Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome

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

Ofatumumab in Children With Steroid- and Calcineurin-inhibitor-resistant Nephrotic Syndrome: a Double-blind Randomized, Controlled, Superiority Trial

Double-blind, two-parallel-arm, placebo-controlled randomized clinical trial testing the superiority of Ofatumumab versus placebo in the treatment of children with DR-INS. Participants will be stratified according to eGFR at enrollment.

Eligible participants will enter a 3-months run-in period, during which instructions on urine collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes:

  • prednisone will be tapered off by 0.3 mg/kg per week until complete withdrawal;
  • calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or started in all patients.

After run-in period, children will be randomized to the intervention arm (Ofatumumab) or comparator arm (placebo). Randomization will be stratified by eGFR at randomization: ≥90 and <90 ml/min/1.73 m2.

All patients will be followed up to 12 months and they will leave the study at time of relapse.

Relapse will be defined as uPCR ≥2000 mg/g (≥200 mg/mmol) or ≥ 3+ protein on urine dipstick for 3 consecutive days.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

13

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 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Drug resistance: it signifies lack of antiproteinuric effect of a double therapy based on steroid plus CNI or mofetil mycophenolate (MMF). Steroid resistance is defined by failure to achieve complete remission after 6 weeks with prednisone 60 mg/m2. CNI (cyclosporine/tacrolimus) resistance is defined by failure to achieve complete remission within 6 months after the plasma concentration of cyclosporine (started at dosage of 4 mg/kg/day) or tacrolimus (started at dosage of 0,1 mg/kg/day) reached effective plasma concentrations. Mofetil Mycophenolate resistance is defined by failure to achieve complete remission after at least 6 months of treatment with 1200mg/mq/day.
  • 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 18 years
  • Histological pattern of minimal change disease, mesangial proliferation with IgM deposits or focal segmental glomerulosclerosis

Exclusion Criteria:

  • Positivity to autoimmunity tests (ANA, dsDNA, ANCA).
  • Reduction of C3 levels.
  • eGFR < 30 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.
  • Hystological pattern characterized by elements suggestive for congenital disease: diffuse mesangial sclerosis without IgM deposits, cystic-like tubular dilatation, mitochondrial abnormalities evident on electron microscopy, IF suggestive for congenital collagen 4 disease.
  • Histological pattern not suitable with INS in the pediatric age (membranous glomerulonephritis, lupus nephritis, diffuse and/or localized vasculitis, amyloidosis)
  • Homozygous or heterozygous mutations of podocitary genes, commonly involved in the etiology of INS (NPHS1, NPHS2, NPHS3, NPHS6, WT1, COQ2, COQ6, MYO1E, SMARCAL1, LAMB2, SCARB2, CD2AP, TRPC6, ACTN4, INF2, LMX1B, MYH9 )
  • Pregnancy
  • Neoplasm
  • Infections: Previous or actual HBV (with HBeAb positivity) or HCV

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: Quadruple

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
  • Who provides: registered nurse
  • How: Ofatumumab IV 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.
  • Where: in Hospital
  • When and how much: once; diluted in 1000 ml of normal saline
  • Tailoring: 1500 mg/1.73m2
  • How well: expert nurse would assist administration
Drug: Ofatumumab
Ofatumumab 1500 mg/1.73m2 administered once, diluted in 1000 ml of normal saline
Other Names:
  • Arzerra
Placebo Comparator: Placebo
  • Drug Name: Normal Saline (NaCl 0,9%)
  • Why: standard therapy could not be used as comparator for Ofatumumab, given its toxicity and lack of effectiveness. Moreover, although Rituximab, a chimeric monoclonal anti-CD20 antibody, is increasingly being used as a steroid-sparing treatment option for children with certain forms of INS (those that respond to and are dependent of steroids), this drug does not work in DR-INS and could not be used as a comparator.
  • Materials and Procedures: The placebo arm will receive the same infusion as the Ofatumumab Arm with the exception of the Ofatumumab.
Other: Placebo
Normal saline, 1000 ml, administered once
Other Names:
  • Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete or partial disease remission
Time Frame: 6 months from randomization
Complete remission in defined by urinary protein/creatinine ratio (uPCR) <200 mg/g (<20mg/mmol) for 3 consecutive days. Partial remission is defined as proteinuria reduction of 50% or greater from the presenting value and absolute uPCR between 200 and 2000 mg/g. for 3 consecutive days (according to KDIGO Clinical Practice Guideline for Glomerulonephritis)
6 months from randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete or partial disease remission
Time Frame: 12 months from randomization;
Complete remission in defined by urinary protein/creatinine ratio (uPCR) <200 mg/g (<20mg/mmol) for 3 consecutive days. Partial remission is defined as proteinuria reduction of 50% or greater from the presenting value and absolute uPCR between 200 and 2000 mg/g. for 3 consecutive days (according to KDIGO Clinical Practice Guideline for Glomerulonephritis)
12 months from randomization;
Adverse events
Time Frame: At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Measurement of frequency and severity of adverse events due to drug infusion
At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Abnormal laboratory values
Time Frame: At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Record of abnormal values in biochemical tests and hematology assessments.
At 1, 3, 6, 9 and 12 months after drug/placebo 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

July 1, 2015

Primary Completion (Actual)

June 1, 2019

Study Completion (Actual)

June 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 29, 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

  • OFA1

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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