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

Istituto Giannina Gaslini

Status and phase: Completed; Phase 2

Conditions: Nephrotic Syndrome

Treatments: Drug: Rituximab; Drug: Ofatumumab

Study type: Interventional

Funder types: Other

Identifiers

NCT02394119

OFA2

Details and patient eligibility

About

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collection and dipstick readings will be carefully reviewed, compliance assessed, and therapy with RAS inhibitors withdrawn and, in hypertensive children replaced by other anti-hypertensive drug.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One week after the steroid withdrawal calcineurin inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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One week after the steroid withdrawal calcineurin-inhibitors will be decreased by 50% and withdrawn within 2 additional weeks.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

Enrollment: 140 patients

Sex: All

Ages: 2 to 24 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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140 participants in 2 patient groups

Ofatumumab

Experimental group

Description:

* 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.

Treatment:

Drug: Ofatumumab

Rituximab

Active Comparator group

Description:

* 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.

Treatment:

Drug: Rituximab