Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis
- Conditions
- Systemic Lupus Erythematosus, Lupus Nephritis
- Interventions
- Registration Number
- NCT01773616
- Lead Sponsor
- Imperial College London
- Brief Summary
The treatment of the multisystem autoimmune disease systemic lupus erythematosus (SLE) remains a challenge, particularly when there is renal involvement (lupus nephritis). For the last 60 years corticosteroids have been the backbone of the treatment of lupus nephritis but they are associated with significant toxicity.
Although randomized placebo controlled trials of Rituximab in non-renal lupus and lupus nephritis did not meet their primary end-points, there is accumulating data that suggests that B cell depletion with Rituximab may be efficacious in lupus disease refractory to conventional therapy. Furthermore, our pilot data suggests that the addition of Rituximab to mycophenolate mofetil (MMF) without oral steroids is at least as effective at inducing a renal response as the standard of care therapy comprising MMF and high dose oral corticosteroids.
RITUXILUP is a proof of concept, open labeled, randomized, controlled, multicentre trial that aims to demonstrate whether the addition of Rituximab to MMF therapy is useful in treating a new flare of lupus nephritis and whether it has a long lasting steroid-sparing, beneficial effect with equal efficacy and greater safety than a conventional regimen of MMF and oral prednisolone. If successful, this trial has the potential to dramatically change the management of lupus nephritis.
- Detailed Description
TRIAL SUMMARY
TITLE RITUXILUP - An open label randomised multicentre controlled trial of RITUXImab and mycophenolate mofetil (MMF) without oral steroids for the treatment of LUPus nephritis
OBJECTIVES
1. Is the combination of Rituximab, Methyl prednisolone and MMF as effective in treating lupus nephritis as Methyl prednisolone, oral steroids and MMF?
2. Does the omission of oral steroids increase the safety of the treatment regimen?
DESIGN This is a 1:1 randomised, international open label, controlled phase III multicentre trial
SAMPLE SIZE A total of 252 patients: 126 patients in each arm (As of April 2017 decided 25 patients will be maximum recruited following decision to close the study early)
ELIGIBILITY Children (12 years and above) and adults with lupus nephritis ISN/RPS Class III A or A/C, Class IV-G A or A/C, Class IV-S A or A/C, and/or Class V with a urine protein/creatinine ratio (PCR) ≥ 100mg/mmol.
TREATMENT
1. Experimental group - Rituximab, IV methyl prednisolone and mycophenolate mofetil
2. Control group - oral prednisolone, IV methyl prednisolone and mycophenolate mofetil.
PRIMARY OUTCOME The primary outcome is to demonstrate non-inferiority of the Rituximab arm in comparison to the control arm in the proportion of patients achieving complete renal response (CR) at week 52 without the need for steroid prescription.
SECONDARY OUTCOMES
Safety outcomes:
* Serious Infectious Episodes
* Serious Adverse Events
* Evidence of metabolic abnormalities particularly new onset diabetes
Disease control over time:
* Proportion of patients achieving Partial Response (PR)
* Time to stable CR
* Time to PR
* Proportion of patients in PR who achieve histological remission in those who have a repeat biopsy as part of local standard of care
* Proportion of patients with renal or extra flare
* Cumulative steroid exposure
* Deviation from the steroid taper in the steroid arm and/or introduction of steroids in the steroid-free arm
* Proportion of patients achieving a response as defined by the SLE Responder Index (SRI) at week 52 and annually thereafter as defined by:
* a \>4 point reduction in SELENA-SLEDAI score;
* no new BILAG A organ domain score;
* no more than I new BILAG B score;
* no worsening in physician's global assessment (PGA) by \>10%;
* must not have received non-protocol treatment.
* Proportion of patients achieving a response as defined by the BILAG-based Composite Lupus Assessment (BICLA) at week 52 and annually thereafter as defined by: BILAG-2004 improvement (BILAG A to B/C/D, BILAG B to C/D and no BILAG worsening, no deterioration in SLEDAI total score, no worsening in physician's global assessment (PGA) by \>10% and must not have received non-protocol treatment.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 24
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Oral prednisolone Oral prednisolone Oral prednisolone, methyl prednisolone and mycophenolate mofetil Oral prednisolone Methyl prednisolone Oral prednisolone, methyl prednisolone and mycophenolate mofetil Rituximab Methyl prednisolone Rituximab, methyl prednisolone and mycophenolate mofetil Rituximab Mycophenolate mofetil Rituximab, methyl prednisolone and mycophenolate mofetil Rituximab Rituximab Rituximab, methyl prednisolone and mycophenolate mofetil Oral prednisolone Mycophenolate mofetil Oral prednisolone, methyl prednisolone and mycophenolate mofetil
- Primary Outcome Measures
Name Time Method Complete renal response (CR) at week 52 without the need to prescribe oral steroids within 1 year 1 year The proportion of participants who achieve a complete renal response at week 52 without the need to prescribe oral steroids within 1 year, except for one course of maximum 30mg for a maximum of 14 days OR one intramuscular or intra-articular injection of steroids
- Secondary Outcome Measures
Name Time Method Mean time to stable CR and mean time to PR 2 years Metabolic abnormalities related to steroid exposure 2 years Mean time to renal flare in patients achieving CR and PR 2 years Proportion of patients achieving CR at 6, 18 and 24 months 2 years Proportion of patients with renal flare 2 years Flare is identified by:
i) Proteinuria \>50% increase ii) AND above 100mg/mmol for 2 visits iii) and / or in those with normal renal function and normal urinary sediment, a fall of \>20% in eGFR on 2 occasions Where possible flare should be proven by repeat renal biopsy.Introduction of oral steroids in the B cell depleted patients 2 years Proportion of patients with only 1 or fewer BILAG 2004 Bs in any non-renal organ system at 1 year 2 years Serious Infectious Episodes, Serious Adverse Events and Adverse events 2 years 4. Metabolic abnormalities related to steroid exposure: 5. Cumulative steroid exposure over 1 and 2 years 6. Introduction of oral steroids in the B cell depleted patients 7. Patients requiring \>10mg oral prednisolone at 1 year and 2 year
Cumulative steroid exposure over 1 and 2 years 2 years Patients requiring >10mg oral prednisolone at 1 year and 2 year 2 years Proportion of patients achieving PR at 6,12,8 and 24 months 2 years PR is defined as:
i) eGFR at baseline or \<20% decrease, ii) AND if not nephrotic at baseline (PCR\<300mg/mmol), 50% improvement in urine PCR iii) OR if nephrotic at baseline (PCR \>300mg/mmol), 50% improvement in urine PCR AND PCR \<300mg/mmolProportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52 2 years Proportion of patients in PR who achieve histological remission as judged by absence of proliferative lesions and no new subendothelial or subepithelial deposits 2 years
Trial Locations
- Locations (11)
Royal Stoke Hospital, University Hospitals of North Midlands NHS Trust
🇬🇧Stoke-on-Trent, United Kingdom
Hammersmith Hospital, Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
Churchill Hospital, Oxford University Hospitals NHS Trust
🇬🇧Oxford, United Kingdom
Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Great Ormond Street Hospital for Children NHS Foundation Trust
🇬🇧London, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom
Leicester General Hospital, University Hospitals of Leicester NHS Trust
🇬🇧Leicester, United Kingdom
Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust
🇬🇧Leeds, United Kingdom
Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Royal Free London NHS Foundation Trust
🇬🇧London, United Kingdom
Guy's and St Thomas' NHS Foundation Trust
🇬🇧London, United Kingdom