Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
Primary Purpose
Idiopathic Nephrotic Syndrome, Minimal Change Disease, Focal Segmental Glomerulosclerosis
Status
Unknown status
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Rituximab
Prednisone
Sponsored by
About this trial
This is an interventional treatment trial for Idiopathic Nephrotic Syndrome focused on measuring Idiopathic nephrotic syndrome, Minimal change disease, Focal segmental glomerulosclerosis, Rituximab, Randomized clinical trial
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
Sites / Locations
- Radboud University Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Rituximab
Prednisone
Arm Description
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 1 mg/kg/day (max 80 mg/day) for 8 weeks
Outcomes
Primary Outcome Measures
Complete remission
The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g
Secondary Outcome Measures
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
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
Time to remission
Time between start of treatment and reaching partial or complete remission
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
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
Proportion of patients treated with additional immunosuppressive drugs
Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone
General health assessment
Difference in general health measured by RAND-36
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
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)
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
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.
Difference in kidney function
Difference in creatinine clearance and estimated glomerular filtration rate
Proportion of patients with an increase of baseline serum creatinine ≥ 50%
The percentage of patients with an increase > 50% of serum creatinine from baseline.
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)
Benefit-risk ratio 2
Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk)
Full Information
NCT ID
NCT03298698
First Posted
August 24, 2017
Last Updated
August 23, 2018
Sponsor
Radboud University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT03298698
Brief Title
Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
Official Title
Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome Unresponsive to 8 Weeks of High Dose Prednisone
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Unknown status
Study Start Date
August 22, 2018 (Actual)
Primary Completion Date
August 22, 2021 (Anticipated)
Study Completion Date
January 22, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Nephrotic Syndrome, Minimal Change Disease, Focal Segmental Glomerulosclerosis
Keywords
Idiopathic nephrotic syndrome, Minimal change disease, Focal segmental glomerulosclerosis, Rituximab, Randomized clinical trial
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Rituximab
Arm Type
Experimental
Arm Description
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).
Arm Title
Prednisone
Arm Type
Active Comparator
Arm Description
Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Prednisolone
Intervention Description
Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks
Primary Outcome Measure Information:
Title
Complete remission
Description
The proportion of patients reaching complete remission defined as proteinuria <0.3 g/day or < 300 mg/g
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Partial remission
Description
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
Time Frame
8 weeks
Title
Late complete or partial remission
Description
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
Time Frame
2-12 months
Title
Time to remission
Description
Time between start of treatment and reaching partial or complete remission
Time Frame
12 months
Title
Time to relapse
Description
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
Time Frame
12 months
Title
Proportion of patients with a relapse
Description
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
Time Frame
12 months
Title
Proportion of patients treated with additional immunosuppressive drugs
Description
Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone
Time Frame
12 months
Title
General health assessment
Description
Difference in general health measured by RAND-36
Time Frame
at 2, 6, 9 and 12 months
Title
Quality of life measured with TAAQOL
Description
Difference in quality of life measured with TNO-academisch Ziekenhuis Leiden Questionnaire for Adult's Health-Difference in Quality of Life
Time Frame
at 2, 6, 9 and 12 months
Title
Proportion of patients with adverse events
Description
The proportion of patients with adverse events. Adverse events graded according to Common Terminology Criteria For Adverse Events (NCI-CTCAE v4.03)
Time Frame
at 2 and 12 months
Title
Cost-effectiveness analysis
Description
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
Time Frame
at 2, 6, 9 and 12 months
Title
Cost-utility analysis
Description
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.
Time Frame
at 2, 6, 9 and 12 months
Title
Difference in kidney function
Description
Difference in creatinine clearance and estimated glomerular filtration rate
Time Frame
at 2 and 12 months
Title
Proportion of patients with an increase of baseline serum creatinine ≥ 50%
Description
The percentage of patients with an increase > 50% of serum creatinine from baseline.
Time Frame
at 2 and 12 months
Title
Benefit-risk ratio 1
Description
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)
Time Frame
at 2 and 12 months
Title
Benefit-risk ratio 2
Description
Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk)
Time Frame
at 2 and 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jeroen Deegens, MD,PhD
Phone
+31243614761
Email
Jeroen.Deegens@radboudumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeroen K Deegens, MD,PhD
Organizational Affiliation
Radboud University Nijmegen Medical center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jack F Wetzels, MD, PhD
Organizational Affiliation
Radboud University Nijmegen Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Radboud University Medical Center
City
Nijmegen
ZIP/Postal Code
6500HB
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeroen K Deegens, MD, PhD
Phone
+31243614761
Email
Jeroen.Deegens@radboudumc.nl
First Name & Middle Initial & Last Name & Degree
Jack F Wetzels, MD, PhD
Phone
+31243614761
Email
Jack.Wetzels@radboudumc.nl
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
35230699
Citation
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.
Results Reference
derived
PubMed Identifier
35224732
Citation
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.
Results Reference
derived
Learn more about this trial
Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
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