Clinical Study of Rituximab for the Treatment for Idiopathic Membranous Nephropathy With Nephrotic Syndrome

Study Overview
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Brief Summary
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To confirm the efficacy and safety of rituximab (genetical recombination) intravenously administered to idiopathic membranous nephropathy with nephrotic syndrome.

Official Title
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The Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Rituximab (Genetical Recombination) for the Treatment for Idiopathic Membranous Nephropathy With Nephrotic Syndrome （PRIME Study）

Conditions
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Glomerulonephritis, Membranous, Nephrotic Syndrome，Idiopathic

Intervention / Treatment
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* Drug: Rituximab (genetical recombination)
* Drug: Placebo
* Drug: Rituximab (genetical recombination)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who undergo kidney biopsy and are diagnosed as having idiopathic membranous nephropathy prior to the obtainment of informed consent Patients who are diagnosed as having nephrotic syndrome prior to the obtainment of informed consent and receive no steroids or immunosuppressants within 12 weeks prior to the obtainment of informed consent Patients with urine protein-creatinine ratio ≥ 3.5 g/gCr at the screening Patients with hypoalbuminemia (serum albumin ≤ 3.0 g/dL) at the screening Patients aged 15 years or older at informed consent Patients who give voluntary written consent after having received adequate information on this study (legally acceptable representatives should also give consent for underage patients, and informed assent should be obtained from children) Exclusion Criteria: Patients with primary nephrotic syndrome other than membranous nephropathy (IgA nephropathy, minimal change disease, focal segmental glomerulosclerosis and so forth), and patients with secondary nephrotic syndrome (autoimmune disease, metabolic disease, infection, allergic/hypersensitive disease, tumor, and drug-induced disease) Patients with the renal function lowered (eGFR <30 mL/min/1.73 m2 based on CKD-EPIcr formula) at the screening Patients who have used anti-CD20 antibody including rituximab (genetical recombination) prior to the informed consent for idiopathic membranous nephropathy Patients who have participated in another clinical study within 12 weeks prior to the informed consent (enrollment is allowed for those participating in a clinical study in the range of 'Indications' or 'Dosage and Administration' in Japan) or patients who are participating in another study Patients with history of renal transplant Patients with poorly controlled diabetes (HbA1c of 8.0% or higher) Patients who have or are suspected to have active infection (infection requiring treatment with systemic antimicrobial, antifungal, or antiviral agents) at the time of the screening Patients tested positive for HBs antigen, HBs antibody, HBc antibody, and/or HCV antibody (patients with positive HBs antibody and/or HBc antibody can be enrolled only when HBV-DNA test is negative [less than the detection limit]), or patients with positive HIV antibody or HTLV-1 antibody at the time of the screening Patients with leukopenia (less than 2,000 /mm3), neutropenia (less than 1,000 /mm3), or lymphopenia (less than 500 /mm3) at the time of the screening Patients with history of serious hypersensitivity or anaphylactic reaction to one of the ingredients in the investigational drug or murine protein-containing products Patients who are judged to be life-threatening nephrotic syndrome by the investigator or a subinvestigator Patients with serious comorbidity (e.g., hepatic, renal (excluding idiopathic membranous nephropathy with nephrotic syndrome), cardiac, lung, hematologic, or brain disease) Female patients who are pregnant, lactating, or potentially pregnant, or patients who are not willing to use contraceptive measures during the study period Patients who are judged to be unsuitable by the investigator or a subinvestigator

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab group in double-blind phase<br> | Drug: Rituximab (genetical recombination)<br>* Administer 1,000 mg of rituximab (genetical recombination) IV infusion every two weeks for two doses in double-blind phase.<br>|
| Placebo Comparator: Placebo group in double-blind phase<br> | Drug: Placebo<br>* Administer placebo IV infusion every two weeks for two doses in double-blind phase.<br>|
| Other: Rituximab group in open-label phase<br> | Drug: Rituximab (genetical recombination)<br>* Patients who remain to be ICR II (Incomplete Remission Type II) or NR (No Response) until Week 26 in the double-blind phase, if the patients wish to move to the open-label phase and the investigator or a subinvestigator considers the move necessary, the patient will move to the open-label phase and receive 1,000 mg of rituximab (genetical recombination) IV infusion every two weeks for two doses after the readministration criteria are confirmed to be met.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients achieving ICR I | Achieving ICR I is defined as Urine protein-creatinine ratio < 1.0 g/gCr. | up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients who are CR, ICR I, ICR II, NR or PR | CR, ICR I, ICR II, NR or PR are defied as below; CR (Complete Remission): Urine protein-creatinine ratio < 0.3 g/gCr ICR I (Incomplete Remission Type I): 0.3 g/gCr ≤ Urine protein-creatinine ratio < 1.0 g/gCr ICR II (Incomplete Remission Type II): 1.0 g/gCr ≤ Urine protein-creatinine ratio < 3.5 g/gCr NR (No Response): 3.5 g/gCr ≤ Urine protein-creatinine ratio PR (Partial Remission): Decrease in urine protein-creatinine ratio from base line ≥50%, and urine protein-creatinine ratio 0.3 to 3.5 g/gCr | up to 26 weeks | 
| Duration before achieving CR, ICR I, ICR II or PR | Duration of achieving CR, ICR I, ICR II or PR is summarized. | up to 26 weeks | 
| Urine protein-creatinine ratio | The differences of urine protein-creatinine ratio between prior to treatment and at each timepoint are summarized. | up to 26 weeks | 
| eGFR | The differences of eGFR between prior to treatment and at each timepoint are summarized. | up to 26 weeks | 
| B-cells (CD19-positive and CD20-positive cells) | B cell counts (CD19 positive and CD20 positive cell counts) at each timepoint are summarized. | up to 26 weeks | 
| Expression of HACA | The number of patients expressing HACA, and the proportion of these patients at each timepoint are summarized. | up to 26 weeks | 
| Serum rituximab (genetical recombination) concentration | Serum rituximab (genetical recombination) level at each timepoint are summarized. | up to 26 weeks |