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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Experimental | 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). |
|
| Prednisone | Active Comparator | Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | 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). |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jeroen Deegens, MD,PhD | Contact | +31243614761 | Jeroen.Deegens@radboudumc.nl |
| Name | Affiliation | Role |
|---|---|---|
| Jeroen K Deegens, MD,PhD | Radboud University Nijmegen Medical center | Principal Investigator |
| Jack F Wetzels, MD, PhD | Radboud University Nijmegen Medical Center | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Radboud University Medical Center | Recruiting | Nijmegen | 6500HB | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35230699 | Derived | Azukaitis K, Palmer SC, Strippoli GF, Hodson EM. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2022 Mar 1;3(3):CD001537. doi: 10.1002/14651858.CD001537.pub5. | |
| 35224732 | Derived | Hodson EM, Sinha A, Cooper TE. Interventions for focal segmental glomerulosclerosis in adults. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD003233. doi: 10.1002/14651858.CD003233.pub3. |
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|
|
| Prednisone | Drug | Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks |
|
|
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 |
| ID | Term |
|---|---|
| D009402 | Nephrosis, Lipoid |
| D005923 | Glomerulosclerosis, Focal Segmental |
| ID | Term |
|---|---|
| D009401 | Nephrosis |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D005921 | Glomerulonephritis |
| D009393 | Nephritis |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| D011241 | Prednisone |
| D011239 | Prednisolone |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011246 | Pregnadienetriols |
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