Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis
Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis
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.
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.
1. Adults aged 18-75 years old and children aged 12-17 years old.

 2. Active lupus nephritis, as defined by kidney biopsy within prior 8 weeks assessed by
 the International Society of Nephrology/Renal Pathology Society (ISN/RPS)
 classification:

 1. class III (A or A/C) with active lesions in at least 20% of the viable glomeruli,
 or

 2. class IV-S (A or A/C) with active lesions in at least 20% of the viable
 glomeruli, or

 3. class IV-G (A or A/C) with active lesions in at least 20% of the viable glomeruli
 and / or

 4. class V and

 5. urine protein-to-creatinine ratio equal to or greater than 100mg/mmol (>1mg/mg )
 at randomisation or at any time within 28 days before randomisation

 3. No contraindications to the use of IV methyl prednisolone, MMF, oral steroids or
 rituximab or any other required medications such as antipyretics, antihistamines

 4. Ability to provide informed consent

 5. As MMF is teratogenic and on basis of advice from NHS England (The updated
 recommendations
 (https://www.gov.uk/drug-safety-update/mycophenolate-mofetil-mycophenolic-acid-new-pre
 gnancy-prevention-advice-for-women-and-men) for patients whilst on MMF and after
 stopping are:

 -  Women who have child bearing potential should be willing to use 2 forms of
 effective contraception during treatment and for 6 weeks after stopping treatment

 -  Men (including those who have had a vasectomy) should be willing to use condoms
 during treatment and for at least 90 days after stopping treatment. This advice
 is a precautionary measure due to the genotoxicity of these products

 -  Female partners of male patients treated with mycophenolate mofetil should use
 highly effective contraception during treatment and for 90 days after the last
 dose

 Exclusion criteria:

 1. Obsolescence of >50% of the glomeruli or tubulointerstitial scarring of >50% or
 cellular crescents in >50% of the glomeruli

 2. Severe "critical" SLE flare defined as:

 1. BILAG 2004 A flare in CNS system

 2. or any SLE manifestation requiring more immunosuppression than allowed within the
 protocol in the physician's opinion

 3. Pregnant or lactating. Woman who have child bearing potential must have two negative
 pregnancy test results with a sensitivity of ≥ 25 mIU/mL: one from a serum pregnancy
 test at day -8 to day -10 of screening and another from a urine pregnancy test at day
 1 prior to randomisation. If the timeline is shortened because of clinical urgency,
 then there must be a negative serum pregnancy test with a sensitivity of ≥ 25 mIU/mL
 within 1-2 days before study start

 4. Patients not willing for their GP to be informed of their participation in this study

 5. Patients should not be on or require maintenance steroids and should not have had more
 than 12 weeks of steroids in the period immediately preceding recruitment irrespective
 of dose

 6. Patients that had received more than 2.0g of IV methyl prednisolone in the previous 4
 weeks

 7. Prior use within 12 months of screening visit of therapeutic monoclonal antibody, or B
 or T cell modulating 'biologic' use

 8. Prior use within 6 months of the screening visit of Intravenous immunoglobulin /
 plasma exchange OR Cyclophosphamide

 9. Active infections, including but not limited to the human immunodeficiency virus
 (HIV), and hepatitis B (including prior infection as judged by positive Hepatitis B
 core antibody) or Hepatitis C or tuberculosis

 10. Receipt of a live-attenuated vaccine within 3 months of study enrolment

 11. In the investigator's opinion, patients that are at high risk for infection (including
 but not limited to indwelling catheter, dysphagia with aspiration, decubitus ulcer,
 history of prior aspiration pneumonia or recurrent severe urinary tract infection)

 12. Prior history of invasive fungal infections

 13. History of any cancer

 14. 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. The patient will
 be eligible after the condition has resolved (e.g., follow-up HPV test is negative or
 cervical abnormality has been effectively treated >1 year ago)

 15. Any concomitant medical condition or abnormal blood results that in the investigator's
 opinion, or after discussion with the CI, places the participant at risk by
 participating in this study.

 16. Comorbidities requiring systemic corticosteroid therapy.

 17. Current substance abuse.