A Phase IIa Study of Intravenous Rituximab in Pediatric Participants With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis

Study Overview
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Brief Summary
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This Phase IIa international multicenter, open-label, uncontrolled study will evaluate the safety and pharmacokinetics of rituximab (MabThera/Rituxan) in pediatric participants with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Participants will receive rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, 15 and 22.

Official Title
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A Phase IIA, International, Multicenter, Open-label, Uncontrolled Study to Evaluate The Safety And Pharmacokinetics of 4 × 375 mg/m2 Intravenous Rituximab in Pediatric Patients With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis

Conditions
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Granulomatosis With Polyangiitis

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood Wegener's granulomatosis) or diagnosis of MPA (according to the Chapel Hill Consensus Conference) Newly diagnosed participants or participants with relapsing disease according to the following definition: The recurrence or new onset of potentially organ- or life-threatening disease (i.e. one or more major Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [BVAS/WG] items or disease severe enough to require treatment with cyclophosphamide) For participants of reproductive potential (males and females), use of reliable means of contraception throughout the study participation For all eligible participants mandatory prophylactic treatment for Pneumocystis jirovecii infection Exclusion Criteria: Diagnosis of Churg-Strauss syndrome, as defined by the Chapel Hill Consensus Conference Limited disease that would not normally be treated with cyclophosphamide Severe disease requiring mechanical ventilation due to alveolar hemorrhage Requirement for plasmapheresis or dialysis at screening Incomplete recovery from recent surgery or less than (<) 12 weeks since surgery prior to baseline or planned within 24 weeks of baseline Lack of peripheral venous access Pregnancy or breast-feeding Evidence of other significant uncontrolled concomitant disease, or of disorder or condition that, in the investigator's opinion, would preclude or interfere with participation of participant Primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (HIV) infection Evidence of active tuberculosis (participants receiving chemoprophylaxis for latent tuberculosis infection are eligible for the study) Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks of baseline or completion of oral anti-infective agents within 2 weeks prior to baseline. Entry into this study may be reconsidered once the infection has fully resolved History of deep space/tissue infection within 24 weeks prior to baseline History of serious recurrent or chronic infection History of cancer (except for basal cell and squamous cell carcinoma of the skin that have been excised and cured) Currently active alcohol or drug abuse or history of alcohol or drug abuse History of severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins Treatment with rituximab or other biologic B cell-targeted therapy (e.g., anti- Cluster of Differentiation [CD] 19, anti-CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/B-cell activating factor [BAFF]) within 6 months prior to baseline visit Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator Previous treatment with other cell-depleting therapies, including, but not limited to, investigational agents (e.g., alemtuzumab, anti-CD4, anti-CD5, anti-CD3, and anti-CD11a) Receipt of oral or IV cyclophosphamide within the previous 4 months prior to the baseline visit Receipt of infliximab within 3 months, adalimumab within 2 months or etanercept within 1 month prior to the baseline visit Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is longer) Receipt of any live attenuated vaccine within 28 days prior to baseline Intolerance or contraindications to IV glucocorticoids Positive serum human chorionic gonadotropin measured at screening or a positive pregnancy test prior to the first rituximab infusion for participants of childbearing potential Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B virus (HBV), or hepatitis C serology Level of Immunoglobulin (Ig) M below lower limit of normal of age-specific reference range Level of IgG below 5.65 milligram per milliliter Absolute neutrophil count < 1.5 × 10^3 per microliter and platelet count < 130 × 10^3 per microliter Estimated Glomerular Filtration Rate < 15 milliliter per minute per 1.73 m^2 Alanine aminotransferase or aspartate aminotransferase levels greater than 2.5 times the upper limit of normal (for age and sex) that cannot be attributed to underlying granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br> | Drug: Rituximab<br>* Participants will receive rituximab 375 mg/m^2 IV infusion on Days 1, 8, 15 and 22. Rituximab infusions will be given at a rate of 25 milligrams per hour (mg/h). This may be escalated at a rate of 25 mg/h increments every 30 minutes to a maximum of 200 mg/h.<br>* Other names: MabThera/Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs), Including Serious AEs | An AE is any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporarily associated with the use of a study drug, whether or not considered related to the study drug. A SAE is any experience that results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant. | Baseline (Day 1) up to last visit (1.5-5 years) | 
| Pharmacokinetics: Rituximab Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. The following allometric scaling equation was used for the estimation of CL in children: CL= qCL X (BSA/1.9) 0.92 X 1.31*ADA where qCL is a typical value of clearance in millilitres per day (mL/day) for a typical participant (i.e., Body Surface Area (BSA) of 1.9 m^2 and absence of anti-rituximab antibodies (ADA)) and is equal to 258 mL/day; BSA is in m^2 and ADA is 1 when anti-rituximab antibodies are present (0 otherwise). The allometric scaling factor was 0.92. CL was calculated in millilitres per day (mL/day). | From Day 1 to Day 180 | 
| Pharmacokinetics: Volume of Distribution (Vd) of Rituximab | Vd is defined as the theoretical central volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vd was calculated in millilitres (mL). | From Day 1 to Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC-180) of Rituximab | The AUC0-180 is a measure of the plasma concentration of rituximab over time. The AUC0-180 was calculated in micrograms per millilitres times day (mcg/mL*day). | From Day 1 to Day 180 | 
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab | Cmax is the maximum observed plasma rituximab concentration. Cmax was assessed at each visit following 1st, 2nd, 3rd, and 4th IV dose of rituximab 375 mg/m^2 on Days 1, 8, 15, and 22. Cmax was calculated in micrograms per millilitre (mcg/mL). | From Day 1 to Day 180 |