RAVE: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00104299
• Collaborator: Immune Tolerance Network (ITN) (Other), Genentech, Inc. (Industry)
• Enrollment: 197
• Locations: 8
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 24.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Vasculitis; Wegener's Granulomatosis; Microscopic Polyangiitis	Drug: Rituximab plus cyclophosphamide placebo (rituximab group); Drug: Cyclophosphamide plus rituximab placebo (control group); Drug: Azathioprine; Drug: Methylprednisolone (or other glucocorticoid); Drug: Prednisone	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 197 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Rituximab Therapy for the Induction of Remission and Tolerance in ANCA-Associated Vasculitis (ITN021AI)
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab	Drug: Rituximab plus cyclophosphamide placebo (rituximab group); 375 mg/m^2 infusions once weekly for 4 week; Other Names: Rituxan ; Drug: Methylprednisolone (or other glucocorticoid); 1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab; Other Names: Medrol ; Drug: Prednisone; 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.; Other Names: Deltasone, Liquid Pred, Meticorten, Orasone
Active Comparator: Control Group	Drug: Cyclophosphamide plus rituximab placebo (control group); 2 mg/kg/day orally for months 1-3; Other Names: Cytoxan ; Drug: Azathioprine; 2 mg/kg/day orally for months 4-6; Other Names: imuran ; Drug: Methylprednisolone (or other glucocorticoid); 1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab; Other Names: Medrol ; Drug: Prednisone; 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.; Other Names: Deltasone, Liquid Pred, Meticorten, Orasone

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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.

5. 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

6. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	Johns Hopkins University	Baltimore	Maryland	United States	21224
3	Boston University	Boston	Massachusetts	United States	02118
4	Mayo Clinic Foundation	Rochester	Minnesota	United States	55905
5	Hospital for Special Surgery	New York	New York	United States	10128
6	Duke University	Durham	North Carolina	United States	27710
7	The Cleveland Clinic	Cleveland	Ohio	United States	44195
8	University Hospital Groningen	Groningen		Netherlands	9713 GZ

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)
• Genentech, Inc.

Investigators

• Study Chair: John H. Stone, MD, MPH, Johns Hopkins University
• Study Chair: Ulrich Specks, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network website
• Genentech website

Publications

• Zarin DA. Participant-level data and the new frontier in trial transparency. N Engl J Med. 2013 Aug 1;369(5):468-9. doi: 10.1056/NEJMe1307268.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00104299
• Other Study ID Numbers: DAIT ITN021AI
• First Posted: Feb 25, 2005
• Last Update Posted: Apr 21, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): ANCA; Vasculitis; Wegener's Granulomatosis; microscopic polyangiitis; ANCA-positive; ANCA-associated; ANCA-associated vasculitis; MPA
• Additional relevant MeSH terms: Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Vasculitis; Systemic Vasculitis; Prednisone; Methylprednisolone; Cyclophosphamide; Rituximab; Azathioprine; Glucocorticoids

Study Results

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 Detail	At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	99	98
COMPLETED	90	88
NOT COMPLETED	9	10

Baseline Characteristics

Arm/Group Title	Rituximab	Control Group	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	99	98	197
Age (Count of Participants)
<=18 years	3 3%	3 3.1%	6 3%
Between 18 and 65 years	60 60.6%	76 77.6%	136 69%
>=65 years	36 36.4%	19 19.4%	55 27.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.0 (16.8)	51.5 (14.1)	52.8 (15.5)
Sex: Female, Male (Count of Participants)
Female	52 52.5%	45 45.9%	97 49.2%
Male	47 47.5%	53 54.1%	100 50.8%
Region of Enrollment (participants) [Number]
United States	91 91.9%	90 91.8%	181 91.9%
Netherlands	8 8.1%	8 8.2%	16 8.1%
BVAS/WG (score units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score units]	8.1 (2.8)	8.0 (3.4)	8.0 (3.1)
VDI (score units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score units]	1.4 (1.8)	1.0 (1.4)	1.2 (1.7)

Outcome Measures

1. Primary Outcome

Title	Disease Remission
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) sample with worst case imputation

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
Number [Participants]	63 63.6%	52 53.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	non-inferiority margin of -20%
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is adjusted for interim analysis using a Lan-DeMets alpha spending function with an O'Brien-Fleming boundary, allocating 0.003 alpha to the interim analysis and 0.049 alpha to the final analysis.
	Method	95.1% CI of difference
	Comments	Calculate 95.1% CI around the difference in success rates between arms. Lower bound above non-inferiority margin of -20% indicates non-inferiority.
Method of Estimation	Estimation Parameter	Difference between group success rates
	Estimated Value	10.6
	Confidence Interval	() 95.1%; -3.2 to 24.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Sample

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
Death	2 2%	2 2%
Grade 2 or Higher Leukopenia	7 7.1%	23 23.5%
Grade 2 or Higher Thrombocytopenia	4 4%	1 1%
Grade 3 or Higher Infections	18 18.2%	16 16.3%
Hemorrhagic Cystitis (Grade 2 or Lower)	2 2%	1 1%
Malignancy	5 5.1%	2 2%
Venous Thromboembolic Event	6 6.1%	8 8.2%
Hospitalization Resulting from the Disease	16 16.2%	7 7.1%
Cerebrovascular Accident (CVA)	1 1%	1 1%
Infusion Reactions Leading to Infusion Disc.	1 1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.927
	Comments	P-value is from the Poisson regression model adjusting for clinical study site and ANCA type. The natural logarithm of participant-months is used as an offset in this model
	Method	Poisson regression model
	Comments

3. Secondary Outcome

Title	Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization
Description	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

Outcome Measure Data

Analysis Population Description

Safety Sample

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
Number [participants]	62 62.6%	51 52%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	The p-value is from a chi-square test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.133
	Comments
	Method	Chi-squared
	Comments	At 6 months, the confidence interval is 95.1%.
Method of Estimation	Estimation Parameter	95.1% Confidence Interval of Difference
	Estimated Value	10.6
	Confidence Interval	(2-Sided) 95.1%; -3.2 to 24.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
25% Quartile (95%CI)	243	230
50% Quartile (95%CI)	NA	NA
75% Quartile (95%CI)	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	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 Visit
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.761
	Comments	The log-rank test assesses the difference between the two treatment arms in the flaring pattern after complete remission
	Method	Log Rank
	Comments	The log-rank test assesses the difference between the two treatment arms in the flaring pattern after complete remission
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
25% Quartile (95%CI)	246	168
50% Quartile (95%CI)	NA	NA
75% Quartile (95%CI)	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	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 Visit
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.861
	Comments
	Method	Log Rank
	Comments	The log-rank test assesses the difference between the two treatment arms in the flaring pattern after remission
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.6 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
25% Quartile (95%CI)	30	29
50% Quartile (95%CI)	57	43
75% Quartile (95%CI)	119	112

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.497
	Comments
	Method	Log Rank
	Comments	The log-rank test assesses the difference between the two treatment arms in the pattern of achieving remission
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio and confidence interval are based on a Cox proportional hazard model comparing rituximab to the control group, adjusting for clinical study site, ANCA type, and glucocorticoid use prior to baseline.

7. Secondary Outcome

Title	Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
25% Quartile (95%CI)	176	177
50% Quartile (95%CI)	180	183
75% Quartile (95%CI)	189	266

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.147
	Comments
	Method	Log Rank
	Comments	The log-rank test assesses the difference between the two treatment arms in the pattern of achieving complete remission
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio and confidence interval are based on a Cox proportional hazard model comparing rituximab to the control group, adjusting for clinical study site, ANCA type, and glucocorticoid use prior to baseline.

8. Post-Hoc Outcome

Title	Number of Subjects Experiencing Serious Adverse Events
Description	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)

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Rituximab	Control Group
Arm/Group Description	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.	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.
Measure Participants	99	98
# Participants with at least one SAE	42 42.4%	37 37.8%
Blood and Lymphatic System Disorders	4 4%	5 5.1%
Cardiac Disorders	2 2%	2 2%
Eye Disorders	1 1%	1 1%
Gastrointestinal Disorders	4 4%	1 1%
General Disorders and Administration Site	5 5.1%	3 3.1%
Immune System Disorders	2 2%	2 2%
Infections and Infestations	12 12.1%	12 12.2%
Injury, Poisoning, and Procedural Complications	2 2%	0 0%
Investigations	2 2%	0 0%
Metabolism and Nutrition Disorders	2 2%	2 2%
Musculoskeletal and Connective Tissue Disorders	2 2%	3 3.1%
Neoplasms Benign, Malignant, and Unspecified	1 1%	2 2%
Nervous System Disorders	1 1%	0 0%
Pregnancy, Puerperium, and Perinatal Conditions	1 1%	0 0%
Psychiatric Disorders	1 1%	1 1%
Renal and Urinary Disorders	4 4%	3 3.1%
Respiratory, Thoracic, and Mediastinal Disorders	8 8.1%	8 8.2%
Vascular Disorders	1 1%	7 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Control Group
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.504
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	From randomization through common close out (defined as 18 months after the last participant is enrolled in the trial)
Adverse Event Reporting Description	Adverse events reported include both disease and non-disease related events by originally assigned treatment. No participants are censored from these results. NCI-CTCAE version 3.0 (published June 10, 2003) was used to grade severity.
Arm/Group Title	Rituximab		Control Group
Arm/Group Description	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.		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.
All Cause Mortality
	Rituximab		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rituximab		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/99 (60.6%)		47/98 (48%)
Blood and lymphatic system disorders
Anaemia	3/99 (3%)	3	4/98 (4.1%)	6
Autoimmune thrombocytopenia	1/99 (1%)	1	0/98 (0%)	0
Febrile neutropenia	0/99 (0%)	0	2/98 (2%)	2
Leukopenia	3/99 (3%)	5	0/98 (0%)	0
Pancytopenia	0/99 (0%)	0	1/98 (1%)	1
Cardiac disorders
Atrial fibrillation	2/99 (2%)	2	0/98 (0%)	0
Atrial tachycardia	1/99 (1%)	1	0/98 (0%)	0
Myocardial infarction	0/99 (0%)	0	1/98 (1%)	1
Supraventricular tachycardia	0/99 (0%)	0	1/98 (1%)	1
Ear and labyrinth disorders
Sudden hearing loss	0/99 (0%)	0	1/98 (1%)	1
Eye disorders
Keratitis	1/99 (1%)	1	0/98 (0%)	0
Ulcerative keratitis	0/99 (0%)	0	1/98 (1%)	1
Gastrointestinal disorders
Colitis ischaemic	2/99 (2%)	2	0/98 (0%)	0
Diarrhoea	2/99 (2%)	2	0/98 (0%)	0
Gastritis	1/99 (1%)	1	0/98 (0%)	0
Impaired gastric emptying	1/99 (1%)	1	0/98 (0%)	0
Pancreatitis acute	0/99 (0%)	0	2/98 (2%)	2
Upper gastrointestinal haemorrhage	1/99 (1%)	1	0/98 (0%)	0
General disorders
Adverse drug reaction	1/99 (1%)	1	1/98 (1%)	1
Asthenia	1/99 (1%)	1	0/98 (0%)	0
Chest pain	1/99 (1%)	1	1/98 (1%)	1
Chills	0/99 (0%)	0	2/98 (2%)	2
Multi-organ failure	1/99 (1%)	1	0/98 (0%)	0
Pyrexia	2/99 (2%)	2	0/98 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/99 (0%)	0	1/98 (1%)	1
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis	1/99 (1%)	1	0/98 (0%)	0
Drug hypersensitivity	0/99 (0%)	0	2/98 (2%)	2
Hypersensitivity	1/99 (1%)	1	0/98 (0%)	0
Infections and infestations
Abdominal abscess	1/99 (1%)	1	0/98 (0%)	0
Abscess limb	1/99 (1%)	1	0/98 (0%)	0
Acute sinusitis	0/99 (0%)	0	1/98 (1%)	1
Bronchitis	1/99 (1%)	1	1/98 (1%)	1
Cellulitis	1/99 (1%)	1	0/98 (0%)	0
Cellulitis orbital	1/99 (1%)	1	0/98 (0%)	0
Cellulitis staphylococcal	1/99 (1%)	1	0/98 (0%)	0
Central line infection	0/99 (0%)	0	1/98 (1%)	1
Clostridial infection	1/99 (1%)	2	0/98 (0%)	0
Clostridium difficile colitis	1/99 (1%)	1	0/98 (0%)	0
Escherichia infection	1/99 (1%)	1	0/98 (0%)	0
Gastroenteritis viral	1/99 (1%)	1	1/98 (1%)	1
Infective exacerbation of chronic obstructive airways disease	1/99 (1%)	1	0/98 (0%)	0
Influenza	1/99 (1%)	1	0/98 (0%)	0
Lobar pneumonia	0/99 (0%)	0	1/98 (1%)	1
Osteomyelitis	1/99 (1%)	1	0/98 (0%)	0
Periorbital cellulitis	0/99 (0%)	0	1/98 (1%)	2
Pneumocystis jiroveci pneumonia	0/99 (0%)	0	1/98 (1%)	1
Pneumonia	8/99 (8.1%)	10	10/98 (10.2%)	11
Pneumonia bacterial	0/99 (0%)	0	1/98 (1%)	1
Post streptococcal glomerulonephritis	1/99 (1%)	1	0/98 (0%)	0
Respiratory tract infection	0/99 (0%)	0	1/98 (1%)	1
Sepsis	0/99 (0%)	0	1/98 (1%)	1
Septic shock	0/99 (0%)	0	1/98 (1%)	1
Skin infection	0/99 (0%)	0	1/98 (1%)	1
Upper respiratory tract infection	0/99 (0%)	0	1/98 (1%)	1
Urinary tract infection	2/99 (2%)	2	1/98 (1%)	1
Viral upper respiratory tract infection	1/99 (1%)	1	1/98 (1%)	1
Injury, poisoning and procedural complications
Accidental overdose	1/99 (1%)	1	0/98 (0%)	0
Clavicle fracture	1/99 (1%)	1	0/98 (0%)	0
Fall	1/99 (1%)	1	0/98 (0%)	0
Pelvic fracture	1/99 (1%)	1	0/98 (0%)	0
Subdural haematoma	1/99 (1%)	1	0/98 (0%)	0
Investigations
Blood creatinine increased	1/99 (1%)	1	1/98 (1%)	1
C-reactive protein increased	1/99 (1%)	1	0/98 (0%)	0
Haemoglobin decreased	1/99 (1%)	1	0/98 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/99 (0%)	0	2/98 (2%)	2
Gout	1/99 (1%)	1	0/98 (0%)	0
Hypercalcaemia	0/99 (0%)	0	2/98 (2%)	2
Hypovolaemia	1/99 (1%)	1	0/98 (0%)	0
Type 2 diabetes mellitus	1/99 (1%)	1	0/98 (0%)	0
Musculoskeletal and connective tissue disorders
Bone disorder	0/99 (0%)	0	1/98 (1%)	1
Intervertebral disc protrusion	0/99 (0%)	0	1/98 (1%)	1
Osteoarthritis	1/99 (1%)	2	1/98 (1%)	1
Osteonecrosis	1/99 (1%)	1	0/98 (0%)	0
Spinal column stenosis	1/99 (1%)	1	0/98 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma	1/99 (1%)	1	0/98 (0%)	0
Colon cancer	1/99 (1%)	1	0/98 (0%)	0
Colon cancer metastatic	1/99 (1%)	1	0/98 (0%)	0
Lung neoplasm malignant	1/99 (1%)	1	0/98 (0%)	0
Prostate cancer	1/99 (1%)	1	1/98 (1%)	1
Squamous cell carcinoma of skin	0/99 (0%)	0	2/98 (2%)	6
Thyroid cancer	0/99 (0%)	0	1/98 (1%)	1
Uterine cancer	1/99 (1%)	1	0/98 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/99 (1%)	1	0/98 (0%)	0
Haemorrhagic stroke	0/99 (0%)	0	1/98 (1%)	1
Somnolence	1/99 (1%)	1	0/98 (0%)	0
Syncope	1/99 (1%)	1	0/98 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/99 (1%)	1	0/98 (0%)	0
Pregnancy	1/99 (1%)	1	0/98 (0%)	0
Psychiatric disorders
Depression	0/99 (0%)	0	1/98 (1%)	1
Suicidal ideation	0/99 (0%)	0	1/98 (1%)	1
Suicide attempt	1/99 (1%)	1	0/98 (0%)	0
Renal and urinary disorders
Acute prerenal failure	0/99 (0%)	0	1/98 (1%)	1
Bladder disorder	0/99 (0%)	0	1/98 (1%)	1
Nephrolithiasis	1/99 (1%)	1	1/98 (1%)	1
Renal failure	4/99 (4%)	4	2/98 (2%)	2
Renal failure acute	2/99 (2%)	2	3/98 (3.1%)	3
Renal failure chronic	1/99 (1%)	1	0/98 (0%)	0
Urinary incontinence	1/99 (1%)	1	0/98 (0%)	0
Reproductive system and breast disorders
Endometriosis	1/99 (1%)	1	0/98 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/99 (1%)	1	1/98 (1%)	1
Chronic obstructive pulmonary disease	0/99 (0%)	0	1/98 (1%)	1
Dyspnoea	2/99 (2%)	2	0/98 (0%)	0
Interstitial lung disease	1/99 (1%)	1	0/98 (0%)	0
Laryngeal stenosis	2/99 (2%)	2	2/98 (2%)	3
Lung infiltration	1/99 (1%)	1	0/98 (0%)	0
Pulmonary alveolar haemorrhage	2/99 (2%)	2	2/98 (2%)	2
Pulmonary embolism	3/99 (3%)	3	2/98 (2%)	2
Pulmonary haemorrhage	1/99 (1%)	1	1/98 (1%)	1
Wegener's granulomatosis	8/99 (8.1%)	9	4/98 (4.1%)	5
Vascular disorders
Aortic dissection	1/99 (1%)	1	0/98 (0%)	0
Deep vein thrombosis	1/99 (1%)	1	8/98 (8.2%)	8
Peripheral arterial occlusive disease	1/99 (1%)	1	0/98 (0%)	0
Thrombosis	1/99 (1%)	1	0/98 (0%)	0
Other (Not Including Serious) Adverse Events
	Rituximab		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/99 (98%)		97/98 (99%)
Blood and lymphatic system disorders
Anaemia	22/99 (22.2%)	28	18/98 (18.4%)	23
Leukopenia	13/99 (13.1%)	30	39/98 (39.8%)	80
Thrombocytopenia	9/99 (9.1%)	13	5/98 (5.1%)	6
Ear and labyrinth disorders
Ear pain	7/99 (7.1%)	8	5/98 (5.1%)	5
Endocrine disorders
Cushingoid	5/99 (5.1%)	6	6/98 (6.1%)	6
Eye disorders
Vision blurred	4/99 (4%)	4	7/98 (7.1%)	7
Gastrointestinal disorders
Diarrhoea	27/99 (27.3%)	35	20/98 (20.4%)	25
Dyspepsia	7/99 (7.1%)	7	8/98 (8.2%)	8
Gastrooesophageal reflux disease	10/99 (10.1%)	10	6/98 (6.1%)	6
Nausea	25/99 (25.3%)	28	31/98 (31.6%)	41
Vomiting	8/99 (8.1%)	12	13/98 (13.3%)	18
General disorders
Chest discomfort	6/99 (6.1%)	7	4/98 (4.1%)	4
Chest pain	6/99 (6.1%)	6	4/98 (4.1%)	4
Chills	6/99 (6.1%)	7	5/98 (5.1%)	5
Fatigue	26/99 (26.3%)	32	30/98 (30.6%)	42
Oedema peripheral	22/99 (22.2%)	26	14/98 (14.3%)	19
Pyrexia	10/99 (10.1%)	12	17/98 (17.3%)	25
Infections and infestations
Bronchitis	7/99 (7.1%)	11	8/98 (8.2%)	11
Herpes zoster	9/99 (9.1%)	10	8/98 (8.2%)	8
Influenza	5/99 (5.1%)	6	5/98 (5.1%)	5
Nasopharyngitis	11/99 (11.1%)	18	14/98 (14.3%)	22
Sinusitis	16/99 (16.2%)	28	17/98 (17.3%)	29
Upper respiratory tract infection	29/99 (29.3%)	43	24/98 (24.5%)	40
Urinary tract infection	18/99 (18.2%)	24	7/98 (7.1%)	10
Viral upper respiratory tract infection	7/99 (7.1%)	8	4/98 (4.1%)	4
Investigations
Alanine aminotransferase increased	15/99 (15.2%)	23	22/98 (22.4%)	30
Aspartate aminotransferase increased	11/99 (11.1%)	14	16/98 (16.3%)	21
Blood creatinine increased	8/99 (8.1%)	10	10/98 (10.2%)	12
C-reactive protein increased	8/99 (8.1%)	10	9/98 (9.2%)	11
Haematocrit decreased	8/99 (8.1%)	8	16/98 (16.3%)	19
Haemoglobin decreased	6/99 (6.1%)	7	7/98 (7.1%)	8
Red blood cell sedimentation rate increased	5/99 (5.1%)	9	12/98 (12.2%)	14
Weight increased	6/99 (6.1%)	8	8/98 (8.2%)	8
White blood cell count decreased	6/99 (6.1%)	9	21/98 (21.4%)	43
Metabolism and nutrition disorders
Hyperglycaemia	12/99 (12.1%)	15	11/98 (11.2%)	11
Hyperkalaemia	8/99 (8.1%)	19	5/98 (5.1%)	6
Hypokalaemia	3/99 (3%)	4	7/98 (7.1%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	34/99 (34.3%)	42	24/98 (24.5%)	34
Back pain	13/99 (13.1%)	13	10/98 (10.2%)	10
Joint swelling	8/99 (8.1%)	9	3/98 (3.1%)	3
Muscle spasms	20/99 (20.2%)	26	21/98 (21.4%)	23
Muscular weakness	6/99 (6.1%)	7	4/98 (4.1%)	5
Musculoskeletal pain	11/99 (11.1%)	11	4/98 (4.1%)	4
Myalgia	5/99 (5.1%)	6	8/98 (8.2%)	8
Pain in extremity	13/99 (13.1%)	17	10/98 (10.2%)	10
Nervous system disorders
Dizziness	14/99 (14.1%)	17	12/98 (12.2%)	16
Dysgeusia	6/99 (6.1%)	7	6/98 (6.1%)	6
Headache	28/99 (28.3%)	31	25/98 (25.5%)	41
Hypoaesthesia	9/99 (9.1%)	10	8/98 (8.2%)	9
Paraesthesia	4/99 (4%)	7	7/98 (7.1%)	9
Tremor	10/99 (10.1%)	15	6/98 (6.1%)	6
Psychiatric disorders
Depression	7/99 (7.1%)	7	6/98 (6.1%)	6
Insomnia	18/99 (18.2%)	20	14/98 (14.3%)	15
Renal and urinary disorders
Haematuria	6/99 (6.1%)	8	14/98 (14.3%)	16
Respiratory, thoracic and mediastinal disorders
Cough	32/99 (32.3%)	40	24/98 (24.5%)	31
Dysphonia	10/99 (10.1%)	12	5/98 (5.1%)	7
Dyspnoea	16/99 (16.2%)	18	15/98 (15.3%)	19
Epistaxis	18/99 (18.2%)	26	15/98 (15.3%)	23
Haemoptysis	8/99 (8.1%)	10	7/98 (7.1%)	8
Nasal congestion	13/99 (13.1%)	13	8/98 (8.2%)	9
Oropharyngeal pain	11/99 (11.1%)	14	3/98 (3.1%)	4
Paranasal sinus hypersecretion	5/99 (5.1%)	7	6/98 (6.1%)	8
Productive cough	7/99 (7.1%)	8	7/98 (7.1%)	11
Rhinorrhoea	6/99 (6.1%)	6	5/98 (5.1%)	5
Skin and subcutaneous tissue disorders
Acne	7/99 (7.1%)	9	5/98 (5.1%)	5
Alopecia	11/99 (11.1%)	13	21/98 (21.4%)	21
Rash	14/99 (14.1%)	19	23/98 (23.5%)	28
Vascular disorders
Flushing	6/99 (6.1%)	11	7/98 (7.1%)	8
Hypertension	14/99 (14.1%)	18	10/98 (10.2%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.