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

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

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.

Study Overview

• Status: Unknown
• Conditions: Focal Segmental Glomerulosclerosis; Minimal Change Disease; Idiopathic Nephrotic Syndrome
• Intervention / Treatment: Drug: Rituximab; Drug: Prednisone

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jeroen Deegens, MD,PhD; Phone Number: +31243614761; Email: Jeroen.Deegens@radboudumc.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500HB
    • Recruiting
    • Radboud university medical center
    • Contact: Jeroen K Deegens, MD, PhD; Phone Number: +31243614761; Email: Jeroen.Deegens@radboudumc.nl
    • Contact: Jack F Wetzels, MD, PhD; Phone Number: +31243614761; Email: Jack.Wetzels@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab; 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; 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).; Other Names: Mabthera
Active Comparator: Prednisone; Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks	Drug: Prednisone; Prednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks; 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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Jeroen K Deegens, MD,PhD, Radboud University Nijmegen Medical Center; Study Chair: Jack F Wetzels, MD, PhD, Radboud University Nijmegen Medical Center

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2018
• Primary Completion (Anticipated): August 22, 2021
• Study Completion (Anticipated): January 22, 2022

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: September 26, 2017
• First Posted (Actual): October 2, 2017

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: August 23, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Randomized clinical trial; Rituximab; Minimal change disease; Focal segmental glomerulosclerosis; Idiopathic nephrotic syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Nephritis; Glomerulonephritis; Syndrome; Glomerulosclerosis, Focal Segmental; Nephrotic Syndrome; Nephrosis; Nephrosis, Lipoid; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Prednisolone; Rituximab; Prednisone
• Other Study ID Numbers: RSRNS17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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