior to receipt of B cell-depleting therapy (whichever is lower). IV) Traditional Chinese medicines administered within 30 days prior to randomization Active viral, bacterial or other infections requiring intravenous or intramuscular treatment for clinically significant infection Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) Evidence of active tuberculosis infection History of primary or secondary immunodeficiency, including a positive human immunodeficiency virus (HIV) test result at screening Any one of the following abnormal laboratory values prior to randomization: Platelets < 25000/ mm^3 (< 25 x 10^3/ μL) Hemoglobin (Hgb) < 8.0 g/dL (< 5 mmol/L), or < 7.0 g/dL (< 4.3 mmol/L) if related to participant's SLE such as in active hemolytic anaemia Absolute neutrophil count (ANC) (< 0.8 x 10^3/ μL) Severe organ dysfunction or life-threatening disease at screening Presence of severe lupus kidney disease as defined by proteinuria above 2 g/day or equivalent using spot urine protein creatinine ratio, or serum creatinine greater than 2.0 mg/dL (176.84 µmol/L), or requiring immune-suppressive induction or maintenance treatment at screening Receipt of live/attenuated vaccine within a 4-week period before first dosing Any uncontrolled, co-existing serious disease, which in the opinion of the investigator will place the participant at risk for participation or interfere with evaluation for SLE-related symptoms Non-lupus conditions such as asthma, gout or urticaria, requiring intermittent or chronic treatment with systemic CS History of malignancy of any organ system other than localized basal cell carcinoma of the skin or in situ cervical cancer Pregnant or nursing (lactating) women. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while on study treatment and for 6 months after stopping of investigational drug. Any surgical, medical, psychiatric or additional physical condition that may jeopardize participation in this study

Ages Eligible for Study
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Minimum Age: 12 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ianalumab s.c. monthly<br>ianalumab s.c. monthly | Drug: ianalumab<br>* ianalumab s.c. monthly<br>* Other names: VAY736;|
| Placebo Comparator: placebo s.c. monthly<br>placebo s.c. monthly | Drug: placebo<br>* placebo s.c. monthly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving Systemic Lupus Erythematosus Responder Index -4 (SRI-4) | SRI-4 response is defined as: Systemic Lupus Erythematosus Disease Activity Index - 2000 (SLEDAI-2K) reduction from baseline of ≥ 4 points No British Isles Lupus Assessment Group-2004 (BILAG-2004) worsening, defined as ≥ 1 new A or ≥ 2 new B items compared to baseline No worsening in Physician Global Assessment of Disease Activity (PhGA), defined as an increase of ≥ 0.3 from baseline on a 0 to 3 visual analog scale | Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with no moderate or severe BILAG flare | Moderate BILAG flare is defined as 2 or more new BILAG-2004 B items compared to the previous visit; severe BILAG flare is defined as 1 or more new BILAG-2004 A items compared to the previous visit | Baseline to Week 60 | 
| Proportion of participants maintaining between Week 36 and Week 60 a reduced corticosteroid (CS) dose of predniso(lo)ne ≤ 5 mg/day or ≤ baseline dose, whichever is lower | Maintaining reduced CS dose from Week 36 to Week 60 | Week 36 to Week 60 | 
| Proportion of participants achieving BILAG-based Composite Lupus Assessment (BICLA) | BICLA response is defined as: Reduction of all baseline BILAG-2004 A to B/C/D and baseline B to C/D and no worsening in other organ systems defined as ≥ 1 new A or ≥ 2 new B items compared to baseline No worsening from baseline in SLEDAI-2K defined as an increase from baseline of > 0 points No worsening in PhGA defined as an increase of ≥ 0.3 from baseline on a 0 to 3 PhGA visual analog scale | Week 60 | 
| Proportion of participants achieving Lupus Low Disease Activity State (LLDAS) | LLDAS response is defined as: SLEDAI-2K ≤ 4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) (Golder et al 2019) No new lupus disease activity compared with the previous assessment, defined as any new SLEDAI-2K component that was not present at the previous assessment PhGA (scale 0-3) ≤ 1 Current predniso(lo)ne (or equivalent) dose ≤ 7.5 mg daily Well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents | Week 60 | 
| Time to first occurrence of SRI-4 | Time to first occurrence of SRI-4 from baseline to Week 60 | Baseline to Week 60 | 
| Proportion of participants achieving SRI-4 at Week 60 while maintaining between Week 36 and Week 60 a reduced CS dose of predniso(lo)ne ≤ 5 mg/day or ≤ baseline dose, whichever is lower | Achieving SRI-4 at Week 60 while maintaining between Week 36 and Week 60 a reduced CS dose of predniso(lo)ne ≤ 5 mg/day or ≤ baseline dose, whichever is lower | Week 36 to Week 60 | 
| Proportion of participants achieving SRI-6 | SRI-6 response is defined as: SLEDAI-2K reduction from baseline of ≥ 6 points No BILAG-2004 worsening, defined as ≥ 1 new A or ≥ 2 new B items compared to baseline No worsening in PhGA, defined as an increase of ≥ 0.3 from baseline on a 0 to 3 visual analog scale | Week 60 | 
| Proportion of participants achieving SF-36 Bodily Pain response | Achieving Short Form 36 (SF-36) Bodily Pain response | Week 60 | 
| Proportion of participants with Adverse Events (AEs) | To evaluate safety and tolerability of ianalumab s.c. monthly | Baseline to Week 60 | 
| Incidence and titer of anti-drug (ianalumab) antibodies (ADAs) in serum over time | To evaluate immunogenicity of ianalumab s.c. monthly | Baseline to Week 164 | 
| Ianalumab concentration in serum during the treatment and follow-up | Concentration of Ianalumab in serum | Baseline to Week 164 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Lupus Erythematosus, SLE, B cell depletion, SLEDAI-2K, BILAG-2004, SRI, ANA