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

Phase 3
Conditions
Idiopathic Nephrotic Syndrome
Minimal Change Disease
Focal Segmental Glomerulosclerosis
Interventions
Registration Number
NCT03298698
Lead Sponsor
Radboud University Medical Center
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.

Recruitment & Eligibility

Status
UNKNOWN
Sex
All
Target Recruitment
40
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
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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
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
RituximabRituximabRituximab: 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).
PrednisonePrednisonePrednisone 1 mg/kg/day (max 80 mg/day) for 8 weeks
Primary Outcome Measures
NameTimeMethod
Complete remission8 weeks

The proportion of patients reaching complete remission defined as proteinuria \<0.3 g/day or \< 300 mg/g

Secondary Outcome Measures
NameTimeMethod
Partial remission8 weeks

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 remission2-12 months

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 remission12 months

Time between start of treatment and reaching partial or complete remission

Time to relapse12 months

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 relapse12 months

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 drugs12 months

Proportion of patients treated with immunosuppressive drugs other than the assigned treatment with rituximab or prednisolone

General health assessmentat 2, 6, 9 and 12 months

Difference in general health measured by RAND-36

Quality of life measured with TAAQOLat 2, 6, 9 and 12 months

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 eventsat 2 and 12 months

The proportion of patients with adverse events. Adverse events graded according to Common Terminology Criteria For Adverse Events (NCI-CTCAE v4.03)

Cost-effectiveness analysisat 2, 6, 9 and 12 months

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 analysisat 2, 6, 9 and 12 months

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 functionat 2 and 12 months

Difference in creatinine clearance and estimated glomerular filtration rate

Proportion of patients with an increase of baseline serum creatinine ≥ 50%at 2 and 12 months

The percentage of patients with an increase \> 50% of serum creatinine from baseline.

Benefit-risk ratio 1at 2 and 12 months

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 2at 2 and 12 months

Difference in the percentage of remissions (benefit) divided by the difference in the total number of adverse events (risk)

Trial Locations

Locations (1)

Radboud University Medical Center

🇳🇱

Nijmegen, Netherlands

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