Clinical trial NCT01750697: A Phase IIa Study of Intravenous Rituximab in Pediatric Participants With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Granulomatosis With Polyangiitis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2012-12-17
Enrollment: 25
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs), Including Serious AEs
timeFrame: Baseline (Day 1) up to last visit (1.5-5 years)
measure: Pharmacokinetics: Rituximab Clearance (CL)
timeFrame: From Day 1 to Day 180
measure: Pharmacokinetics: Volume of Distribution (Vd) of Rituximab
timeFrame: From Day 1 to Day 180
Secondary outcomes:
measure: Pharmacokinetics: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC-180) of Rituximab
timeFrame: From Day 1 to Day 180
measure: Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab
timeFrame: From Day 1 to Day 180
Other outcomes:
Locations:
city: Louisville
country: United States
facility: University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: COLUMBIA PRESBYTERIAN MEDICAL CENTER, Research Pharmacy, William Black Medical Research Building
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation; Rheumatic and Immunologic Diseases
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah; Immunology/Rheumatology/Allergy
state: Utah
city: Calgary
country: Canada
facility: Alberta Children'S Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's and Women's Health Center / BC Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: The Hospital for Sick Children Research Institute
state: Ontario
city: Bron
country: France
facility: Hopital Femme Mere Enfant; Ped Nephrologie Rhumatologie
city: Paris
country: France
facility: Hop Necker Enfants Malades;UIH
city: Hamburg
country: Germany
facility: Universitätsklinikum für Kinder und Jugendmedizin Hamburg
city: Heidelberg
country: Germany
facility: KfH-Nierenzentrum fur Kinder und Jugendliche
city: Roma
country: Italy
facility: Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina
state: Lazio
city: Genova
country: Italy
facility: Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
state: Liguria
city: Padova
country: Italy
facility: Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica
state: Veneto
city: Belgrade
country: Serbia
facility: Childrens University Hospital
city: NIS
country: Serbia
facility: Clinical Center Nis
city: Ankara
country: Turkey
facility: Hacettepe University, School of Medicine; Pediatrics Department
city: Istanbul
country: Turkey
facility: Istanbul University, Cerrahpasa Medical Faculty; Pediatrics Department
city: Liverpool
country: United Kingdom
facility: Alder Hey Children s Hospital; Department of Pediatrics
city: London
country: United Kingdom
facility: Great Ormond Street Children's Hospital; Centre of Paediatric & Adolescent Rheumatology
city: Nottingham
country: United Kingdom
facility: Nottingham Children's Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Melega S, Brogan P, Cleary G, Hersh AO, Kasapcopur O, Rangaraj S, Yeung RSM, Zeft A, Cooper J, Pordeli P, Kirchner P, Lehane PB. Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis. Rheumatol Ther. 2022 Apr;9(2):721-734. doi: 10.1007/s40744-022-00433-0. Epub 2022 Mar 12.
citation: Brogan P, Yeung RSM, Cleary G, Rangaraj S, Kasapcopur O, Hersh AO, Li S, Paripovic D, Schikler K, Zeft A, Bracaglia C, Eleftheriou D, Pordeli P, Melega S, Jamois C, Gaudreault J, Michalska M, Brunetta P, Cooper JC, Lehane PB; PePRS Study Group. Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis. Arthritis Rheumatol. 2022 Jan;74(1):124-133. doi: 10.1002/art.41901. Epub 2021 Dec 5.