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

July 28, 2020 updated by: Gian Marco Ghiggeri MD, PhD, Istituto Giannina Gaslini

Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor-dependent Idiopathic Nephrotic Syndrome: an Open-label, Randomized, Controlled, Superiority Trial.

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urine collection and dipstick readings will be carefully reviewed, compliance assessed, and therapy with RAS inhibitors withdrawn and, in hypertensive children replaced by other anti-hypertensive drug.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One week after the steroid withdrawal calcineurin inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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One week after the steroid withdrawal calcineurin-inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

140

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Italy/GE
      • Genoa, Italy/GE, Italy, 16147
        • IRCCS Istituto Giannina Gaslini

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 24 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ofatumumab
  • 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: Ofatumumab
1500 mg/1.73m2, administered once diluted in 1000 ml of normal saline
Other Names:
  • Arzerra
Active Comparator: Rituximab
  • 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.
Drug: Rituximab
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.
Other Names:
  • Mabthera

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Risk of relapse
Time Frame: 12 months
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).
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Amount of steroids required to maintain complete disease remission
Time Frame: 6 and 24 months after Ofatumumab or Rituximab pulse
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).
6 and 24 months after Ofatumumab or Rituximab pulse
Adverse events
Time Frame: At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.
Measurement of frequency and severity of adverse events due to drug infusion
At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.
Abnormal laboratory values
Time Frame: At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.
Record of abnormal values in biochemical tests and hematology assessments due to drug infusion
At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Giannina Gaslini

Investigators

  • Principal Investigator: Gianmarco Ghiggeri, MD, Istituto Giannina Gaslini

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Actual)

June 1, 2018

Study Completion (Actual)

May 1, 2019

Study Registration Dates

First Submitted

March 6, 2015

First Submitted That Met QC Criteria

March 16, 2015

First Posted (Estimate)

March 20, 2015

Study Record Updates

Last Update Posted (Actual)

July 30, 2020

Last Update Submitted That Met QC Criteria

July 28, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OFA2

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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