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

June 7, 2019 updated by: Hoffmann-La Roche

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T3B 6A8
        • Alberta Children's Hospital
    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3V4
        • Children's and Women's Health Center / BC Children's Hospital
    • Ontario
      • Toronto, Ontario, Canada, M5G 1L7
        • The Hospital for Sick Children Research Institute
  • France
      • Bron, France, 69677
        • Hopital Femme Mere Enfant; Ped Nephrologie Rhumatologie
      • Paris, France, 75743
        • Hop Necker Enfants Malades;UIH
  • Germany
      • Hamburg, Germany, 20246
        • Universitätsklinikum für Kinder und Jugendmedizin Hamburg
      • Heidelberg, Germany, 69120
        • KfH-Nierenzentrum für Kinder und Jugendliche
  • Italy
    • Lazio
      • Roma, Lazio, Italy, 00165
        • Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina
    • Liguria
      • Genova, Liguria, Italy, 16147
        • Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
    • Veneto
      • Padova, Veneto, Italy, 35128
        • Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica
  • Serbia
      • Belgrade, Serbia, 11000
        • Childrens University Hospital
      • NIS, Serbia, 18000
        • Clinical Center Nis
  • Turkey
      • Ankara, Turkey, 06100
        • Hacettepe University, School of Medicine; Pediatrics Department
      • Istanbul, Turkey, 34098
        • Istanbul University, Cerrahpasa Medical Faculty; Pediatrics Department
  • United Kingdom
      • Liverpool, United Kingdom, L12 2AP
        • Alder Hey Children s Hospital; Department of Pediatrics
      • London, United Kingdom, WC1N 1EH
        • Great Ormond Street Children's Hospital; Centre of Paediatric & Adolescent Rheumatology
      • Nottingham, United Kingdom, NG7 2UH
        • Nottingham Children's Hospital
  • United States
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10032
        • COLUMBIA PRESBYTERIAN MEDICAL CENTER, Research Pharmacy, William Black Medical Research Building
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Childrens Hospital
      • Cleveland, Ohio, United States, 44195
        • The Cleveland Clinic Foundation; Rheumatic and Immunologic Diseases
    • Utah
      • Salt Lake City, Utah, United States, 84109
        • University of Utah; Immunology/Rheumatology/Allergy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 17 years (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Rituximab
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.
Other Names:
  • MabThera/Rituxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Adverse Events (AEs), Including Serious AEs
Time Frame: Baseline (Day 1) up to last visit (1.5-5 years)
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)
Time Frame: From Day 1 to Day 180

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
Time Frame: From Day 1 to Day 180
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
Time Frame: From Day 1 to Day 180
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
Time Frame: From Day 1 to Day 180
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hoffmann-La Roche

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 23, 2013

Primary Completion (ACTUAL)

May 10, 2018

Study Completion (ACTUAL)

May 10, 2018

Study Registration Dates

First Submitted

December 13, 2012

First Submitted That Met QC Criteria

December 13, 2012

First Posted (ESTIMATE)

December 17, 2012

Study Record Updates

Last Update Posted (ACTUAL)

June 26, 2019

Last Update Submitted That Met QC Criteria

June 7, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • WA25615
  • 2012-002062-13 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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