E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
OBJECTIVE: To test whether RTX is efficacious to achieve complete renal response (CR) in LN patients with persistent proteinuria (≥1g/d) despite at least 6 months of standard of care (SOC).
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E.2.2 | Secondary objectives of the trial |
1.Number of deaths ;2.Number of side-effects ;3.Number of SAEs ;4.Number of infections requiring antibiotics ;5.Number of discontinuations for toxicity ;6.Number of patients reaching ESRD ;7.Number of patients with sustained doubling of serum creatinine or sustained fall >25% in eGFR ;8.Number of renal flares, nephritic or proteinuric according to Moroni et al. (Kidney Int 1996; 50 : 2047) ;9.Time to CR ;10.Time to CR for patients achieving CR at w104 ;11.Number of patients achieving a proteinuria <0.2g/d ;12.Number of patients achieving the ACR response criteria for renal disease in SLE (Arthritis Rheum 2006; 54 : 421) ;13.Number of mild/moderate and severe flares according the to SELENA-SLEDAI flare index ;14.Number of patients with normalized serum complement levels (centrally measured on stored samples);15.Number of patients with decrease in serum anti-DNA Ab titers by 2 compared to baseline (centrally measured on stored samples);16.Grams equivalent prednisolone exposure.
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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 |
REFRACT sub-study
Patients participating to RING will be invited to participate to the
REFRACT sub-study, a translational pathophysiological tissue-based
research project aimed at unraveling i) the mechanisms underlying
refractoriness of lupus nephritis to standard immunosuppression; and ii)
the modes of action of rituximab in this setting. The REFRACT substudy
requires a second renal biopsy performed after 6 months of
treatment. An additional Consent Form is required for RING patients
agreeing to participate to REFRACT. |
REFRACT - Refractory lupus nephritis: a tissue-based
pathophysiological approach performed within the frame of a
clinical trial designed to test the efficacy of rituximab
Lupus nephritis (LN) still impacts renal and patient survival, despite availability of more and more immunosuppressive regimens. Refractory LN, i. e. not responding to standard of care (SOC) treatment, represents an unmet need. The cellular and molecular mechanisms underlying refractoriness are ignored, in particular at the kidney tissue level itself, and treatment of such cases remains poorly defined. The current project addresses these issues, taking advantage of a newly launched European investigator-initiated randomized trial, entitled RING (RItuximab In lupus Nephritis with remission as a Goal), aimed at testing the efficacy of rituximab (RTX) in LN patients displaying significant proteinuria despite 6 months of SOC. Half of the patients will
receive RTX while the others will pursue SOC. At week 104, the percentage of patients achieving remission will be compared (WP1). For the purpose of REFRACT, a repeat renal biopsy (at week 24) and repeated circulating lymphocyte sampling will be performed in selected
RING centers (WP1 collaborators). Renal and peripheral blood cellular and molecular profiling will be compared at baseline and after treatment (WP2). Long-lived plasma cells will be tracked
in baseline and repeat kidney biopsies. Their presence (persistence) will be correlated with clinical outcome (WP3). At last, we shall derive anti-DNA-producing EBV-transformed B-cell clones from post-treatment biopsies to test the hypothesis that persisting local production of
autoantibodies is triggered by cross-reactive ubiquitous renal antigens (WP4). |
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E.3 | Principal inclusion criteria |
Inclusion criteria (at screening)
All the following inclusion criteria are to be met :
1. SLE, according to ACR and/or SLICC (Arthritis Rheum 2012; May 2; doi: 10.1002/art.34473) criteria ;
2. Age ≥15y (except if local ethics committee imposes ≥18y) ;
3. ISN/RPS 2003 Class III (A or A/C), IV (A or A/C ; S or G) or V lupus GN confirmed on renal biopsy performed within 24 months before screening ;
4. Having received one out of four following immunosuppressive regimens: i): Euro-Lupus (EL) intravenous (IV) cyclophosphamide (CY) (6x 500 mg q2w) followed by AZA/MMF for 3 months; ii): NIH IVCY for 6M (6 monthly pulses) followed by AZA/MMF for 3 months; iii): MMF for at least 6 months; iv): AZA for at least 6 months
All patients should be on AZA or MMF at screening. In all regimens, MMF can be replaced by enteric-coated mycophenolic acid (eMPA) ;
5. If on GC, being on maximum 10 mg equivalent prednisolone/d at screening (for at least 2 weeks) ;
6. uP/C ratio ≥1 (expressed in mg/mg) measured in a 24-h urine collection, confirmed at randomization (w-2) ;
7. Contraception (any type ; sexual abstinence is an alternative to
contraception in paediatric patients) ;
8. Signed informed consent (drafted according to local practice and approved by the local ethics committee).
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E.4 | Principal exclusion criteria |
Exclusion criteria (at screening, except exclusion criteria 1 at randomization).
Any of the following :
1. Recent or ongoing renal flare defined as either i) : fall in estimated glomerular filtration rate (eGFR ; MDRD) ≥25% within 3 month prior to screening or between screening and randomization ; or ii) : increase in urine protein by ≥100% to >3.5g/d compared to previous assessment ;
2. 24-h proteinuria decline >50% over previous 6 months ;
3. Treatment with ≥10 mg equivalent prednisolone/d in the last 2 weeks before screening ;
4. Pregnancy or breast-feeding ;
5. Anticipated non-compliance with the protocol ;
6. History of malignancy (except non-melanoma skin and cervical intraepithelial cancer) ;
7. Previous treatment with RTX (whenever) and previous treatment with another biologic agent within the last 6 months ;
8. HIV infection ;
9. Active HBV/HCV/TB infection ;
10. Severe liver, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, haematologic or psychiatric disturbances, that would contraindicate inclusion in the protocol, as judged by the clinician.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint
The primary endpoint is the percentage of patients achieving renal complete response (CR) at w104.
CR is defined as :
- uP/C ratio ≤0.5 (expressed in mg/mg) measured in a 24-h urine collection;
and
- eGFR >= 60ml/min or, if <60ml/min at screening, not fallen by >20% compared to screening;
and
- no increase of GC throughout the study (except for two limited courses as per protocol; vide infra);
and
- no introduction of another immunosuppressant. |
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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) |
The secondary endpoints (evaluated at w104) are:
1. Number of deaths ;
2. Number of side-effects ;
3. Number of SAEs ;
4. Number of infections requiring antibiotics ;
5. Number of drops for toxicity ;
6. Number of patients reaching ESRD ;
7. Number of patients with sustained doubling of serum creatinine or sustained fall >25% in eGFR ;
8. Number of renal flares, nephritic or proteinuric according to Moroni et al. (Kidney Int 1996; 50 : 2047) ;
9. Time to CR ;
10. Time to CR for patients achieving CR at w104 ;
11. Number of patients achieving a proteinuria <0.2g/d ;
12. Number of patients achieving the ACR response criteria for renal disease
in SLE (Arthritis Rheum 2006; 54 : 421) ;
13. Number of mild/moderate and severe flares according the to SELENASLEDAI flare index ;
14. Number of patients with normalized serum complement levels (centrally
measured on stored samples);
15. Number of patients with decrease in serum anti-DNA Ab titers by 2
compared to baseline (centrally measured on stored samples);
16. Grams equivalent prednisolone exposure.
Analyses will be performed on the Intent-To-Treat (ITT) population and the |
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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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Colombia |
European Union |
Morocco |
Russian Federation |
Switzerland |
Turkey |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |