- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01773616
Trial of Rituximab and Mycophenolate Mofetil Without Oral Steroids for Lupus Nephritis (RITUXILUP)
Phase 3 Open Label Randomised Multicentre Controlled Trial of Rituxmab and Mycophenolate Mofetil Without Oral Steroids for the Treatment of 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.
Study Overview
Status
Intervention / Treatment
Detailed Description
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
- Is the combination of Rituximab, Methyl prednisolone and MMF as effective in treating lupus nephritis as Methyl prednisolone, oral steroids and MMF?
- 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
- Experimental group - Rituximab, IV methyl prednisolone and mycophenolate mofetil
- 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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
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Birmingham, United Kingdom, B15 2TH
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust
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Leeds, United Kingdom, LS7 4SA
- Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust
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Leicester, United Kingdom, LE5 4PW
- Leicester General Hospital, University Hospitals of Leicester NHS Trust
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London, United Kingdom, NW3 2QG
- Royal Free London NHS Foundation Trust
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London, United Kingdom
- King's College Hospital
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London, United Kingdom, SE1 7EH
- Guy's and St Thomas' NHS Foundation Trust
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London, United Kingdom, W12 0HS
- Hammersmith Hospital, Imperial College Healthcare NHS Trust
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London, United Kingdom, WC1N 3JN
- Great Ormond Street Hospital for Children NHS Foundation Trust
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Manchester, United Kingdom, M13 9WL
- Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust
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Oxford, United Kingdom, OX3 7LE
- Churchill Hospital, Oxford University Hospitals NHS Trust
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Stoke-on-Trent, United Kingdom, ST4 6QG
- Royal Stoke Hospital, University Hospitals of North Midlands NHS Trust
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
- Adults aged 18-75 years old and children aged 12-17 years old.
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:
- class III (A or A/C) with active lesions in at least 20% of the viable glomeruli, or
- class IV-S (A or A/C) with active lesions in at least 20% of the viable glomeruli, or
- class IV-G (A or A/C) with active lesions in at least 20% of the viable glomeruli and / or
- class V and
- 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
- No contraindications to the use of IV methyl prednisolone, MMF, oral steroids or rituximab or any other required medications such as antipyretics, antihistamines
- Ability to provide informed consent
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:
- Obsolescence of >50% of the glomeruli or tubulointerstitial scarring of >50% or cellular crescents in >50% of the glomeruli
Severe "critical" SLE flare defined as:
- BILAG 2004 A flare in CNS system
- or any SLE manifestation requiring more immunosuppression than allowed within the protocol in the physician's opinion
- 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
- Patients not willing for their GP to be informed of their participation in this study
- 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
- Patients that had received more than 2.0g of IV methyl prednisolone in the previous 4 weeks
- Prior use within 12 months of screening visit of therapeutic monoclonal antibody, or B or T cell modulating 'biologic' use
- Prior use within 6 months of the screening visit of Intravenous immunoglobulin / plasma exchange OR Cyclophosphamide
- 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
- Receipt of a live-attenuated vaccine within 3 months of study enrolment
- 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)
- Prior history of invasive fungal infections
- History of any cancer
- 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)
- 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.
- Comorbidities requiring systemic corticosteroid therapy.
- Current substance abuse.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Rituximab
Rituximab, methyl prednisolone and mycophenolate mofetil
|
Other Names:
Other Names:
|
Active Comparator: Oral prednisolone
Oral prednisolone, methyl prednisolone and mycophenolate mofetil
|
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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 years
|
Metabolic abnormalities related to steroid exposure
Time Frame: 2 years
|
2 years
|
|
Cumulative steroid exposure over 1 and 2 years
Time Frame: 2 years
|
2 years
|
|
Introduction of oral steroids in the B cell depleted patients
Time Frame: 2 years
|
2 years
|
|
Patients requiring >10mg oral prednisolone at 1 year and 2 year
Time Frame: 2 years
|
2 years
|
|
Proportion of patients achieving CR at 6, 18 and 24 months
Time Frame: 2 years
|
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 |
2 years
|
Mean time to stable CR and mean time to PR
Time Frame: 2 years
|
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
|
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
|
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. |
2 years
|
Mean time to renal flare in patients achieving CR and PR
Time Frame: 2 years
|
2 years
|
|
Proportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52
Time Frame: 2 years
|
2 years
|
Other Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Patients requiring repeat dosing with Rituximab
Time Frame: 2 years
|
2 years
|
Patients requiring the addition of any new cytotoxic
Time Frame: 2 years
|
2 years
|
Patients with non-renal BILAG 2004 A scores or flare and time to A flare
Time Frame: 2 years
|
2 years
|
Improvement in LupusQoL©, SF-36, EQ5D between baseline, 1 year, 2, 3 and 4 years
Time Frame: 2 years
|
2 years
|
Patients achieving therapeutic drug levels as a measure of adherence - as judged by mycophenolic acid and hydroxychloroquine levels
Time Frame: 2 years
|
2 years
|
Relationship between completeness and duration of B cell depletion and achievement of primary end point
Time Frame: 2 years
|
2 years
|
Patients with decreased immunoglobulin levels
Time Frame: 2 years
|
2 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Liz Lightstone, Dr, Imperial College London
Publications and helpful links
General 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immune System Diseases
- Autoimmune Diseases
- Kidney Diseases
- Urologic Diseases
- Connective Tissue Diseases
- Glomerulonephritis
- Lupus Erythematosus, Systemic
- Nephritis
- Lupus Nephritis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antineoplastic Agents
- Immunologic Factors
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Neuroprotective Agents
- Protective Agents
- Antineoplastic Agents, Immunological
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antitubercular Agents
- Antibiotics, Antitubercular
- Prednisolone
- Methylprednisolone Acetate
- Methylprednisolone
- Methylprednisolone Hemisuccinate
- Prednisolone acetate
- Prednisolone hemisuccinate
- Prednisolone phosphate
- Rituximab
- Mycophenolic Acid
Other Study ID Numbers
- CRO2035
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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