| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of the kidneys that is a severe complication of systemic lupus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025140 |
| E.1.2 | Term | Lupus nephritis |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of ianalumab, compared to placebo, in achieving stable complete response (CRR) at week 72 |
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate the superioity of ianalumab versus placebo in time to first occurrence of reduction in protein to creatinine ratio; stable overall renal response at week 48; stable CRR at week 72; coricosteriod dose <5mg/day between week 24 and 72; in preventing renal flare related events or deaths from Week 24 through 72; in BILAG-2004 at week 72; in FACIT-Fatigue at week 72; to evaulate the safety and tolerability of ianalumab, to charterize the pharmacokinetics of ianalumab; and to evalue immogenicity of ianalumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Adult male and female patients aged 18 years or older at the time of screening
2. Signed informed consent must be obtained prior to participation in the study.
3. Have a confirmed clinical diagnosis of SLE according to EULAR/ACR SLE classification criteria (Aringer et al 2019; see Section 16.3)
4.Have a positive anti-nuclear antibody (ANA) test result defined as an ANA titer ≥1:80 at screening based on central laboratory results or a documented, positive historical result.
5. Presence of active LN at screening requiring induction therapy, as defined by meeting the 3 following criteria, requiring:
• 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.
• Urine protein creatinine ratio (UPCR) ≥1.0 g/g on 24-hour urine collection at Screening
• Threshold renal function requirement or eGFR ≥25 mL/min/1.73 m2 (Patients with eGFR <30 mL/min/1.73 m2 require renal biopsy during the screening period showing sclerosis in ≤50% of glomeruli)Induction therapy, as defined by starting high dose corticosteroids and MPA, may begin before Screening but should be initiated upon or within 60 days prior to randomization. Participants who have been on MPA for SLE including LN may be eligible if they have received, or will receive, the induction therapy within 60 days prior to or on Day 0. This is comprised of initiation of high dose corticosteroids with MPA dose increased to reach the target dose for induction in the participant.
6. Newly diagnosed patients, 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 the 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.
7. 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 the past 60 days prior to or at screening/randomization
8. Within 60 days prior to randomization, participants who cannot take pulse i.v corticosteroid therapy should directly start on 0.8 - 1.0 mg/kg/day (max 80 mg/day) oral predniso(lo)ne
9. Ability to communicate well with the Investigator to understand and comply with the requirements of the study |
|
| E.4 | Principal exclusion criteria |
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. 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.
2. Sclerosis in >50% of glomeruli on renal biopsy.
3. 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, whichever is longer, or longer if required by local regulations
4. Prior use of any B cell depleting therapy (e.g., ianalumab, rituximab or other anti-CD20 mAb, anti-CD22 mAb, or anti-CD52 mAb) administered 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 patients own baseline value prior to having received B cell depleting therapy
5. Prior treatment with any of the following within 12 weeks prior to randomization:
• belimumab (anti-BAFF mAb), telitacicept, abatacept (CTLA4-Fc Ig), anti-tumor necrosis factor-alpha (TNF-α) mAb, immunoglobulins (i.v./s.c.) plasmapheresis
• any other immuno-suppressants (e.g., i.v. or oral cyclophosphamide), calcineurin inhibitors (e.g., cyclosporine, voclosporin, tacrolimus), JAK inhibitors or other kinase inhibitors
• thalidomide treatment and/or one of the following DMARDs:
methotrexate or an imidazole derivative (e.g. mizoribine)
• Use of anti-malarials permitted if stable dosing regimen prior to randomization. Combination of other DMARDs is not permitted.
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone
(cumulative dose) within 12 weeks prior to randomization
7. History of major organ transplant or hematopoietic stem cell/bone marrow transplant or are due to receive transplantation
8. Any one of the following laboratory values at screening:
• Hemoglobin levels <8.0 g/dL (one re-test is allowed during the
screening period)
• Platelet count <25 x 103/μL
• Absolute neutrophil count (ANC) <0.8 x 103/μL (one re-test is allowed during the screening period)
9. Active viral, bacterial or other infections requiring systemic treatment at the time of screening , or history of recurrent clinically significant infection
10. History of known intolerance/hypersensitivity to MPA, or oral corticosteroids, or any component of the study drug(s) or its excipients or to drugs of similar chemical classes (e.g., mAb of IgG1 class) or to any of the constituents of the study drug
(sucrose, L-arginine hydrochloride, L-histidine, polysorbate 80,
hydrochloric acid)
11. Receipt of live/attenuated vaccine within a 4-week period prior to randomization
12. History of primary or secondary immunodeficiency, including a positive human immunodeficiency virus (Enzyme-linked immunosorbent assay [ELISA] and Western blot) test result
13. History of malignancy of any organ system (other than localized basal cell carcinoma or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
14. 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.
15.Chronic infection with hepatitis B or hepatitis C. Positive serology for HBsAg excludes the participant.
• HBsAg negative participants who are HBcAb positive are also excluded except if both following criteria are met:
•HBV DNA is negative, and
•hepatitis B monitoring is implemented.
•In these participants, monthly testing of HBsAg and HBV DNA must be performed while on study and at least every 12 weeks after end of treatment for the entire duration of safety follow up; and antiviral prophylaxis must be implemented while on study and up to 12 months after end of study treatment.
•Participants with a positive HCV antibody test should have HCV
ribonucleic acid (RNA) levels measured. Participants with positive (detectable) HCV RNA must be excluded.
16.Evidence of active tuberculosis infection (after anti-TB treatment, patients with history of TB or latent TB may become eligible according to national local guidelines). Testing for tuberculosis will be done at Screening unless such testing has been performed in the past 6 months prior to Screening with documented negative result.
17. Pregnant or nursing (lactating) women
18. Women of childbearing 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 IM.
- Women of childbearing potential who are taking hormonal
contraceptives are required to use additional barrier method because MMF/MPA may affect effectiveness of hormonal contraception.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence of stable complete renal response (CRR) at Week 72 without treatment discontinuation before Week 72 or renal flares after Week 24.
CRR is defined as
• eGFR ≥90 ml/min/1.73 m2 or no less than 85% of baseline; AND,
• 24-hour UPCR <0.5.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
A stable CRR response at Week 72 is defined as CRR at Week 68 and Week 72
|
|
| E.5.2 | Secondary end point(s) |
1. Time to first occurrence of UPCR <0.5 or ≥50% reduction from baseline up to Week 72
2. Incidence of stable ORR at Week 52 without treatment discontinuation before Week 52 or renal flares after Week 24
3. Incidence of stable CRR at Week 72 and average daily corticosteroid dose ≤5mg/day between Week 24 and Week 72 without treatment discontinuation before Week 72 or renal flares after Week 24.
4. Incidence of renal flares from Week 24 through Week 72 or treatment discontinuation before Week 72
5. Change from baseline in BILAG-2004 at Week 72
6. Change from baseline in FACIT-Fatigue at Week 72
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. UPCR <0.5 or 50% reduction from baseline up to Week 72
2. Stable ORR at Week 52
3. Stable CRR at Week 72 and average daily corticosteroid dose 5mg/day between Week 24 and Week 72
4. Renal flares from Week 24 through Week 72
5. BILAG-2004 at Week 72
6. FACIT-Fatigue at Week 72
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Colombia |
| Guatemala |
| Malaysia |
| Peru |
| Singapore |
| Hong Kong |
| Taiwan |
| Brazil |
| Canada |
| China |
| Czechia |
| Estonia |
| France |
| Germany |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Mexico |
| Romania |
| Russian Federation |
| Spain |
| Thailand |
| United Kingdom |
| United States |
| Viet Nam |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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