|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Respiratory Tract Diseases [C08]
|E.1.2 Medical condition or disease under investigation
|Non-cystic fibrosis bronchiectasis
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To determine the efficacy of QBW251 compared to placebo with respect to change from baseline in bacterial load of colony forming units (CFU/mL, 1CFU/mL= 1 CFU/g) of potentially pathogenic microorganisms in spontaneous sputum at week 12.
|Secondary objectives of the trial
|-To assess the change of QBW251 compared to placebo on sputum bacterial clearance
-To assess the change on patient reported outcomes on bronchiectasis symptom assessment
-To assess the change of fibrinogen plasma concentration
-To assess the change in rescue medication use
-To assess the change on lung function
-To assess the change in airway structure and function
-To assess the pharmacokinetics of QBW251 in patients with bronchiectasis
-To assess the safety and tolerability of QBW251 in patients with bronchiectasis
|Trial contains a sub-study
|Principal 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 at screening as determined by the investigator. The screening HRCT can be used to
confirm the diagnosis if no historical chest CT is available.
-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 nonfermenting Gram negative bacteria measured by dilution/outgrowth.)
NOTE: H. parainfluenzae is not considered pathogenic in this study
and therefore growth of this organism alone does not satisfy this criterion.
-Documented history of at least one bronchiectasis exacerbation
between January 2019 and 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 doses 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. Patients will be allowed to use mucolytics or hyperosmolar agents if they were treated with them before study start.
- If prescribed, patients are included in the study with unchanged chest physiotherapy for at least 4 weeks prior to screening.
-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.
|Principal 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 in 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, as determined by investigator. 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
-Clinically significant laboratory values abnormalities (including G-GT, AST, ALT, total bilirubin or creatinine) in the opinion of the investigator at screening
-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 as determined by the investigator
-Patients with another concomitant pulmonary disease according to the definition of the International ERS/ATS guidelines, including but not limited to 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 as determined by investigator
-Patients currently receiving treatment for NTM pulmonary disease. Patients with a diagnosis of PCD may be allowed to participate with approval of Sponsor
-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) or recurrent history of clinically significant autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc...) as determined by investigator
-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 uncontrolled Type I diabetes or uncontrolled Type II diabetes
-Known or suspected history of ongoing, chronic or recurrent infectious disease of HIV, Hepatitis B/C
|E.5 End points
|Primary end point(s)
|Change from baseline in bacterial load of colony forming units ( CFU/mL, 1 CFU/mL = 1 CFU/g) of potentially pathogenic microorganisms in spontaneous sputum with QBW251 compared to placebo at week 12.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|-Proportion of subjects with absence of any CFU of potentially pathogenic bacteria in sputum culture after 12 weeks of treatment.
-Changes from baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory symptoms domain) after 12 weeks of treatment.
-Change from baseline in fibrinogen plasma concentration after 12 weeks of treatment.
-Change from baseline in rescue medication use (salbutamol/albuterol) after 12 weeks of treatment.
-Changes from baseline in pre- and postbronchodilator FEV1, FVC after 12 weeks treatment, measured by spirometry.
-Change from baseline in airway wall and lumen parameters along with extent of global and regional air trapping after 12 weeks of treatment, as measured by HRCT.
-Assessment of drug exposure (Cmax, AUC) on Days 1 and 28; pre- and post-dose concentration (Ctrough and Cmax) on Days 56 and 84 (for a subset of patients at selected sites). Pre- and post- dose concentration (Ctrough and around Cmax) on Days 1, 28, 56 and 84 (for all other patients).
-All safety endpoints (including adverse events, vital signs, ECG, and safety laboratory changes) during the study.
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Other scope of the trial description
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months