Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome

Nephrotic Syndrome Clinical Trial

Official title:

Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor-dependent Idiopathic Nephrotic Syndrome: an Open-label, Randomized, Controlled, Superiority Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02394119
• Other study ID #: OFA2
• Status: Completed
• Phase: Phase 2
• Start date: June 2015
• Est. completion date: May 2019

Study information

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

Clinical Trial Summary

Open-label, two-parallel-arm, controlled randomized clinical trial testing the superiority of Ofatumumab over Rituximab in maintaining steroid- and calcineurin-inhibitor-free disease remission in SD-INS.

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urine collection and dipstick readings will be carefully reviewed, compliance assessed, and therapy with RAS inhibitors withdrawn and, in hypertensive children replaced by other anti-hypertensive drug.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One week after the steroid withdrawal calcineurin inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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One week after the steroid withdrawal calcineurin-inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: May 2019
• Est. primary completion date: June 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 24 Years

Eligibility

Inclusion Criteria:

To be eligible for inclusion into this study, participants will have to fulfill the following 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:

Children will be excluded if any of the following criteria apply:

• 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

Related Conditions & MeSH terms

• Nephrosis
• Nephrotic Syndrome
• Syndrome

Intervention

Drug:
• 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.

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

Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001533. Review. Update in: Cochrane Database Syst Rev. 2007;(4):CD001533. — View Citation

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. — 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

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, 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. — 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	Risk of relapse	The primary endpoints will be risk of relapse at 12 months without steroid or calcineurin-inhibitors. Relapse is defined by uPCR =2000 mg/g (= 200 mg/mmol) or > 3+ protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).	12 months
Secondary	Amount of steroids required to maintain complete disease remission	Complete remission is defined by uPCR <200 mg/g (<20 mg/mmol) or o1+ of protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).	6 and 24 months after Ofatumumab or Rituximab pulse
Secondary	Adverse events	Measurement of frequency and severity of adverse events due to drug infusion	At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.
Secondary	Abnormal laboratory values	Record of abnormal values in biochemical tests and hematology assessments due to drug infusion	At 1, 3, 6, 9 ,12, 15, 18, 21 and 24 months after drug infusion, during protocol visits.