Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome

Sponsor
Istituto Giannina Gaslini (Other)
Overall Status
Terminated
CT.gov ID
NCT02394106
Collaborator
(none)
13
1
2
47
0.3

Study Details

Study Description

Brief Summary

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collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes: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  • calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
13 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Ofatumumab in Children With Steroid- and Calcineurin-inhibitor-resistant Nephrotic Syndrome: a Double-blind Randomized, Controlled, Superiority Trial
Study Start Date :
Jul 1, 2015
Actual Primary Completion Date :
Jun 1, 2019
Actual Study Completion Date :
Jun 1, 2019

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. Complete or partial disease remission [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)

    Secondary Outcome Measures

    1. Complete or partial disease remission [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)

    2. Adverse events [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

    3. Abnormal laboratory values [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 IRCCS Istituto Giannina Gaslini Genoa Italy/GE Italy 16147

    Sponsors and Collaborators

    • Istituto Giannina Gaslini

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Gian Marco Ghiggeri MD, PhD, MD, director of Nephrology, Dialysis and Transplantation Unit, Istituto Giannina Gaslini
    ClinicalTrials.gov Identifier:
    NCT02394106
    Other Study ID Numbers:
    • OFA1
    First Posted:
    Mar 20, 2015
    Last Update Posted:
    Jul 29, 2020
    Last Verified:
    Jul 1, 2020
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 29, 2020