Back to resultsOfatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
Primary Purpose
Nephrotic Syndrome
Status
Terminated
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Ofatumumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Nephrotic Syndrome
Eligibility 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any study-related procedure not part of the subject's normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her future medical care.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
Sites / Locations
- IRCCS Istituto Giannina Gaslini
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Ofatumumab
Placebo
Arm Description
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 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.
Outcomes
Primary Outcome Measures
Complete or partial disease remission
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
Complete or partial disease remission
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)
Adverse events
Measurement of frequency and severity of adverse events due to drug infusion
Abnormal laboratory values
Record of abnormal values in biochemical tests and hematology assessments.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02394106
Brief Title
Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
Official Title
Ofatumumab in Children With Steroid- and Calcineurin-inhibitor-resistant Nephrotic Syndrome: a Double-blind Randomized, Controlled, Superiority Trial
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Terminated
Study Start Date
July 2015 (undefined)
Primary Completion Date
June 2019 (Actual)
Study Completion Date
June 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Istituto Giannina Gaslini
4. Oversight
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nephrotic Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ofatumumab
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ofatumumab
Other Intervention Name(s)
Arzerra
Intervention Description
Ofatumumab 1500 mg/1.73m2 administered once, diluted in 1000 ml of normal saline
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Normal saline
Intervention Description
Normal saline, 1000 ml, administered once
Primary Outcome Measure Information:
Title
Complete or partial disease remission
Description
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)
Time Frame
6 months from randomization
Secondary Outcome Measure Information:
Title
Complete or partial disease remission
Description
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)
Time Frame
12 months from randomization;
Title
Adverse events
Description
Measurement of frequency and severity of adverse events due to drug infusion
Time Frame
At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Title
Abnormal laboratory values
Description
Record of abnormal values in biochemical tests and hematology assessments.
Time Frame
At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gianmarco Ghiggeri, MD
Organizational Affiliation
Istituto Giannina Gaslini
Official's Role
Principal Investigator
Facility Information:
Facility Name
IRCCS Istituto Giannina Gaslini
City
Genoa
State/Province
Italy/GE
ZIP/Postal Code
16147
Country
Italy
12. IPD Sharing Statement
Citations:
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24670185
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PubMed Identifier
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Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
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