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
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EudraCT number |
2012-002062-13 |
Trial protocol |
GB DE IT |
Global end of trial date |
10 May 2018
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Results information
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Results version number |
v1 |
This version publication date |
24 Nov 2018
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First version publication date |
24 Nov 2018
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WA25615
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01750697 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000308-PIP02-01 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Jul 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 May 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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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.
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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
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
54 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 13
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Serbia: 1
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Country: Number of subjects enrolled |
Turkey: 2
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
United States: 4
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Worldwide total number of subjects |
25
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
6
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Adolescents (12-17 years) |
19
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Remission Induction Phase (up to 6 mos.)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
Arms
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Arm title
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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
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Investigational medicinal product code |
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Other name |
MabThera Rituxan
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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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.
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Period 2
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Period 2 title |
Overall Follow-up Phase (up to 4.5 yrs)
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Is this the baseline period? |
No | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
Arms
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Arm title
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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
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Investigational medicinal product code |
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Other name |
MabThera Rituxan
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Rituximab
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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). | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rituximab
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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
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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
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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.
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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.
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End point type |
Primary
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End point timeframe |
Up to approximately 5 years
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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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
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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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
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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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
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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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
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to approximately 5 years
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Adverse event reporting additional description |
The safety population included all subjects who received at least part of one infusion of rituximab.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Overall Follow-up Phase: Rituximab
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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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Remission Induction Phase: Rituximab
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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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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). |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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%). |