Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome

Study Overview
=================
Brief Summary
-----------------
This will be an open-label, randomized controlled trial which compares continued treatment with high dose prednisone (standard therapy) to treatment with rituximab in patients with minimal change disease or focal segmental glomerulosclerosis unresponsive to 8 weeks of high dose prednisone . patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with termination of prednisone or standard therapy which consist of 8 additional weeks of high dose prednisone treatment.

Detailed Description
-----------------
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are important causes of idiopathic nephrotic syndrome. First-line treatment with high dose prednisone up to 16 weeks is associated with serious side effects. Especially if treatment continues for more than 8 weeks. Retrospective studies suggested that Rituximab may be more effective in patients unresponsive to 8 weeks of high dose prednisone. Treatment with rituximab was associated with a higher proportion of patients attaining remission of proteinuria and with fewer side effects. This will be an open-label, randomized controlled trial which compares continued treatment with high dose prednisone (standard therapy) to treatment with rituximab in patients with an idiopathic nephrotic syndrome due to biopsy proven MCD or FSGS age 18 years or older. All patients will be treated with high dose prednisone (1 mg/kg/day) for 8 weeks. Patients can be included in the trial in case of persistent persistent proteinuria ≥ 2 g/ 24 hours or a protein-to-creatinine ratio ≥ 2 g/10mmol (2 g/g) after 8 weeks of treatment with high dose prednisone Patients either receive 2 doses of Rituximab 375 mg/m2 iv at time 0 and 14 days with termination of prednisone or standard therapy which consist of 8 additional weeks of high dose prednisone treatment. In the Rituximab group, B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval (maximum of 2 additional doses) until complete B cell depletion. Expected duration of the follow-up is 12 months, consisting of 9 visits.

Official Title
-----------------
Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome Unresponsive to 8 Weeks of High Dose Prednisone

Conditions
-----------------
Idiopathic Nephrotic Syndrome, Minimal Change Disease, Focal Segmental Glomerulosclerosis

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Persistent proteinuria ≥ 2 g/ 24 hours or a protein-to-creatinine ratio ≥ 2 g/10mmol (2 g/g) after 8 weeks of treatment with high dose prednisone 1 mg/kg/day (max 80 mg/day) Idiopathic nephrotic syndrome caused by biopsy proven minimal change disease or focal segmental glomerulosclerosis Exclusion Criteria: Severe nephrotic syndrome with hypotension Previous treatment with immunosuppressive medication other than prednisone Treatment with prednisone > 10 weeks in last six months Secondary form of FSGS or minimal change disease Patients who test positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc). Patients infected with HIV or suffering from other active infections Patients inoculated with a vaccine within 4 weeks prior to inclusion Pregnancy, breast feeding, women with inadequate contraception Malignancy Kidney transplantation Previous treatment with monoclonal antibodies within 2 years prior to inclusion Neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease Active peptic ulcer Known hypersensitivity to glucocorticoids Insulin resistant diabetes mellitus Treatment with carbamazepine, phenobarbital, phenytoin en rifampicin Severe osteoporosis with vertebral fracture

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses). | Drug: Rituximab<br>* Rituximab: 375 mg/m2 intravenously on day 0 and day 14 B-cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of Rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses).<br>* Other names: Mabthera;|
| Active Comparator: Prednisone<br>Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks | Drug: Prednisone<br>* Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks<br>* Other names: Prednisolone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission | The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial remission | The proportion of patients reaching partial remission defined as proteinuria < 3.5 g/24 h or < 3.5 g/g and 50% lower than baseline proteinuria | 8 weeks | 
| Late complete or partial remission | The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g or The proportion of patients reaching partial remission defined as proteinuria < 3.5 g/24 h or < 3500 mg/g and 50% lower than baseline proteinuria | 2-12 months | 
| Time to remission | Time between start of treatment and reaching partial or complete remission | 12 months | 
| Time to relapse | The time between partial or complete remission and relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine | 12 months | 
| Proportion of patients with a relapse | The proportion of patients with relapse (defined as urinary protein excretion to ≥3.5 g/24 h or ≥3.5 g/g creatinine in patients who had at least attained a partial remission and the time to relapse | 12 months | 
| Proportion of patients treated with additional immunosuppressive drugs | Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone | 12 months | 
| General health assessment | Difference in general health measured by RAND-36 | at 2, 6, 9 and 12 months | 
| Quality of life measured with TAAQOL | Difference in quality of life measured with TNO-academisch Ziekenhuis Leiden Questionnaire for Adult's Health-Difference in Quality of Life | at 2, 6, 9 and 12 months | 
| Proportion of patients with adverse events | The proportion of patients with adverse events. Adverse events graded according to Common Terminology Criteria For Adverse Events (NCI-CTCAE v4.03) | at 2 and 12 months | 
| Cost-effectiveness analysis | Cost-effectiveness will be calculated by dividing the difference in costs by the difference in effectiveness (based on the number of patients in remission) derived from the two groups. The resulting cost-effectiveness ratio will be expressed as costs per one more patient in remission | at 2, 6, 9 and 12 months | 
| Cost-utility analysis | Cost-utility analysis will be calculated by dividing the difference in costs by the difference in Quality Adjusted Life Years (QALY's). QALY's will be derived from the EuroQol-5d-5L questionnaire. | at 2, 6, 9 and 12 months | 
| Difference in kidney function | Difference in creatinine clearance and estimated glomerular filtration rate | at 2 and 12 months | 
| Proportion of patients with an increase of baseline serum creatinine ≥ 50% | The percentage of patients with an increase > 50% of serum creatinine from baseline. | at 2 and 12 months | 
| Benefit-risk ratio 1 | Difference in the percentage of remissions (benefit) divided by the difference in adverse events grade 3 or 4, including Serious Adverse Events and Suspected Unexpected Serious Adverse Reaction (risk) | at 2 and 12 months | 
| Benefit-risk ratio 2 | Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk) | at 2 and 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Idiopathic nephrotic syndrome, Minimal change disease, Focal segmental glomerulosclerosis, Rituximab, Randomized clinical trial