| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The study population will consist of Children (14 years and above) and adults (until 75 years old) 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. |
| La population étudiée sera composée d'enfants (à partir de 14 ans) et d'adultes (jusqu'à 75 ans) présentant un lupus néphrétique ISN/RPS de classe III ou IV (A ou A/C) ± V avec des lésions actives dans au moins 10 % des glomérules viables, ET un rapport protéines/créatinine urinaire (uPCR) ≥ 0,5 g/g. |
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| E.1.1.1 | Medical condition in easily understood language |
| Children (14 years and above) and adults (until 75 years old) with lupus nephritis |
| Enfants (à partir de 14 ans) et adultes (jusqu'à 75 ans) atteints de lupus néphrétique |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 (CR) at week 52 without receiving corticosteroids above a prespecified dose |
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| E.2.2 | Secondary objectives of the trial |
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
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
several ancillary studies will be performed: establishing a biobank , systematically analysing the pharmacological data on MMF levels (measured routinely in France), systematically analysing the histological data (renal biopsies) and analysing the long-term data on renal function and damage.
Objectves of ancillary studies :
- 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.
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| E.3 | Principal inclusion criteria |
- Children aged 14-17 years old and adults (until 75 years old)
- 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
- Ability to provide informed and signed consent
- For child-bearing aged women, willingness to use appropriate and efficient contraception, as recommended when using MMF and obinutuzumab (18 months after inclusion)
- Affiliation to a French social security system (beneficiary or legal)
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| E.4 | Principal exclusion criteria |
- Severe "critical" SLE flare defined as any SLE manifestation requiring more immunosuppression than allowed within the protocol, in the physician's opinion
- Patients who cannot be prescribed 10 mg prednisone corticosteroids "only", after inclusion according to their physician
- Prior use within 6 months preceding 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
- Contraindications to the use of IV methylprednisolone, MMF, oral corticosteroids or obinutuzumab, or its premedication drugs listed in the corresponding SmPCs
- Hypersensitivity to the active substances or to any of the excipients
- 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)
- Patients with gastro-intestinal ulcer with active bleeding
- 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 before study enrolment
- Patient who has presented a malignant pathology in the previous 2 years (with the exception of cervical cancer in situ)
- In female patients, known 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) within the past 3 years. However, the patient will be eligible after the condition has resolved (e.g., follow-up HPV test is negative or cervical abnormality was effectively treated >1 year ago).
- Patients with hepatic or pulmonary insufficiency
- Progressive cardiac pathology
- Patients with uncontrolled hypertension or hypotension
- Participation in another interventional study or being in the exclusion period at the end of a previous study.
- Pregnancy and breast feeding
- Patient under tutorship or guardianship, and incapable to give informed consent
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome is complete renal response (CR) at week 52 without receiving corticosteroids above a prespecified dose.
Complete renal response (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:
o In the obinutuzumab arm: with no corticosteroids 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, see Appendix A).
o 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 PNDS for SLE, see Appendix A).
Proteinuria will be measured at week 52 with the proteinuria/creatininuria ratio on a collection done during 24 hour.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy
- Partial renal response (PR) will be defined as:
o 50% improvement in spot uPCR
o AND uPCR between 0.5 and 3 g/g
o 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)
- Complete renal response (independently of the treatment): see primary outcome
- Proteinuria measurement: see primary outcome [1]
- Extrarenal flare will be defined according to the SELENA-SLEDAI flare index (appendix B).
- Changes in the SELENA-SLEDAI score will be measured between inclusion and week 52
Safety
- Toxicity of corticosteroids will be measured with the Glucocorticoid Toxicity Index (GTI) (see Appendix D)
- The number of serious adverse events will be measured per patient according to the CTCAE (version 5.0) 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.
- 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.
- New damage will be assessed by measuring changes in the SLICC/ACR damage index (see Appendix C).
Non-adherence to treatment will be assessed with hydroxychloroquine blood levels and with questionnaires.
Efficiency: incremental cost effectiveness ratio in cost per QALY.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| Prednisone + MMF (or Azatiprine) |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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