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

Granulomatosis With Polyangiitis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01750697
• Other study ID #: WA25615
• Secondary ID: 2012-002062-13
• Status: Completed
• Phase: Phase 2
• Start date: May 23, 2013
• Est. completion date: May 10, 2018

Study information

• Verified date: June 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: May 10, 2018
• Est. primary completion date: May 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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)

Related Conditions & MeSH terms

• Granulomatosis With Polyangiitis
• Microscopic Polyangiitis
• Systemic Vasculitis

Intervention

Drug:
• Rituximab
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.

Locations

Country	Name	City	State
Canada	Alberta Children'S Hospital	Calgary	Alberta
Canada	The Hospital for Sick Children Research Institute	Toronto	Ontario
Canada	Children's and Women's Health Center / BC Children's Hospital	Vancouver	British Columbia
France	Hopital Femme Mere Enfant; Ped Nephrologie Rhumatologie	Bron
France	Hop Necker Enfants Malades;UIH	Paris
Germany	Universitätsklinikum für Kinder und Jugendmedizin Hamburg	Hamburg
Germany	KfH-Nierenzentrum fur Kinder und Jugendliche	Heidelberg
Italy	Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS	Genova	Liguria
Italy	Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica	Padova	Veneto
Italy	Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina	Roma	Lazio
Serbia	Childrens University Hospital	Belgrade
Serbia	Clinical Center Nis	NIS
Turkey	Hacettepe University, School of Medicine; Pediatrics Department	Ankara
Turkey	Istanbul University, Cerrahpasa Medical Faculty; Pediatrics Department	Istanbul
United Kingdom	Alder Hey Children s Hospital; Department of Pediatrics	Liverpool
United Kingdom	Great Ormond Street Children's Hospital; Centre of Paediatric & Adolescent Rheumatology	London
United Kingdom	Nottingham Children's Hospital	Nottingham
United States	Cincinnati Childrens Hospital	Cincinnati	Ohio
United States	The Cleveland Clinic Foundation; Rheumatic and Immunologic Diseases	Cleveland	Ohio
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky
United States	COLUMBIA PRESBYTERIAN MEDICAL CENTER, Research Pharmacy, William Black Medical Research Building	New York	New York
United States	University of Utah; Immunology/Rheumatology/Allergy	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Serbia,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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	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
Secondary	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