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Safety, Efficacy and Tolerability of Ianalumab Versus Placebo, Combination With SoC Therapy, in Participants With Active Lupus Nephritis (SIRIUS-LN)

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ClinicalTrials.gov Identifier: NCT05126277
Recruitment Status : Recruiting
First Posted : November 19, 2021
Last Update Posted : April 29, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
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

Condition or disease Intervention/treatment Phase
Lupus Nephritis Drug: ianalumab s.c. q4w Drug: ianalumab s.c. q12w Drug: placebo s.c. Phase 3

Detailed Description:
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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 420 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: 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).
Actual Study Start Date : July 14, 2022
Estimated Primary Completion Date : March 1, 2027
Estimated Study Completion Date : July 15, 2030

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm 1 - ianalumab s.c. q4w
ianalumab s.c. q4w in addition to standard of care (SoC)
 Drug: ianalumab s.c. q4w
ianalumab s.c. q4w in addition to SoC
Other Name: VAY736
Experimental: Arm 2 - ianalumab s.c. q12w
ianalumab s.c. q12w in addition to SoC
 Drug: ianalumab s.c. q12w
ianalumab s.c. q12w in addition to SoC
Other Name: VAY736
Placebo Comparator: Arm 3 - placebo s.c. q4w
Placebo s.c. q4w in addition to SoC
 Drug: placebo s.c.
placebo s.c. q4w in addition to SoC
Other Name: placebo


Outcome Measures
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Primary Outcome Measures :
  1. Frequency and percentage of participants achieving stable Complete Renal Response (CRR) [ Time Frame: Week 72 ]
    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.


Secondary Outcome Measures :
  1. Time to first occurrence of stable urine protein-to-creatinine ratio (UPCR) <0.5 g/g or ≥50% reduction from baseline [ Time Frame: Week 72 ]
    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

  2. Percentage of participants achieving stable Overall Renal Response (ORR), defined as achievement as either Complete Renal Response (CRR) or Partial Renal Response (PRR) [ Time Frame: Week 48 ]
    To demonstrate superiority of ianalumab, compared to placebo, in achieving stable Overall Renal Response (ORR) at Week 48

  3. Incidence of stable Complete Renal Response (CRR) while maintaining daily corticosteroid dose ≤5 mg/day [ Time Frame: Week 72 ]
    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

  4. Incidence of renal-related event or death [ Time Frame: Week 72 ]
    To demonstrate superiority of ianalumab, compared to placebo, in preventing renal-related event or death through Week 72

  5. Change in British Isles Lupus Activity Group (BILAG) score [ Time Frame: Week 72 ]
    To demonstrate superiority of ianalumab, compared to placebo in BILAG-2004 at Week 72

  6. Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score [ Time Frame: Week 72 ]
    To demonstrate superiority of ianalumab, compared to placebo, in FACIT-Fatigue at Week 72

  7. Number of participants with treatment-emergent Adverse Events (AEs) [ Time Frame: Week 72 ]
    AEs are any untoward sign or symptom that occurs during the study treatment

  8. Ianalumab concentration in serum [ Time Frame: Week 72 ]
    To characterize the pharmacokinetics (PK) of ianalumab mean, median, minimum and maximum concentrations will be provided

  9. Incidence and titer of anti-ianalumab antibodies in serum (ADA assay) over time [ Time Frame: Week 72 ]
    To evaluate immunogenicity of ianalumab


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Participant who cannot take the pulse i.v. corticosteroid therapy should directly start on 0.8-1.0 mg/day (max 80mg/day) oral predniso(lo)ne.
  • 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. Use of certain Traditional Chinese Medicines
  • Prior use of ianalumab (ever); or prior use other 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 methotrexate
    • Combination of DMARDs
  • Imidazole derivative (e.g., azathioprine, mizoribine) must be discontinued prior to starting treatment with MPA
  • 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 intravenous or intramuscular treatment for clinically significant infection or history of recurrent clinically significant infection which in the opinion of the investigator will place the participant at risk for participation.
  • 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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05126277


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05126277    
Other Study ID Numbers: CVAY736K12301
2020-005830-14 ( EudraCT Number )
First Posted: November 19, 2021    Key Record Dates
Last Update Posted: April 29, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
SLE
Systemic Lupus Erythematosus (SLE)
Kidney inflammation
Anti-BAFF-receptor
 B cell depletion
Ianalumab
VAY736
Additional relevant MeSH terms:
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Nephritis
Lupus Nephritis
Kidney Diseases
Urologic Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
 Male Urogenital Diseases
Glomerulonephritis
Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases