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

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Brief Title

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

Official Title

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

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 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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change from baseline in bacterial load Colony forming units (CFU/mL) of potentially pathogenic microorganisms in sputum at week 12

Secondary Outcome

 Proportion of subjects with absence of any colony forming units (CFU/mL) of porentially pathogenic bacteria sputum

Condition

Bronchiectasis

Intervention

Active drug

Study Arms / Comparison Groups

 placebo
Description:  Placebo controlled arm

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

72

Start Date

November 30, 2020

Completion Date

February 1, 2022

Primary Completion Date

February 1, 2022

Eligibility Criteria

        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 HRCT

          -  Evidence of sputum bacterial load of ≥106 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.) Any organism that is to be included and that is not included in
             the list of 7 protocol defined pathogens, requires approval by the steering committee
             in collaboraton with Novartis for inclusion

          -  Documented history of at least one bronchiectasis exacerbation in the 12 months prior
             to 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.

          -  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 or an aspartate
             aminotransferase (AST) to alanine aminotransferase(ALT) ratio(AST/ALT) or prothrombin
             time international normalized ratio(PT/INR) of more than 1.5xULN at screening.

          -  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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, +41613241111, [email protected]



Administrative Informations


NCT ID

NCT04396366

Organization ID

CQBW251C12201


Responsible Party

Sponsor

Study Sponsor

Novartis Pharmaceuticals

Collaborators

 Innovative Medicines Initiative

Study Sponsor

, , 


Verification Date

May 2020