Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Subjects With Bronchiectasis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in patients with bronchiectasis will demonstrate clinical safety and efficacy related to improved mucociliary clearance with reduced bacterial colonization as potential drivers of airway obstruction, reduced airway inflammation, exacerbations and mucus load, improved lung function, clinical symptoms and quality of life to support further development in bronchiectasis.

Detailed Description
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This is a randomized, subject- and investigator-blinded, placebo-controlled, parallel-group study investigating the preliminary efficacy and safety of QBW251 administered orally for 12 weeks in subjects with bronchiectasis. Approximately 72 subjects will be randomized in a 1:1 ratio to receive either QBW251 or placebo in order to achieve 60 subjects who complete the treatment period based on the assumption of a 16% drop-out rate. The sample size assumptions will be reviewed in an interim analysis in a blinded manner when approximately 14 subjects complete the treatment period. The study consists of the following periods: Screening, baseline/Day 1, treatment period, and end of study assessments (EOS) visit followed by an additional post-treatment safety follow up via phone call. The total duration for each patient in the study is up to approximately 18 weeks.

Official Title
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A Randomized, Subject- and Investigator-blinded, Placebo-controlled, Parallel Group Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Patients With Bronchiectasis

Conditions
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Bronchiectasis

Intervention / Treatment
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* Drug: Active drug
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Male or female patients aged ≥18 years at screening. Proven diagnosis of bronchiectasis by chest CT. Evidence of sputum bacterial load of ≥10^6 CFU/mL with at least one potentially pathogenic microorganism at screening (H. Influenzae, M catarrhalis, S aureus, S pneumoniae, Enterobacteriaceae, P aeruginosa, Stenotrophomonous maltophilia, or any potential pathogenic non-fermenting Gram negative bacteria measured by dilution/outgrowth). Documented history of at least one bronchiectasis exacerbation between January 2019 to study screening. Patients with bronchial hypersecretion, defined as productive cough that occurs on most days (defined as >50% days) for at least three consecutive months within 12 months prior to screening, as assessed by documentation of patient recollection (anamnesis) or documented in patients' record. Patients are allowed to stay on fixed or free combinations of LABA/LAMA or LABA/ICS or LABA/LAMA/ICS as maintenance therapy if they are treated with them at a stable dose for the last 3 months prior to screening. Patients are also allowed to stay on macrolides as maintenance therapy if they are treated with them at a stable dose 3 months before screening. If prescribed, patients are included in the study with unchanged chest physiotherapy for at least 4 weeks prior to screening. Patients will be allowed to use mucolytics or hyperosmolar agents if they were treated with them before study start. Clinically stable pulmonary status in the opinion of the investigator and unlikely to require any change in the standard regimen of care during the course of the study. Able to perform reliable, reproducible pulmonary function test maneuvers per American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines at screening. At screening, patients who have failed to meet ATS/ERS requirements for acceptability and reproducibility for spirometry will be allowed one additional repeat testing session during the screening period. Exclusion Criteria: Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations. Current or planned participation to another clinical trial during this study. History of hypersensitivity to the study drugs or to drugs of similar chemical classes or excipients. Patients with a history of long-QT syndrome or the QTcF interval at Screening or baseline is prolonged (QTcF >450 ms in males, >460 ms in females). Patients who have a clinically significant ECG abnormality before randomization Note: Clinically significant abnormalities may include but are not limited to the following: left bundle branch block, Wolff-Parkinson-White syndrome, clinically significant arrhythmias (e.g. atrial fibrillation, ventricular tachycardia). Patients with a history or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure. A history of resolved Hepatitis A is not exclusionary. Patients with prothrombin time international normalized ratio(PT/INR) of more than 1.5xULN at screening. Patients excluded for the PT/INR of more than 1.5xULN can be re-screened when the values have returned to normal. History of lung transplant or malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients with segmentectomy for other reasons than cancer are allowed to be included in the study. Patients with a history of cancer and 5 years or more disease free survival time may be included in the study by agreement with Novartis Medical Monitor on a case-by-case basis. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory blood test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using acceptable effective methods of contraception during study participation. Use of prescription drugs prohibited as stated in the Section 6.2.2 within 1 week prior to Day 1. Clinical significant laboratory values abnormalities (including G-GT, AST, ALT, total bilirubin or creatinine) in the opinion of the investigator at screening. For additional guidance on hepatic parameters refer to exclusion criterion #5. Patients requiring long-term oxygen therapy for chronic hypoxemia. This is typically patients requiring oxygen therapy >12 h per day delivered by home oxygen cylinder or concentrator. Note: Nocturnal oxygen therapy for transient oxygen desaturations during sleep is allowed. Patients with bronchiectasis who have had a pulmonary exacerbation with a deterioration in three or more of key symptoms for at least 48 h and a clinicians determines that a change bronchiectasis treatment is required within 4 weeks prior to screening. Hemoptysis, requiring medical intervention at any time within 4 weeks prior to screening. Bronchiectasis predominantly characterized by isolated cavitary lung lesions. Patients with bronchiectasis requiring therapy that may interfere with the assessment of QBW251 efficiency or that are unlikely to respond to QBW251 Current or ex-smokers with severe emphysema. Patients with another concomitant pulmonary disease according to the definition of the International ERS/ATS guidelines, including but not limited to COPD, asthma, interstitial pulmonary fibrosis (IPF), sarcoidosis or other granulomatous or infectious process. Concomitant COPD and asthma with characteristics of airway hyperresponsiveness as well as COPD Asthma overlap syndrome are allowed as long as it is not the main, primary diagnosis. Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease. Patients with a known history of non-compliance to medication or who are unable or unwilling to complete an electronic patient diary or patient reported outcome questionnaire. Recent (within three years of screening) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc). Patients with a major vascular surgery in the 6 months prior to the screening visit. Patients who have clinically significant renal, cardiovascular (such as but not limited to unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial infarction), neurological, endocrine, immunological, psychiatric, gastrointestinal, or hematological abnormalities, which could interfere with the assessment of the efficacy and safety of the study treatment, or patients with Type I diabetes or uncontrolled Type II diabetes. Known or suspected history of ongoing, chronic or recurrent infectious disease of HIV, Hepatitis B/C.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Placebo controlled arm | Drug: Placebo<br>* Placebo Capsule 300mg Oral use, one capsule twice daily.<br>* Other names: Comparator;|
| Active Comparator: QBW251<br>Active comparator drug arm | Drug: Active drug<br>* QBW251 Capsule 300mg Oral use, one capsule twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in bacterial load Colony forming units (CFU/mL) of potentially pathogenic microorganisms in sputum at week 12 | Bacterial load is measured by the number of colony forming units (CFU/ml, 1 CFU/mL=1 CFU/g) of potentially pathogenic microorganisms in sputum | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with absence of any colony forming units (CFU/mL) of potentially pathogenic bacteria sputum | Change from baseline on sputum bacterial clearance | Baseline, 12 weeks | 
| Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory symptoms domain) | The Quality of Life Questionnaire for Bronchiectasis (QOL-B) is a disease-specific questionnaire developed for non-cystic fibrosis bronchiectasis. It covers 8 dimensions: physical functioning, role functioning, emotional functioning, social functioning, vitality, treatment burden, health perceptions, and respiratory symptoms. Each dimension is scored separately on a scale of 0 to 100, and higher scores represent better outcomes. Only the respiratory symptoms domain score is reported for this outcome measure. | Baseline, 12 weeks | 
| Fibrinogen plasma concentration | To assess the change from baseline of fibrinogen plasma | Baseline, 12 weeks | 
| Change in rescue medication use (salbutamol/albuterol) | To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on rescue medication use | Baseline, 12 weeks | 
| FEV1 | To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Exploratory Volume in the first second). | Baseline, 12 weeks | 
| Airway wall | Change from baseline in airway wall after 12 weeks of treatment, as measured by high resolution computed tomography (HRCT). | Baseline, 12 weeks | 
| FVC | To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Vital Capacity). | Baseline, 12 weeks | 
| Cmax of QBW251 | Maximum (peak) plasma concentration of QBW251 | 1h, 2h, 3h, 4h, 6h and 8h post-dose on Days 1 and 28, and 3h post-dose on Day 56 and Day 84 | 
| Ctrough of QBW251 | Trough (pre-dose) plasma concentration of QBW251. | Pre-dose Day 1, Day 28, Day 56, Day 84 | 
| Airway lumen | Change from baseline in airway lumen after 12 weeks of treatment, as measured by high resolution computed tomography (HRCT). | Baseline, 12 weeks | 
| Airway extent of global and regional air trapping | Change from baseline in the extent of global and regional air trapping after 12 weeks of treatment, as measured by high resolution computed tomography (HRCT) | Baseline, 12 weeks | 
| AUC of QBW251 | Area under the concentration-time curve (AUC) of QBW251 | Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchiectasis, QBW251, colony forming units