Obinutuzumab for Systemic Lupus Erythematosus Pure Membranous Nephropathy: a Phase II Trial

Phase 2Not Yet RecruitingNCT07721363

Assistance Publique - Hôpitaux de Paris65 enrolled

Overview

Lupus nephritis (LN) is a frequent and severe complication of systemic lupus erythematosus, with important mortality and morbidity. International 2024 guidelines recommend immunosuppressive therapy (MMF, cyclophosphamide, calcineurin inhibitors, rituximab, azathioprine) in patients with heavy or uncontrolled proteinuria, but none of these therapies has been evaluated in robust multicenter prospective. Therefore, no treatment has regulatory approval for pure class V LN. Obinutuzumab, a 2nd-generation B-cell targeting therapy, is more efficient than rituximab in inducing B-cell depletion and complete renal response in patient with class III or IV lupus nephritis. This study aims to assess the efficacy and safety of an obinutuzumab monotherapy in patients with pure class V LN. The primary endpoint is complete renal response at week 52 according to 2024 KDIGO criteria (UPCR \< 0.5 g/g, eGFR ≥ 85% of baseline, and no intercurrent event: treatment failure, rescue therapy, long-term dialysis, renal transplantation, death or early trial withdrawal)

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus and conveys important risk of morbidity and mortality in affected patients. Pure class V LN, also referred to as lupus membranous nephropathy, remains difficult to manage despite available therapy. Current immunosuppressive options proposed in the 2024 international recommendations include mycophenolate mofetil, cyclophosphamide, calcineurin inhibitors, rituximab or azathioprine in situations of uncontrolled or nephrotic proteinuria. However, none of these drugs has been validated through prospective multicenter protocol-based trials specifically dedicated to assess their efficacy and safety in pure class V LN. Therefore no therapy holds specific approval for this condition. Observational data from multiple French centers highlight the heterogeneous therapeutic choices and variable response rates obtained with treatments. Although efficacy appears broadly similar across these strategies, concerns persist regarding infertility, teratogenicity, myelotoxicity and corticosteroid exposure, reinforcing the need for alternatives with improved tolerance. Rituximab is increasingly used to treat pure lupus membranous nephropathy but is less efficient than obinutuzumab in inducing complete renal response in class III or IV lupus nephritis. Obinutuzumab is a second-generation therapy targeting B cells, developed to enhance activity compared with rituximab. Clinical studies conducted in follicular lymphoma and chronic lymphocytic leukemia demonstrated superior outcomes and supported its approval. In LN, evaluations combining obinutuzumab with standard-of-care therapy in proliferative classes (NOBILITY and REGENCY trials) reported higher complete renal response than placebo with acceptable safety, although events such as infections, serious adverse events, neutropenia and infusion-related reactions were documented. In contrast, a study using rituximab with standard-of-care therapy (LUNAR) did not show improvement in complete renal response. Based on these findings, this phase 2 study evaluates obinutuzumab monotherapy in adults with pure class V LN. The main endpoint is complete renal response at week 52 after first infusion, defined by urinary protein creatinine ratio \< 0.5 g/g on 24-hour urine collection, eGFR ≥ 85% of baseline, and absence of intercurrent events including treatment failure, need for rescue therapy, high-dose corticosteroids, long-term dialysis, renal transplantation, death or premature withdrawal. Secondary objectives include: assessment of safety by recording adverse events, serious adverse events and events of interest (neutropenia, infection, infusion-related events, new cancer) from first infusion to week 52; evaluation of renal outcomes documenting no kidney response, partial renal response, complete renal response and renal relapses free of intercurrent event; monitoring of systemic lupus erythematosus activity based on immunologic remission defined by C3 and C4 normalization and anti-dsDNA negativation, as well as renal and extrarenal flares; estimation of participants without corticosteroids at week 52; and evaluation of quality of life at week 52. The trial uses a single-arm, open, non-comparative A'Hern phase II design (Category 2, Phase 2). This protocol aims to generate prospective data on the activity and safety of obinutuzumab monotherapy in pure class V LN, with precise definitions of renal response, systematic follow-up of adverse events and detailed assessment of systemic and renal outcomes over a 52-week period.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Diagnosis of SLE fulfilling the 2019 EULAR/ACR classification criteria (score \> 10) 2. Age from 18 to 75 years old included 3. 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. 4. 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) 5. Signature of informed consent 6. French social security affiliation (beneficiary or legal) 7. Time interval between kidney biopsy showing pure class V LN and baseline visit of no more than 12 months Exclusion Criteria: 1. Ongoing treatment (induction or maintenance) for proliferative LN (class III-A or IV-A) 2. Negativity for anti-nuclear antibodies (\< 1/80) on immunofluorescence assay 3. 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. 4. 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 5. Contraindication to the use of obinutuzumab, its premedication drugs or hypersensitivity to its excipients. 6. Fewer than 10 non-sclerosed glomeruli analyzable on renal biopsy 7. Ongoing pregnancy or breastfeeding women 8. 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). 9. Obsolescence of more than 60% of glomeruli or tubulo-interstitial scarring of more than 60% on kidney biopsy. 10. Patients already included in an interventional study (RIPH1, clinical investigation or clinical trial) 11. Patient under legal protection measure (tutorship or curatorship) and patient deprived of freedom 12. Patients with a previously documented kidney disease causing proteinuria (\> 3 g/g or \> 3 g/day) more than 1 year prior to the diagnosis of pure class V LN. 13. Exclusion of primary membranous nephropathy, defined by positive anti-PLA2R antibodies on serum and/or glomerular PLA2R staining on kidney biopsy

Outcomes

Primary Outcomes

To assess, in patients with pure class V lupus nephritis, the efficacy of obinutuzumab to reach complete renal response as defined by 2024 international KDIGO guidelines, 52 weeks after the first obinutuzumab infusion.

The primary endpoint is therapeutic success at Week 52 (W52) after the first obinutuzumab infusion, defined as: Complete Renal Response (CRR) of pure class V LN, as defined by the international KDIGO 2024 guidelines, as follows: * Urine Protein-to-Creatinine Ratio (UPCR) \< 0.5 g/g measured from a 24-hour urine collection AND * An eGFR ≥ 85% of the baseline value (assessed using the 2021 CKD-EPI creatinine equation), with baseline defined as the last non-missing value prior to receipt of the first obinutuzumab infusion. AND o No intercurrent event, including: * Use of rescue therapy (i.e., another immunosuppressive agent used to achieve remission, including: mycophenolate mofetil, cyclophosphamide, tacrolimus, cyclosporine, or azathioprine) or high-dose corticosteroids (\> 1 mg/kg/day of prednisone equivalent) OR * Occurrence of end-stage renal disease (CKD-EPI 2021 eGFR \< 15 mL/min/1.73 m², long-term dialysis, or pre-emptive kidney transplantation) OR * Death from any cause

Time frame: week 52 (week 48 to week 56) after the first infusion of obinutuzumab.

Secondary Outcomes

To assess the safety of obinutuzumab in patients with pure class V lupus nephritis by quantifying adverse events, serious adverse events, and adverse events of special interest between the first obinutuzumab infusion and W52

collection, analysis and quantification of adverse events according to the CTCAE v5.0