Study of Efficacy and Safety of CSJ117 in Patients With Severe Uncontrolled Asthma

Fractional exhaled Nitric Oxide (FeNO) pre-dose measurements were done at the investigational sites prior to spirometry assessments. FeNO is defined as the mean of two serial measurements. The measurement of exhaled nitric oxide is widely accepted as a non-invasive marker of airway inflammation (inflammation leads to elevation of FeNO).

The baseline FeNO pre-dose measurements were taken at the end of the run-in period.

The least-squares means for change from baseline in FeNO averaged between Week 8 and Week 12 visits for each individual dose group were obtained from a linear mixed effects model for repeated measures (MMRM).

A negative average change from baseline in FeNO is considered a favorable outcome.

PEF (Peak Expiratory Flow) is a person's maximum speed of expiration. All participants were instructed to record PEF twice daily before taking any medication using an electronic peak expiratory flow device (eDiary/ePEF), once in the morning and once approximately 12 hours later in the evening at home. At each timepoint, the participant was instructed to perform 3 consecutive manoeuvres within 10 minutes. These PEF values were captured in the eDiary/ePEF.

Mean morning and evening PEF values were calculated by weekly intervals. The baseline values of PEF were the mean values in the run-in period. A positive change from baseline in PEF is considered a favorable outcome.

PEF (Peak Expiratory Flow) is a person's maximum speed of expiration. All participants were instructed to record PEF twice daily before taking any medication using an electronic peak expiratory flow device (eDiary/ePEF), once in the morning and once approximately 12 hours later in the evening at home. At each timepoint, the participant was instructed to perform 3 consecutive manoeuvres within 10 minutes. These PEF values were captured in the eDiary/ePEF.

Mean morning and evening PEF values were calculated by weekly intervals. The baseline values of PEF were the mean values in the run-in period. A positive change from baseline in PEF is considered a favorable outcome.

The Asthma Control Questionnaire-5 (ACQ-5) is a five-item, self-completed questionnaire, which is used as a measure of asthma symptom control. Patients were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment). The questions are equally weighted and the overall ACQ-5 score is the mean of all 5 questions, therefore between 0 (totally controlled) and 6 (severely uncontrolled).

The baseline values of ACQ-5 were collected at the end of the run-in period. The least-squares means for change from baseline in ACQ-5 score averaged between Week 8 and Week 12 visits for each individual dose group were obtained from a linear mixed effects model for repeated measures (MMRM).

A negative change from baseline in ACQ-5 is considered a favorable outcome.

The Asthma Quality of Life Questionnaire+12 (AQLQ+12) is a disease specific questionnaire, which is used as a measure of health-related quality of life. The AQLQ+12 comprises a total of 32 individual questions that span a total of 4 domains: symptoms, activity limitation, emotional function, and environmental stimuli. Patients are asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale (7 = not at all impaired to 1 = severely impaired). The overall AQLQ+12 score is the mean of all 32 individual responses, therefore between 7 and 1 with higher scores indicating less impairment in health-related quality of life.

The baseline values of AQLQ+12 were collected at the end of the run-in period. The least-squares means for change from baseline in AQLQ+12 score averaged between Week 8 and Week 12 visits were obtained from a linear mixed effects model for repeated measures (MMRM).

A positive change from baseline is considered a favorable outcome.

Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) are patient reported outcome measures of asthma symptom severity.

Patients recorded asthma symptoms twice daily in the eDiary. Severity of daytime asthma symptoms were assessed before going to bed and severity of nighttime symptoms upon waking.

Both diaries comprised of 6 items assessing breathing symptoms (difficulty breathing, wheezing, and shortness of breath), chest symptoms (chest tightness and chest pain), and cough symptoms (cough). All items were assessed using an 11-point numeric rating scale ranging from 0 ('None') to 10 ('As bad as you can imagine'). The overall score is the mean of all 6 individual responses, therefore between 0 and 10 with higher scores indicating more severe symptoms.

Mean daily scores of both diaries were calculated by weekly intervals. The baseline values were defined as the average score during the run-in period.

A negative change from baseline is a favorable outcome.

Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) are patient reported outcome measures of asthma symptom severity.

Patients recorded asthma symptoms twice daily in the eDiary. Severity of daytime asthma symptoms were assessed before going to bed and severity of nighttime symptoms upon waking.

Both diaries comprised of 6 items assessing breathing symptoms (difficulty breathing, wheezing, and shortness of breath), chest symptoms (chest tightness and chest pain), and cough symptoms (cough). All items were assessed using an 11-point numeric rating scale ranging from 0 ('None') to 10 ('As bad as you can imagine'). The overall score is the mean of all 6 individual responses, therefore between 0 and 10 with higher scores indicating more severe symptoms.

Mean daily scores of both diaries were calculated by weekly intervals. The baseline values were defined as the average score during the run-in period.

A negative change from baseline is a favorable outcome.

Participants were given a short acting β2-agonist (SABA) such as salbutamol (100 µg) or albuterol (90 µg) to use as rescue medication throughout the study. Participants recorded in the eDiary, once in the morning and once in the evening, the use of rescue medication (number of puffs of SABA taken in the previous 12 hours). The total number of puffs of SABA taken per day was calculated and the mean daily use of puffs of SABA was derived by weekly intervals.

The baseline value of number of puffs of SABA taken per day is the average of total daily SABA use during the run-in period.

A negative change from baseline is considered a favorable outcome.

Number of participants with AEs and SAEs, including asthma exacerbations, changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during the on-treatment period.

The on-treatment period is between the date of first dose of double-blind study treatment and date of the last dose of randomized study treatment.

Grades to characterize the severity of the adverse events were based on the Common Terminology Criteria for Adverse Events (CTCAE). For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.

The number of participants in each category is reported in the table.

Immunogenicity (antibody formation against CSJ117) was evaluated in serum by a validated bridging electrochemiluminescence immunoassay (ECLIA).

CSJ117 concentration was determined in serum by a validated immunoassay method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero".