Clinical trial NCT02394106: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Nephrotic Syndrome
Lead sponsor: Istituto Giannina Gaslini
Sponsor class: OTHER
First posted: 2015-03-20
Enrollment: 13
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes: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* calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or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


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

Primary outcomes:
measure: Complete or partial disease remission
timeFrame: 6 months from randomization
Secondary outcomes:
measure: Complete or partial disease remission
timeFrame: 12 months from randomization;
measure: Adverse events
timeFrame: At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
measure: Abnormal laboratory values
timeFrame: At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Other outcomes:
Locations:
city: Genoa
country: Italy
facility: IRCCS Istituto Giannina Gaslini
state: Italy/GE
Study officials:
affiliation: Istituto Giannina Gaslini
name: Gianmarco Ghiggeri, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Ravani P, Pisani I, Bodria M, Caridi G, Degl'Innocenti ML, Ghiggeri GM. Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial. Pediatr Nephrol. 2020 Jun;35(6):997-1003. doi: 10.1007/s00467-020-04481-y. Epub 2020 Jan 28.