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

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of multiple CSJ117 doses (0.5; 1; 2; 4 and 8 mg) inhaled once daily compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult patients with uncontrolled asthma with respect to change from baseline in FEV1 at the end of 12 weeks of treatment.

Detailed Description
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This was a randomized, multicenter, multi-national, double-blind, placebo-controlled, parallel-arm study evaluating the effect of 5 dose levels of CSJ117 in adult subjects with inadequately controlled asthma despite medium to high dose inhaled corticosteroid (ICS) plus long-acting beta agonist (LABA). Subjects were assigned to one of the following six treatment arms/groups in a ratio of 2:1:1:1:2:2: Placebo inhaled once daily CSJ117 0.5 mg inhaled once daily CSJ117 1.0 mg inhaled once daily CSJ117 2.0 mg inhaled once daily CSJ117 4.0 mg inhaled once daily CSJ117 8.0 mg inhaled once daily The study included: A screening period of approximately 2 weeks A single blinded placebo run-in period of 4 weeks (extended to 8 weeks for subjects experiencing an asthma exacerbation or respiratory tract infection during the run-in period) A double blinded treatment period of 12 weeks A follow-up period of up to 12 weeks, study drug free, following the last dose of study treatment. Patients who successfully completed 12 weeks of treatment in this study could be offered participation in the Safety Extension Study CCSJ117A12201E1 (NCT04946318).

Official Title
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A 12-week, Multicenter, Randomized, Double-blind, Parallel-arm, Placebo-controlled Study to Assess the Efficacy and Safety of CSJ117, When Added to Existing Asthma Therapy in Patients ≥ 18 Years of Age With Severe Uncontrolled Asthma.

Conditions
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Asthma

Intervention / Treatment
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* Drug: CSJ117
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed asthma Male and female patients aged ≥18 and ≤75 years Patients who have been treated with medium or high dose ICS plus LABA with up to 2 additional controllers Morning pre-BD FEV1 value of ≥ 40% and ≤ 85% of the predicted normal A positive reversibility test ACQ-5 score of ≥ 1.5 at screening and end of run-in visits. Exclusion Criteria: Patients who have a cigarette smoking history of greater than 10 pack years or current smokers Pregnant or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using specified methods of contraception during dosing of study drug and until 12 weeks after last study drug treatment Patients with a history of immunodeficiency disease or hepatitis B, untreated and not cured hepatitis C or HIV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSJ117 0.5mg<br>CSJ117 0.5 mg inhaled once daily | Drug: CSJ117<br>* CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device. CSJ117 = inhaled monoclonal antibody fragment<br>Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|
| Experimental: CSJ117 1mg<br>CSJ117 1 mg inhaled once daily | Drug: CSJ117<br>* CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device. CSJ117 = inhaled monoclonal antibody fragment<br>Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|
| Experimental: CSJ117 2mg<br>CSJ117 2 mg inhaled once daily | Drug: CSJ117<br>* CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device. CSJ117 = inhaled monoclonal antibody fragment<br>Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|
| Experimental: CSJ117 4mg<br>CSJ117 4 mg inhaled once daily | Drug: CSJ117<br>* CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device. CSJ117 = inhaled monoclonal antibody fragment<br>Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|
| Experimental: CSJ117 8mg<br>CSJ117 8 mg inhaled once daily | Drug: CSJ117<br>* CSJ117 inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device. CSJ117 = inhaled monoclonal antibody fragment<br>Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|
| Placebo Comparator: Placebo<br>Placebo inhaled once daily | Drug: Placebo<br>* Run-in period (all arms): Placebo inhaled once daily (in the morning) for 4 weeks. Placebo dosing extended to 8 weeks in case of asthma exacerbation or respiratory tract infection during this period. Treatment period (Placebo arm only): Placebo inhaled once daily (in the morning) for 12 weeks. Delivered via Concept1 device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline in Pre-dose FEV1 at Week 8 and Week 12 | FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Pre-dose FEV1 is defined as average of the two FEV1 measurements taken at approximately 45 minutes and 15 minutes prior to dosing. The baseline pre-dose FEV1 value is defined as the average of the values taken approximately 2 hours 45 minutes and 2 hours 15 minutes prior to the first dose of double-blind treatment at Day 1. The least-squares means for change from baseline in pre-dose FEV1 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 positive average change from baseline in pre-dose FEV1 is considered a favorable outcome. | Baseline, Weeks 8-12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline in FeNO at Week 8 and Week 12 | 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. | Baseline, Weeks 8-12 | 
| Change From Baseline in Morning PEF at Week 12 | 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. | Baseline, Week 12 | 
| Change From Baseline in Evening PEF at Week 12 | 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. | Baseline, Week 12 | 
| Average Change From Baseline in ACQ-5 Score at Week 8 and Week 12 | 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. | Baseline, Weeks 8-12 | 
| Average Change From Baseline in AQLQ+12 Score at Week 8 and Week 12 | 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. | Baseline, Weeks 8-12 | 
| Change From Baseline in ADSD Score at Week 8 and Week 12 | 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. | Baseline, Week 8 and Week 12 | 
| Change From Baseline in ANSD Score at Week 8 and Week 12 | 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. | Baseline, Week 8 and Week 12 | 
| Change From Baseline in Number of Puffs of SABA Taken Per Day at Week 12 | 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. | Baseline, Week 12 | 
| Number of Participants With On-treatment Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | 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. | From first dose of double-blind study treatment up to last dose (Week 12) | 
| Number of Participants With Anti-CSJ117 Antibodies | Immunogenicity (antibody formation against CSJ117) was evaluated in serum by a validated bridging electrochemiluminescence immunoassay (ECLIA). | Day 1 and Weeks 2, 4, 8, 12, 14, 16, 20 and 24 | 
| CSJ117 Serum Concentration | CSJ117 concentration was determined in serum by a validated immunoassay method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero. | Day 1 and Week 12: pre-dose, 2 and 4 hours post-dose; Weeks 2, 4 and 8: pre-dose and 4 hours post-dose; Weeks 14, 16, 20 and 24: pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CSJ117, uncontrolled asthma