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 | 18.0 |
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 infectionsrequiringantibiotics ;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 | No |
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) ;(minors will be included as LN is not uncommon in female teenagers. The disease can be very refractory to SOC)
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 ;(excluded at screening by test)
9. Active HBV/HCV/TB infection (excluded at screening by test);
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
11. history of severe allergic or anaphylactic reaction to humanized or monoclonal antibodies or murine monoclonal antibodies, or known hypersensitivity to any component of RTX
12. active infections requiring hospitalizations or treatment with IV anti-infectives within 4 weeks prior screening
13.treatment with a life or attenuated vaccine within 28 days prior to randomization
14. grade 3 laboratoy abnormalities, dealing with haematology and liver tests, will be excluded, unless these are lupus-related |
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E.5 End points |
E.5.1 | Primary end point(s) |
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
17. SLICC/ACR DI
18. All secondary outcomes will be tested (and compared) on the AZA- and the MMF-treated polulations. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |