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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05126277

Collaborator

(none)

420

Enrollment

Locations

Arms

Anticipated Duration (Months)

26.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Anticipated 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.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 :

Jul 14, 2022

Anticipated Primary Completion Date :

Mar 1, 2027

Anticipated Study Completion Date :

Jul 15, 2030

Arms and Interventions

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 Names: 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 Names: 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 Names: placebo

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 Names:

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 Names:

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 Names:

placebo

Outcome Measures

Primary Outcome Measures

Frequency and percentage of participants achieving complete renal response (CRR) [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) 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

Time to first occurrence of urine protein/creatinine ratio (UPCR) <0.5 or ≥50% reduction from baseline [Week 72]
To demonstrate superiority of ianalumab, compared to placebo, in time to first occurrence of UPCR < (urine protein-to-creatinine ratio) (UPCR) 0.5 or ≥50% reduction from baseline up to Week 72
Percentage of participants achieving stable Overall Renal Response (ORR), defined as achievement as either CRR or Partial Renal Response (PRR) [Week 52]
To demonstrate superiority of ianalumab, compared to placebo, in achieving stable ORR at Week 52
Incidence of stable Complete Renal Response (CRR) and average daily corticosteroid dose ≤5mg/day [Week 72]
To demonstrate superiority of ianalumab, compared to placebo, in achieving stable CRR at Week 72 and average daily corticosteroid dose ≤5mg/day between Week 24 and Week 72
Incidence of renal flares [Week 72]
To demonstrate superiority of ianalumab, compared to placebo, in reducing renal flares from Week 24 through Week 72
Change in British Isles Lupus Activity Group (BILAG) score [Week 72]
To demonstrate superiority of ianalumab, compared to placebo in BILAG-2004 at Week 72
Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score [Week 72]
To demonstrate superiority of ianalumab, compared to placebo, in FACIT-Fatigue at Week 72
Number of participants with adverse events [Week 72]
Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment period
Mean pulse rate of participants per treatment group [Week 72]
Beats per minute (BPM)
Mean Blood Pressure of participants [Week 72]
Blood pressure is measured using two numbers: The first number, called systolic blood pressure, measures the pressure in your arteries when your heart beats. The second number, called diastolic blood pressure, measures the pressure in your arteries when your heart rests between beats.
Ianalumab concentration in serum [Week 72]
To characterize the pharmacokinetics (PK) of ianalumab mean, median, minimum and maximum concentrations will be provided
Incidence and titer of anti-ianalumab antibodies in serum (ADA assay) over time [Week 72]
To evaluate immunogenicity of ianalumab

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 baseline

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 laboratory result

Active LN at screening, as defined by meeting the 3 following criteria:

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 on 24h urine collection at Screening
eGFR ≥25mL/min/1.73 m2

Participants must be currently on, or willing to initiate SoC induction therapy for LN according to the institutional practices using MPA

Receipt of at least one dose of pulse methylprednisolone i.v. (500-1000 mg) or equivalent for treatment of current episode of active LN during past 60 days prior screening

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.) Stage 4 Chronic Kidney Disease (CKD), or ii.) presence of oliguria (defined as a documented urine volume <400 mL/24 hrs), or iii.) 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 as long as B cell count <50 cells/μL

Prior treatment with any of the following within 12 weeks prior to randomization

belimumab, 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., azathioprine, mizoribine)

Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within 12 weeks prior to Baseline

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
Platelet count <75 x 1000/µL
Absolute neutrophil count (ANC) <1.0 x 1000/µL

Active viral, bacterial or other infections requiring systemic treatment at the time of screening, or history of recurrent clinically significant infection or of bacterial infections with encapsulated organisms

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 patient 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Fairfax	Virginia	United States	22033
2	Novartis Investigative Site	Guang Zhou		China	510080
3	Novartis Investigative Site	Prague 2		Czechia	128 50
4	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
5	Novartis Investigative Site	Aachen		Germany	52074
6	Novartis Investigative Site	Herne		Germany	44625
7	Novartis Investigative Site	Budapest		Hungary	1097
8	Novartis Investigative Site	Debrecen		Hungary	4032
9	Novartis Investigative Site	Kaposvar		Hungary	7400
10	Novartis Investigative Site	Gwangju		Korea, Republic of	61469
11	Novartis Investigative Site	Seoul		Korea, Republic of	04763
12	Novartis Investigative Site	Seoul		Korea, Republic of	05030
13	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
14	Novartis Investigative Site	El Palmar	Murcia	Spain	30120
15	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife	Spain	38320
16	Novartis Investigative Site	Madrid		Spain	28041