Granulomatosis With PolyangiitisPhase 2NCT01750697
A Phase IIa Study of Intravenous Rituximab in Pediatric Participants With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis
A Phase 2 study testing Rituximab in people with Granulomatosis With Polyangiitis, run by Hoffmann-La Roche at 23 sites in 8 countries.
Trial summary
This Phase IIa international multicenter, open-label, uncontrolled study will evaluate the safety and pharmacokinetics of rituximab (MabThera/Rituxan) in pediatric participants with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Read more about this study
- Who is it for?
- Ages 2 to 17 years
- Conditions the study is for
- Granulomatosis With Polyangiitis
- What is being tested?
- Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 23 sitesin 8 countries
- Study dates
- 23 May 2013to 10 May 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood Wegener's granulomatosis) or diagnosis of MPA (according to the Chapel Hill Consensus Conference)
- Newly diagnosed participants or participants with relapsing disease according to the following definition:
- The recurrence or new onset of potentially organ- or life-threatening disease (i.e. one or more major Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [BVAS/WG] items or disease severe enough to require treatment with cyclophosphamide)
- For participants of reproductive potential (males and females), use of reliable means of contraception throughout the study participation
- For all eligible participants mandatory prophylactic treatment for Pneumocystis jirovecii infection
Who cannot join
- Diagnosis of Churg-Strauss syndrome, as defined by the Chapel Hill Consensus Conference
- Limited disease that would not normally be treated with cyclophosphamide
- Severe disease requiring mechanical ventilation due to alveolar hemorrhage
- Requirement for plasmapheresis or dialysis at screening
- Incomplete recovery from recent surgery or less than (<) 12 weeks since surgery prior to baseline or planned within 24 weeks of baseline
- Lack of peripheral venous access
Show all 31Show fewer
- Pregnancy or breast-feeding
- Evidence of other significant uncontrolled concomitant disease, or of disorder or condition that, in the investigator's opinion, would preclude or interfere with participation of participant
- Primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (HIV) infection
- Evidence of active tuberculosis (participants receiving chemoprophylaxis for latent tuberculosis infection are eligible for the study)
- Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks of baseline or completion of oral anti-infective agents within 2 weeks prior to baseline. Entry into this study may be reconsidered once the infection has fully resolved
- History of deep space/tissue infection within 24 weeks prior to baseline
- History of serious recurrent or chronic infection
- History of cancer (except for basal cell and squamous cell carcinoma of the skin that have been excised and cured)
- Currently active alcohol or drug abuse or history of alcohol or drug abuse
- History of severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins
- Treatment with rituximab or other biologic B cell-targeted therapy (e.g., anti- Cluster of Differentiation [CD] 19, anti-CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/B-cell activating factor [BAFF]) within 6 months prior to baseline visit
- Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator
- Previous treatment with other cell-depleting therapies, including, but not limited to, investigational agents (e.g., alemtuzumab, anti-CD4, anti-CD5, anti-CD3, and anti-CD11a)
- Receipt of oral or IV cyclophosphamide within the previous 4 months prior to the baseline visit
- Receipt of infliximab within 3 months, adalimumab within 2 months or etanercept within 1 month prior to the baseline visit
- Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is longer)
- Receipt of any live attenuated vaccine within 28 days prior to baseline
- Intolerance or contraindications to IV glucocorticoids
- Positive serum human chorionic gonadotropin measured at screening or a positive pregnancy test prior to the first rituximab infusion for participants of childbearing potential
- Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B virus (HBV), or hepatitis C serology
- Level of Immunoglobulin (Ig) M below lower limit of normal of age-specific reference range
- Level of IgG below 5.65 milligram per milliliter
- Absolute neutrophil count < 1.5 × 10^3 per microliter and platelet count < 130 × 10^3 per microliter
- Estimated Glomerular Filtration Rate < 15 milliliter per minute per 1.73 m^2
- Alanine aminotransferase or aspartate aminotransferase levels greater than 2.5 times the upper limit of normal (for age and sex) that cannot be attributed to underlying granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)
Trial locations and contacts
23 sites in 8 countries.
23 sites in 8 countries
United States6 sites
Cincinnati Childrens Hospital
Cincinnati, Ohio, 45229
The Cleveland Clinic Foundation; Rheumatic and Immunologic Diseases
Cleveland, Ohio, 44195
Hackensack University Medical Center
Hackensack, New Jersey, 07601
University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit
Louisville, Kentucky, 40202
COLUMBIA PRESBYTERIAN MEDICAL CENTER, Research Pharmacy, William Black Medical Research Building
New York, New York, 10032
University of Utah; Immunology/Rheumatology/Allergy
Salt Lake City, Utah, 84109
Canada3 sites
Alberta Children'S Hospital
Calgary, Alberta, T3B 6A8
The Hospital for Sick Children Research Institute
Toronto, Ontario, M5G 1L7
Children's and Women's Health Center / BC Children's Hospital
Vancouver, British Columbia, V6H 3V4
Italy3 sites
Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
Genoa, Liguria, 16147
Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica
Padova, Veneto, 35128
Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina
Rome, Lazio, 00165
United Kingdom3 sites
Alder Hey Children s Hospital; Department of Pediatrics
Liverpool, L12 2AP
Great Ormond Street Children's Hospital; Centre of Paediatric & Adolescent Rheumatology
London, WC1N 1EH
Nottingham Children's Hospital
Nottingham, NG7 2UH
France2 sites
Hopital Femme Mere Enfant; Ped Nephrologie Rhumatologie
Bron, 69677
Hop Necker Enfants Malades;UIH
Paris, 75743
Germany2 sites
Universitätsklinikum für Kinder und Jugendmedizin Hamburg
Hamburg, 20246
KfH-Nierenzentrum fur Kinder und Jugendliche
Heidelberg, 69120
Serbia2 sites
Childrens University Hospital
Belgrade, 11000
Clinical Center Nis
Niš, 18000
Turkey (Türkiye)2 sites
Hacettepe University, School of Medicine; Pediatrics Department
Ankara, 06100
Istanbul University, Cerrahpasa Medical Faculty; Pediatrics Department
Istanbul, 34098
About this study
Official title: A Phase IIA, International, Multicenter, Open-label, Uncontrolled Study to Evaluate The Safety And Pharmacokinetics of 4 × 375 mg/m2 Intravenous Rituximab in Pediatric Patients With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis
This Phase IIa international multicenter, open-label, uncontrolled study will evaluate the safety and pharmacokinetics of rituximab (MabThera/Rituxan) in pediatric participants with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Participants will receive rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, 15 and 22.
- Conditions
- Granulomatosis With Polyangiitis
- Being tested
- Rituximab
- Medical subject headings
- Granulomatosis with Polyangiitis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called MabThera/Rituxan
Participants will receive rituximab 375 mg/m^2 IV infusion on Days 1, 8, 15 and 22. Rituximab infusions will be given at a rate of 25 milligrams per hour (mg/h). This may be escalated at a rate of 25 mg/h increments every 30 minutes to a maximum of 200 mg/h.
| Study group | Role | What they receive |
|---|---|---|
| Rituximab | Experimental | Not described Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Adverse Events (AEs), Including Serious AEs
An AE is any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporarily associated with the use of a study drug, whether or not considered related to the study drug. A SAE is any experience that results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
Measured: Baseline (Day 1) up to last visit (1.5-5 years)
Pharmacokinetics: Rituximab Clearance (CL)
CL is a quantitative measure of the rate at which a drug substance is removed from the body. The following allometric scaling equation was used for the estimation of CL in children:
CL= qCL X (BSA/1.9) 0.92 X 1.31*ADA
where qCL is a typical value of clearance in millilitres per day (mL/day) for a typical participant (i.e., Body Surface Area (BSA) of 1.9 m^2 and absence of anti-rituximab antibodies (ADA)) and is equal to 258 mL/day; BSA is in m^2 and ADA is 1 when anti-rituximab antibodies are present (0 otherwise). The allometric scaling factor was 0.92. CL was calculated in millilitres per day (mL/day).
Measured: From Day 1 to Day 180
Pharmacokinetics: Volume of Distribution (Vd) of Rituximab
Vd is defined as the theoretical central volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vd was calculated in millilitres (mL).
Measured: From Day 1 to Day 180
Secondary outcomes (2)
Pharmacokinetics: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC-180) of Rituximab
The AUC0-180 is a measure of the plasma concentration of rituximab over time. The AUC0-180 was calculated in micrograms per millilitres times day (mcg/mL*day).
Measured: From Day 1 to Day 180
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab
Cmax is the maximum observed plasma rituximab concentration. Cmax was assessed at each visit following 1st, 2nd, 3rd, and 4th IV dose of rituximab 375 mg/m^2 on Days 1, 8, 15, and 22. Cmax was calculated in micrograms per millilitre (mcg/mL).
Measured: From Day 1 to Day 180
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2012 (estimated)
- Study start23 May 2013
- Primary completion10 May 2018
- Study completion10 May 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Granulomatosis With PolyangiitisStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01750697
- Sponsor's protocol ID
- WA25615
- Other IDs
- 2012-002062-13
- Status last verified
- Jun 2019
- First submitted
- 13 Dec 2012
- Last updated
- 26 Jun 2019
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Melega S, Brogan P, Cleary G, Hersh AO, Kasapcopur O, Rangaraj S, Yeung RSM, Zeft A, Cooper J, Pordeli P, Kirchner P, Lehane PB. Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis. Rheumatol Ther. 2022 Apr;9(2):721-734. doi: 10.1007/s40744-022-00433-0. Epub 2022 Mar 12.
PubMed 35279811Brogan P, Yeung RSM, Cleary G, Rangaraj S, Kasapcopur O, Hersh AO, Li S, Paripovic D, Schikler K, Zeft A, Bracaglia C, Eleftheriou D, Pordeli P, Melega S, Jamois C, Gaudreault J, Michalska M, Brunetta P, Cooper JC, Lehane PB; PePRS Study Group. Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis. Arthritis Rheumatol. 2022 Jan;74(1):124-133. doi: 10.1002/art.41901. Epub 2021 Dec 5.
PubMed 34164952
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IIA, International, Multicenter, Open-label, Uncontrolled Study to Evaluate The Safety And Pharmacokinetics of 4 × 375 mg/m2 Intravenous Rituximab in Pediatric Patients With Severe Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis
- ClinicalTrials.gov ID
- NCT01750697
- Acronym / sponsor ID
- WA25615
- Conditions
- Granulomatosis With Polyangiitis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Study start
- 23 May 2013 (actual)
- Primary completion
- 10 May 2018 (actual)
- Study completion
- 10 May 2018 (actual)
- First posted
- 17 Dec 2012 (estimated)
- Results
- Posted 26 Jun 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This Phase IIa international multicenter, open-label, uncontrolled study will evaluate the safety and pharmacokinetics of rituximab (MabThera/Rituxan) in pediatric participants with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Participants will receive rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, 15 and 22.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Rituximab | Experimental | Drug: Rituximab |
Who may qualify
- Ages
- 2 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood Wegener's granulomatosis) or diagnosis of MPA (according to the Chapel Hill Consensus Conference)
- Newly diagnosed participants or participants with relapsing disease according to the following definition:
- The recurrence or new onset of potentially organ- or life-threatening disease (i.e. one or more major Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [BVAS/WG] items or disease severe enough to require treatment with cyclophosphamide)
- For participants of reproductive potential (males and females), use of reliable means of contraception throughout the study participation
- For all eligible participants mandatory prophylactic treatment for Pneumocystis jirovecii infection
Key exclusion criteria (31 listed)
- Diagnosis of Churg-Strauss syndrome, as defined by the Chapel Hill Consensus Conference
- Limited disease that would not normally be treated with cyclophosphamide
- Severe disease requiring mechanical ventilation due to alveolar hemorrhage
- Requirement for plasmapheresis or dialysis at screening
- Incomplete recovery from recent surgery or less than (<) 12 weeks since surgery prior to baseline or planned within 24 weeks of baseline
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: MabThera/RituxanParticipants will receive rituximab 375 mg/m^2 IV infusion on Days 1, 8, 15 and 22. Rituximab infusions will be given at a rate of 25 milligrams per hour (mg/h). This may be escalated at a rate of 25 mg/h increments every 30 minutes to a maximum of 200 mg/h. | Drug | Rituximab |
Primary outcome
Percentage of Participants With Adverse Events (AEs), Including Serious AEs
Time frame: Baseline (Day 1) up to last visit (1.5-5 years)
An AE is any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporarily associated with the use of a study drug, whether or not considered related to the study drug. A SAE is any experience that results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
Pharmacokinetics: Rituximab Clearance (CL)
Time frame: From Day 1 to Day 180
CL is a quantitative measure of the rate at which a drug substance is removed from the body. The following allometric scaling equation was used for the estimation of CL in children: CL= qCL X (BSA/1.9) 0.92 X 1.31*ADA where qCL is a typical value of clearance in millilitres per day (mL/day) for a typical participant (i.e., Body Surface Area (BSA) of 1.9 m^2 and absence of anti-rituximab antibodies (ADA)) and is equal to 258 mL/day; BSA is in m^2 and ADA is 1 when anti-rituximab antibodies are present (0 otherwise). The allometric scaling factor was 0.92. CL was calculated in millilitres per day (mL/day).
Pharmacokinetics: Volume of Distribution (Vd) of Rituximab
Time frame: From Day 1 to Day 180
Vd is defined as the theoretical central volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vd was calculated in millilitres (mL).
2 secondary outcomes
Pharmacokinetics: Area Under the Concentration-Time Curve From Time 0 to 180 Days (AUC-180) of Rituximab
Time frame: From Day 1 to Day 180
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Rituximab
Time frame: From Day 1 to Day 180
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35279811Melega S, Brogan P, Cleary G, Hersh AO, Kasapcopur O, Rangaraj S, Yeung RSM, Zeft A, Cooper J, Pordeli P, Kirchner P, Lehane PB. Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis. Rheumatol Ther. 2022 Apr;9(2):721-734. doi: 10.1007/s40744-022-00433-0. Epub 2022 Mar 12.
- Derived from this study: PubMed 34164952Brogan P, Yeung RSM, Cleary G, Rangaraj S, Kasapcopur O, Hersh AO, Li S, Paripovic D, Schikler K, Zeft A, Bracaglia C, Eleftheriou D, Pordeli P, Melega S, Jamois C, Gaudreault J, Michalska M, Brunetta P, Cooper JC, Lehane PB; PePRS Study Group. Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis. Arthritis Rheumatol. 2022 Jan;74(1):124-133. doi: 10.1002/art.41901. Epub 2021 Dec 5.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trials study director
Hoffmann-La Roche
23 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rituximab in people with Granulomatosis With Polyangiitis, run by Hoffmann-La Roche at 23 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in United States, Canada, Italy, United Kingdom, France and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jun 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Adverse Events (AEs), Including Serious AEs (time frame: Baseline (Day 1) up to last visit (1.5-5 years)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01750697, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jun 2019.