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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by Imperial College London
Sponsor:
Collaborators:
Karolinska Institutet
Ohio State University
Dutch Working Party on Systemic Lupus Erythematosus
EULAR Lupus Nephritis Trial Network Study Group
Imperial Clinical Trials Unit
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01773616
First received: November 1, 2012
Last updated: August 10, 2015
Last verified: August 2015
  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: April 2015
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 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
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 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 >100mg/mmol (>1mg/mg ) 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 or any other required medications such as antipyretics, antihistamines
  4. Ability to provide informed consent
  5. Willing to use appropriate contraception if female and at risk of pregnancy - (progesterone only pill, progesterone implant, combined oral contraceptive if not contraindicated, intrauterine contraceptive device, barrier methods)

Exclusion criteria:

  1. Obsolescence of >50% of the glomeruli or tubulointerstitial scarring of >50%
  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. Pregnancy
  4. Breast feeding
  5. Patients not willing for their GP to be informed of their participation in this study
  6. 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
  7. Patients that had received more than 1.5g of IV methyl prednisolone in the previous 4 weeks
  8. Prior use within 12 months of visit -1 of therapeutic monoclonal antibody, or B or T cell modulating 'biologic' use
  9. Prior use within 6 months of visit -1 of Intravenous immunoglobulin / plasma exchange OR Cyclophosphamide
  10. eGFR <30mls/min/1.73m2
  11. 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
  12. Receipt of a live-attenuated vaccine within 3 months of study enrolment
  13. 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)
  14. Prior history of invasive fungal infections
  15. History of any cancer
  16. 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)
  17. Any concomitant medical condition that in the investigator's opinion, or after discussion with the CI, places the participant at risk by participating in this study.
  18. Comorbidities requiring systemic corticosteroid therapy.
  19. Current substance abuse.
  20. IgG below lower limit of local laboratory range
  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: Natalia Klimowska-Nassar, BA, M.St 020 759 40994 rituxilup@imperial.ac.uk
Contact: Liz Lightstone, Reader and Honorary Consultant 0208 383 2309 l.lightstone@imperial.ac.uk

Locations
United Kingdom
Birmingham City Hospital, Sandwell and West Birmingham Hospitals NHS Trust Recruiting
Birmingham, United Kingdom, B18 7QH
Great Ormond Street Hospital for Children NHS Foundation Trust Recruiting
London, United Kingdom, WC1N 3JN
Hammersmith Hospital, Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom, W12 0HS
Royal Free London NHS Foundation Trust Recruiting
London, United Kingdom, NW3 2QG
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom, NW1 2BU
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
Imperial Clinical Trials Unit
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: August 10, 2015
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 Nephritis
Nephritis
Lupus Erythematosus, Systemic
Autoimmune Diseases
Connective Tissue Diseases
Glomerulonephritis
Immune System Diseases
Kidney Diseases
Urologic Diseases
Methylprednisolone
Methylprednisolone Hemisuccinate
Methylprednisolone acetate
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 August 26, 2015