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Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome

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ClinicalTrials.gov Identifier: NCT02394106
Recruitment Status : Unknown
Verified May 2017 by Gian Marco Ghiggeri MD, PhD, Istituto Giannina Gaslini.
Recruitment status was:  Recruiting
First Posted : March 20, 2015
Last Update Posted : May 4, 2017
Sponsor:
Information provided by (Responsible Party):
Gian Marco Ghiggeri MD, PhD, Istituto Giannina Gaslini

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collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes: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  • calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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 : July 2015
Estimated Primary Completion Date : September 2017
Estimated Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Ofatumumab

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 Name: 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 Name: Normal saline




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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

  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02394106


Contacts
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Contact: Gianmarco Ghiggeri, MD +39 010 395214 gmarcoghiggeri@ospedale-gaslini.ge.it

Locations
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Italy
IRCCS Istituto Giannina Gaslini Recruiting
Genoa, Italy/GE, Italy, 16147
Contact: Gian Marco Ghiggeri, MD    0039 010 5636 2419    gmarcoghiggeri@ospedale-gaslini.ge.it   
Principal Investigator: Gian Marco Ghiggeri, MD         
Sub-Investigator: Alice Bonanni, MD         
Sponsors and Collaborators
Istituto Giannina Gaslini
Investigators
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Principal Investigator: Gianmarco Ghiggeri, MD Istituto Giannina Gaslini

Publications:

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Responsible Party: Gian Marco Ghiggeri MD, PhD, MD, director of Nephrology, Dialysis and Transplantation Unit, Istituto Giannina Gaslini
ClinicalTrials.gov Identifier: NCT02394106     History of Changes
Other Study ID Numbers: OFA1
First Posted: March 20, 2015    Key Record Dates
Last Update Posted: May 4, 2017
Last Verified: May 2017

Additional relevant MeSH terms:
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Syndrome
Nephrotic Syndrome
Nephrosis
Disease
Pathologic Processes
Kidney Diseases
Urologic Diseases
Ofatumumab
Antibodies, Monoclonal
Calcineurin Inhibitors
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action