Clinical trial NCT04702256: Induction Therapy for Lupus Nephritis With no Added Oral Steroids: A Trial Comparing Oral Corticosteroids Plus Mycophenolate Mofetil (MMF) Versus Obinutuzumab and MMF
Official title: Induction Therapy for Lupus Nephritis With no Added Oral Steroids: An Open Label Randomised Multicentre Controlled Trial Comparing Oral Corticosteroids Plus Mycophenolate Mofetil (MMF) Versus Obinutuzumab and MMF
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Lupus Nephritis
Systemic Lupus Erythematosus (SLE)
Keywords: lupus nephritis
obinutuzumab
corticosteroids
non-inferiority
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2021-01-08
Enrollment: 196
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised, open label, controlled non-inferiority phase III multicentre trial.

As primary objective, the study aims to demonstrate that a regimen free of additional oral corticosteroids but with obinutuzumab (and MMF) is non-inferior to a regimen based on oral corticosteroids and MMF in achieving the primary outcome of complete renal response at week 52 without receiving corticosteroids above a prespecified dose.

As secondary objectives, the study aims:

* To compare the efficacy of the treatments in both arms in terms of:

  * partial plus complete renal response at week 52;
  * proteinuria \< 0.8g/g at week 52;
  * extrarenal flares;
  * response as defined by a \>4 points reduction in SELENA-SLEDAI score at week 52.
* To compare the safety of the treatments in both arms in terms of occurrence of:

  * toxicity of corticosteroids;
  * serious Adverse Events;
  * serious Infectious Episodes;
  * new damage.
* To compare the number of patients with non-adherence to treatment in both arms.
* To estimate the efficiency of obinutuzumab in this indication.

The ancillary studies will allow:

* To implement a biobank (serum, plasma, DNA, cells and urine) and a bank of renal biopsies for studies that will be part of separate research funding bids (patients will be informed that their samples and data may be used for subsequent studies and offered to consent or not).
* To identify which target therapeutic levels of MMF best predicts response with least toxicity (ancillary study).
* To have long term data on renal function and damage.

Detailed description: Preliminary data show that the anti CD20 monoclonal antibody may effectively replace oral corticosteroids in the induction treatment of lupus glomerulonephritis. The concept of avoiding significant use of corticosteroids would mark a step change in the approach to the treatment of lupus nephritis but the efficacy of such a strategy first needs to be confirmed in a randomised controlled study.

The main aim of this study is to demonstrate that patients with lupus nephritis could be treated successfully without using damaging doses of oral corticosteroids.

Eligible patients will be randomised with 1:1 ratio, between interventional group (obinutuzumab, IV methylprednisolone, no or low dose corticosteroids and MMF) and control group (oral prednisone, IV methylprednisolone and MMF), after signed informed consent obtaining. Randomization will be blocked and stratified by level of proteinuria (\<1 g/g versus ≥ 1 g/g). Previous 52 centers will participate to the trial.

Study assessments will occur on a standard of care basis at 15 days, 1, 3, 6, 9 and 12 months (and at any flare or according to the wishes of the investigator). Study assessment will include assessment of disease activity, disease- and treatment-related damage, quality of life, and blood and urine tests as standard of care. In addition, a biobank will be sampled at inclusion. Long-term data on damage and renal function will be collected during standard of care (18 months, 2, 5 and 10 years) in patients who consented.

Population involved: Children (14 years and above) and adults with lupus nephritis ISN/RPS class III or IV (A or A/C) ± V with active lesions in at least 10% of the viable glomeruli, AND urine protein-to-creatinine ratio (uPCR) ≥ 0.5 g/g.

Data Analysis

In summary, the primary outcome is complete renal response (CR), initial analysis will be descriptive, using odds ratios and 95% confidence intervals (CIs). Formally CR will be analysed using Intention-To-Treat (ITT) analysis via logistic regression. Following the ITT principle, missing data will be imputed. The model will include the treatment effect, and the factors used for stratification in the randomisation as covariates. Odd ratios and 95% CIs derived from the logistic regression will be provided. The results (comparison between the groups) will be presented as an Odds Ratio (OR) (and a two-sided 95% CI) and the trial will be deemed to have met its objective of non-inferiority if the lower bound of the CI (equivalent to a one-sided 97.5% CI) is above a critical value of 0.45 as described above.

Secondary outcomes will be analysed using analogous models with logistic regression for binary endpoints, Cox regression for time-to-event endpoints and multiple linear regression for continuous endpoints. Where appropriate, repeated measures analyses will also be used. The tests will however be two-sided at 5%.

Eligibility criteria: Inclusion Criteria:

* Children aged 14-17 years old and adults;
* Active lupus nephritis, as defined by kidney biopsy within the preceding 8 weeks, assessed by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification: class III or IV (A or A/C) ± V with active lesions in at least 10% of the viable glomeruli;
* Urine protein-to-creatinine ratio (uPCR) ≥ 0.5 g/g at any time in the 14 days before inclusion;
* No contraindications to the use of IV methylprednisolone, MMF, oral corticosteroids or obinutuzumab;
* Ability to provide informed consent;
* Willingness to use appropriate contraception, as recommended when using MMF.

Exclusion Criteria:

* Severe "critical" SLE flare defined as any SLE manifestation requiring more immunosuppression than allowed in the protocol, in the physician's opinion;
* Patients who cannot be prescribed 10 mg prednisone corticosteroids "only", after inclusion according to the physician's opinion;
* Pregnant and breastfeeding woman;
* Prior use within 6 months of inclusion of therapeutic monoclonal antibody and/or B- or T cell modulating 'biologic' except belimumab that can be used up to 7 days before inclusion;
* Obsolescence of \>60% of the glomeruli or tubulointerstitial scarring of \>60%;
* CKD stage 4 or stage 5 defined as eGFR \<30 ml/min/1.73 m2 according to CKD-EPI (to be differentiated from acute renal injury);
* Active infections, including but not limited to human immunodeficiency virus (HIV), hepatitis B in the absence of a specific therapy, hepatitis C or tuberculosis;
* Receipt of a live-attenuated vaccine in the 4 weeks prior to study enrolment;
* History of cervical dysplasia CIN Grade III, cervical high-risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) in the past 3 years in female patients. However, the patient will be eligible in the following conditions: follow-up HPV test is negative or cervical abnormality was effectively treated \>1 year ago.

Primary outcomes:
measure: Complete renal response (CR)
timeFrame: at week 52
measure: Proteinuria measurement
timeFrame: at baseline
measure: Proteinuria measurement
timeFrame: at week 52
Secondary outcomes:
measure: Efficacy: partial renal response (PR)
timeFrame: at baseline and at week 52
measure: Efficacy: complete renal response
timeFrame: at baseline and at week 52
measure: Efficacy: proteinuria measurement
timeFrame: at baseline and at week 52
measure: Efficacy: extrarenal flare
timeFrame: at baseline and at week 52
measure: Efficacy: changes in the SELENA-SLEDAI score
timeFrame: at baseline and at week 52
measure: Safety: toxicity of corticosteroids measurement
timeFrame: at inclusion, at Month 6 and Month 12
measure: Safety: serious adverse events (SAE) report
timeFrame: through study completion, an average of 10 years
measure: Safety: number of serious infectious episodes
timeFrame: through study completion, an average of 10 years
measure: Safety: changes in the SLICC/ACR damage index.
timeFrame: at inclusion, at Month 6 and Month 12
measure: Non-adherence to treatment: hydroxychloroquine blood levels
timeFrame: at Month 6 and Month 12
measure: Non-adherence to treatment: questionnaires MASRI
timeFrame: at Month 6 and Month 12
measure: Efficiency
timeFrame: at one year
Other outcomes:
Locations:
city: Paris
country: France
facility: Internal medicine, Cochin hospital, APHP
Study officials:
affiliation: Centre de référence maladies auto-immunes et systémiques rares, Internal medicine, Cochin hospital, APHP
name: Nathalie COSTEDOAT-CHALUMEAU, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nephrology department, Bichat Hospital, APHP, Paris
name: Eric DAUGAS, MD, PhD
role: STUDY_DIRECTOR
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