NCT02394106TerminatedPhase 2
Ofatumumab in Children With Steroid- and Calcineurin-inhibitor-resistant Nephrotic Syndrome: a Double-blind Randomized, Controlled, Superiority Trial
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Istituto Giannina Gaslini
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Complete or partial disease remission
Study Overview
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collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes: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- calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 2 Years to 18 Years (Child, Adult)
- Sex
- 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/m
- •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
- •Infections: Previous or actual HBV (with HBeAb positivity) or HCV
Arms & Interventions
Ofatumumab
Experimental
- 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
Intervention: Ofatumumab (Drug)
Placebo
Placebo Comparator
- 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: Placebo (Other)
Outcomes
Primary Outcomes
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 Outcomes
- Complete or partial disease remission(12 months from randomization;)
- Adverse events(At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits)
- Abnormal laboratory values(At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits)
Investigators
Gian Marco Ghiggeri MD, PhD
MD, director of Nephrology, Dialysis and Transplantation Unit
Istituto Giannina Gaslini
Study Sites (1)
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