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

Phase 2

Terminated

Conditions: Bronchiectasis

Interventions: Drug: QBW251
Drug: Placebo

Registration Number: NCT04396366

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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: This was a randomized, participant- and investigator-blinded, placebo-controlled, parallel-group study investigating the preliminary efficacy and safety of QBW251 administered orally for 12 weeks in participants with bronchiectasis. Approximately 72 subjects were planned to be randomized in a 1:1 ratio to receive either QBW251 or placebo in order to achieve 60 subjects to complete the treatment period based on the assumption of a 16% drop-out rate. However, the study was prematurely terminated due to a Novartis strategic decision. As a result, only 42 participants were randomized to either the QBW251 300 mg b.i.d group or the placebo group.

The study consisted of the 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 was up to approximately 19 weeks.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 42

Inclusion Criteria

Male or female patients aged ≥18 years at screening.
Proven diagnosis of bronchiectasis by chest CT at screening as determined by investigator.
Evidence of sputum bacterial load of ≥106 CFU/mL with at least one potentially pathogenic microorganism (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 and study screening.
Patients with bronchial hypersecretion, defined as productive cough that occurred 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 were allowed to stay on fixed or free combinations of LABA/LAMA or LABA/ICS or LABA/LAMA/ICS as maintenance therapy if they were treated with them at a stable dose for the last 3 months prior to screening. Patients were also allowed to stay on macrolides as maintenance therapy if they were treated with them at a stable dose, 3 months before screening. Patients were allowed to use mucolytics or hyperosmolar agents if they were treated with them before study start.
If prescribed, patients were 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.

Exclusion Criteria

Patients with a history of long-QT syndrome or the QTcF interval at screening and baseline was prolonged (QTcF > 450 ms in males, > 460 ms in females).
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 was not exclusionary. Patients with a prothrombin time international normalized ratio (PT/INR) of more than 1.5 × ULN at screening. Patients excluded for the PT/INR of more than 1.5 x ULN could be re-screened when the values 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 was evidence of local recurrence or metastases. Patients with segmentectomy for other reasons than cancer were allowed to be included in the study. Patients with a history of cancer and 5 years or more disease free survival time might be included in the study by agreement with Novartis Medical Monitor on a case-by-case basis.
Patients requiring long-term oxygen therapy for chronic hypoxemia. This was 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 was allowed.
Patients with bronchiectasis who had a pulmonary exacerbation with a deterioration in three or more of the following key symptoms for at least 48 h:
- cough;
- sputum volume and/or consistency;
- sputum purulence;
- breathlessness and/or exercise tolerance;
- fatigue and/or malaise;
- hemoptysis And A clinician determined that a change in bronchiectasis treatment was required (e.g., requiring systemic glucocorticosteroid treatment and/or systemic or inhaled antibiotics) within 4 weeks prior to screening.

In the event of an exacerbation occurring 4 weeks before screening, or between the screening and baseline (please see definition above), the participant was not to be enrolled. The participant might be rescreened once, 4 weeks after the resolution of exacerbation.

Participants with bronchiectasis requiring therapy that might interfere with the assessment of QBW251 efficiency or who were unlikely to respond to QBW251 as follows:
Participants with suspected active pulmonary tuberculosis or currently being treated for active pulmonary tuberculosis were not allowed. Note: Participants with a history of pulmonary tuberculosis could be enrolled if they met the following requirements: history of appropriate drug treatment followed by negative imaging results within 12 months prior to baseline visit suggesting low probability of recurrent active tuberculosis
Patients with active allergic bronchopulmonary aspergillosis and asthma as primary diagnosis.
Patients with cystic fibrosis
Current or ex-smokers with severe emphysema.
Participants with another concomitant pulmonary disease according to the definition of the International ERS/ATS guidelines, including but not limited to idiopathic 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 were allowed as long as it was not the main, primary diagnosis in the opinion of the investigator. Primary ciliary dyskinesia (PCD) was allowed.
Participants currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease. If performed, patients with one or more positive cultures in the last 12 months for M. avium complex, M. abscessus complex, M. kansasii, M. malmoense, M. xenopi, M. simiae or M. chelonae, unless all subsequent NTM cultures (at least two) were negative and in the opinion of the investigator the patient did not met ATS criteria for NTM-pulmonary disease.
Patients receiving any medication that might influence the response to treatment within 4 weeks prior to screening including systemic or inhaled steroids (ICS alone), or other systemic immunomodulators, recombinant human DNAse, any systemic or inhaled antibiotics.
Patients with a body mass index (BMI) of more than 40 kg/m^2

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
QBW251 300 mg b.i.d	QBW251	Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks.
Placebo	Placebo	Participants received matching placebo, b.i.d., for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline In Bacterial Load Colony-forming Units of Potentially Pathogenic Microorganisms in Sputum at Week 12	Baseline, 12 weeks	This measure reflects the amount of bacteria present in a patient's lungs.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Absence of Any Colony-forming Units of Potentially Pathogenic Bacteria Sputum	Baseline, 12 weeks
Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory Symptoms Domain)	Baseline, Days 28, 56, 84	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.
Change From Baseline in Fibrinogen Plasma Concentration	Baseline, 12 weeks
Change From Baseline in Daily Rescue Medication Use (Salbutamol/Albuterol)	Baseline, 12 weeks	The total number of puffs of rescue medication was divided by the total number of (full or half) days with non-missing rescue data to derive the mean daily number of puffs of rescue medication taken for the patient for the given visit interval.
Change From Baseline in Pre-bronchodilator Forced Exploratory Volume in the First Second (FEV1)	Baseline, Days 28, 56, 84	FEV1 is the amount of air that can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC)	Baseline, Days 28, 56, 84	Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible.
Change From Baseline in Bronchus Region Pi10	Baseline, 12 weeks	Pi10 is the square root of the wall area for an idealized airway with a luminal perimeter of 10 mm. Pi10 is the most commonly used measure of wall thickening and represents a regional estimate of the small airways across the whole lung or a particular lobe. Measured by high resolution computed tomography (HRCT).
Change From Baseline in Region Percent Below or Equal to -856 Hounsfield Units (HU)	Baseline, 12 weeks	The region percent below or equal to -856 HU represents air trapping, which was evaluated by HRCT in the whole lung and in the regions (thirds, lobes).
Change From Baseline in Region Air Volume	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Average Inner Area	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Average Major Inner Diameter	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Average Minor Inner Diameter	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Average Outer Area	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Average Wall Area Fraction	Baseline, 12 weeks	Wall area fraction or ratio was calculated by dividing the wall area of the corresponding segment to the total airway area. Measured by HRCT.
Change From Baseline in Segment Average Wall Thickness	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Wall Area Percent	Baseline, 12 weeks	Measured by HRCT
Change From Baseline in Segment Wall Area	Baseline, 12 weeks	Measured by HRCT
Cmax 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	Maximum (peak) plasma concentration of QBW251
Ctrough of QBW251	Pre-dose Day 1, Day 28, Day 56, Day 84	Trough (pre-dose) plasma concentration of QBW251
Cmax of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
Ctrough of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
AUClast of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28	Area under the concentration-time curve up to the last measurable concentration of QBW251 (AUClast)
Tmax of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28	Time to reach maximum (peak) plasma concentration after single-dose administration
AUC0-12h of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28	Twelve-hour AUC
Tlast of QBW251 for a Serial PK Set	Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28	Tlast is the last measurable concentration sampling time.