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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2013 by Imperial College London
Sponsor:
Collaborator:
Unit for Clinical Therapy Research, Karolinska University Hospital, Stockholm, Sweden
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01773616
First received: November 1, 2012
Last updated: January 18, 2013
Last verified: January 2013
  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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
  • Cumulative steroid exposure over 1 and 2 years [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Introduction of oral steroids in the B cell depleted patients [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Patients requiring >10mg oral prednisolone at 1 year and 2 year [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Proportion of patients achieving CR at 6, 18 and 24 months [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Proportion of patients achieving PR at 6,12,8 and 24 months [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Proportion of patients with only 1 or fewer BILAG 2004 Bs in any non-renal organ system at 1 year [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Proportion of patients with renal flare [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
  • Proportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52 [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Patients requiring repeat dosing with Rituximab [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Patients requiring the addition of any new cytotoxic [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Patients with non-renal BILAG 2004 A scores or flare and time to A flare [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Improvement in LupusQoL©, SF-36, EQ5D between baseline, 1 year, 2, 3 and 4 years [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Patients achieving therapeutic drug levels as a measure of adherence - as judged by mycophenolic acid and hydroxychloroquine levels [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Relationship between completeness and duration of B cell depletion and achievement of primary end point [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Patients with decreased immunoglobulin levels [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 252
Study Start Date: September 2013
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2016 (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

  Eligibility

Ages Eligible for Study:   12 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion 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 the prior 6 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), or
    3. class IV-G (A or A/C) and / or
    4. class V and
    5. urine protein-to-creatinine ratio >100 at visit -1 or at any time within 14 days before visit -1.
  3. No contraindications to the use of IV methyl prednisolone, MMF, oral steroids or rituximab
  4. Ability to provide informed consent.
  5. Willing to use appropriate contraception

Exclusion Criteria:

  1. Aged <12 years or >75 years
  2. Inactive lupus nephritis, as defined by kidney biopsy within the prior 6 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 fewer than 20% of the viable glomeruli , or
    2. class III C or
    3. class IV-S (C), or
    4. class IV-G (C)
  3. Obsolescence of >50% of the glomeruli or tubulointerstitial scarring of >50%
  4. Unable or unwilling to give informed consent
  5. Severe "critical" SLE flare defined as:

    1. BILAG 2004 A flare in CNS system
    2. Total of more than 3 BILAG 2004 As simultaneously
    3. or any SLE manifestation requiring high dose steroids in the physician's opinion
  6. Pregnancy
  7. Breast feeding
  8. At risk of pregnancy and unwillingness to use a medically acceptable form of birth control (including but not limited to a diaphragm, an intrauterine device, progesterone implants or injections, oral contraceptives, the double-barrier method, or a condom).
  9. Patients should not be on or require maintenance steroids and should not have had more than 4 weeks of steroids in the period immediately preceding recruitment irrespective of dose.
  10. Therapeutic monoclonal antibody, or B or T cell modulating 'biologic' use within 12 months of visit -1.
  11. Intravenous immunoglobulin / plasma exchange or pulsed intravenous steroid within 12 months of visit -1
  12. Use of cyclophosphamide within the previous 12 months
  13. Use of other experimental therapeutic agents within the past 60 days.
  14. eGFR <30mls/min/1.73m2
  15. Serious infection with the previous 3 months requiring hospitalization or IV antibiotic therapy
  16. Active infections, including but not limited to the human immunodeficiency virus (HIV), and hepatitis B or C and tuberculosis. Exclude latent TB unless proof of adequate treatment
  17. Receipt of a live-attenuated vaccine within 3 months of study enrollment.
  18. 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)
  19. Prior history of invasive fungal infections
  20. History of cancer, except carcinoma in situ and treated basal and squamous cell carcinomas.
  21. Known history of cervical dysplasia CIN Grade III cervical high risk human papillomavirus (HPV) positivity 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 (eg, follow-up HPV test is negative or cervical abnormality has been effectively treated >1 year ago
  22. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study) with the exception of diseases or conditions related to active SLE.
  23. Comorbidities requiring corticosteroid therapy.
  24. 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

Contacts
Contact: Sobiya Nadaraja, PhD 020 759 41319 sobiya.nadaraja@imperial.ac.uk
Contact: Liz Lightstone, Reader and Honorary Consultant 0208 383 2309 l.lightstone@imperial.ac.uk

Sponsors and Collaborators
Imperial College London
Unit for Clinical Therapy Research, Karolinska University Hospital, Stockholm, Sweden
  More Information

No publications provided

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: January 18, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

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

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Lupus Nephritis
Nephritis
Autoimmune Diseases
Connective Tissue Diseases
Glomerulonephritis
Immune System Diseases
Kidney Diseases
Urologic Diseases
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Mycophenolate mofetil
Mycophenolic Acid
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Rituximab
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Antirheumatic Agents
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids

ClinicalTrials.gov processed this record on October 22, 2014