Induction Therapy for Lupus Nephritis With no Added Oral Steroids: A Trial Comparing Oral Corticosteroids Plus Mycophenolate Mofetil (MMF) Versus Obinutuzumab and MMF (OBILUP)

March 15, 2023 updated by: Assistance Publique - Hôpitaux de Paris

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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%.

Study Type

Interventional

Enrollment (Anticipated)

196

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Paris, France, 75014
        • Recruiting
        • Internal medicine, Cochin hospital, APHP
        • Contact:
          • Nathalie COSTEDOAT-CHALUMEAU, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Obinutuzumab arm
Obinutuzumab administration plus oral mycophenolate mofetil (MMF)
Drug: Obinutuzumab administration

Obinutuzumab administration by intravenous infusion (IV), IV of methylprednisolone, oral mycophenolate mofetil, no prednisone (or if required for extrarenal manifestation(s): less than 10mg/day at any time, less than 7.5mg/day after 6 months and less than 5mg/day after 9 months).

Hydroxychloroquine will be strongly recommended for all the patients.

Other Names:
  • GAZYVARO® administration
Drug: Administration of methylprednisolone, paracetamol and dexchlorpheniramine
Prior to infusion of obinutuzumab, patients receiving obinutuzumab will receive premedication including 100 mg of methylprednisolone, paracetamol and dexchlorpheniramine.
Other Names:
  • Premedication
Active Comparator: Corticosteroids arm
Oral corticosteroids plus MMF
Drug: Administration of Methylprednisolone + Prednisone + Mycophenolate mofetil

IV of methylprednisolone, oral prednisone (according to the PNDS), and oral mycophenolate mofetil.

Hydroxychloroquine will be strongly recommended for all the patients.

Other Names:
  • Corticosteroid Series

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete renal response (CR)
Time Frame: at week 52

CR at week 52 without receiving corticosteroids above a prespecified dose.

CR at week 52 is defined as:

  • Urine PCR (protein to creatinine ratio) < 0.5 g/g in a spot urine AND:
  • eGFR (estimated glomerular filtration rate using CKD-epi) ≥ 60 ml/min, or if < 60 ml/min at screening, no decline >20% compared to screening/randomisation (whichever worse)

  • AND:

    • In the obinutuzumab arm: with no steroids or without receiving oral corticosteroids > 10 mg/day within the first 6 month, and then, without receiving oral corticosteroids > 7.5 mg/day between 6 and 9 months and > 5 mg/day between 9 and 12 months for SLE indication (according to the French PNDS for SLE after 6 months).
    • In the steroid arm: without receiving corticosteroids above the prescribed taper (according to the French PNDS for SLE, see Appendix A), including without receiving oral corticosteroids > 7.5 mg/day between 6 and 9 months and > 5 mg/day between 9 and 12 months for SLE indication (according to the French
at week 52
Proteinuria measurement
Time Frame: at baseline
Proteinuria measurement: the proteinuria/creatinuria ratio will be assessed on a 24-hour urine collection.
at baseline
Proteinuria measurement
Time Frame: at week 52
Proteinuria measurement: the proteinuria/creatinuria ratio will be assessed on a 24-hour urine collection.
at week 52

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy: partial renal response (PR)
Time Frame: at baseline and at week 52

Partial renal response (PR) will be defined as:

  • 50% improvement in uPCR;
  • AND: uPCR between 0.5 and 3 g/g;
  • AND: no more than a 20% decrease of eGFR from the baseline value (using CKD-epi).
at baseline and at week 52
Efficacy: complete renal response
Time Frame: at baseline and at week 52
Complete renal response: same as in primary outcome.
at baseline and at week 52
Efficacy: proteinuria measurement
Time Frame: at baseline and at week 52
Proteinuria measurement (same as in primary outcome): the proteinuria/creatinuria ratio will be assessed on a 24-hour urine collection.
at baseline and at week 52
Efficacy: extrarenal flare
Time Frame: at baseline and at week 52
Extrarenal flare will be defined according to the SELENA-SLEDAI flare index.
at baseline and at week 52
Efficacy: changes in the SELENA-SLEDAI score
Time Frame: at baseline and at week 52
Changes in the SELENA-SLEDAI score will be measured between inclusion and week 52.
at baseline and at week 52
Safety: toxicity of corticosteroids measurement
Time Frame: at inclusion, at Month 6 and Month 12

The toxicity of corticosteroids will be measured by the Glucocorticoid Toxicity Index (GTI).

This Composite GTI will be scored (will not be measured separately) with BMI, glucose tolerance, blood pressure, lipid profile, steroid myopathy, skin, neuropsychiatric and ophthalmological toxicity and infections.
at inclusion, at Month 6 and Month 12
Safety: serious adverse events (SAE) report
Time Frame: through study completion, an average of 10 years
The number of serious adverse events will be measured per patient according to the CTCAE toxicity grading system for the following adverse events combined: death (all causes), grade 3 or higher infections, hospitalization resulting either from the disease or from a complication due to the study treatment.
through study completion, an average of 10 years
Safety: number of serious infectious episodes
Time Frame: through study completion, an average of 10 years
The number of serious infectious episodes will be measured per patient according to the CTCAE toxicity grading system for the following adverse events combined: death (all causes), grade 3 or higher infections.
through study completion, an average of 10 years
Safety: changes in the SLICC/ACR damage index.
Time Frame: at inclusion, at Month 6 and Month 12
New damage will be assessed by measuring changes in the SLICC/ACR damage index.
at inclusion, at Month 6 and Month 12
Non-adherence to treatment: hydroxychloroquine blood levels
Time Frame: at Month 6 and Month 12

Non-adherence will be defined by otherwise unexplained HCQ drug level < 200 ng/ml and/or undetectable metabolite, at least once during the follow-up visits.

Non-adherence to treatment will be assessed with hydroxychloroquine blood levels as routinely done in France.
at Month 6 and Month 12
Non-adherence to treatment: questionnaires MASRI
Time Frame: at Month 6 and Month 12
Non-adherence to treatment will be assessed using questionnaires MASRI.
at Month 6 and Month 12
Efficiency
Time Frame: at one year
The 1-year total costs of treatment in both arms will be estimated and the incremental cost effectiveness ratio as the difference in costs divided by the difference in QALys estimated from the EQ 5D self-administered questionnaire.
at one year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Roche Pharma AG

Investigators

  • Principal Investigator: Nathalie COSTEDOAT-CHALUMEAU, MD, PhD, Centre de référence maladies auto-immunes et systémiques rares, Internal medicine, Cochin hospital, APHP
  • Study Director: Eric DAUGAS, MD, PhD, Nephrology department, Bichat Hospital, APHP, Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 9, 2021

Primary Completion (Anticipated)

December 1, 2031

Study Completion (Anticipated)

December 1, 2031

Study Registration Dates

First Submitted

November 30, 2020

First Submitted That Met QC Criteria

January 7, 2021

First Posted (Actual)

January 8, 2021

Study Record Updates

Last Update Posted (Actual)

March 16, 2023

Last Update Submitted That Met QC Criteria

March 15, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APHP200038
  • 2020-005835-60 (EudraCT Number)
  • MEDAECNAT-2021-05-0070 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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