Phase II Study of Obinutuzumab in Patients with Systemic Lupus Erythematosus Pure Membranous Nephropathy (Class V Lupus Nephritis)

Trial ID: 2024-519985-35-00
Protocol: APHP240937
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Systemic lupus erythematosus

Objectives

Primary objective: to assess the efficacy of obinutuzumab in patients with pure class V lupus nephritis by achieving a complete renal response defined by the 2024 KDIGO guidelines at week 52, an outcome that signifies remission of proteinuria and preservation of renal function, which are critical for long‑term prognosis in systemic lupus erythematosus pure membranous nephropathy.

Secondary objectives:

Evaluate the safety of obinutuzumab in this patient population.
Determine the overall efficacy of obinutuzumab on pure class V lupus nephritis.
Assess the effect of obinutuzumab on overall systemic lupus erythematosus activity.
Quantify the proportion of patients who are corticosteroid‑free at week 52.
Assess health‑related quality of life at week 52.

Participants

The trial enrolled adult patients aged 18 to 75 years of both sexes who met the diagnostic criteria for systemic lupus erythematosus and had biopsy‑confirmed pure class V lupus nephritis within the preceding 12 months. Eligible individuals exhibited either nephrotic‑range proteinuria (urine protein‑creatinine ratio > 3 g/g) or persistent proteinuria > 1 g/g despite maximally tolerated anti‑proteinuric therapy, and were required to have French social security affiliation. Women of childbearing potential were required to use effective contraception or abstain from heterosexual intercourse for at least 18 months after the last obinutuzumab infusion. General health status was otherwise typical for patients with active lupus nephritis, and no specific dietary or physical‑activity restrictions were stipulated. The sponsor did not provide information on the total number of participants enrolled in the study.

Plans and Procedures

The OBLUMEN phase II trial evaluates the efficacy of obinutuzumab in adults 18–75 years with systemic lupus erythematosus pure membranous nephropathy who meet the 2019 EULAR/ACR classification criteria and have biopsy‑confirmed class V lupus nephritis; eligible participants must present nephrotic‑range proteinuria or persistent proteinuria despite maximal anti‑proteinuric therapy. After informed consent, a screening visit confirms eligibility, followed by a baseline visit (within 12 months of the qualifying biopsy) during which the first 1000 mg infusion of Gazyvaro is administered. Subsequent study visits are scheduled at weeks 4, 12, 24, 36, and 52 to assess renal response, safety, immunologic remission, corticosteroid use, and quality of life, with the week‑52 visit serving as the end‑of‑study assessment. Participant involvement therefore spans approximately 52 weeks from the initial infusion, and the overall recruitment period is planned from April 2026 to April 2029. Early termination may occur for serious adverse events, intercurrent clinical events that prevent evaluation of the primary endpoint, or withdrawal of consent. The primary endpoint is complete renal response at week 52 without intercurrent events; secondary endpoints include safety outcomes, renal response categories, immunologic remission, corticosteroid‑free status, and quality‑of‑life measures.

Treatment

The investigational product is Gazyvaro 1,000 mg concentrate for solution for infusion, containing the monoclonal antibody obinutuzumab. The pharmaceutical form is a solution for infusion administered intravenously. Each dose consists of 1000 mg (milligram(s)) delivered by infusion; the frequency and total number of infusions are defined in the study protocol and are recorded for each participant to ensure compliance.

Standard‑of‑care therapy may be continued as medically indicated, but no additional investigational or comparator agents are specified in the protocol. All drug administrations are documented in the clinical record, and adherence to the dosing schedule is monitored through infusion logs and site‑based verification procedures.

Efficacy

Efficacy will be evaluated primarily by the proportion of participants achieving Complete Renal Response at week 52 after the first obinutuzumab infusion, without any intercurrent event. Secondary efficacy assessments will include the rates of no‑kidney response, partial renal response, renal relapse, and the proportion achieving immunologic remission (defined by normalized C3 and C4 levels and negative anti‑dsDNA) at the same time point. Additional secondary measures comprise the number of renal and extrarenal flares, the proportion of patients free from corticosteroids, and health‑related quality‑of‑life scores at week 52. All laboratory parameters (C3, C4, anti‑dsDNA) and clinical outcomes will be collected at baseline and at week 52 for comparative analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age from 18 to 75 years old included
Diagnosis of SLE fulfilling the 2019 EULAR/ACR classification criteria (score ≥ 10)
Pure class V lupus nephritis, defined on a renal biopsy sample following the ISN/RPS 2003 criteria AND - Nephrotic range proteinuria (UPCr or UACr > 3 g/g) at screening visit OR - Uncontrolled proteinuria after at least 3 months of well-conducted anti-proteinuric therapy [UPCR> 1 g/g despite maximal or maximally tolerated dose of ACEi or ARB + SGLT2i therapy +/- diuretic therapy] and up to 12 months after pure class V lupus nephritis diagnosis.
For women of childbearing age, agreement to remain abstinent (refrain from heterosexual intercourse) or willingness to use appropriate and effective contraception, as recommended when using obinutuzumab (18 months after last infusion)
Signature of informed consent
French social security affiliation (beneficiary or legal)
Time interval between kidney biopsy showing pure class V LN and baseline visit of no more than 12 months

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Exclusion Criteria

Ongoing treatment (induction or maintenance) for proliferative LN (class III-A or IV-A)
CKD stage 4 or 5, defined as eGFR <30 ml/min/1.73m2 according to CKD-EPI creatinine equation measured two times in an interval of 3 months (to be dissociated from acute kidney injury).
Obsolescence of more than 60% of glomeruli or tubulo-interstitial scarring of more than 60% on kidney biopsy
Patients with a previously documented kidney disease causing proteinuria (> 0.3 g/g or > 0.3 g/day) more than 1 year prior to the diagnosis of pure class V LN.
Exclusion of primary membranous nephropathy, defined by positive anti-PLA2R antibodies on serum and/or glomerular PLA2R staining on kidney biopsy
Patients already included in an interventional study (RIPH1, clinical investigation or clinical trial)
Patient under legal protection measure (tutorship or curatorship) and patient deprived of freedom
Negativity for anti-nuclear antibodies (< 1/80) on immunofluorescence assay
Severe extra-renal (i.e but not limited to : cardiac, central nervous system, pulmonary, enteric) lupus flare requiring high dose (> 1 mg/kg/day) corticosteroids.
Receipt of any of the following excluded therapies: - Any anti-CD20 therapy such as rituximab, ocrelizumab, or ofatumumab less than 6 months prior to screening or during screening. If an anti-CD20 therapy has been received between 6 and 12 months prior to screening, the peripheral CD19+ B-cell count by flow cytometry must be > 25 cells/µL - Cyclophosphamide, tacrolimus, ciclosporin, mycophenolate mofetil, pulse methylprednisolone or voclosporin during the 2 months prior to screening or during screening. Patients maintained on low-dose corticosteroids (<10 mg/day prednisone equivalent) for a prolonged period as part of the management of a previous and resolved flare are eligible for trial participation. - Any biologic therapy (other than anti-CD20) such as, but not limited to, belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to screening or during screening - Oral inhibitors of Janus-associated kinase (JAK), Bruton’s tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening - Any live vaccine during the 28 days prior to screening or during screening
Contraindication to the use of obinutuzumab, its premedication drugs or hypersensitivity to its excipients
Fewer than 10 non-sclerosed glomeruli analyzable on renal biopsy establishing the diagnosis of pure class V lupus nephritis
Ongoing pregnancy or breastfeeding women
Active bacterial, viral or fungal infection requiring treatment, including active hepatitis B infection (HBsAg-positive with detectable HBV DNA)
Unexplained fever
Pre-existing neutropenia (absolute neutrophil count <1.5 × 10⁹/L) or other clinically significant haematological abnormality (e.g., platelet count <100 × 109/L), given the increased risk of severe or febrile neutropenia with obinutuzumab.
History of progressive multifocal leukoencephalopathy (PML), or current unexplained neurological signs or symptoms suggestive of PML.
Need for a live attenuated vaccine that cannot be deferred until after B-cell reconstitution