Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
COPD
Brief summary
This clinical study was designed to support the dose selection for future studies by evaluating efficacy and safety of different QBW251 doses in Chronic obstructive pulmonary disease (COPD) patients with chronic bronchitis and a history of exacerbations, compared to placebo, when added to a triple inhaled therapy of LABA, LAMA and ICS.
Detailed description
This study used a 6 treatment arm, parallel-group, randomized, double-blind study design. 974 male and female COPD patients were randomized into the trial. The study consisted of four distinct study periods: * Screening (Weeks -3 to -2): Participants underwent a screening period of 1 week where were assessed for eligibility and tapered off disallowed medications. * Run-in (Days -14 to 1): Subsequently, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy (triple combination LABA/LAMA/ICS), and to complete eligibility assessments. * Treatment (Day 1 to Week 24): Eligible participants moved into the Day 1 visit where they were stratified according to their smoking status (current or ex-smoker) and severity of airflow limitation (FEV1 ≥ 30% to \< 50% and ≥ 50% to \< 80%) and then randomized into 1 of 6 treatment arms with a randomization ratio of 2:2:1:1:1:2 (450 mg b.i.d., 300 mg b.i.d., 150 mg b.i.d., 75 mg b.i.d., 25 mg b.i.d., placebo). The treatment period consisted of 24 weeks, during which the participant returned to the site for regular visits (Day 1 - Week 24). QBW251 450 mg arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule. * Follow-up (Weeks 25-28): Upon completion of the treatment period, participants were followed up for safety assessments for 30 days.
Interventions
DRUGQBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks
DRUGPlacebo
Placebo oral capsules administered twice a day for 24 weeks
DRUGCOPD maintenance background therapy
Combination of fluticasone furoate, vilanterol and umeclidinium bromide
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female COPD patients aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure. * Current or ex-smokers who have a smoking history of at least 10 pack years. * Patients who have been treated with a triple combination of LABA/LAMA/ICS for the last 3 months prior to screening. * Patients featuring chronic bronchitis
Exclusion criteria
* Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization, or a respiratory tract infection in the 4 weeks prior to screening, or between screening and randomization. * Patients with any documented history of asthma, or with an onset of chronic respiratory symptoms, including a COPD diagnosis, prior to age 40 years. * Patients with a body mass index (BMI) of more than 40 kg/m2. * Use of other investigational drugs (approved or unapproved) within 30 days or 5 half-lives prior to screening, or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer; or longer if required by local regulations. * Pregnant or nursing (lactating) women, and women of childbearing potential not willing to use acceptable effective methods of contraception during study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | Baseline and Week 12 | The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters on Week 12. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Baseline, weeks 12 and 24 | The E-RS assesses overall daily respiratory COPD symptoms (Total score) and it is derived as the sum of 11 severity items; a higher scores indicate more severe symptoms. E-RS total score has a range of 0 to 40. Change from baseline in the E-RS Total weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. The mean baseline E-RS Total score was the average of the corresponding daily scores from the run-in period. A negative change from baseline corresponds to improvement in symptoms severity. |
| Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Baseline, weeks 12 and 24 | The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest Symptoms). The E-RS comprises 11 severity items and higher scores indicate more severe symptoms. The Cough and Sputum subscale score has a range of 0 to 11 and was derived as the sum of items 2 - 4. Change from baseline in the E-RS Cough and Sputum weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. The mean baseline E-RS Cough & Sputum subscale score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity. |
| Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Baseline, weeks 12 and 24 | The PGI-S questionnaire is a patient-reported outcomes score that rates the severity of the respiratory symptoms and of cough and mucus. The change in severity scores (Better, No change and Worse) from baseline were reported at weeks 12 and 24. Thus, the number of participants with a Better change in the severity score are reported in the table below. |
| Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Baseline, weeks 12 and 24 | The CASA-Q is a validated questionnaire instrument used to measure cough and sputum production, and their impact in patients COPD and/or chronic bronchitis. It contains a total of 20 items on a 5-step scale distributed in 4 domains: Cough symptoms, Cough impact, Sputum symptoms and Sputum impact. All items are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher scores. The four domains are ranged from 0-100 where higher scores associated with fewer symptoms/less impact due to cough or sputum. Change from baseline in the CASA-Q cough and symptoms scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Baseline, weeks 4, 8, 16, 20 and 24 | The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters compared to placebo on Weeks 4, 8, 16, 20 and 24. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome. |
| Minimum Plasma Concentration (Cmin) for QBW251 | Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169 | Venous whole blood samples were collected for pharmacokinetics characterization. Cmin was measured pre dose at all visits and was summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero. |
| Maximum Plasma Concentration (Cmax) for QBW251 | Days 1, 15 and 169 | Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmax was measured in the samples taken at 3 hours post-dose with the exception of the participants included in the Serial PK set on Days 1 and 15 for whom all samples (1, 2, 4, 6, and 8 hours post-dose) were taken into consideration for the measurement of Cmax. All concentrations below the lower limit of quantification (LLOQ) were treated as zero. |
| Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 | Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero. |
| Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 | Venous whole blood samples were collected for pharmacokinetics characterization. AUC0-24h was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero. |
| Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Baseline, weeks 12 and 24 | SGRQ measures health impairment and contains 50 items divided into three components: Symptoms, Activity and Impacts. A score was calculated for each component and a Total score was also calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of quality of life. Change from baseline in the SGRQ scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + baseline SGRQ score + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Colombia, Czechia, Denmark, France, Germany, Greece, Guatemala, Hong Kong, Hungary, Italy, Japan, Netherlands, Philippines, Poland, Slovakia, South Korea, Spain, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited from 149 sites in 26 countries.
Pre-assignment details
Participants underwent a Screening period of up to 1 week. Then, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy and to complete eligibility assessments.
Participants by arm
| Arm | Count |
|---|---|
| QBW251 450 mg QBW251 was orally administered 450 mg b.i.d for 24 weeks | 99 |
| QBW251 300 mg QBW251 was orally administered 300 mg b.i.d for 24 weeks | 250 |
| QBW251 150 mg QBW251 was orally administered 150 mg b.i.d for 24 weeks | 124 |
| QBW251 75 mg QBW251 was orally administered 75 mg b.i.d for 24 weeks | 126 |
| QBW251 25 mg QBW251 was orally administered 25 mg b.i.d for 24 weeks | 124 |
| Placebo Placebo was orally administered b.i.d for 24 weeks | 251 |
| Total | 974 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 1 | 4 | 0 | 1 |
| Overall Study | Death | 0 | 2 | 0 | 2 | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 8 | 1 | 3 | 3 | 13 |
Baseline characteristics
| Characteristic | Total | QBW251 450 mg | QBW251 300 mg | QBW251 150 mg | QBW251 75 mg | QBW251 25 mg | Placebo |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.6 Years STANDARD_DEVIATION 7.55 | 66.5 Years STANDARD_DEVIATION 7.28 | 66.6 Years STANDARD_DEVIATION 7.56 | 66.7 Years STANDARD_DEVIATION 6.58 | 65.7 Years STANDARD_DEVIATION 8.3 | 67.0 Years STANDARD_DEVIATION 7.83 | 66.7 Years STANDARD_DEVIATION 7.59 |
| Race (NIH/OMB) American Indian or Alaska Native | 26 Participants | 2 Participants | 10 Participants | 1 Participants | 4 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 166 Participants | 9 Participants | 42 Participants | 27 Participants | 20 Participants | 25 Participants | 43 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 1 Participants | 5 Participants | 2 Participants | 6 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 761 Participants | 87 Participants | 193 Participants | 94 Participants | 96 Participants | 93 Participants | 198 Participants |
| Sex: Female, Male Female | 373 Participants | 36 Participants | 99 Participants | 47 Participants | 50 Participants | 49 Participants | 92 Participants |
| Sex: Female, Male Male | 601 Participants | 63 Participants | 151 Participants | 77 Participants | 76 Participants | 75 Participants | 159 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 99 | 2 / 250 | 0 / 124 | 2 / 126 | 3 / 124 | 0 / 251 | 7 / 974 |
| other Total, other adverse events | 48 / 99 | 117 / 250 | 59 / 124 | 55 / 126 | 60 / 124 | 107 / 251 | 446 / 974 |
| serious Total, serious adverse events | 10 / 99 | 33 / 250 | 6 / 124 | 14 / 126 | 12 / 124 | 15 / 251 | 90 / 974 |
Outcome results
Primary
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12
The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters on Week 12. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction.
Time frame: Baseline and Week 12
Population: The overall number of participants analyzed includes all randomized participants with a value at both baseline and week 12. Results for the QBW251 450 mg arm need to be interpreted with caution as the arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.013 Liter | Standard Error 0.021 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.013 Liter | Standard Error 0.0103 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.014 Liter | Standard Error 0.0142 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.021 Liter | Standard Error 0.0141 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.006 Liter | Standard Error 0.0144 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12 | 0.001 Liter | Standard Error 0.0101 |
p-value: 0.62890% CI: [-0.027, 0.05]ANCOVA
p-value: 0.42590% CI: [-0.012, 0.035]ANCOVA
p-value: 0.46390% CI: [-0.016, 0.041]ANCOVA
p-value: 0.24490% CI: [-0.008, 0.049]ANCOVA
p-value: 0.79390% CI: [-0.024, 0.034]ANCOVA
Secondary
Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set
Venous whole blood samples were collected for pharmacokinetics characterization. AUC0-24h was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.
Time frame: 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15
Population: The overall number of participants analyzed includes the Serial PK analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 1 | 10900 ng*h/mL | Standard Deviation 3740 |
| QBW251 450 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 15 | 30000 ng*h/mL | Standard Deviation 22600 |
| QBW251 300 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 1 | 8480 ng*h/mL | Standard Deviation 3660 |
| QBW251 300 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 15 | 16500 ng*h/mL | Standard Deviation 8380 |
| QBW251 150 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 1 | 2920 ng*h/mL | Standard Deviation 1140 |
| QBW251 150 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 15 | 4740 ng*h/mL | Standard Deviation 2390 |
| QBW251 75 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 15 | 1390 ng*h/mL | Standard Deviation 679 |
| QBW251 75 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 1 | 769 ng*h/mL | Standard Deviation 330 |
| QBW251 25 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 1 | 185 ng*h/mL | Standard Deviation 107 |
| QBW251 25 mg | Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set | Day 15 | 333 ng*h/mL | Standard Deviation 209 |
Secondary
Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score
The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest Symptoms). The E-RS comprises 11 severity items and higher scores indicate more severe symptoms. The Cough and Sputum subscale score has a range of 0 to 11 and was derived as the sum of items 2 - 4. Change from baseline in the E-RS Cough and Sputum weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. The mean baseline E-RS Cough & Sputum subscale score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity.
Time frame: Baseline, weeks 12 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. QBW251 450 mg arm was excluded from the analysis as it was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 12 | -0.78 Score on a scale | Standard Error 0.077 |
| QBW251 450 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 24 | -0.90 Score on a scale | Standard Error 0.078 |
| QBW251 300 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 12 | -0.63 Score on a scale | Standard Error 0.105 |
| QBW251 300 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 24 | -0.68 Score on a scale | Standard Error 0.107 |
| QBW251 150 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 12 | -0.52 Score on a scale | Standard Error 0.104 |
| QBW251 150 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 24 | -0.51 Score on a scale | Standard Error 0.106 |
| QBW251 75 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 24 | -0.26 Score on a scale | Standard Error 0.109 |
| QBW251 75 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 12 | -0.22 Score on a scale | Standard Error 0.106 |
| QBW251 25 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 12 | -0.44 Score on a scale | Standard Error 0.074 |
| QBW251 25 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score | Week 24 | -0.50 Score on a scale | Standard Error 0.076 |
Secondary
Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score
The E-RS assesses overall daily respiratory COPD symptoms (Total score) and it is derived as the sum of 11 severity items; a higher scores indicate more severe symptoms. E-RS total score has a range of 0 to 40. Change from baseline in the E-RS Total weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction. The mean baseline E-RS Total score was the average of the corresponding daily scores from the run-in period. A negative change from baseline corresponds to improvement in symptoms severity.
Time frame: Baseline, weeks 12 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. QBW251 450 mg arm was excluded from the analysis as it was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 12 | -1.75 Score on a scale | Standard Error 0.234 |
| QBW251 450 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 24 | -2.16 Score on a scale | Standard Error 0.239 |
| QBW251 300 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 12 | -1.26 Score on a scale | Standard Error 0.323 |
| QBW251 300 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 24 | -1.37 Score on a scale | Standard Error 0.327 |
| QBW251 150 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 12 | -1.66 Score on a scale | Standard Error 0.317 |
| QBW251 150 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 24 | -1.36 Score on a scale | Standard Error 0.325 |
| QBW251 75 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 24 | -1.36 Score on a scale | Standard Error 0.333 |
| QBW251 75 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 12 | -1.30 Score on a scale | Standard Error 0.324 |
| QBW251 25 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 12 | -1.41 Score on a scale | Standard Error 0.228 |
| QBW251 25 mg | Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score | Week 24 | -1.31 Score on a scale | Standard Error 0.232 |
Secondary
Change From Baseline in Forced Expiratory Volume in One Second (FEV1)
The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters compared to placebo on Weeks 4, 8, 16, 20 and 24. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome.
Time frame: Baseline, weeks 4, 8, 16, 20 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. Results for the QBW251 450 mg arm need to be interpreted with caution as the arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | -0.031 Liter | Standard Deviation 0.2 |
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | 0.013 Liter | Standard Deviation 0.18 |
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.007 Liter | Standard Deviation 0.14 |
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | 0.033 Liter | Standard Deviation 0.13 |
| QBW251 450 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | 0.028 Liter | Standard Deviation 0.14 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.007 Liter | Standard Deviation 0.15 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | 0.003 Liter | Standard Deviation 0.16 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | 0.005 Liter | Standard Deviation 0.18 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | 0.013 Liter | Standard Deviation 0.16 |
| QBW251 300 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | 0.023 Liter | Standard Deviation 0.19 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | 0.004 Liter | Standard Deviation 0.16 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.009 Liter | Standard Deviation 0.13 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | -0.002 Liter | Standard Deviation 0.13 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | 0.005 Liter | Standard Deviation 0.14 |
| QBW251 150 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | 0.012 Liter | Standard Deviation 0.13 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.000 Liter | Standard Deviation 0.14 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | 0.001 Liter | Standard Deviation 0.16 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | 0.011 Liter | Standard Deviation 0.15 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | 0.003 Liter | Standard Deviation 0.19 |
| QBW251 75 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | 0.002 Liter | Standard Deviation 0.15 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | 0.003 Liter | Standard Deviation 0.16 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | 0.007 Liter | Standard Deviation 0.17 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | 0.016 Liter | Standard Deviation 0.16 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.009 Liter | Standard Deviation 0.14 |
| QBW251 25 mg | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | 0.003 Liter | Standard Deviation 0.17 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 8 | 0.009 Liter | Standard Deviation 0.15 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 16 | -0.011 Liter | Standard Deviation 0.14 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 24 | -0.013 Liter | Standard Deviation 0.16 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 20 | -0.007 Liter | Standard Deviation 0.15 |
| Placebo | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Week 4 | 0.005 Liter | Standard Deviation 0.13 |
Secondary
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)
SGRQ measures health impairment and contains 50 items divided into three components: Symptoms, Activity and Impacts. A score was calculated for each component and a Total score was also calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of quality of life. Change from baseline in the SGRQ scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + baseline SGRQ score + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction.
Time frame: Baseline, weeks 12 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. Results for the QBW251 450 mg arm need to be interpreted with caution as the arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -5.24 Score on a scale | Standard Error 21.16 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -2.93 Score on a scale | Standard Error 10.58 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -0.34 Score on a scale | Standard Error 11.17 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -7.90 Score on a scale | Standard Error 22.47 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -2.00 Score on a scale | Standard Error 10.83 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -1.25 Score on a scale | Standard Error 12.5 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | 2.03 Score on a scale | Standard Error 14.28 |
| QBW251 450 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -2.21 Score on a scale | Standard Error 8.24 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -10.59 Score on a scale | Standard Error 21.06 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -6.04 Score on a scale | Standard Error 17.455 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -5.84 Score on a scale | Standard Error 14.82 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | -5.69 Score on a scale | Standard Error 17.06 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -5.12 Score on a scale | Standard Error 17.36 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -8.23 Score on a scale | Standard Error 18.73 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -6.48 Score on a scale | Standard Error 15.35 |
| QBW251 300 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -4.80 Score on a scale | Standard Error 17.67 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -3.69 Score on a scale | Standard Error 12.39 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -5.70 Score on a scale | Standard Error 18.39 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -7.09 Score on a scale | Standard Error 17.02 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -2.63 Score on a scale | Standard Error 14.18 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -4.72 Score on a scale | Standard Error 17.35 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -3.69 Score on a scale | Standard Error 16.37 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | -1.49 Score on a scale | Standard Error 13.88 |
| QBW251 150 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -3.14 Score on a scale | Standard Error 12.67 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | -6.42 Score on a scale | Standard Error 16.63 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -5.80 Score on a scale | Standard Error 20.47 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -7.27 Score on a scale | Standard Error 17.48 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -6.78 Score on a scale | Standard Error 14.64 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -6.93 Score on a scale | Standard Error 19.29 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -8.42 Score on a scale | Standard Error 18.21 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -5.44 Score on a scale | Standard Error 16.05 |
| QBW251 75 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -6.06 Score on a scale | Standard Error 14.88 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -1.04 Score on a scale | Standard Error 13.95 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -3.85 Score on a scale | Standard Error 10.82 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -4.06 Score on a scale | Standard Error 14.68 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -1.20 Score on a scale | Standard Error 14.36 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | -3.13 Score on a scale | Standard Error 13.11 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -1.70 Score on a scale | Standard Error 10.97 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -5.59 Score on a scale | Standard Error 16.52 |
| QBW251 25 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -5.16 Score on a scale | Standard Error 15.61 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Impacts score | -3.68 Score on a scale | Standard Error 14.95 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Activity score | -2.40 Score on a scale | Standard Error 15.21 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Symptoms score | -6.07 Score on a scale | Standard Error 17.14 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Symptoms score | -6.97 Score on a scale | Standard Error 17.39 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Activity score | -4.27 Score on a scale | Standard Error 16.07 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 24 - Total score | -4.37 Score on a scale | Standard Error 13 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Impacts score | -3.11 Score on a scale | Standard Error 15.9 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Week 12 - Total score | -3.36 Score on a scale | Standard Error 13.27 |
Secondary
Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q)
The CASA-Q is a validated questionnaire instrument used to measure cough and sputum production, and their impact in patients COPD and/or chronic bronchitis. It contains a total of 20 items on a 5-step scale distributed in 4 domains: Cough symptoms, Cough impact, Sputum symptoms and Sputum impact. All items are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher scores. The four domains are ranged from 0-100 where higher scores associated with fewer symptoms/less impact due to cough or sputum. Change from baseline in the CASA-Q cough and symptoms scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment\*time interval interaction + baseline score\*time interval interaction.
Time frame: Baseline, weeks 12 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. QBW251 450 mg arm was excluded from the analysis as it was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 12 | 6.06 Score on a scale | Standard Error 1.082 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 24 | 10.49 Score on a scale | Standard Error 1.148 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 12 | 7.74 Score on a scale | Standard Error 1.142 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 24 | 10.52 Score on a scale | Standard Error 1.242 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 12 | 5.88 Score on a scale | Standard Error 1.011 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 24 | 7.14 Score on a scale | Standard Error 1.032 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 12 | 4.97 Score on a scale | Standard Error 0.983 |
| QBW251 450 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 24 | 7.08 Score on a scale | Standard Error 0.983 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 24 | 11.34 Score on a scale | Standard Error 1.685 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 12 | 8.51 Score on a scale | Standard Error 1.571 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 24 | 7.66 Score on a scale | Standard Error 1.401 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 24 | 10.59 Score on a scale | Standard Error 1.556 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 12 | 8.82 Score on a scale | Standard Error 1.488 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 12 | 6.58 Score on a scale | Standard Error 1.391 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 24 | 8.29 Score on a scale | Standard Error 1.334 |
| QBW251 300 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 12 | 5.94 Score on a scale | Standard Error 1.352 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 24 | 8.04 Score on a scale | Standard Error 1.575 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 12 | 5.89 Score on a scale | Standard Error 1.359 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 24 | 7.51 Score on a scale | Standard Error 1.349 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 12 | 7.01 Score on a scale | Standard Error 1.58 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 24 | 7.75 Score on a scale | Standard Error 1.417 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 24 | 5.81 Score on a scale | Standard Error 1.704 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 12 | 6.98 Score on a scale | Standard Error 1.398 |
| QBW251 150 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 12 | 6.68 Score on a scale | Standard Error 1.498 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 24 | 4.64 Score on a scale | Standard Error 1.756 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 12 | 5.03 Score on a scale | Standard Error 1.394 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 24 | 5.84 Score on a scale | Standard Error 1.623 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 24 | 4.40 Score on a scale | Standard Error 1.46 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 12 | 6.73 Score on a scale | Standard Error 1.535 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 12 | 5.74 Score on a scale | Standard Error 1.62 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 12 | 4.35 Score on a scale | Standard Error 1.433 |
| QBW251 75 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 24 | 4.02 Score on a scale | Standard Error 1.391 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 12 | 6.06 Score on a scale | Standard Error 1.077 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 24 | 7.04 Score on a scale | Standard Error 1.007 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 24 | 9.05 Score on a scale | Standard Error 1.211 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 12 | 5.26 Score on a scale | Standard Error 0.978 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough symptoms score, week 24 | 7.25 Score on a scale | Standard Error 1.118 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum impact score, week 12 | 4.72 Score on a scale | Standard Error 1.005 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Cough impact score, week 24 | 7.12 Score on a scale | Standard Error 0.958 |
| QBW251 25 mg | Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) | Sputum symptoms score, week 12 | 6.96 Score on a scale | Standard Error 1.136 |
Secondary
Maximum Plasma Concentration (Cmax) for QBW251
Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmax was measured in the samples taken at 3 hours post-dose with the exception of the participants included in the Serial PK set on Days 1 and 15 for whom all samples (1, 2, 4, 6, and 8 hours post-dose) were taken into consideration for the measurement of Cmax. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.
Time frame: Days 1, 15 and 169
Population: The overall number of participants analyzed includes the PK analysis set. The number analyzed per row represents participants with evaluable data at each time point. Results for the QBW251 450 mg arm need to be interpreted with caution as the arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 169 | 2370 ng/mL | Standard Deviation 1160 |
| QBW251 450 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 1 | 1280 ng/mL | Standard Deviation 847 |
| QBW251 450 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 15 | 2500 ng/mL | Standard Deviation 1710 |
| QBW251 300 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 15 | 1320 ng/mL | Standard Deviation 1030 |
| QBW251 300 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 169 | 1210 ng/mL | Standard Deviation 797 |
| QBW251 300 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 1 | 751 ng/mL | Standard Deviation 598 |
| QBW251 150 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 1 | 251 ng/mL | Standard Deviation 238 |
| QBW251 150 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 169 | 361 ng/mL | Standard Deviation 303 |
| QBW251 150 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 15 | 411 ng/mL | Standard Deviation 368 |
| QBW251 75 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 15 | 114 ng/mL | Standard Deviation 101 |
| QBW251 75 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 1 | 68.9 ng/mL | Standard Deviation 64.5 |
| QBW251 75 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 169 | 104 ng/mL | Standard Deviation 86.6 |
| QBW251 25 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 1 | 14.4 ng/mL | Standard Deviation 15.2 |
| QBW251 25 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 169 | 22.5 ng/mL | Standard Deviation 16.4 |
| QBW251 25 mg | Maximum Plasma Concentration (Cmax) for QBW251 | Day 15 | 26.1 ng/mL | Standard Deviation 20.6 |
Secondary
Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set
Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.
Time frame: 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15
Population: The overall number of participants analyzed includes the Serial PK analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 1 | 1510 ng/mL | Standard Deviation 928 |
| QBW251 450 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 15 | 2700 ng/mL | Standard Deviation 1170 |
| QBW251 300 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 1 | 1280 ng/mL | Standard Deviation 622 |
| QBW251 300 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 15 | 1870 ng/mL | Standard Deviation 844 |
| QBW251 150 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 1 | 478 ng/mL | Standard Deviation 241 |
| QBW251 150 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 15 | 542 ng/mL | Standard Deviation 523 |
| QBW251 75 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 15 | 175 ng/mL | Standard Deviation 127 |
| QBW251 75 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 1 | 96.6 ng/mL | Standard Deviation 72.7 |
| QBW251 25 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 1 | 25.3 ng/mL | Standard Deviation 29.7 |
| QBW251 25 mg | Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set | Day 15 | 39.4 ng/mL | Standard Deviation 27 |
Secondary
Minimum Plasma Concentration (Cmin) for QBW251
Venous whole blood samples were collected for pharmacokinetics characterization. Cmin was measured pre dose at all visits and was summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.
Time frame: Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169
Population: The overall number of participants analyzed includes the PK analysis set. The number analyzed per row represents participants with evaluable data at each time point. Results for the QBW251 450 mg arm need to be interpreted with caution as the arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 113 | 859 ng/mL | Standard Deviation 1150 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 169 | 637 ng/mL | Standard Deviation 349 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 85 | 1080 ng/mL | Standard Deviation 1360 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 57 | 1040 ng/mL | Standard Deviation 1330 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 15 | 1280 ng/mL | Standard Deviation 1700 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 29 | 951 ng/mL | Standard Deviation 1050 |
| QBW251 450 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 141 | 1150 ng/mL | Standard Deviation 1150 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 169 | 465 ng/mL | Standard Deviation 618 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 85 | 587 ng/mL | Standard Deviation 951 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 15 | 619 ng/mL | Standard Deviation 1230 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 29 | 571 ng/mL | Standard Deviation 923 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 113 | 593 ng/mL | Standard Deviation 1000 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 141 | 552 ng/mL | Standard Deviation 923 |
| QBW251 300 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 57 | 572 ng/mL | Standard Deviation 833 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 169 | 128 ng/mL | Standard Deviation 147 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 15 | 143 ng/mL | Standard Deviation 158 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 29 | 125 ng/mL | Standard Deviation 123 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 57 | 116 ng/mL | Standard Deviation 103 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 85 | 119 ng/mL | Standard Deviation 147 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 113 | 120 ng/mL | Standard Deviation 130 |
| QBW251 150 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 141 | 118 ng/mL | Standard Deviation 103 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 85 | 49.7 ng/mL | Standard Deviation 71.2 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 113 | 52.7 ng/mL | Standard Deviation 73.9 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 57 | 47.7 ng/mL | Standard Deviation 62.2 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 15 | 44.0 ng/mL | Standard Deviation 49 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 141 | 66.8 ng/mL | Standard Deviation 226 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 29 | 47.8 ng/mL | Standard Deviation 47.3 |
| QBW251 75 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 169 | 44.9 ng/mL | Standard Deviation 61.1 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 57 | 14.2 ng/mL | Standard Deviation 25.5 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 169 | 8.97 ng/mL | Standard Deviation 8.08 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 141 | 15.9 ng/mL | Standard Deviation 45.7 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 113 | 9.89 ng/mL | Standard Deviation 9.2 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 85 | 9.93 ng/mL | Standard Deviation 10.3 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 29 | 10.1 ng/mL | Standard Deviation 10.1 |
| QBW251 25 mg | Minimum Plasma Concentration (Cmin) for QBW251 | Day 15 | 12.7 ng/mL | Standard Deviation 15.5 |
Secondary
Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline
The PGI-S questionnaire is a patient-reported outcomes score that rates the severity of the respiratory symptoms and of cough and mucus. The change in severity scores (Better, No change and Worse) from baseline were reported at weeks 12 and 24. Thus, the number of participants with a Better change in the severity score are reported in the table below.
Time frame: Baseline, weeks 12 and 24
Population: The overall number of participants analyzed includes all randomized participants. The number analyzed per row represents participants with evaluable data at each time point. QBW251 450 mg arm was excluded from the analysis as it was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| QBW251 450 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Respiratory Symptoms | 66 Participants |
| QBW251 450 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Respiratory Symptoms | 72 Participants |
| QBW251 450 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Cough and mucus | 85 Participants |
| QBW251 450 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Cough and mucus | 104 Participants |
| QBW251 300 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Cough and mucus | 55 Participants |
| QBW251 300 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Cough and mucus | 57 Participants |
| QBW251 300 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Respiratory Symptoms | 28 Participants |
| QBW251 300 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Respiratory Symptoms | 27 Participants |
| QBW251 150 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Cough and mucus | 54 Participants |
| QBW251 150 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Respiratory Symptoms | 40 Participants |
| QBW251 150 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Cough and mucus | 50 Participants |
| QBW251 150 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Respiratory Symptoms | 35 Participants |
| QBW251 75 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Respiratory Symptoms | 33 Participants |
| QBW251 75 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Cough and mucus | 37 Participants |
| QBW251 75 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Respiratory Symptoms | 31 Participants |
| QBW251 75 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Cough and mucus | 41 Participants |
| QBW251 25 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Cough and mucus | 78 Participants |
| QBW251 25 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Cough and mucus | 96 Participants |
| QBW251 25 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 24 - Respiratory Symptoms | 79 Participants |
| QBW251 25 mg | Number of Participants With a Better Change in the Patient Global Impression of Severity (PGI-S) From Baseline | Week 12 - Respiratory Symptoms | 64 Participants |