Microscopic Polyangiitis, Vasculitis, Wegener's Granulomatosis
Conditions
Keywords
ANCA, Vasculitis, Wegener's Granulomatosis, microscopic polyangiitis, ANCA-positive, ANCA-associated, ANCA-associated vasculitis, MPA
Brief summary
Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is the most common type of small blood vessel inflammation in adults. ANCA-associated vasculitis includes Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Rituximab is a man-made antibody used to treat certain types of cancer. The purpose of this study is to determine the effectiveness of rituximab in treating patients with WG and MPA. Study hypothesis: Rituximab is not inferior to conventional therapy in its ability to induce disease remission by Month 6.
Detailed description
Current conventional therapies for ANCA-associated vasculitis (AAV) are associated with high incidences of treatment failure, disease relapse, substantial toxicity, and patient morbidity and mortality. Rituximab is a monoclonal antibody used to treat non-Hodgkin's lymphoma. This study will evaluate the efficacy of rituximab with glucocorticoids in inducing disease remission in patients with severe forms of AAV (WG and MPA). The study consists of two phases: a 6-month remission induction phase, followed by a 12-month remission maintenance phase. All participants will receive at least 1 g of pulse intravenous methylprednisolone or a dose-equivalent of another glucocorticoid preparation. Depending on the participant's condition, he or she may receive up to 3 days of intravenous methylprednisolone for a total of 3 g of methylprednisolone (or a dose-equivalent). During the remission induction phase, all participants will receive oral prednisone daily (1 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6 study visit. Next, participants will be randomly assigned to one of two arms. Arm 1 participants will receive rituximab (375 mg/m\^2) infusions once weekly for 4 weeks and cyclophosphamide (CYC) placebo daily for 3 to 6 months. Arm 2 participants will receive rituximab placebo infusions once weekly for 4 weeks and CYC daily for 3 to 6 months. During the remission maintenance phase, participants in Arm 1 will discontinue CYC placebo and start oral azathioprine (AZA) placebo daily until Month 18. Participants in Arm 2 will discontinue CYC and start AZA daily until Month 18. Participants who fail treatment before Month 6 will be crossed over to the other treatment arm unless there are specific contraindications. Participants in either group who reach clinical remission before they complete 6 months of therapy may switch from CYC/placebo to AZA/placebo if directed by their physicians. All participants will be followed for at least 18 months. Initially, study visits are weekly, progressing to monthly and then quarterly visits as the study proceeds. Blood collection will occur at each study visit.
Interventions
DRUGRituximab plus cyclophosphamide placebo (rituximab group)
375 mg/m\^2 infusions once weekly for 4 week
DRUGCyclophosphamide plus rituximab placebo (control group)
2 mg/kg/day orally for months 1-3
DRUGAzathioprine
2 mg/kg/day orally for months 4-6
DRUGMethylprednisolone (or other glucocorticoid)
1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab
DRUGPrednisone
During the remission induction phase, all participants will receive oral prednisone daily (1 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6 study visit.
Sponsors
Immune Tolerance Network (ITN)
Genentech, Inc.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Weight of at least 88 pounds(40 kilograms) * Diagnosis of Wegener's granulomatosis or microscopic polyangiitis according to the definitions of the Chapel Hill Consensus Conference * Newly diagnosed patient of Wegener's granulomatosis or microscopic polyangiitis OR must be experiencing a disease flare characterized by: (a) active disease with a Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) of 3 or greater that would normally require treatment with CYC; OR (b) disease severe enough to require treatment with CYC; OR (c) must be positive for either PR3-ANCA (ANCA directed against proteinase 3) or MPO-ANCA (ANCA directed against myeloperoxidase)at the screening * Willing to use acceptable forms of contraception for the duration of the study and for up to 1 year after stopping study medications * Willing to report pregnancies (female participants or male participants' partners) occurring at any time during the study and for up to 1 year after stopping study medications * Parent or guardian willing to provide informed consent, if applicable
Exclusion criteria
* Diagnosis of Churg-Strauss Syndrome according to the definitions of the Chapel Hill Consensus Conference * Have limited disease that would not normally be treated with CYC * Requires mechanical ventilation because of alveolar hemorrhage * History of severe allergic reactions to human or chimeric monoclonal antibodies * Active systemic infection * Have a deep-space infection, such as osteomyelitis, septic arthritis, or pneumonia complicated by pleural cavity or lung abscess, within 6 months prior to study entry * History of or current hepatitis B or C infection * HIV (human immunodeficiency virus) infected * Acute or chronic liver disease that, in the opinion of the investigator, may interfere with the study * History of or active cancer diagnosed within the last 5 years. Individuals with squamous cell or basal cell carcinomas of the skin and individuals with cervical carcinoma in situ who have received curative surgical treatment may be eligible for this study. * History of anti-glomerular basement membrane (anti-GBM) disease * Other uncontrolled disease, including drug and alcohol abuse, that may interfere with the study * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Remission | 6 months post-randomization | A Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) score of 0 with prednisone taper successfully completed at six months. The BVAS/WG is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization | 6 months post-randomization | The 2-sided 95% CI of the percentage of participants who have a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and have successfully completed the glucocorticoid taper by 6 months post-randomization and the 2-sided 95% CI of the difference between two arms for assessing the superiority of rituximab to control \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease |
| The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 18 months post-randomization | Duration of complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and a completing taper of Prednisone to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease |
| Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Through common close-out (defined as 18 months after the last participant is enrolled in the trial) | The adverse event rate for the following events considered related to vasculitis: Death; Grade 2 or higher leukopenia or thrombocytopenia; Grade 3 or higher infections; Hemorrhagic cystitis (grade 2 or lower needs confirmation by cytoscopy); Malignancy; Venous thromboembolic event (deep venous thrombosis or pulmonary embolism); Hospitalization resulting either from the disease or from a complication due to study treatment; Infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions (including cytokine release allergic reaction); Cerebrovascular accident |
| Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 18 months post-randomization | Time to complete remission is defined as the number of days from baseline visit (Visit 1) to a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease |
| Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 18 months post-randomization | Time to complete remission is defined as the number of days from baseline visit (Visit 1) to a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and completing taper of glucocorticoid by 6 months post-randomization. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease |
| The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 18 months post-randomization | Duration of remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and a completing taper of glucocorticoid by 6 months post-randomization to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing. |
Countries
Netherlands, United States
Participant flow
Recruitment details
Eight centers in the United States and one center in the Netherlands (Groningen) enrolled 197 Antineutrophil cytoplasmic antibodies (ANCA)-positive patients with either Wegener's granulomatosis or microscopic polyangiitis between December 30, 2004 and June 30, 2008.
Pre-assignment details
At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Participants received intravenous rituximab (Rituxan, Genentech) (at a dose of 375 mg per square meter of body-surface area once weekly for 4 weeks) plus daily placebo-cyclophosphamide. Refer to section titled Detailed Description for additional treatment information. | 99 |
| Control Group Participants received placebo-rituximab infusions plus daily cyclophosphamide (2 mg per kilogram of body weight, adjusted for renal insufficiency). Refer to section titled Detailed Description for additional treatment information. | 98 |
| Total | 197 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | To have renal transplant | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Rituximab | Total | Control Group |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 6 Participants | 3 Participants |
| Age, Categorical >=65 years | 36 Participants | 55 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 60 Participants | 136 Participants | 76 Participants |
| Age, Continuous | 54.0 years STANDARD_DEVIATION 16.8 | 52.8 years STANDARD_DEVIATION 15.5 | 51.5 years STANDARD_DEVIATION 14.1 |
| BVAS/WG | 8.1 score units STANDARD_DEVIATION 2.8 | 8.0 score units STANDARD_DEVIATION 3.1 | 8.0 score units STANDARD_DEVIATION 3.4 |
| Region of Enrollment Netherlands | 8 participants | 16 participants | 8 participants |
| Region of Enrollment United States | 91 participants | 181 participants | 90 participants |
| Sex: Female, Male Female | 52 Participants | 97 Participants | 45 Participants |
| Sex: Female, Male Male | 47 Participants | 100 Participants | 53 Participants |
| VDI | 1.4 score units STANDARD_DEVIATION 1.8 | 1.2 score units STANDARD_DEVIATION 1.7 | 1.0 score units STANDARD_DEVIATION 1.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 97 / 99 | 97 / 98 |
| serious Total, serious adverse events | 60 / 99 | 47 / 98 |
Outcome results
Primary
Disease Remission
A Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) score of 0 with prednisone taper successfully completed at six months. The BVAS/WG is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease.
Time frame: 6 months post-randomization
Population: Intent-to-treat (ITT) sample with worst case imputation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Disease Remission | 63 Participants |
| Control Group | Disease Remission | 52 Participants |
Comparison: In calculating the sample size, we assumed that the percentage of patients in both treatment groups would achieve disease remission off prednisone by 6 months was 70%. We specified a non-inferiority margin of -20% on the difference in remission rates (rituximab rate minus cyclophosphamide rate) and a one-sided 0.025 level test. Assuming a 10% dropout rate, RAVE required 100 patients in each arm to have 83% power to conclude non-inferiority.p-value: <0.00195.1% CI: [-3.2, 24.3]95.1% CI of difference
Secondary
Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization
The 2-sided 95% CI of the percentage of participants who have a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and have successfully completed the glucocorticoid taper by 6 months post-randomization and the 2-sided 95% CI of the difference between two arms for assessing the superiority of rituximab to control \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease
Time frame: 6 months post-randomization
Population: Safety Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization | 62 participants |
| Control Group | Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization | 51 participants |
Comparison: The p-value is from a chi-square test.p-value: 0.13395.1% CI: [-3.2, 24.4]Chi-squared
Secondary
Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy
The adverse event rate for the following events considered related to vasculitis: Death; Grade 2 or higher leukopenia or thrombocytopenia; Grade 3 or higher infections; Hemorrhagic cystitis (grade 2 or lower needs confirmation by cytoscopy); Malignancy; Venous thromboembolic event (deep venous thrombosis or pulmonary embolism); Hospitalization resulting either from the disease or from a complication due to study treatment; Infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions (including cytokine release allergic reaction); Cerebrovascular accident
Time frame: Through common close-out (defined as 18 months after the last participant is enrolled in the trial)
Population: Safety Sample
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 2 or Higher Thrombocytopenia | 4 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 2 or Higher Leukopenia | 7 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Venous Thromboembolic Event | 6 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 3 or Higher Infections | 18 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Hospitalization Resulting from the Disease | 16 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Death | 2 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Cerebrovascular Accident (CVA) | 1 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Hemorrhagic Cystitis (Grade 2 or Lower) | 2 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Infusion Reactions Leading to Infusion Disc. | 1 participants |
| Rituximab | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Malignancy | 5 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Infusion Reactions Leading to Infusion Disc. | 0 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Death | 2 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 2 or Higher Leukopenia | 23 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 2 or Higher Thrombocytopenia | 1 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Grade 3 or Higher Infections | 16 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Hemorrhagic Cystitis (Grade 2 or Lower) | 1 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Malignancy | 2 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Venous Thromboembolic Event | 8 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Hospitalization Resulting from the Disease | 7 participants |
| Control Group | Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy | Cerebrovascular Accident (CVA) | 1 participants |
Comparison: Participant-months are defined as duration in months from the first study drug dosing date to the last date of the participant in the protocol. The rate of selected AEs is defined as the total number of selected AEs divided by total participant-months, and indicates the number of events per participant per month on average. Participants are grouped according to their originally received treatment.p-value: 0.927Poisson regression model
Secondary
The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Duration of complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and a completing taper of Prednisone to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease
Time frame: 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 25% Quartile (95%CI) | 243 Days |
| Rituximab | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 50% Quartile (95%CI) | NA Days |
| Rituximab | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 75% Quartile (95%CI) | NA Days |
| Control Group | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 25% Quartile (95%CI) | 230 Days |
| Control Group | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 50% Quartile (95%CI) | NA Days |
| Control Group | The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 75% Quartile (95%CI) | NA Days |
Comparison: Participants are censored at the time of crossover, open label rituximab, or best medical judgement, if applicable. If a participant has no flare after complete remission prior to their Month 18 visit, the duration is censored at the date of the Month 18 Visitp-value: 0.76195% CI: [0.5, 1.7]Log Rank
Secondary
The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Duration of remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and a completing taper of glucocorticoid by 6 months post-randomization to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing.
Time frame: 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 25% Quartile (95%CI) | 246 Days |
| Rituximab | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 50% Quartile (95%CI) | NA Days |
| Rituximab | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 75% Quartile (95%CI) | NA Days |
| Control Group | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 25% Quartile (95%CI) | 168 Days |
| Control Group | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 50% Quartile (95%CI) | NA Days |
| Control Group | The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups | 75% Quartile (95%CI) | NA Days |
Comparison: Participants are censored at the time of crossover, open label rituximab, or best medical judgement, if applicable. If a participant has no flare after complete remission prior to their Month 18 visit, the duration is censored at the date of the Month 18 Visitp-value: 0.86195% CI: [0.6, 1.5]Log Rank
Secondary
Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups
Time to complete remission is defined as the number of days from baseline visit (Visit 1) to a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0 and completing taper of glucocorticoid by 6 months post-randomization. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease
Time frame: 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 25% Quartile (95%CI) | 176 Days |
| Rituximab | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 50% Quartile (95%CI) | 180 Days |
| Rituximab | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 75% Quartile (95%CI) | 189 Days |
| Control Group | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 25% Quartile (95%CI) | 177 Days |
| Control Group | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 50% Quartile (95%CI) | 183 Days |
| Control Group | Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups | 75% Quartile (95%CI) | 266 Days |
p-value: 0.14795% CI: [0.9, 1.8]Log Rank
Secondary
Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups
Time to complete remission is defined as the number of days from baseline visit (Visit 1) to a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)\[1\] of 0. \[1\] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease
Time frame: 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 25% Quartile (95%CI) | 30 Days |
| Rituximab | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 50% Quartile (95%CI) | 57 Days |
| Rituximab | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 75% Quartile (95%CI) | 119 Days |
| Control Group | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 25% Quartile (95%CI) | 29 Days |
| Control Group | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 50% Quartile (95%CI) | 43 Days |
| Control Group | Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups | 75% Quartile (95%CI) | 112 Days |
p-value: 0.49795% CI: [0.7, 1.3]Log Rank
Post Hoc
Number of Subjects Experiencing Serious Adverse Events
Number of subjects according to originally received treatment that experienced a serious adverse event through 18 months post-randomization or prior to being censored from analyses due to crossover, switching to open-label treatment, or best medical judgment for censor. Events are categorized by coded system organ classes (SOC). Within each SOC, a participant was counted once if the participant reported one or more events coded to that SOC.
Time frame: Randomization to censor at Crossover, Open-label or Best Medical Judgment (up to 18 months post-randomization)
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | General Disorders and Administration Site | 5 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Metabolism and Nutrition Disorders | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Eye Disorders | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Musculoskeletal and Connective Tissue Disorders | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Immune System Disorders | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Neoplasms Benign, Malignant, and Unspecified | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Cardiac Disorders | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Nervous System Disorders | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Infections and Infestations | 12 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Pregnancy, Puerperium, and Perinatal Conditions | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Gastrointestinal Disorders | 4 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Psychiatric Disorders | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Injury, Poisoning, and Procedural Complications | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Renal and Urinary Disorders | 4 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Blood and Lymphatic System Disorders | 4 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Respiratory, Thoracic, and Mediastinal Disorders | 8 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Investigations | 2 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | Vascular Disorders | 1 participants |
| Rituximab | Number of Subjects Experiencing Serious Adverse Events | # Participants with at least one SAE | 42 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Vascular Disorders | 7 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | # Participants with at least one SAE | 37 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Blood and Lymphatic System Disorders | 5 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Cardiac Disorders | 2 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Eye Disorders | 1 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Gastrointestinal Disorders | 1 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | General Disorders and Administration Site | 3 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Immune System Disorders | 2 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Infections and Infestations | 12 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Injury, Poisoning, and Procedural Complications | 0 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Investigations | 0 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Metabolism and Nutrition Disorders | 2 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Musculoskeletal and Connective Tissue Disorders | 3 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Neoplasms Benign, Malignant, and Unspecified | 2 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Nervous System Disorders | 0 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Pregnancy, Puerperium, and Perinatal Conditions | 0 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Psychiatric Disorders | 1 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Renal and Urinary Disorders | 3 participants |
| Control Group | Number of Subjects Experiencing Serious Adverse Events | Respiratory, Thoracic, and Mediastinal Disorders | 8 participants |
Comparison: Proportions of subjects experiencing a serious adverse event through 18 months and prior to censoring for open-label, crossover, or best medical judgment according to originally assigned treatment arm were compared using a two-sided Chi-squared test.p-value: 0.504Chi-squared