Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT ID: NCT02394119
Last Updated: 2020-07-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE2
140 participants
INTERVENTIONAL
2015-06-30
2019-05-31
Brief Summary
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Eligible participants will enter a 1-month run-in period, during which instruction on urine collection and dipstick readings will be carefully reviewed, compliance assessed, and therapy with RAS inhibitors withdrawn and, in hypertensive children replaced by other anti-hypertensive drug.
After run-in period, children will be randomized to either the intervention arm (Ofatumumab) or the comparator arm (Rituximab).
After infusion of intervention or comparator, steroids will be maintained at initial dose for 30 days and then tapered off by 0.3 mg/kg per week until complete withdrawal.
One week after the steroid withdrawal calcineurin inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.
All patients will be followed for up to 24 months. In case of relapses during the study (see outcome section for definition) patients will be treated with 60 mg/m2of prednisone p.o. in order to achieve remission. At remission, patients will be treated with another infusion of either Oftumumab or Rituximab, according to the initial randomization.
After infusion of intervention or comparator, steroids will be maintained at initial dose for 30 days and then tapered off by 0.3 mg/kg per week until complete withdrawal.
One week after the steroid withdrawal calcineurin-inhibitors will be decreased by 50% and withdrawn within 2 additional weeks. This strategy will be repeated to treat full relapses during the study.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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
* How: Ofatumumab IV: 1500 mg/1.73m2 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.
* When and how much: once; diluted in 1000 ml of normal saline.
Ofatumumab
1500 mg/1.73m2, administered once diluted in 1000 ml of normal saline
Rituximab
* Drug Name: Rituximab (RTX)
* Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities
* Procedures: the same as for Ofatumumab Arm
* How: Rituximab IV: 375 mg/m2; for dosage between 100 and 250 mg RTX will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg RTX will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg RTX will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.
* When and how much: once; diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.
Rituximab
375 mg/m2, administered once diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.
Interventions
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Ofatumumab
1500 mg/1.73m2, administered once diluted in 1000 ml of normal saline
Rituximab
375 mg/m2, administered once diluted in 100/250/500 ml of normal saline for dosage respectively between 100-250 mg, 260-500 mg, 510-1000 mg.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* To be in complete disease remission
* Drug dependence: remission has to be maintained with both steroids and CNI steroid dependence is defined by two consecutive relapses during corticosteroid therapy or within 14 days of ceasing therapy. CNI (cyclosporine/tacrolimus) dependence is defined by presence of relapse at discontinuation.
* Ability to provide consent and assent: 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 24 years
Exclusion Criteria
* Positivity to autoimmunity tests (ANA, nDNA, ANCA)
* Reduction of C3 levels.
* eGFR\<90/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.
* Pregnancy
* Neoplasm
* Infections: previous or actual HBV (with HBeAb positivity) or HCV infection
* CD20 B lymphocytes count \<2,5%
* Treatment with Rituximab or cyclophosphamide in the last 6 months
2 Years
24 Years
ALL
No
Sponsors
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Istituto Giannina Gaslini
OTHER
Responsible Party
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Gian Marco Ghiggeri MD, PhD
MD, director of Nephrology, Dialysis and Transplantation Unit
Principal Investigators
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Gianmarco Ghiggeri, MD
Role: PRINCIPAL_INVESTIGATOR
Istituto Giannina Gaslini
Locations
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IRCCS Istituto Giannina Gaslini
Genoa, Italy/GE, Italy
Countries
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References
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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. No abstract available.
Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001533. doi: 10.1002/14651858.CD001533.pub3.
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.
Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K, Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H, Nakamura H, Ishikura K, Ito S, Ohashi Y; Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014 Oct 4;384(9950):1273-81. doi: 10.1016/S0140-6736(14)60541-9. Epub 2014 Jun 22.
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.
Basu B. Ofatumumab for rituximab-resistant nephrotic syndrome. N Engl J Med. 2014 Mar 27;370(13):1268-70. doi: 10.1056/NEJMc1308488. No abstract available.
Robak T. Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders. Curr Opin Mol Ther. 2008 Jun;10(3):294-309.
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.
Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F, Bodria M, Caridi G, Wei C, Belingheri M, Ghio L, Merscher-Gomez S, Edefonti A, Pasini A, Montini G, Murtas C, Wang X, Muruve D, Vaglio A, Martorana D, Pani A, Scolari F, Reiser J, Ghiggeri GM. Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome. Kidney Int. 2013 Nov;84(5):1025-33. doi: 10.1038/ki.2013.211. Epub 2013 Jun 5.
Larkins NG, Hahn D, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2024 Nov 8;11(11):CD002290. doi: 10.1002/14651858.CD002290.pub6.
Ravani P, Colucci M, Bruschi M, Vivarelli M, Cioni M, DiDonato A, Cravedi P, Lugani F, Antonini F, Prunotto M, Emma F, Angeletti A, Ghiggeri GM. Human or Chimeric Monoclonal Anti-CD20 Antibodies for Children with Nephrotic Syndrome: A Superiority Randomized Trial. J Am Soc Nephrol. 2021 Oct;32(10):2652-2663. doi: 10.1681/ASN.2021040561. Epub 2021 Sep 20.
Ravani P, Bonanni A, Ghiggeri GM. Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol. BMJ Open. 2017 Mar 17;7(3):e013319. doi: 10.1136/bmjopen-2016-013319.
Other Identifiers
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OFA2
Identifier Type: -
Identifier Source: org_study_id
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