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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02394119
Recruitment Status : Completed
First Posted : March 20, 2015
Last Update Posted : July 30, 2020
Sponsor:
Information provided by (Responsible Party):
Gian Marco Ghiggeri MD, PhD, Istituto Giannina Gaslini

Tracking Information
First Submitted Date  ICMJE March 6, 2015
First Posted Date  ICMJE March 20, 2015
Last Update Posted Date July 30, 2020
Study Start Date  ICMJE June 2015
Actual Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
  • 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).
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
Official Title  ICMJE Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor-dependent Idiopathic Nephrotic Syndrome: an Open-label, Randomized, Controlled, Superiority Trial.
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Nephrotic Syndrome
Intervention  ICMJE
  • Drug: Ofatumumab
    1500 mg/1.73m2, administered once diluted in 1000 ml of normal saline
    Other Name: Arzerra
  • 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 Name: Mabthera
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Ofatumumab
  • 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.
    Intervention: Drug: Rituximab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 16, 2015)
140
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2019
Actual Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 24 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02394119
Other Study ID Numbers  ICMJE OFA2
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Gian Marco Ghiggeri MD, PhD, Istituto Giannina Gaslini
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Istituto Giannina Gaslini
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Gianmarco Ghiggeri, MD Istituto Giannina Gaslini
PRS Account Istituto Giannina Gaslini
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP