Clinical trial NCT03298698: 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
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Idiopathic Nephrotic Syndrome
Minimal Change Disease
Focal Segmental Glomerulosclerosis
Keywords: Idiopathic nephrotic syndrome
Minimal change disease
Focal segmental glomerulosclerosis
Rituximab
Randomized clinical trial
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2017-10-02
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Complete remission
timeFrame: 8 weeks
Secondary outcomes:
measure: Partial remission
timeFrame: 8 weeks
measure: Late complete or partial remission
timeFrame: 2-12 months
measure: Time to remission
timeFrame: 12 months
measure: Time to relapse
timeFrame: 12 months
measure: Proportion of patients with a relapse
timeFrame: 12 months
measure: Proportion of patients treated with additional immunosuppressive drugs
timeFrame: 12 months
measure: General health assessment
timeFrame: at 2, 6, 9 and 12 months
measure: Quality of life measured with TAAQOL
timeFrame: at 2, 6, 9 and 12 months
measure: Proportion of patients with adverse events
timeFrame: at 2 and 12 months
measure: Cost-effectiveness analysis
timeFrame: at 2, 6, 9 and 12 months
measure: Cost-utility analysis
timeFrame: at 2, 6, 9 and 12 months
measure: Difference in kidney function
timeFrame: at 2 and 12 months
measure: Proportion of patients with an increase of baseline serum creatinine ≥ 50%
timeFrame: at 2 and 12 months
measure: Benefit-risk ratio 1
timeFrame: at 2 and 12 months
measure: Benefit-risk ratio 2
timeFrame: at 2 and 12 months
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
Study officials:
affiliation: Radboud University Nijmegen Medical center
name: Jeroen K Deegens, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Nijmegen Medical Center
name: Jack F Wetzels, MD, PhD
role: STUDY_CHAIR
References:
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.
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.