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

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

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.

Study Overview

• Status: Terminated
• Conditions: Bronchiectasis
• Intervention / Treatment: Drug: Placebo; Drug: Active drug

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• China
  • Shanghai, China, 200433
    • Novartis Investigative Site
  • Guang Dong Province
    • Guang Zhou, Guang Dong Province, China, 510120
      • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60596
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Mainz, Germany, 55128
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Girona, Catalunya, Spain, 17007
      • Novartis Investigative Site
• United Kingdom
  • Edinburgh, United Kingdom, EH10 5HF
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
  • London, United Kingdom, SW 6NP
    • Novartis Investigative Site
  • Manchester, United Kingdom, M23 9LT
    • Novartis Investigative Site
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
      • Novartis Investigative Site
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L9 7AL
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; Placebo controlled arm	Drug: Placebo; Placebo Capsule 300mg Oral use, one capsule twice daily.; Other Names: Comparator
Active Comparator: QBW251; Active comparator drug arm	Drug: Active drug; QBW251 Capsule 300mg Oral use, one capsule twice daily.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Innovative Medicines Initiative

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2021
• Primary Completion (Actual): June 15, 2023
• Study Completion (Actual): June 21, 2023

Study Registration Dates

• First Submitted: May 18, 2020
• First Submitted That Met QC Criteria: May 18, 2020
• First Posted (Actual): May 20, 2020

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Bronchiectasis; QBW251; colony forming units
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Bronchial Diseases; Bronchiectasis
• Other Study ID Numbers: CQBW251C12201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No