Safety, Efficacy and Tolerability of Ianalumab Versus Placebo, Combination With SoC Therapy, in Participants With Active Lupus Nephritis

Study Overview
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Brief Summary
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This trial will evaluate efficacy, safety, and tolerability of subcutaneous (s.c.) ianalumab given every 4 weeks (q4w) or every 12 weeks (q12w) compared to placebo, in combination with SoC, in adult participants with active LN

Detailed Description
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This trial will evaluate the efficacy, safety, and tolerability of subcutaneous (s.c.) ianalumab given every 4 weeks (q4w) or ianalumab given every 12 weeks (q12w) compared to placebo, in combination with SoC, in adult participants with active LN (ISN/RPS class III, IV active glomerulonephritis with or without co-existing class V features, or pure class V membranous). using the 2003 International Society for Nephrology (ISN)/Renal Pathology Society (RPS) criteria).

Official Title
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A Randomized, Double-blind, Parallel Group, Placebo-controlled, Multicenter Phase 3 Trial to Evaluate Efficacy, Safety and Tolerability of Ianalumab on Top of Standard-of-care Therapy in Participants With Active Lupus Nephritis (SIRIUS-LN).

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: ianalumab s.c. q4w
* Drug: ianalumab s.c. q12w
* Drug: placebo s.c.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants eligible for inclusion in this study must meet all of the following criteria: Adult male and female participants aged 18 years or older at the time of screening Weigh at least 35 kg at screening Have a confirmed clinical diagnosis of SLE according to European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Systemic Lupus Erythematosus (SLE) classification criteria Have a positive anti-nuclear antibody (ANA) test result; ANA titer ≥ 1:80 at screening visit based on central or local laboratory result Active LN at screening, as defined by meeting the 3 following criteria: Renal biopsy within 6 months prior to screening period indicating ISN/RPS class III or IV active glomerulonephritis with or without co-existing class V features, or pure class V membranous LN. If no biopsy was performed within 6 months prior to screening period, a biopsy will need to be performed during the screening period after having met all other inclusion/exclusion criteria. UPCR ≥ 1.0 g/g on 24h urine collection at Screening eGFR ≥ 25mL/min/1.73 m2. Participants with eGFR < 30 mL/min/1.73 m2 require renal biopsy during the screening period showing sclerosis in ≤ 50% of glomeruli Newly diagnosed participants as well as pre-treated LN participants (including refractory cases) can be included, as long as they are currently on, or willing to initiate SoC induction therapy for LN using MPA Induction therapy, as defined by treatment including both high dose corticosteroids and MPA, should be initiated prior to or on day of randomization Anti-malarial treatment at stable dosing prior to randomization is strongly recommended, in the absence of contraindications Participants on azathioprine treatment at Screening must be switched to MPA prior to randomization Receipt of at least one dose of pulse methylprednisolone i.v. (250 - 1000 mg per day up to 3000 mg cumulative dose) or equivalent for treatment of current episode of active LN within 60 days prior randomization. Able to communicate well with the Investigator to understand and comply with the requirements of the study Exclusion Criteria: Participants meeting any of the following criteria are not eligible for inclusion in this study: Severe renal impairment as defined by i.) presence of oliguria (defined as a documented urine volume < 400 mL/24 hrs) or ii.) End-Stage Renal Disease (ESRD) requiring dialysis or transplantation Sclerosis in > 50% of glomeruli on renal biopsy Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or until the expected pharmacodynamic effect has returned to baseline Prior use of any B cell depleting therapy within 36 weeks prior to randomization or if therapy was administered < 36 weeks prior to randomization B cell count less than the lower limit of normal or patient's own baseline value prior to having received an earlier B cell-depleting therapy Prior treatment with any of the following within 12 weeks prior to randomization Belimumab, telitacicept, abatacept, TNF-α mAb, immunoglobulins (i.v./s.c.) plasmapheresis Any other immuno-suppressants (i.v. or oral cyclophosphamide, calcineurin inhibitors, JAK inhibitors or other kinase inhibitors) Thalidomide treatment and/or one of the following DMARDs: methotrexate or an imidazole derivative (e.g., mizoribine) Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within 12 weeks prior to randomization History of major organ transplant or hematopoietic stem cell/bone marrow transplant or are due to receive transplantation Any one of the following laboratory values at screening: Hemoglobin levels < 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 Platelet count < 25 x 1000/µL Absolute neutrophil count (ANC) < 0.8 x 1000/µL Active viral, bacterial or other infections requiring systemic treatment at the time of screening, or history of recurrent clinically significant infection History of known intolerance/hypersensitivity to MPA, oral corticosteroids, or any component of the study drug(s) or its excipients Receipt of live/attenuated vaccine within a 4-week period prior to randomization History of primary or secondary immunodeficiency, including a positive HIV test result History of malignancy of any organ system (other than localized basal cell carcinoma or squamous cell carcinoma of the skin or or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes), psychiatric or additional physical condition that the Investigator feels may jeopardize the participants in case of participation in this study Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Positive serology for hepatitis B surface antigen (HBsAg) excludes the participant Evidence of active tuberculosis (TB) infection (after anti-TB treatment, participants with history of TB may become eligible according to national local guidelines) Pregnant or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 6 months after stopping of investigational medication Sexually active male participants, who do not agree to use barrier protection during intercourse with women of child-bearing potential while taking study treatment Other protocol -defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: This is a pivotal double-blind, randomized, placebo-controlled, multi-center three-arm study, evaluating at Week 72 efficacy and safety of ianalumab administered s.c. every 4 weeks or ianalumab administered s.c. every 12 weeks versus placebo, administered s.c. every 4 weeks, in adult participants with active LN receiving SoC. In addition, long-term efficacy, safety and tolerability will be collected up to Week 144.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - ianalumab s.c. q4w<br>ianalumab s.c. q4w in addition to standard of care (SoC) | Drug: ianalumab s.c. q4w<br>* ianalumab s.c. q4w in addition to SoC<br>* Other names: VAY736;|
| Experimental: Arm 2 - ianalumab s.c. q12w<br>ianalumab s.c. q12w in addition to SoC | Drug: ianalumab s.c. q12w<br>* ianalumab s.c. q12w in addition to SoC<br>* Other names: VAY736;|
| Placebo Comparator: Arm 3 - placebo s.c. q4w<br>Placebo s.c. q4w in addition to SoC | Drug: placebo s.c.<br>* placebo s.c. q4w in addition to SoC<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and percentage of participants achieving stable Complete Renal Response (CRR) | The primary objective is to demonstrate superiority of ianalumab compared to placebo, in achieving stable CRR (defined as estimated glomerular filtration rate (eGFR) ≥90 ml/min/1.73 m2 or no less than 85% of baseline, AND, 24-hour UPCR <0.5 g/g) at Week 72 in active lupus nephritis (ISN/RPS class III, IV active glomerulonephritis with or without co-existing class V features, or pure class V membranous) participants on background SoC therapy. | Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of stable urine protein-to-creatinine ratio (UPCR) <0.5 g/g or ≥50% reduction from baseline | To demonstrate superiority of ianalumab, compared to placebo, in time to first occurrence of stable urine protein-to-creatinine ratio (UPCR) <0.5 g/g or ≥50% reduction from baseline up to Week 72 | Week 72 | 
| Percentage of participants achieving stable Overall Renal Response (ORR), defined as achievement as either Complete Renal Response (CRR) or Partial Renal Response (PRR) | To demonstrate superiority of ianalumab, compared to placebo, in achieving stable Overall Renal Response (ORR) at Week 48 | Week 48 | 
| Incidence of stable Complete Renal Response (CRR) while maintaining daily corticosteroid dose ≤5 mg/day | To demonstrate superiority of ianalumab, compared to placebo, in achieving stable Complete Renal Response (CRR) at Week 72 while maintaining daily corticosteroid dose ≤5 mg/day between Week 24 and Week 72 | Week 72 | 
| Incidence of renal-related event or death | To demonstrate superiority of ianalumab, compared to placebo, in preventing renal-related event or death through Week 72 | Week 72 | 
| Change in British Isles Lupus Activity Group (BILAG) score | To demonstrate superiority of ianalumab, compared to placebo in BILAG-2004 at Week 72 | Week 72 | 
| Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score | To demonstrate superiority of ianalumab, compared to placebo, in FACIT-Fatigue at Week 72 | Week 72 | 
| Number of participants with treatment-emergent Adverse Events (AEs) | AEs are any untoward sign or symptom that occurs during the study treatment | Week 72 | 
| Ianalumab concentration in serum | To characterize the pharmacokinetics (PK) of ianalumab mean, median, minimum and maximum concentrations will be provided | Week 72 | 
| Incidence and titer of anti-ianalumab antibodies in serum (ADA assay) over time | To evaluate immunogenicity of ianalumab | Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLE, Systemic Lupus Erythematosus (SLE), Kidney inflammation, Anti-BAFF-receptor, B cell depletion, Ianalumab, VAY736