The Use of Rituximab In the treatment of Nephrotic Glomerulonephritis
Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are auto-immune renal diseases that present with a common clinical phenotype, the nephrotic syndrome (NS), characterised by heavy proteinuria and debilitating oedema. When nephrotic, patients require frequent hospital admissions; infections and venous thrombo-embolism are common and can be fatal. With treatment, patients with MCD usually have preserved renal function, however, those with FSGS frequently still progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT). Patients with FSGS and NS have five-year renal survival rates (without dialysis or transplantation) of 60-90% and ten-year renal survival rates of 30-55%. 10-year survival improves to 80% if remission from proteinuria is achieved.
MCD/FSGS are rare auto-immune kidney diseases. Untreated, they result in considerable morbidity including kidney failure and death. Current treatments have serious limitations: whilst glucocorticoids are effective in the majority of patients, repeated courses are usually required, and the side effect burden of cumulative steroid exposure itself carries extensive morbidity and mortality for patients. In other autoimmune diseases where immunosuppression is required, steroid-sparing regimens (including the use of biologics) are now the norm. In MCD/FSGS there is an urgent need for such steroid-sparing regimes, that are both effective and safe, and do not adversely affect kidney function. Rituximab is the most promising candidate treatment. Indeed, it is currently used where other treatments have failed, or where the risk of toxicity from existing treatments is deemed unacceptably high. However, such use lacks supporting evidence from robust interventional trials, leading the KDIGO expert group to identify trials with rituximab in adults with MCD/FSGS as a key research priority. Given pressures on healthcare resources, studies assessing both the efficacy and cost-effectiveness of rituximab as treatment for MCD/FSGS within the context of the NHS are urgently needed.
MCD/FSGS often affects patients younger than 65 years5, when they are economically active. The symptoms of NS and the requirement for hospital-based treatment result in time off work and loss of income. Complications arising from the disease or its treatment, such as serious infections, may require further hospital admissions. Loss of kidney function can result in ESKD requiring dialysis at great cost. Indeed, glomerulonephritides account for 18.9% of patients requiring RRT, and this is higher in those under 65 years of age (21.3%). Although MCD/FSGS make up only a proportion of this number, treatments that delay the onset of ESKD should result in a significant cost saving. Currently, patients are treated with multiple courses of a variety of different immunosuppressants over many years or even decades in an effort to reduce steroid exposure. Even if these treatments are successful in a steroid-sparing capacity, they have significant toxicity themselves - oral cyclophosphamide, in particular, carries a high risk of leucopenia and sepsis. There is a clear need for alternative effective treatment such as rituximab for MCD/FSGS. Given that rituximab is now off-patent and biosimilar preparations are available, the cost of rituximab is likely to reduce further. TURING is therefore designed to assess the efficacy, safety, cost and cost-effectiveness of rituximab at inducing sustained remission in patients with NS caused by primary MCD/FSGS.
This is a randomised, two-arm (1:1 ratio), double-blind, placebo-controlled phase III trial to assess the efficacy, safety, cost and cost-effectiveness of rituximab in treating de novo or relapsing NS in patients with MCD/FSGS. In addition to the main phase of the trial, the participating Renal Units will also offer the Open-Label Phase to the participants on the placebo arm who relapse after the achievement of partial or complete remission. We plan to include approximately 40 UK Renal Units within this trial; however, we may increase the number of centres if required in order to recruit the required number of participants. We plan to randomise approximately 112 participants in this trial. Participants will have a minimum of 24 months follow up from Day 0 (Start of Protocolised Prednisolone Regimen) unless a partial remission is not achieved at week 16 or the primary outcome measure event is observed earlier (see section 11.6 end of trial visit). Participants who achieve the primary endpoint and subsequently enter the Open-Label Phase (OLP) will have a minimum of 26 weeks follow up in the OLP. All participants in whom the primary outcome measure event is not observed will remain in the trial, in follow-up for a minimum of 24 months. All participants will return to their standard of care after end of trial participation.
Main inclusion criteria
To be included in the trial the participant must:
- Have given written informed consent to participate
- Age 16 years or older at the time of consent
- Have confirmed NS at Day 0 (Start of Protocolised Prednisolone regimen (SPPR)) (defined as serum albumin < 35g/l and PCR>300mg/mmol) secondary to MCD/FSGS with,
- De novo disease, or;
- Relapsing disease in a patient previously steroid or CNI responsive (this is defined as patients who have achieved complete or partial remission from their NS in response to treatment with steroid or CNI).
- Biopsy proven MCD or FSGS (from medical records)
- Agreed to be enrolled in the National Registry of Rare Renal Diseases (RaDaR)
Main exclusion criteria
The presence of any of the following will preclude participant inclusion:
- MCD or FSGS due to secondary causes, including obesity-driven hyperfiltration, remnant kidneys, malignancy of a type likely to be associated with MCD /FSGS and genetic polymorphisms known to be associated with nephrosis
- MCD/FSGS secondary to malignancy, including lymphoproliferative disorders
- Family history of MCD or FSGS in a first degree relative
- Previous rituximab within 18 months preceding Day 0 (SPPR), or 12 months if there is evidence of B cell return in peripheral lymphocyte subsets
- Previous cyclophosphamide within 6 months preceding Day 0 (SPPR)
- Prednisolone daily dose equal to or greater than 60mg, with a course length of greater than4 weeks, immediately prior to randomisation
- Evidence of current or past infection with Hepatitis B, C or HIV (unless appropriate prophylaxis is given and no replicating virus is detected)
- Positive serum pregnancy test (within 14 days prior to treatment with IMP in main trial and rituximab in OLP)
- Evidence of active severe infection
- Severe heart failure or severe, uncontrolled cardiac disease
- Pregnant or breast-feeding women
- Live vaccine administration in the four weeks prior to enrolment and while remaining on IMP treatment
- Previous/known hypersensitivity to prednisolone or IMP or to murine proteins (and any excipients as described in section 6.1 of the SmPC)
- Co-enrolment in another clinical trial of an investigational medicinal product
- Any other reason which, in the opinion of the Principal Investigator (PI), renders the patient unsuitable for the trial
- An increase in CNI dose in the four weeks preceding randomisation
Funders and sponsors
Dr Lisa Willcocks
Clinical Trial Coordinator: Sonakshi Kadyan
Telephone: 01223 349007 | Email: firstname.lastname@example.org