Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome

Nephrotic Syndrome Clinical Trial

Official title:

Ofatumumab in Children With Steroid- and Calcineurin-inhibitor-resistant Nephrotic Syndrome: a Double-blind Randomized, Controlled, Superiority Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02394106
• Other study ID #: OFA1
• Status: Terminated
• Phase: Phase 2
• Start date: July 2015
• Est. completion date: June 2019

Study information

• Verified date: July 2020
• Source: Istituto Giannina Gaslini
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

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collection and dipstick readings will be carefully reviewed, compliance assessed and any immunosuppressive therapies withdrawn according to the following schemes: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• calcineurin inhibitors and mofetile mycophenolate will be decreased by 50% and withdrawn after 2 additional weeks In order to minimize the risk of complications of uncontrolled INS a treatment with ACE-inhibitor at 6 mg/m2 will be maintained or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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Nephrosis
• Nephrotic Syndrome
• Syndrome

Intervention

Drug:
• Ofatumumab
Ofatumumab 1500 mg/1.73m2 administered once, diluted in 1000 ml of normal saline

Other:
• Placebo
Normal saline, 1000 ml, administered once

Locations

Country	Name	City	State
Italy	IRCCS Istituto Giannina Gaslini	Genoa	Italy/GE

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Giannina Gaslini

Country where clinical trial is conducted

Italy, 

References & Publications (9)

Basu B. Ofatumumab for rituximab-resistant nephrotic syndrome. N Engl J Med. 2014 Mar 27;370(13):1268-70. doi: 10.1056/NEJMc1308488. — View Citation

Caridi G, Bertelli R, Di Duca M, Dagnino M, Emma F, Onetti Muda A, Scolari F, Miglietti N, Mazzucco G, Murer L, Carrea A, Massella L, Rizzoni G, Perfumo F, Ghiggeri GM. Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol. 2003 May;14(5):1278-86. — View Citation

Ghiggeri GM, Catarsi P, Scolari F, Caridi G, Bertelli R, Carrea A, Sanna-Cherchi S, Emma F, Allegri L, Cancarini G, Rizzoni GF, Perfumo F. Cyclosporine in patients with steroid-resistant nephrotic syndrome: an open-label, nonrandomized, retrospective study. Clin Ther. 2004 Sep;26(9):1411-8. — View Citation

Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM. Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol. 2012 Jun;23(6):1117-24. doi: 10.1681/ASN.2011080775. Epub 2012 May 10. — View Citation

McEnery PT, Strife CF. Nephrotic syndrome in childhood. Management and treatment in patients with minimal change disease, mesangial proliferation, or focal glomerulosclerosis. Pediatr Clin North Am. 1982 Aug;29(4):875-94. Review. — View Citation

Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient. Kidney Int. 2012 Oct;82(8):840-56. doi: 10.1038/ki.2012.280. Epub 2012 Aug 15. Review. — View Citation

Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, Benetti E, Scozzola F, Pasini A, Dallera N, Sica F, Belingheri M, Scolari F, Ghiggeri GM. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin J Am Soc Nephrol. 2011 Jun;6(6):1308-15. doi: 10.2215/CJN.09421010. Epub 2011 May 12. — View Citation

Ravani P, Rossi R, Bonanni A, Quinn RR, Sica F, Bodria M, Pasini A, Montini G, Edefonti A, Belingheri M, De Giovanni D, Barbano G, Degl'Innocenti L, Scolari F, Murer L, Reiser J, Fornoni A, Ghiggeri GM. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial. J Am Soc Nephrol. 2015 Sep;26(9):2259-66. doi: 10.1681/ASN.2014080799. Epub 2015 Jan 15. — View Citation

Robak T. Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders. Curr Opin Mol Ther. 2008 Jun;10(3):294-309. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	6 months from randomization
Secondary	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)	12 months from randomization;
Secondary	Adverse events	Measurement of frequency and severity of adverse events due to drug infusion	At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits
Secondary	Abnormal laboratory values	Record of abnormal values in biochemical tests and hematology assessments.	At 1, 3, 6, 9 and 12 months after drug/placebo infusion, during protocol visits