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Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome

Primary Purpose

Nephrotic Syndrome

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Ofatumumab
Rituximab
Sponsored by
Istituto Giannina Gaslini
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nephrotic Syndrome

Eligibility Criteria

2 Years - 24 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

To be eligible for inclusion into this study, participants will have to fulfill the following criteria:

  • To be in complete disease remission
  • Drug dependence: remission has to be maintained with both steroids and CNI steroid dependence is defined by two consecutive relapses during corticosteroid therapy or within 14 days of ceasing therapy. CNI (cyclosporine/tacrolimus) dependence is defined by presence of relapse at discontinuation.
  • Ability to provide consent and assent: parents'/guardian's written informed consent, and child's assent given before any study-related procedure not part of the subject's normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her future medical care.
  • Age between 2 and 24 years

Exclusion Criteria:

Children will be excluded if any of the following criteria apply:

  • Positivity to autoimmunity tests (ANA, nDNA, ANCA)
  • Reduction of C3 levels.
  • eGFR<90/ml/min/1,73 m2 valuated according to revised Bedside Schwartz Formula for patients between 2 and 17 years and with CKD-EPI Creatinine 2009 Equation for 18 years old patients.
  • Pregnancy
  • Neoplasm
  • Infections: previous or actual HBV (with HBeAb positivity) or HCV infection
  • CD20 B lymphocytes count <2,5%
  • Treatment with Rituximab or cyclophosphamide in the last 6 months

Sites / Locations

  • IRCCS Istituto Giannina Gaslini

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ofatumumab

Rituximab

Arm Description

Drug Name: Ofatumumab Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities Procedures: methylprednisolone 2 mg/kg infused in 30' IV diluted in 100 ml of normal saline (NaCl 0,9%); oral paracetamol 15 mg/kg ; cetirizine 0,4 mg/kg IV infused slowly in 5 ml of normal saline (NaCl 0,9%) prior to Ofatumumab infusion to reduce common reactions How: Ofatumumab IV: 1500 mg/1.73m2 at 12 ml/hour in the first 30'. Thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 200 ml/hour. When and how much: once; diluted in 1000 ml of normal saline.

Drug Name: Rituximab (RTX) Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities Procedures: the same as for Ofatumumab Arm How: Rituximab IV: 375 mg/m2; for dosage between 100 and 250 mg RTX will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg RTX will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg RTX will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h. When and how much: once; diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.

Outcomes

Primary Outcome Measures

Risk of relapse
The primary endpoints will be risk of relapse at 12 months without steroid or calcineurin-inhibitors. Relapse is defined by uPCR ≥2000 mg/g (≥ 200 mg/mmol) or > 3+ protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).

Secondary Outcome Measures

Amount of steroids required to maintain complete disease remission
Complete remission is defined by uPCR <200 mg/g (<20 mg/mmol) or o1+ of protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).
Adverse events
Measurement of frequency and severity of adverse events due to drug infusion
Abnormal laboratory values
Record of abnormal values in biochemical tests and hematology assessments due to drug infusion

Full Information

First Posted
March 6, 2015
Last Updated
July 28, 2020
Sponsor
Istituto Giannina Gaslini
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1. Study Identification

Unique Protocol Identification Number
NCT02394119
Brief Title
Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
Official Title
Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor-dependent Idiopathic Nephrotic Syndrome: an Open-label, Randomized, Controlled, Superiority Trial.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
June 2015 (undefined)
Primary Completion Date
June 2018 (Actual)
Study Completion Date
May 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Istituto Giannina Gaslini

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Open-label, two-parallel-arm, controlled randomized clinical trial testing the superiority of Ofatumumab over Rituximab in maintaining steroid- and calcineurin-inhibitor-free disease remission in SD-INS. Eligible participants will enter a 1-month run-in period, during which instruction on urine collection and dipstick readings will be carefully reviewed, compliance assessed, and therapy with RAS inhibitors withdrawn and, in hypertensive children replaced by other anti-hypertensive drug. After run-in period, children will be randomized to either the intervention arm (Ofatumumab) or the comparator arm (Rituximab). After infusion of intervention or comparator, steroids will be maintained at initial dose for 30 days and then tapered off by 0.3 mg/kg per week until complete withdrawal. One week after the steroid withdrawal calcineurin inhibitors will be decreased by 50% and withdrawn within 2 additional weeks. All patients will be followed for up to 24 months. In case of relapses during the study (see outcome section for definition) patients will be treated with 60 mg/m2of prednisone p.o. in order to achieve remission. At remission, patients will be treated with another infusion of either Oftumumab or Rituximab, according to the initial randomization. After infusion of intervention or comparator, steroids will be maintained at initial dose for 30 days and then tapered off by 0.3 mg/kg per week until complete withdrawal. One week after the steroid withdrawal calcineurin-inhibitors will be decreased by 50% and withdrawn within 2 additional weeks. This strategy will be repeated to treat full relapses during the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nephrotic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
140 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ofatumumab
Arm Type
Experimental
Arm Description
Drug Name: Ofatumumab Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities Procedures: methylprednisolone 2 mg/kg infused in 30' IV diluted in 100 ml of normal saline (NaCl 0,9%); oral paracetamol 15 mg/kg ; cetirizine 0,4 mg/kg IV infused slowly in 5 ml of normal saline (NaCl 0,9%) prior to Ofatumumab infusion to reduce common reactions How: Ofatumumab IV: 1500 mg/1.73m2 at 12 ml/hour in the first 30'. Thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 200 ml/hour. When and how much: once; diluted in 1000 ml of normal saline.
Arm Title
Rituximab
Arm Type
Active Comparator
Arm Description
Drug Name: Rituximab (RTX) Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities Procedures: the same as for Ofatumumab Arm How: Rituximab IV: 375 mg/m2; for dosage between 100 and 250 mg RTX will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg RTX will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg RTX will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h. When and how much: once; diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.
Intervention Type
Drug
Intervention Name(s)
Ofatumumab
Other Intervention Name(s)
Arzerra
Intervention Description
1500 mg/1.73m2, administered once diluted in 1000 ml of normal saline
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
375 mg/m2, administered once diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.
Primary Outcome Measure Information:
Title
Risk of relapse
Description
The primary endpoints will be risk of relapse at 12 months without steroid or calcineurin-inhibitors. Relapse is defined by uPCR ≥2000 mg/g (≥ 200 mg/mmol) or > 3+ protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Amount of steroids required to maintain complete disease remission
Description
Complete remission is defined by uPCR <200 mg/g (<20 mg/mmol) or o1+ of protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).
Time Frame
6 and 24 months after Ofatumumab or Rituximab pulse
Title
Adverse events
Description
Measurement of frequency and severity of adverse events due to drug infusion
Time Frame
At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.
Title
Abnormal laboratory values
Description
Record of abnormal values in biochemical tests and hematology assessments due to drug infusion
Time Frame
At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
24 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: To be eligible for inclusion into this study, participants will have to fulfill the following criteria: To be in complete disease remission Drug dependence: remission has to be maintained with both steroids and CNI steroid dependence is defined by two consecutive relapses during corticosteroid therapy or within 14 days of ceasing therapy. CNI (cyclosporine/tacrolimus) dependence is defined by presence of relapse at discontinuation. Ability to provide consent and assent: parents'/guardian's written informed consent, and child's assent given before any study-related procedure not part of the subject's normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her future medical care. Age between 2 and 24 years Exclusion Criteria: Children will be excluded if any of the following criteria apply: Positivity to autoimmunity tests (ANA, nDNA, ANCA) Reduction of C3 levels. eGFR<90/ml/min/1,73 m2 valuated according to revised Bedside Schwartz Formula for patients between 2 and 17 years and with CKD-EPI Creatinine 2009 Equation for 18 years old patients. Pregnancy Neoplasm Infections: previous or actual HBV (with HBeAb positivity) or HCV infection CD20 B lymphocytes count <2,5% Treatment with Rituximab or cyclophosphamide in the last 6 months
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gianmarco Ghiggeri, MD
Organizational Affiliation
Istituto Giannina Gaslini
Official's Role
Principal Investigator
Facility Information:
Facility Name
IRCCS Istituto Giannina Gaslini
City
Genoa
State/Province
Italy/GE
ZIP/Postal Code
16147
Country
Italy

12. IPD Sharing Statement

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Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome

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