Dose-range Finding Efficacy and Safety Study for QBW251 in COPD Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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A 24-week Multi-center, Double-blind, Placebo Controlled Dose-range Finding Study to Investigate the Efficacy and Safety of Oral QBW251 in COPD Patients on Triple Inhaled Therapy (LABA / LAMA / ICS)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: QBW251
* Drug: Placebo
* Drug: COPD maintenance background therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QBW251 450 mg<br>QBW251 was orally administered 450 mg b.i.d for 24 weeks | Drug: QBW251<br>* 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<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|
| Experimental: QBW251 300 mg<br>QBW251 was orally administered 300 mg b.i.d for 24 weeks | Drug: QBW251<br>* 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<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|
| Experimental: QBW251 150 mg<br>QBW251 was orally administered 150 mg b.i.d for 24 weeks | Drug: QBW251<br>* 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<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|
| Experimental: QBW251 75 mg<br>QBW251 was orally administered 75 mg b.i.d for 24 weeks | Drug: QBW251<br>* 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<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|
| Experimental: QBW251 25 mg<br>QBW251 was orally administered 25 mg b.i.d for 24 weeks | Drug: QBW251<br>* 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<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|
| Placebo Comparator: Placebo<br>Placebo was orally administered b.i.d for 24 weeks | Drug: Placebo<br>* Placebo oral capsules administered twice a day for 24 weeks<br>Drug: COPD maintenance background therapy<br>* Combination of fluticasone furoate, vilanterol and umeclidinium bromide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, weeks 4, 8, 16, 20 and 24 | 
| 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. | Baseline, weeks 12 and 24 | 
| 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. | Baseline, weeks 12 and 24 | 
| 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. | Baseline, weeks 12 and 24 | 
| 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. | Baseline, weeks 12 and 24 | 
| 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. | Baseline, weeks 12 and 24 | 
| 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. | Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169 | 
| 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. | Days 1, 15 and 169 | 
| 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. | 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 | 
| 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. | 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD