Sirukumab is a fully human anti interleukin (IL)-6 immunoglobulin G1-kappa monoclonal antibody (MAb) which is in development for the treatment of rheumatoid arthritis (RA). The continuing unmet need in subjects with asthma refractory to corticosteroid therapy and increased understanding of asthma pathogenesis have stimulated the development of targeted biologics based on predictive biomarkers. The majority of approaches to date have targeted T Helper 2 (Th2) cytokines or their downstream effects. Targeting IL-6 in severe asthma represents an unprecedented approach that has potential to address non-Th2 drivers of severe asthma. This multicenter, randomized, double-blind (sponsor-unblind), placebo-controlled, parallel group study will investigate the efficacy of sirukumab compared to placebo in subjects having uncontrolled severe asthma despite use of high dose inhaled corticosteroid (ICS) in combination with long-acting Beta-agonist (LABA). The study will employ a variable treatment period for individual subjects. Dosing will continue every 4 weeks until week 44 (inclusive), or until 24 weeks after the final subject has been randomized, whichever the sooner. Upon receiving the final dose of study medicine or placebo, subjects will enter a 16 week Follow Up period. Overall, the duration of participation for subjects who complete the full 44-week treatment period and Follow Up period may be up to 64 weeks. Approximately 175 subjects will be randomized such that 140 evaluable subjects complete the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
This intervention will be provided in a 1.0 mL pre-filled syringe (PFS) fitted with spring-powered, disposable autoinjector device for single SC use that is permanently assembled on the syringe. The sirukumab PFS is aseptically filled to deliver a dose of 50 mg/1.0 mL of sirukumab.
This intervention will be provided in a 1.0 mL pre-filled syringe (PFS) fitted with spring-powered, disposable autoinjector device for single SC use that is permanently assembled on the syringe. The sirukumab PFS is aseptically filled to deliver a dose of 50 mg/1.0 mL of sirukumab.
Rescue medication (salbutamol/albuterol) shall be supplied to subjects at Screening for use when needed during the study.
GSK Investigational Site
Long Beach, California, United States
GSK Investigational Site
Aventura, Florida, United States
GSK Investigational Site
Cincinnati, Ohio, United States
GSK Investigational Site
Richmond, Virginia, United States
GSK Investigational Site
Richmond, Virginia, United States
GSK Investigational Site
Alcorcón (Madrid), Spain
GSK Investigational Site
Girona, Spain
GSK Investigational Site
Santiago de Compostela. La Coruña., Spain
Change from Baseline in Asthma Control Questionnaire-7 (ACQ-7) at Week 24
The ACQ-7 is a seven-item questionnaire that is a measure of a subject's asthma control. Six of the questions will be self-completed by the subject, recalling over the previous 7 days. The six questions enquire about the frequency and/or severity of symptoms (nocturnal awakening, activity limitation, shortness of breath and wheeze), and rescue bronchodilator use. The response options for all these questions consist of a zero (no impairment/limitation) to six (total impairment/ limitation) scale. The final question is a rating of forced expiratory volume in 1 second FEV1% predicted. The questions are equally weighted and the ACQ score is the mean of the 7 questions and therefore between 0 (totally controlled) and 6 (severely uncontrolled). Baseline value is the value obtained at Day 1 before administration of investigational product (IP). Change from baseline in ACQ-7 score will be analysed using a Bayesian repeated measures model.
Time frame: Baseline and Week 24
Safety as assessed by number of subjects with adverse events (AE) and serious adverse events (SAE)
AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement.
Time frame: Up to 60 Weeks
Safety as assessed by body temperature
Body temperature will be measured in semi-supine position after 5 minutes rest.
Time frame: Up to 60 Weeks
Safety as assessed by systolic and diastolic blood pressure
Blood pressure will be measured in semi-supine position after 5 minutes rest.
Time frame: Up to 60 Weeks
Safety as assessed by pulse rate
Pulse rate will be measured in semi-supine position after 5 minutes rest.
Time frame: Up to 60 Weeks
Safety as assessed by electrocardiogram (ECG)
Centralized 12-lead ECG will be performed in triplicate at baseline and singly thereafter. ECG will also be performed when clinically indicated. ECG measurements will be made after the subject has rested in the supine position for 5 minutes. The ECG will be obtained after the vital signs assessments but before lung function testing followed by other study procedures. Collection shortly after a meal or during sleep will be avoided since QT prolongation can occur at these times.
Time frame: Up to 60 Weeks
Safety as assessed by number of subjects with abnormal hematology parameters
Hematology will include hemoglobin, hematocrit, red blood cells (RBC) count, white blood cells (WBC) count, absolute neutrophils, neutrophils segmented percentage with differential, neutrophils bands percentage, basophils percentage, eosinophils percentage, absolute eosinophils, lymphocytes percentage, monocytes percentage, platelet count.
Time frame: Up to 48 Weeks
Safety assessed by serum chemistry
Serum chemistry will include potassium, chloride, sodium, calcium, blood Urea nitrogen (BUN), creatinine, glucose, aspartate transaminase (SGOT), alanine transaminase (SGPT), alkaline phosphatise, phosphate, albumin, total protein, direct, indirect and total bilirubin.
Time frame: Up to 48 Weeks
Safety assessed by lipid profile
Lipid profile will include total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides.
Time frame: Up to 48 Weeks
Change from baseline in ACQ-7 during the treatment period
The ACQ-7 is a seven-item questionnaire that is as a measure of a subject's asthma control.
Time frame: Baseline and Up to 48 Weeks
Change from baseline in ACQ-5 during the treatment period
The ACQ-5 is a five-item questionnaire that is as a measure of a subject's asthma control. The five ACQ-5 questions are scored on a 7-point scale (0 = good control, 7 = poor control), and the overall score is the mean of the five responses. Baseline value is the value obtained at Day 1 before administration of investigational product (IP). Change from baseline in ACQ-5 score will be analysed using a Bayesian repeated measures model.
Time frame: Baseline and Up to 48 Weeks
Number of subjects who achieve an ACQ-7 response
The ACQ-7 is a seven-item questionnaire that is as a measure of a subject's asthma control.
Time frame: Up to 48 Weeks
Change from baseline in pre-bronchodilator FEV1 during the treatment period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline value is the value obtained at Day 1 before administration of IP. Change from Baseline is the difference between the value at Indicated visit and value at Baseline.
Time frame: Baseline and Up to 48 Weeks
Change from baseline in average morning peak expiratory flow rate (PEFR)
PEFR is the maximum flow rate generated during a forceful exhalation, starting from full lung inflation. Baseline value is the value obtained at Day 1 before administration of IP. Change from Baseline is the difference between the value at Indicated visit and value at Baseline.
Time frame: Baseline and Up to 48 Weeks
Change from baseline in St. George's Respiratory Questionnaire (SGRQ)
The SGRQ comprises 50 questions designed to measure health status (quality of life) in subjects with diseases of airways obstruction. The SGRQ includes a total score and three domain scores: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units is considered to be established as clinically relevant. A one month recall period shall be used for assessment of the SGRQ. Baseline value is the value obtained at Day 1 before administration of IP. Change from Baseline is the difference between the value at Indicated visit and value at Baseline.
Time frame: Baseline and Up to 48 Weeks
Number of subjects who achieve SGRQ response
The SGRQ comprises 50 questions designed to measure health status (quality of life) in subjects with diseases of airways obstruction.
Time frame: Up to 48 Weeks
Change from baseline in daily salbutamol/albuterol use
Subjects will complete the Asthma Daily Symptom Diary (ADSD), a novel asthma symptom diary and record daily use of rescue medication (salbutamol/albuterol) via an electronic diary. Baseline value is the value obtained at Day 1 before administration of IP. Change from Baseline is the difference between the value at Indicated visit and value at Baseline.
Time frame: Baseline and Up to 48 Weeks
Annualized rate of severe asthma exacerbations during the treatment period
Severe asthma exacerbations are defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalisation and/or Emergency Department (ED) visits.
Time frame: Baseline and Up to 48 Weeks
Assessment of pharmacokinetics (PK) of sirukumab
Serum concentrations of sirukumab and derived population PK parameters will be evaluated. Blood samples for PK analyses of sirukumab serum concentrations will be drawn prior to the administration of study drug.
Time frame: Blood sample for PK analysis would be collected at Baseline, Week 1, Week 4, Week 8, Week 12, Week 24, Week 48, Week 54 and Early Withdrawal/Week 60.
Change from baseline in blood or serum pharmacodynamic (PD) biomarkers including but not limited to interleukin (IL)-6 and C-reactive protein (CRP)
Baseline value is the value obtained at Day 1 before administration of investigational product (IP). Change from Baseline is the difference between the value at Indicated visit and value at Baseline.
Time frame: Blood sample for analysis of PD biomarkers would be collected at Baseline, Week 1, Week 4, Week 8, Week 12, Week 24, Week 48, Week 54 and Early Withdrawal/Week 60.
Incidence and titres of serum anti-sirukumab antibodies post-dosing
Analysis of anti-sirukumab antibodies will be performed using validated bioanalytical assays.
Time frame: Blood sample for testing antibodies against sirukumab would be collected at Baseline, Week 12, Week 24, Week 48 and Early Withdrawal/Week 60.
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