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History of Changes for Study: NCT01773616
Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis (RITUXILUP)
Latest version (submitted January 31, 2018) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 January 18, 2013 None (earliest Version on record)
2 August 10, 2015 Recruitment Status, Study Status, Contacts/Locations, Sponsor/Collaborators, References, Eligibility, Study Description and Oversight
3 October 27, 2015 Contacts/Locations and Study Status
4 January 20, 2016 Contacts/Locations and Study Status
5 February 19, 2016 Study Status and Contacts/Locations
6 March 16, 2016 Contacts/Locations and Study Status
7 April 11, 2016 Contacts/Locations and Study Status
8 May 19, 2017 Recruitment Status, Study Status, Contacts/Locations, Study Design, Eligibility and Study Description
9 June 30, 2017 Study Status and Contacts/Locations
10 January 31, 2018 Recruitment Status, Study Status and Contacts/Locations
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Study NCT01773616
Submitted Date:  January 18, 2013 (v1)

Open or close this module Study Identification
Unique Protocol ID: CRO2035
Brief Title: Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis (RITUXILUP)
Official Title: Phase 3 Open Label Randomised Multicentre Controlled Trial of Rituxmab and Mycophenolate Mofetil Without Oral Steroids for the Treatment of Lupus Nephritis
Secondary IDs:
Open or close this module Study Status
Record Verification: January 2013
Overall Status: Not yet recruiting
Study Start: September 2013
Primary Completion: August 2016 [Anticipated]
Study Completion: August 2017 [Anticipated]
First Submitted: November 1, 2012
First Submitted that
Met QC Criteria:
January 18, 2013
First Posted: January 23, 2013 [Estimate]
Last Update Submitted that
Met QC Criteria:
January 18, 2013
Last Update Posted: January 23, 2013 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Imperial College London
Responsible Party: Sponsor
Collaborators: Karolinska University Hospital
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
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:
Open or close this module Conditions
Conditions: Systemic Lupus Erythematosus, Lupus Nephritis
Keywords: Systemic lupus erythematosus
Lupus
Nephritis
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Single Group Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Randomized
Enrollment: 252 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Rituximab
Rituximab, methyl prednisolone and mycophenolate mofetil
Drug: Rituximab
Other Names:
  • MabThera
Drug: Mycophenolate mofetil
Other Names:
  • Cellcept
  • Myfenax
Drug: Methyl prednisolone
Active Comparator: Oral prednisolone
Oral prednisolone, methyl prednisolone and mycophenolate mofetil
Drug: Oral prednisoloneDrug: Mycophenolate mofetil
Other Names:
  • Cellcept
  • Myfenax
Drug: Methyl prednisolone
Open or close this module Outcome Measures
Primary Outcome Measures:
1. 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:
1. 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
2. Metabolic abnormalities related to steroid exposure
[ Time Frame: 2 years ]

3. Cumulative steroid exposure over 1 and 2 years
[ Time Frame: 2 years ]

4. Introduction of oral steroids in the B cell depleted patients
[ Time Frame: 2 years ]

5. Patients requiring >10mg oral prednisolone at 1 year and 2 year
[ Time Frame: 2 years ]

6. Proportion of patients achieving CR at 6, 18 and 24 months
[ Time Frame: 2 years ]

7. 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

8. Mean time to stable CR and mean time to PR
[ Time Frame: 2 years ]

9. 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 ]

10. Proportion of patients with only 1 or fewer BILAG 2004 Bs in any non-renal organ system at 1 year
[ Time Frame: 2 years ]

11. 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.

12. Mean time to renal flare in patients achieving CR and PR
[ Time Frame: 2 years ]

13. Proportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52
[ Time Frame: 2 years ]

Other Outcome Measures:
1. Patients requiring repeat dosing with Rituximab
[ Time Frame: 2 years ]

2. Patients requiring the addition of any new cytotoxic
[ Time Frame: 2 years ]

3. Patients with non-renal BILAG 2004 A scores or flare and time to A flare
[ Time Frame: 2 years ]

4. Improvement in LupusQoL©, SF-36, EQ5D between baseline, 1 year, 2, 3 and 4 years
[ Time Frame: 2 years ]

5. Patients achieving therapeutic drug levels as a measure of adherence - as judged by mycophenolic acid and hydroxychloroquine levels
[ Time Frame: 2 years ]

6. Relationship between completeness and duration of B cell depletion and achievement of primary end point
[ Time Frame: 2 years ]

7. Patients with decreased immunoglobulin levels
[ Time Frame: 2 years ]

Open or close this module Eligibility
Minimum Age: 12 Years
Maximum Age: 75 Years
Sex: All
Gender Based:
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.
Open or close this module Contacts/Locations
Central Contact Person: Sobiya Nadaraja, PhD
Telephone: 020 759 41319
Email: sobiya.nadaraja@imperial.ac.uk
Central Contact Backup: Liz Lightstone, Reader and Honorary Consultant
Telephone: 0208 383 2309
Email: l.lightstone@imperial.ac.uk
Locations:
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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