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    Clinical Trial Results:
    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 Granulomatosis with Polyangiitis (Wegener’s) or Microscopic Polyangiitis

    Summary
    EudraCT number
    		 2012-002062-13
    Trial protocol
    		 GB   DE   IT  
    Global end of trial date
    10 May 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 May 2019
    First version publication date
    24 Nov 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    WA25615
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01750697
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000308-PIP02-01
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the safety, tolerability, and pharmacokinetic (PK) parameters of rituximab in paediatric subjects with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
    Protection of trial subjects
    All study subjects, parent or legal guardian were required to read and sign an Informed Consent Form. An Internal Monitoring Committee (IMC) composed of a Clinical Scientist, a Statistician, a Statistical Programmer Analyst, and a safety representative reviewed safety data from subjects participating in this study on a regular basis. The IMC was responsible for monitoring the overall safety of the subjects in this study to help to minimize subject exposure to unacceptable risk.
    Background therapy
    		 Subjects must have received three daily doses of 30 milligrams per kilogram (mg/kg) of methylprednisolone (up to 1 g/day) or the equivalent dose of other glucocorticoids by intravenous (IV) infusion, which could occur at any time, up to and including Day 1. If clinically indicated, and at the discretion of the investigator, additional doses (up to three) of methylprednisolone (30 mg/kg, up to 1 g/day, or equivalent) could be given by IV infusion. No more than six doses of methylprednisolone in total could be given. All methylprednisolone doses must have been completed prior to the first rituximab infusion. On Day 1 and following completion of IV glucocorticoids, all subjects received concomitant oral prednisolone or prednisone (1 mg/kg/day or up to 60 mg/day or equivalent, whichever was lower), the dose of which was tapered to a minimum of 0.2 mg/kg/day (or 10 mg/day, whichever was the lowest) no later than Month 6. Prophylactic treatment for Pneumocystis jiroveci was in accordance with local, routine clinical practise. Treatment of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) after Month 6: subjects who had failed to achieve clinical remission or who exhibited progressive disease or flare that could not be controlled by glucocorticoids alone were to receive treatment for their GPA or MPA in accordance with local standard of care, which could include rituximab and/or other therapies, at the discretion of the investigator and were to remain in the study. Repeat treatment with rituximab was given at the discretion of the investigator, per their clinical judgement (including dose and treatment regimen) based on disease activity, previous response to treatment, and the investigator’s assessment of the benefit/risk of additional rituximab treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 54 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    25
    EEA total number of subjects
    14
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    6
    Adolescents (12-17 years)
    19
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 25 subjects were enrolled in the study over a 3.5 year period from 11 sites across the United Kingdom, Italy, Serbia, Turkey, Canada, and the United States.

    Pre-assignment
    Screening details
    		 The screening visit occurred up to 28 days prior to the Day 1 baseline visit. Following successful screening, eligible subjects entered the 6 month Remission Induction Phase of the study.

    Period 1
    Period 1 title
    Remission Induction Phase (up to 6 mos.)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Rituximab
    Arm description
    		 Subjects received rituximab as an intravenous (IV) infusion of 375 milligrams per metre squared (mg/m^2) once a week on Days 1, 8, 15, and 22 during Remission Induction Phase (Day 1 (baseline) to Month 6).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered as an IV infusion of 375 mg/m^2 once a week for 4 consecutive weeks, starting at the baseline visit.

    Number of subjects in period 1
    		Rituximab
    Started
    25
    Completed
    25
    Period 2
    Period 2 title
    Overall Follow-up Phase (up to 4.5 yrs)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Rituximab
    Arm description
    		 Subjects who received rituximab during 6-month Remission Induction Phase were followed for 12 months during the Follow-up Phase ((Month 6 to Month 18)) and then an Extended Follow-up Phase (Month 18 to Common-closeout (CCO)).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received additional rituximab infusions (dose and treatment regimen per Investigator's clinical judgement) post Remission Induction Phase (Month 6) up to 4.5 years during the overall Follow-up Phase until the CCO.

    Number of subjects in period 2
    		Rituximab
    Started
    25
    Follow-up Phase (Month 6 to Month 18)
    24
    Completed
    16
    Not completed
    9
         Physician decision
    1
         Subject Transferring Back To Local Hospital
    1
         Transferred to Adult Services
    5
         Withdrawal by Subject
    1
         Physician and Family Decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Subjects received rituximab as an intravenous (IV) infusion of 375 milligrams per metre squared (mg/m^2) once a week on Days 1, 8, 15, and 22 during Remission Induction Phase (Day 1 (baseline) to Month 6).

    Reporting group values
    		 Rituximab Total
    Number of subjects
    		 25 25
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.4 ( 2.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Subjects received rituximab as an intravenous (IV) infusion of 375 milligrams per metre squared (mg/m^2) once a week on Days 1, 8, 15, and 22 during Remission Induction Phase (Day 1 (baseline) to Month 6).
    Reporting group title
    Rituximab
    Reporting group description
    		 Subjects who received rituximab during 6-month Remission Induction Phase were followed for 12 months during the Follow-up Phase ((Month 6 to Month 18)) and then an Extended Follow-up Phase (Month 18 to Common-closeout (CCO)).

    Subject analysis set title
    Overall: Rituximab
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received rituximab as an IV infusion of 375 mg/m^2 once a week on Days 1, 8, 15, and 22.

    Primary: Percentage of Subjects With Adverse Events (AEs) and Serious AEs (SAEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) and Serious AEs (SAEs) [1]
    End point description
    An AE is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 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. The safety population included all subjects who received at least part of one infusion of rituximab.
    End point type
    Primary
    End point timeframe
    Up to approximately 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Rituximab Rituximab
    Number of subjects analysed
    25
    25
    Units: percentage of subjects
    number (not applicable)
        Percentage of subjects with AEs
    100.0
    100.0
        Percentage of subjects with SAEs
    28.0
    48.0
    No statistical analyses for this end point

    Primary: Pharmacokinetics (PK) Parameter: Rituximab Clearance (CL)

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    End point title
    		 Pharmacokinetics (PK) Parameter: Rituximab Clearance (CL) [2]
    End point description
    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 patient (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). The PK analysis population included all subjects in the safety population who provided at least one evaluable PK sample.
    End point type
    Primary
    End point timeframe
    Pre-dose (0 hour) on Days 1, 8, 15, 22; 30 minutes post infusion on Days 1 and 22 and then on Day 29, Months 2, 4, 6, 9, 18, thereafter every 6 months up to approximately 5 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Overall: Rituximab
    Number of subjects analysed
    25
    Units: mL/day
        geometric mean (geometric coefficient of variation)
    204 ( 0.414 )
    No statistical analyses for this end point

    Primary: PK Parameter: Volume of Distribution (Vd) of Rituximab

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    End point title
    		 PK Parameter: Volume of Distribution (Vd) of Rituximab [3]
    End point description
    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). The PK analysis population included all subjects in the safety population who provided at least one evaluable PK sample.
    End point type
    Primary
    End point timeframe
    Pre-dose (0 hour) on Days 1, 8, 15, 22; 30 minutes post infusion on Days 1 and 22 and then on Day 29, Months 2, 4, 6, 9, 18, thereafter every 6 months up to approximately 5 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Overall: Rituximab
    Number of subjects analysed
    25
    Units: mL
        geometric mean (geometric coefficient of variation)
    2220 ( 0.212 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC0-180) of Rituximab

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    End point title
    		 PK Parameter: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC0-180) of Rituximab
    End point description
    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). The PK analysis population included all subjects in the safety population who provided at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Days 1, 8, 15, 22; 30 minutes post infusion on Days 1 and 22 and then on Day 29, Months 2, 4, 6, 9, 18, thereafter every 6 months up to approximately 5 years
    End point values
    		 Overall: Rituximab
    Number of subjects analysed
    25
    Units: mcg/mL*day
        geometric mean (geometric coefficient of variation)
    10120 ( 0.42 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Maximum Plasma Concentration (Cmax) of Rituximab

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    End point title
    		 PK Parameter: Maximum Plasma Concentration (Cmax) of Rituximab
    End point description
    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). The PK analysis population included all subjects in the safety population who provided at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Days 1, 8, 15, 22; 30 minutes post infusion on Days 1 and 22 and then on Day 29, Months 2, 4, 6, 9, 18, thereafter every 6 months up to approximately 5 years
    End point values
    		 Overall: Rituximab
    Number of subjects analysed
    25
    Units: mcg/mL
    geometric mean (geometric coefficient of variation)
        1st dose
    230 ( 0.166 )
        2nd dose
    305 ( 0.181 )
        3rd dose
    353 ( 0.183 )
        4th dose
    378 ( 0.174 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 5 years
    Adverse event reporting additional description
    The safety population included all subjects who received at least part of one infusion of rituximab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Remission Induction Phase: Rituximab
    Reporting group description
    		 Subjects received rituximab as an IV infusion of 375 mg/m^2 once a week on Days 1, 8, 15, and 22 during Remission Induction Phase (Day 1 (baseline) to Month 6).

    Reporting group title
    Overall Follow-up Phase: Rituximab
    Reporting group description
    		 Subjects who received rituximab during the remission induction phase were followed for a minimum of 18 months during the follow-up phase and could receive additional rituximab or other treatments for GPA/MPA (Day 1 (baseline) up to 4.5 yrs).

    Serious adverse events
    		 Remission Induction Phase: Rituximab Overall Follow-up Phase: Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 25 (28.00%)
    12 / 25 (48.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Granulomatosis with polyangiitis
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 25 (16.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Sickle cell anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchostenosis
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye infection bacterial
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Remission Induction Phase: Rituximab Overall Follow-up Phase: Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 25 (88.00%)
    24 / 25 (96.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    Granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
         occurrences all number
    3
    4
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 25 (12.00%)
    7 / 25 (28.00%)
         occurrences all number
    3
    8
    Cough
         subjects affected / exposed
    3 / 25 (12.00%)
    6 / 25 (24.00%)
         occurrences all number
    3
    9
    Dyspnoea
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Insomnia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Investigations
    Blood immunoglobulin G decreased
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    C-reactive protein increased
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Serum ferritin decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    14 / 25 (56.00%)
    16 / 25 (64.00%)
         occurrences all number
    28
    48
    Fall
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    Skin abrasion
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 25 (16.00%)
    9 / 25 (36.00%)
         occurrences all number
    4
    9
    Migraine
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    4
    Tremor
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    7 / 25 (28.00%)
         occurrences all number
    0
    7
    Nausea
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 25 (20.00%)
         occurrences all number
    5
    10
    Abdominal pain upper
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 25 (16.00%)
         occurrences all number
    3
    4
    Vomiting
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 25 (16.00%)
         occurrences all number
    3
    6
    Abdominal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    Constipation
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 25 (12.00%)
         occurrences all number
    3
    8
    Gastritis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Pruritus
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Purpura
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Rash erythematous
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Skin striae
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    6
    Back pain
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    6
    Pain in extremity
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 25 (16.00%)
         occurrences all number
    2
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 25 (16.00%)
    12 / 25 (48.00%)
         occurrences all number
    4
    21
    Conjunctivitis
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 25 (20.00%)
         occurrences all number
    2
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    10
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 25 (16.00%)
         occurrences all number
    2
    4
    Ear infection
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Gastroenteritis
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Pharyngitis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    7
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Fungal skin infection
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Herpes zoster
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Oral herpes
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2012
    Changed the tool used for the exploratory endpoint of the measurement of childhood primary vasculitis from the Vasculitis Damage Index (VDI) to the Paediatric Vasculitis Damage Index (PVDI). Added the quality of life (QOL) instrument the Child Health Questionnaire (CHQ) to the exploratory outcome measures. Changed procedure for rituximab administration. Reduced duration of fasting when glycosylated haemoglobin (HbA1c) measurements are required, from 8 hours to at least 4 hours. Amended criterion related to low immunoglobulin levels. Added criterion based on tuberculosis. Provided absolute contraindications to all infusions subsequent to the first infusion and to retreatment infusions. Included definition of treatment failure. Amended the condition for immunisation with any live or attenuated vaccine to also include corticosteroid taper to 0 prior to immunisation with any live or attenuated vaccine. Replaced the term “courses” with “doses.” Added oral prednisolone as an option along with oral prednisone. Deleted lateral chest x-rays. Clarified that the screening period was 28 days. Replaced the terms “IVRS” and “IWRS” with the term “IxRS” (interactive voice/web-based response system).
    31 May 2013
    Provided new safety information on severe skin reactions. Increased the exclusion limit of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. Provided definitions of progressive disease, disease relapse/flare, and major and minor items for Birmingham Vasculitis Activity Score (BVAS) for Wegener’s granulomatosis (WG) BVAS/WG and Paediatric Vasculitis Activity Score (PVAS). Accordingly, additional exploratory efficacy outcome measures/endpoints were included and clarifications provided. Removed fasting for laboratory assessment of glycosylated haemoglobin (HbA1c). Provided flexibility to the investigator on the use of a corticosteroid premedication subject at his/her discretion. Provided recommendations on non-mandatory treatment for major and minor relapses after Month 6. Added a new section providing information on monitoring of the overall safety of subjects in this study by an Internal Monitoring Committee. Clarified that plasmapheresis was permitted during the study, if absolutely necessary in the opinion of the investigator to treat the subject. Clarified that Pharmacokinetics (PK) samples would be collected from the opposite arm to that into which the rituximab infusion was administered when collected on days of rituximab infusion. Provided clarity about the washout of agents such as mycophenolate mofetil (MMF). Clarified that prophylactic treatment for Pneumocystic jiroveci should be in accordance with local, routine clinical practise. Clarified that the dose of rituximab and the frequency of retreatment for the maintenance of remission will be at the discretion of the investigator, if subjects required retreatment with rituximab after Month 6. Clarified that rituximab is to be diluted to a final concentration of 1–4 mg/mL into an infusion bag containing 0.9% sodium chloride USP or British Pharmacopoeia.
    31 May 2013
    Clarified that subjects who receive any protocol-defined prohibited therapy, granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) treatment other than protocol-defined glucocorticoids, would remain in the study for follow-up, and that they would be included as failing the protocol remission endpoints according to the protocol-defined criteria thereafter (i.e., at timepoints after the receipt of any GPA or MPA treatment other than protocol-defined glucocorticoids), irrespective of BVAS/WG and PVAS scores. Merged the section on “Immunisation” with the “Vaccinations” section.
    26 Apr 2016
    Modified the exclusion criteria related to general health, prior medications and laboratory findings. These changes were made in order to extend the possibility of entry into this clinical study to a wider range of suitable GPA and MPA patients, who would otherwise have limited treatment options in this potentially life-threatening and organ-threatening disease. Exclusions Related to General Health: Current active infection was an exclusion criterion, a statement was added to clarify that entry into this study may be reconsidered once any known active infection had fully resolved. Exclusions Related to Medications: Criteria was amended to permit prior treatment with rituximab and/or other B cell-depleting therapies, provided last dose was more than 6 months before the baseline visit. Exclusions Related to Laboratory Findings: The laboratory exclusion level of serum immunoglobulin G (IgG) was amended from the central laboratory LLN, which varied according to age, to an absolute exclusionary value of below 5.65 mg/mL. This proposed IgG threshold was used as exclusion criteria in rheumatoid arthritis (RA) global clinical trials for rituximab, where adult patients were observed up to 11 years.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    After Month 6, subjects could receive treatment for GPA/MPA in accordance with local standard of care, and this could include additional rituximab infusions and/or other immunosuppressive therapies. Low subject numbers (e.g., 1 subject = 4%).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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