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Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis (RITUXILUP)

This study has suspended participant recruitment.
(Study assessments for patients recruited continuing per protocol so patients receive a minimum of 6 months follow up. No safety concerns have been raised.)
Sponsor:
Collaborators:
Karolinska Institutet
Ohio State University
Dutch Working Party on Systemic Lupus Erythematosus
EULAR Lupus Nephritis Trial Network Study Group
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01773616
First received: November 1, 2012
Last updated: June 30, 2017
Last verified: June 2017
  Purpose

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.


Condition Intervention Phase
Systemic Lupus Erythematosus, Lupus Nephritis Drug: Oral prednisolone Drug: Rituximab Drug: Mycophenolate mofetil Drug: Methyl prednisolone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase 3 Open Label Randomised Multicentre Controlled Trial of Rituxmab and Mycophenolate Mofetil Without Oral Steroids for the Treatment of Lupus Nephritis

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Complete renal response (CR) at week 52 without the need to prescribe oral steroids within 1 year [ Time Frame: 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:
  • Serious Infectious Episodes, Serious Adverse Events and Adverse events [ Time Frame: 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

  • Metabolic abnormalities related to steroid exposure [ Time Frame: 2 years ]
  • Cumulative steroid exposure over 1 and 2 years [ Time Frame: 2 years ]
  • Introduction of oral steroids in the B cell depleted patients [ Time Frame: 2 years ]
  • Patients requiring >10mg oral prednisolone at 1 year and 2 year [ Time Frame: 2 years ]
  • Proportion of patients achieving CR at 6, 18 and 24 months [ Time Frame: 2 years ]
  • Proportion of patients achieving PR at 6,12,8 and 24 months [ Time Frame: 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/mmol


  • Mean time to stable CR and mean time to PR [ Time Frame: 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 [ Time Frame: 2 years ]
  • Proportion of patients with only 1 or fewer BILAG 2004 Bs in any non-renal organ system at 1 year [ Time Frame: 2 years ]
  • Proportion of patients with renal flare [ Time Frame: 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.


  • Mean time to renal flare in patients achieving CR and PR [ Time Frame: 2 years ]
  • Proportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52 [ Time Frame: 2 years ]

Other Outcome Measures:
  • Patients requiring repeat dosing with Rituximab [ Time Frame: 2 years ]
  • Patients requiring the addition of any new cytotoxic [ Time Frame: 2 years ]
  • Patients with non-renal BILAG 2004 A scores or flare and time to A flare [ Time Frame: 2 years ]
  • Improvement in LupusQoL©, SF-36, EQ5D between baseline, 1 year, 2, 3 and 4 years [ Time Frame: 2 years ]
  • Patients achieving therapeutic drug levels as a measure of adherence - as judged by mycophenolic acid and hydroxychloroquine levels [ Time Frame: 2 years ]
  • Relationship between completeness and duration of B cell depletion and achievement of primary end point [ Time Frame: 2 years ]
  • Patients with decreased immunoglobulin levels [ Time Frame: 2 years ]

Enrollment: 24
Actual Study Start Date: April 2015
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab
Rituximab, methyl prednisolone and mycophenolate mofetil
Drug: Rituximab
Other Name: MabThera
Drug: Mycophenolate mofetil
Other Names:
  • Cellcept
  • Myfenax
Drug: Methyl prednisolone
Active Comparator: Oral prednisolone
Oral prednisolone, methyl prednisolone and mycophenolate mofetil
Drug: Oral prednisolone Drug: Mycophenolate mofetil
Other Names:
  • Cellcept
  • Myfenax
Drug: Methyl prednisolone

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Years to 75 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  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-pregnancy-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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01773616

Locations
United Kingdom
Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust
Birmingham, United Kingdom, B15 2TH
Birmingham City Hospital, Sandwell and West Birmingham Hospitals NHS Trust
Birmingham, United Kingdom, B18 7QH
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, United Kingdom, B4 6NH
Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust
Brighton, United Kingdom, BN2 5BE
Southmead Hospital, North Bristol NHS Trust
Bristol, United Kingdom, BS10 5NB
Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust
Cambridge, United Kingdom, CB2 0QQ
University Hospital of Wales
Cardiff, United Kingdom
Broomfield Hospital, Mid Essex Hospital Services NHS Trust
Chelmsford, United Kingdom, CM1 7ET
Royal Devon & Exeter Hospital
Exeter, United Kingdom
Queen Elizabeth University Hospital Glasgow, NHS Greater Glasgow and Clyde
Glasgow, United Kingdom, G51 4TF
Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust
Leeds, United Kingdom, LS7 4SA
Leicester General Hospital, University Hospitals of Leicester NHS Trust
Leicester, United Kingdom, LE5 4PW
University College London Hospitals NHS Foundation Trust
London, United Kingdom, NW1 2BU
Royal Free London NHS Foundation Trust
London, United Kingdom, NW3 2QG
Guy's and St Thomas' NHS Foundation Trust
London, United Kingdom, SE1 7EH
Hammersmith Hospital, Imperial College Healthcare NHS Trust
London, United Kingdom, W12 0HS
Great Ormond Street Hospital for Children NHS Foundation Trust
London, United Kingdom, WC1N 3JN
King's College Hospital
London, United Kingdom
Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom, M13 9WL
Churchill Hospital, Oxford University Hospitals NHS Trust
Oxford, United Kingdom, OX3 7LE
Derriford Hospital, Plymouth Hospitals NHS Trust
Plymouth, United Kingdom, PL6 8DH
Salford Royal Hospital
Salford, United Kingdom
Royal Stoke Hospital, University Hospitals of North Midlands NHS Trust
Stoke-on-Trent, United Kingdom, ST4 6QG
Sponsors and Collaborators
Imperial College London
Karolinska Institutet
Ohio State University
Dutch Working Party on Systemic Lupus Erythematosus
EULAR Lupus Nephritis Trial Network Study Group
Investigators
Study Director: Liz Lightstone, Dr Imperial College London
  More Information

Additional Information:
Publications:
If Rituximab together with MMF is shown to be as good as standard treatment with MMF and oral steroids, it would be the first time in 60 years that patients with lupus nephritis could be spared the burden of long term steroids.

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01773616     History of Changes
Other Study ID Numbers: CRO2035
Study First Received: November 1, 2012
Last Updated: June 30, 2017

Keywords provided by Imperial College London:
Systemic lupus erythematosus
Lupus
Nephritis

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Lupus Nephritis
Nephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Rituximab
Mycophenolic Acid
Prednisolone
Methylprednisolone Hemisuccinate
Mycophenolate mofetil
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antibiotics, Antineoplastic
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Anti-Inflammatory Agents
Glucocorticoids
Hormones

ClinicalTrials.gov processed this record on July 21, 2017