RING - Rituximab for Lupus Nephritis With Remission as a Goal (RING)

RING - Rituximab for Lupus Nephritis With Remission as a Goal, an Investigator-initiated Randomized International Open Multicentric Study

OBJECTIVE To test whether Rituximab (RTX) is efficacious to achieve complete renal response (CR) in Lupus Nephritis (LN) patients with persistent proteinuria (≥1g/d) despite at least 6 months of standard of care (SOC).

STUDY DESIGN Investigator-initiated randomized international open multicentric 104-week study.

Study Overview

• Status: Unknown
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: RTX infusions; Other: Standard of Care

Detailed Description

After screening (week -8), patients enter in a run-in period of 6 weeks during which treatment is unchanged. At week -2, if persistent proteinuria is confirmed (uP/C ratio ≥1 expressed in mg/mg), patients will be randomized in a 1/1 ratio to 1 of 2 treatment groups as follows :

RTX group Subjects will receive a RTX infusion (1g) at w0, w2, w24, w48 and w72.Control group Subjects will not receive RTX infusions. In both arms, azathioprine (AZA) or mycophenolate mofetil (MMF) will be continued. If prescribed, prednisolone dose should not be > 10 mg/day.

• Study Type: Interventional
• Enrollment (Anticipated): 194
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Recruiting
    • Cliniques Universitaires Saint Luc
    • Contact: Frédéric A Houssiau, MD PHD; Phone Number: +32 2 7645391; Email: frederic.houssiau@uclouvain.be
    • Contact: Geneviève J Depresseux, Trial Coord; Phone Number: +32 2 7645395; Email: genevieve.depresseux@uclouvain.be
    • Principal Investigator: Frédéric A Houssiau, MD PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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 at a dose of 2g/day (or the maximal tolerated dose; iv): AZA for at least 6 months at a dose of 2 mg/kg/day (or the maximal toerated dose).

   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).

Exclusion Criteria:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: RTX group; Subjects will receive a RTX infusion (1g) at w0, w2, w24, w48 and w72.	Drug: RTX infusions; RTX + Standard of Care
ACTIVE_COMPARATOR: Control group; Subjects will not receive RTX infusions and will be followed in standard of care	Other: Standard of Care; Standard of Care only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 glucocorticoïds (GC) throughout the study (except for two limited courses as per protocol; vide infra); and; no introduction of another immunosuppressant.	104 weeks

Collaborators and Investigators

• Sponsor: Frédéric A. Houssiau, MD, PhD
• Investigators: Principal Investigator: Frédéric A Houssiau, MD PHD, Cliniques Universitaires Saint-Luc

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (ANTICIPATED): November 1, 2015
• Study Completion (ANTICIPATED): November 1, 2016

Study Registration Dates

• First Submitted: August 22, 2012
• First Submitted That Met QC Criteria: August 24, 2012
• First Posted (ESTIMATE): August 27, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): May 28, 2015
• Last Update Submitted That Met QC Criteria: May 27, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Rituximab; Lupus Nephritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis
• Other Study ID Numbers: P1200_11