Systemic Lupus Erythematosus, Lupus Nephritis Clinical Trial
— RITUXILUPOfficial title:
Phase 3 Open Label Randomised Multicentre Controlled Trial of Rituxmab and Mycophenolate Mofetil Without Oral Steroids for the Treatment of Lupus Nephritis
| Verified date | January 2018 |
| Source | Imperial College London |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 24 |
| Est. completion date | December 2017 |
| Est. primary completion date | December 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 12 Years to 75 Years |
| Eligibility |
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-pre gnancy-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. |
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust | Birmingham | |
| United Kingdom | Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust | Leeds | |
| United Kingdom | Leicester General Hospital, University Hospitals of Leicester NHS Trust | Leicester | |
| United Kingdom | Great Ormond Street Hospital for Children NHS Foundation Trust | London | |
| United Kingdom | Guy's and St Thomas' NHS Foundation Trust | London | |
| United Kingdom | Hammersmith Hospital, Imperial College Healthcare NHS Trust | London | |
| United Kingdom | King's College Hospital | London | |
| United Kingdom | Royal Free London NHS Foundation Trust | London | |
| United Kingdom | Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust | Manchester | |
| United Kingdom | Churchill Hospital, Oxford University Hospitals NHS Trust | Oxford | |
| United Kingdom | Royal Stoke Hospital, University Hospitals of North Midlands NHS Trust | Stoke-on-Trent |
| Lead Sponsor | Collaborator |
|---|---|
| Imperial College London | Dutch Working Party on Systemic Lupus Erythematosus, EULAR Lupus Nephritis Trial Network Study Group, Karolinska Institutet, Ohio State University |
United Kingdom,
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.
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Patients requiring repeat dosing with Rituximab | 2 years | ||
| Other | Patients requiring the addition of any new cytotoxic | 2 years | ||
| Other | Patients with non-renal BILAG 2004 A scores or flare and time to A flare | 2 years | ||
| Other | Improvement in LupusQoL©, SF-36, EQ5D between baseline, 1 year, 2, 3 and 4 years | 2 years | ||
| Other | Patients achieving therapeutic drug levels as a measure of adherence - as judged by mycophenolic acid and hydroxychloroquine levels | 2 years | ||
| Other | Relationship between completeness and duration of B cell depletion and achievement of primary end point | 2 years | ||
| Other | Patients with decreased immunoglobulin levels | 2 years | ||
| Primary | Complete renal response (CR) at week 52 without the need to prescribe oral steroids within 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 | Serious Infectious Episodes, Serious Adverse Events and Adverse events | 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 | |
| Secondary | Metabolic abnormalities related to steroid exposure | 2 years | ||
| Secondary | Cumulative steroid exposure over 1 and 2 years | 2 years | ||
| Secondary | Introduction of oral steroids in the B cell depleted patients | 2 years | ||
| Secondary | Patients requiring >10mg oral prednisolone at 1 year and 2 year | 2 years | ||
| Secondary | Proportion of patients achieving CR at 6, 18 and 24 months | 2 years | ||
| Secondary | Proportion of patients achieving PR at 6,12,8 and 24 months | 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 | |
| Secondary | Mean time to stable CR and mean time to PR | 2 years | ||
| Secondary | Proportion of patients in PR who achieve histological remission as judged by absence of proliferative lesions and no new subendothelial or subepithelial deposits | 2 years | ||
| Secondary | Proportion of patients with only 1 or fewer BILAG 2004 Bs in any non-renal organ system at 1 year | 2 years | ||
| Secondary | Proportion of patients with renal flare | 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 | |
| Secondary | Mean time to renal flare in patients achieving CR and PR | 2 years | ||
| Secondary | Proportion of patients achieving normal serum C3,C4 and anti-dsDNA antibodies at week 52 | 2 years |