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Belimumab in Remission of VASculitis (BREVAS)

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ClinicalTrials.gov Identifier: NCT01663623
Recruitment Status : Completed
First Posted : August 13, 2012
Results First Posted : April 17, 2018
Last Update Posted : April 17, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
GlaxoSmithKline ( Human Genome Sciences Inc., a GSK Company )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Vasculitis
Interventions Biological: Placebo
Biological: Belimumab 10 mg/kg
Drug: Azathioprine
Enrollment 106
Recruitment Details Participants with diagnosis of Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were randomized in this study. The study was conducted at 37 centers in 15 countries in North America, Central America, South America, Western Europe, Eastern Europe, and Australia during 20 March 2013 - 06 February 2017.
Pre-assignment Details A total of 164 participants were screened and 106 were enrolled and randomized in a 1:1 ratio to receive placebo or belimumab 10 milligram per kilogram (mg/kg). Of which, 105 received at least 1 dose of study agent and one participant was randomized in error.
Arm/Group Title Placebo Belimumab 10 mg/kg
Hide Arm/Group Description Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28. Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.
Period Title: Overall Study
Started 52 53
Completed 40 33
Not Completed 12 20
Reason Not Completed
Adverse Event             3             7
Lack of Efficacy             5             6
Protocol Violation             0             1
Other-Study closed/terminated             1             1
Physician Decision             1             4
Withdrawal by Subject             2             1
Arm/Group Title Placebo Belimumab 10 mg/kg Total
Hide Arm/Group Description Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28. Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28. Total of all reporting groups
Overall Number of Baseline Participants 52 53 105
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 52 participants 53 participants 105 participants
53.5  (13.56) 56.2  (13.59) 54.8  (13.58)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 53 participants 105 participants
Female
25
  48.1%
26
  49.1%
51
  48.6%
Male
27
  51.9%
27
  50.9%
54
  51.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 52 participants 53 participants 105 participants
African American/African Heritage
1
   1.9%
1
   1.9%
2
   1.9%
American Indian or Alaskan Native
5
   9.6%
6
  11.3%
11
  10.5%
Central/South Asian Heritage
2
   3.8%
0
   0.0%
2
   1.9%
White
44
  84.6%
46
  86.8%
90
  85.7%
1.Primary Outcome
Title Time to First Relapse
Hide Description Time to relapse is defined as the number of days from Day 0 until the participant experienced a relapse (relapse date – treatment start date +1). Only post-baseline relapses were considered in these analyses. Only relapses occurring up to and including the last visit date in the double-blind treatment period were considered in these analyses. Intent-to-treat population comprised of all randomized participants who received at least one dose of study agent (belimumab or placebo). NA indicates that the data was not available as the Number of events is too low to estimate the value. Median and Inter-quartile range were presented and were based on Kaplan Meier estimates.
Time Frame Approximately up to 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Belimumab 10 mg/kg
Hide Arm/Group Description:
Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.
Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.
Overall Number of Participants Analyzed 52 53
Median (Inter-Quartile Range)
Unit of Measure: Days
NA [1] 
(789.0 to NA)
NA [1] 
(NA to NA)
[1]
Kaplan Meier statistics could not be estimated where the number of events is too low. Hence it is NA.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Belimumab 10 mg/kg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.884
Comments Cox proportional Hazards (Wald Chi Square)
Method Cox Proportional Hazards model
Comments Analysis was adjusted for ANCA type, disease stage at induction and induction regimen
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.44 to 2.59
Estimation Comments Analysis performed using a Cox Proportional Hazards model with covariates treatment group, Actual ANCA type, Actual disease stage at induction and Actual induction regimen.
2.Secondary Outcome
Title Number of Participants With Major Relapse During the Double-blind Phase of the Study
Hide Description Data for number of participants with major relapse [defined as experiencing at least 1 major Birmingham Vasculitis Activity Score (BVAS) item] during the double-bind phase of the study was reported. Analysis was performed using a Cox proportional hazard model.
Time Frame Approximately up to 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Belimumab 10 mg/kg
Hide Arm/Group Description:
Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.
Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.
Overall Number of Participants Analyzed 52 53
Measure Type: Number
Unit of Measure: Participants
0 1
Time Frame Adverse events (AE) were collected from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent (approximately up to 4 years).
Adverse Event Reporting Description Intent to treat population. Participants who discontinued treatment, all AE were collected through 8 weeks following the last dose of study agent. All SAEs were collected until relapse or the study was analyzed for the primary endpoint and study sites are informed that SAE data collection can cease, whichever occurs first.
 
Arm/Group Title Placebo Belimumab 10 mg/kg
Hide Arm/Group Description Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28. Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.
All-Cause Mortality
Placebo Belimumab 10 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/52 (0.00%)   1/53 (1.89%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Belimumab 10 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   16/52 (30.77%)   18/53 (33.96%) 
Blood and lymphatic system disorders     
Anaemia  1  1/52 (1.92%)  0/53 (0.00%) 
Neutropenia  1  0/52 (0.00%)  1/53 (1.89%) 
Pancytopenia  1  1/52 (1.92%)  0/53 (0.00%) 
Thrombocytopenia  1  0/52 (0.00%)  1/53 (1.89%) 
Cardiac disorders     
Sinus bradycardia  1  1/52 (1.92%)  0/53 (0.00%) 
Eye disorders     
Idiopathic orbital inflammation  1  1/52 (1.92%)  0/53 (0.00%) 
Gastrointestinal disorders     
Chronic gastritis  1  0/52 (0.00%)  1/53 (1.89%) 
Colitis ulcerative  1  1/52 (1.92%)  0/53 (0.00%) 
General disorders     
Pyrexia  1  2/52 (3.85%)  0/53 (0.00%) 
General physical health deterioration  1  0/52 (0.00%)  1/53 (1.89%) 
Hepatobiliary disorders     
Cholangitis  1  0/52 (0.00%)  1/53 (1.89%) 
Drug-induced liver injury  1  1/52 (1.92%)  0/53 (0.00%) 
Immune system disorders     
Hypersensitivity  1  0/52 (0.00%)  2/53 (3.77%) 
Anaphylactic reaction  1  0/52 (0.00%)  1/53 (1.89%) 
Infections and infestations     
Bronchitis  1  1/52 (1.92%)  0/53 (0.00%) 
Cellulitis  1  0/52 (0.00%)  1/53 (1.89%) 
Influenza  1  0/52 (0.00%)  1/53 (1.89%) 
Lower respiratory tract infection  1  0/52 (0.00%)  1/53 (1.89%) 
Neutropenic sepsis  1  0/52 (0.00%)  1/53 (1.89%) 
Pyelonephritis acute  1  1/52 (1.92%)  0/53 (0.00%) 
Salmonellosis  1  1/52 (1.92%)  0/53 (0.00%) 
Tuberculosis  1  1/52 (1.92%)  0/53 (0.00%) 
Injury, poisoning and procedural complications     
Hip fracture  1  0/52 (0.00%)  1/53 (1.89%) 
Pneumothorax traumatic  1  0/52 (0.00%)  1/53 (1.89%) 
Post procedural discharge  1  0/52 (0.00%)  1/53 (1.89%) 
Tendon rupture  1  1/52 (1.92%)  0/53 (0.00%) 
Investigations     
Liver function test increased  1  1/52 (1.92%)  0/53 (0.00%) 
Metabolism and nutrition disorders     
Hypercalcaemia  1  0/52 (0.00%)  1/53 (1.89%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/52 (0.00%)  1/53 (1.89%) 
Muscle contracture  1  1/52 (1.92%)  0/53 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Anal cancer  1  0/52 (0.00%)  1/53 (1.89%) 
Basal cell carcinoma  1  0/52 (0.00%)  1/53 (1.89%) 
Plasma cell myeloma  1  0/52 (0.00%)  1/53 (1.89%) 
Nervous system disorders     
Haemorrhagic stroke  1  0/52 (0.00%)  1/53 (1.89%) 
Ischaemic stroke  1  0/52 (0.00%)  1/53 (1.89%) 
Renal and urinary disorders     
Acute kidney injury  1  0/52 (0.00%)  1/53 (1.89%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  1/52 (1.92%)  0/53 (0.00%) 
Pleuritic pain  1  1/52 (1.92%)  0/53 (0.00%) 
Pneumomediastinum  1  0/52 (0.00%)  1/53 (1.89%) 
Vascular disorders     
Vasculitis  1  1/52 (1.92%)  0/53 (0.00%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Belimumab 10 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   33/52 (63.46%)   32/53 (60.38%) 
Gastrointestinal disorders     
Nausea  1  2/52 (3.85%)  7/53 (13.21%) 
Diarrhoea  1  3/52 (5.77%)  5/53 (9.43%) 
Abdominal pain upper  1  4/52 (7.69%)  3/53 (5.66%) 
Vomiting  1  1/52 (1.92%)  5/53 (9.43%) 
Abdominal pain  1  3/52 (5.77%)  1/53 (1.89%) 
General disorders     
Fatigue  1  7/52 (13.46%)  7/53 (13.21%) 
Pyrexia  1  2/52 (3.85%)  6/53 (11.32%) 
Infections and infestations     
Nasopharyngitis  1  10/52 (19.23%)  6/53 (11.32%) 
Upper respiratory tract infection  1  8/52 (15.38%)  7/53 (13.21%) 
Urinary tract infection  1  4/52 (7.69%)  5/53 (9.43%) 
Bronchitis  1  6/52 (11.54%)  1/53 (1.89%) 
Influenza  1  1/52 (1.92%)  5/53 (9.43%) 
Gastroenteritis  1  3/52 (5.77%)  0/53 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  6/52 (11.54%)  6/53 (11.32%) 
Back pain  1  4/52 (7.69%)  3/53 (5.66%) 
Bursitis  1  3/52 (5.77%)  2/53 (3.77%) 
Nervous system disorders     
Headache  1  7/52 (13.46%)  5/53 (9.43%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  8/52 (15.38%)  10/53 (18.87%) 
Epistaxis  1  3/52 (5.77%)  5/53 (9.43%) 
Oropharyngeal pain  1  2/52 (3.85%)  4/53 (7.55%) 
Skin and subcutaneous tissue disorders     
Rash  1  3/52 (5.77%)  5/53 (9.43%) 
Vascular disorders     
Hypertension  1  4/52 (7.69%)  3/53 (5.66%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
The sample size was small as it was truncated from approximately 300 to 100 participants, largely owing to a change in standard of care.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
EMail: GSKClinicalSupportHD@gsk.com
Layout table for additonal information
Responsible Party: GlaxoSmithKline ( Human Genome Sciences Inc., a GSK Company )
ClinicalTrials.gov Identifier: NCT01663623     History of Changes
Other Study ID Numbers: 115466
First Submitted: August 9, 2012
First Posted: August 13, 2012
Results First Submitted: January 30, 2018
Results First Posted: April 17, 2018
Last Update Posted: April 17, 2018