Trial Outcomes & Findings for A Phase IIa Study of Intravenous Rituximab in Pediatric Participants With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis (NCT NCT01750697)

Last Updated: 2019-06-26

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

Baseline (Day 1) up to last visit (1.5-5 years)

Results posted on

2019-06-26

Participant Flow

A total of 25 participants 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.

The screening visit occurred up to 28 days prior to the Day 1 baseline visit. Following successful screening, eligible participants entered the 6 month Remission Induction Phase of the study.

Participant milestones

Participant milestones
Measure	Rituximab Participants received rituximab as an intravenous (IV) infusion of 375 milligrams per meter squared (mg/m\^2) once a week on Days 1, 8, 15 and 22 during the Remission Induction Phase (Day 1 (baseline) to Month 6) and were followed for a minimum of 18 months (maximum 4.5yrs) during the Follow-up Phase until the Common-closeout (CCO))
Overall Study STARTED	25
Overall Study Completed	25
Overall Study Follow-up Phase	24
Overall Study COMPLETED	16
Overall Study NOT COMPLETED	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab Participants received rituximab as an intravenous (IV) infusion of 375 milligrams per meter squared (mg/m\^2) once a week on Days 1, 8, 15 and 22 during the Remission Induction Phase (Day 1 (baseline) to Month 6) and were followed for a minimum of 18 months (maximum 4.5yrs) during the Follow-up Phase until the Common-closeout (CCO))
Overall Study Transferred Back to Local Hospital	1
Overall Study Physician and Family Decision	1
Overall Study Transferred to Adult Services	5
Overall Study Physician Decision	1
Overall Study Withdrawal by Subject	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab n=25 Participants Participants received rituximab as an intravenous (IV) infusion of 375 milligrams per meter squared (mg/m\^2) once a week on Days 1, 8, 15 and 22 during the Remission Induction Phase (Day 1 (baseline) to Month 6) and were followed for a minimum of 18 months (maximum 4.5yrs) during the Follow-up Phase until the Common-closeout (CCO))
Age, Continuous	13.4 years STANDARD_DEVIATION 2.9 • n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=5 Participants
Race/Ethnicity, Customized White	17 participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) up to last visit (1.5-5 years)

Population: The safety population included all participants who received at least part of one infusion of rituximab.

Outcome measures

Outcome measures
Measure	Remission Induction Phase (up to 6 Mos.) Rituximab n=25 Participants Participants 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)	Overall Follow-up Phase (up to 4.5 Yrs) Rituximab n=25 Participants Participants 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)
Percentage of Participants With Adverse Events (AEs), Including Serious AEs Percentage of Participants with AEs	100 percentage of participants	100 percentage of participants
Percentage of Participants With Adverse Events (AEs), Including Serious AEs Percentage of Participants with SAEs	28 percentage of participants	48 percentage of participants

PRIMARY outcome

Timeframe: From Day 1 to Day 180

Population: The PK analysis population included all participants in the safety population who provided at least one evaluable PK sample.

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).

Outcome measures

Outcome measures
Measure	Remission Induction Phase (up to 6 Mos.) Rituximab n=25 Participants Participants 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)	Overall Follow-up Phase (up to 4.5 Yrs) Rituximab Participants 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)
Pharmacokinetics: Rituximab Clearance (CL)	204 mL/day Geometric Coefficient of Variation 0.414	—

PRIMARY outcome

Timeframe: From Day 1 to Day 180

Population: The PK analysis population included all participants in the safety population who provided at least one evaluable PK sample.

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).

Outcome measures

Outcome measures
Measure	Remission Induction Phase (up to 6 Mos.) Rituximab n=25 Participants Participants 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)	Overall Follow-up Phase (up to 4.5 Yrs) Rituximab Participants 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)
Pharmacokinetics: Volume of Distribution (Vd) of Rituximab	2220 mL Geometric Coefficient of Variation 0.212	—

SECONDARY outcome

Timeframe: From Day 1 to Day 180

Population: The PK analysis population included all participants in the safety population who provided at least one evaluable PK sample.

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).

Outcome measures

Outcome measures
Measure	Remission Induction Phase (up to 6 Mos.) Rituximab n=25 Participants Participants 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)	Overall Follow-up Phase (up to 4.5 Yrs) Rituximab Participants 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)
Pharmacokinetics: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC-180) of Rituximab	10120 mcg/mL*day Geometric Coefficient of Variation 0.42	—

SECONDARY outcome

Timeframe: From Day 1 to Day 180

Population: The PK analysis population included all participants in the safety population who provided at least one evaluable PK sample.

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).

Outcome measures

Outcome measures
Measure	Remission Induction Phase (up to 6 Mos.) Rituximab n=25 Participants Participants 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)	Overall Follow-up Phase (up to 4.5 Yrs) Rituximab Participants 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)
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab 1st Dose	230 mcg/mL Geometric Coefficient of Variation 0.166	—
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab 2nd Dose	305 mcg/mL Geometric Coefficient of Variation 0.181	—
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab 3rd Dose	353 mcg/mL Geometric Coefficient of Variation 0.183	—
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab 4th Dose	378 mcg/mL Geometric Coefficient of Variation 0.174	—

Adverse Events

Remission Induction Phase: Rituximab

Serious events: 7 serious events

Other events: 22 other events

Deaths: 0 deaths

Overall Follow-up Phase: Rituximab

Serious events: 12 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Remission Induction Phase: Rituximab n=25 participants at risk Participants 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)	Overall Follow-up Phase: Rituximab n=25 participants at risk Participants 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)
Blood and lymphatic system disorders Sickle cell anaemia with crisis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Congenital, familial and genetic disorders Sickle cell anaemia	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Pancreatitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Immune system disorders Anti-neutrophil cytoplasmic antibody positive vasculitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Device related sepsis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Eye infection bacterial	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Gastroenteritis norovirus	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Gastroenteritis viral	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Influenza	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Lower respiratory tract infection	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Sinusitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Injury, poisoning and procedural complications Infusion related reaction	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Musculoskeletal and connective tissue disorders Myopathy	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Nervous system disorders Seizure	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Psychiatric disorders Suicidal ideation	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Bronchostenosis	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Laryngeal obstruction	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Vascular disorders Granulomatosis with polyangiitis	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Vascular disorders Vasculitis	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	4.0% 1/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.

Measure	Remission Induction Phase: Rituximab n=25 participants at risk Participants 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)	Overall Follow-up Phase: Rituximab n=25 participants at risk Participants 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)
Blood and lymphatic system disorders Neutropenia	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Ear and labyrinth disorders Deafness unilateral	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Abdominal pain	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Abdominal pain upper	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Constipation	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Diarrhoea	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	28.0% 7/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Gastritis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Nausea	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	20.0% 5/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Gastrointestinal disorders Vomiting	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
General disorders Chest pain	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
General disorders Non-cardiac chest pain	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Immune system disorders Hypogammaglobulinaemia	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Conjunctivitis	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	20.0% 5/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Ear infection	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Fungal skin infection	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Gastroenteritis	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Herpes zoster	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Influenza	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Lower respiratory tract infection	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Nasopharyngitis	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	20.0% 5/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Oral herpes	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Pharyngitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Pneumonia	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Sinusitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Tooth infection	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Upper respiratory tract infection	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	48.0% 12/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Urinary tract infection	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Infections and infestations Viral upper respiratory tract infection	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Injury, poisoning and procedural complications Fall	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Injury, poisoning and procedural complications Infusion related reaction	56.0% 14/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	64.0% 16/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Injury, poisoning and procedural complications Skin abrasion	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Investigations Blood immunoglobulin G decreased	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Investigations C-reactive protein increased	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Investigations Serum ferritin decreased	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Metabolism and nutrition disorders Iron deficiency	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Musculoskeletal and connective tissue disorders Arthralgia	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	20.0% 5/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Musculoskeletal and connective tissue disorders Back pain	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	20.0% 5/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Musculoskeletal and connective tissue disorders Pain in extremity	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Nervous system disorders Headache	16.0% 4/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	36.0% 9/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Nervous system disorders Migraine	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Nervous system disorders Tremor	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Psychiatric disorders Depression	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Psychiatric disorders Insomnia	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Reproductive system and breast disorders Amenorrhoea	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Cough	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	24.0% 6/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Epistaxis	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	28.0% 7/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Pruritus	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Purpura	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Rash	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Rash erythematous	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Skin and subcutaneous tissue disorders Skin striae	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Vascular disorders Granulomatosis with polyangiitis	0.00% 0/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.
Vascular disorders Hypertension	8.0% 2/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.	12.0% 3/25 • Up to approximately 5 years The safety population included all participants who received at least part of one infusion of rituximab.