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Clinical Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT04268823
Recruitment Status : Recruiting
First Posted : February 13, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

The purpose of this study is to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in subjects with COPD will be efficacious with regards to reducing lung and systemic inflammation and bacterial colonization as potential drivers of airway obstruction, airway destruction, remodeling and exacerbations.

Furthermore, this study will provide supportive data to investigate the relationship of COPD phenotype and the response in small airway structure, function, mucus load and spirometry indices as well as in improvement of overall COPD symptoms and quality of life.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Drug: QBW251 Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is a randomized, subject and investigator blinded, parallel-group, placebo controlled study investigating the mode of action (MoA) and preliminary efficacy and safety of QBW251 administered orally twice daily (b.i.d.) for 12 weeks in subjects with moderate to very severe COPD (GOLD 2-4).

Approximately 100 subjects will be randomized in a 1:1 ratio to receive either QBW251 or placebo treatment. Based on the assumption of a 15% drop-out rate (% drop out based on completed proof-of-concept COPD study CQBW251X2201), it is expected to have approximately 84 subjects to complete the study. A blinded interim analysis to re-assess the sample size is planned for when approximately 36 subjects have completed their Day 84 visit.

The study consists of the following periods: Screening, Baseline / Day 1, Treatment, and End of the Study followed by an additional post-treatment safety phone call. The total duration for each subject in the study is up to approximately 18 weeks.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Subjects and Investigator Blinded, Placebo Controlled Parallel Group Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Actual Study Start Date : September 10, 2020
Estimated Primary Completion Date : October 15, 2021
Estimated Study Completion Date : October 20, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arm Intervention/treatment
Experimental: QBW251
Oral use, one capsule twice daily.
Drug: QBW251
Capsule 450mg

Placebo Comparator: Placebo
Oral use, one capsule twice daily.
Drug: Placebo
Capsule 450mg




Primary Outcome Measures :
  1. Fibrinogen plasma concentration [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on fibrinogen


Secondary Outcome Measures :
  1. Total bacteria load of colony forming units (CFU/mL) [ Time Frame: Change from baseline at 12 weeks. ]
    Change from baseline in total bacteria load of colony forming units (CFU/mL) of potentially pathogenic microorganisms in sputum.

  2. COPD Assessment Test (CAT) questionnaire. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD patients symptoms burden changes.

  3. Euro Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) questionnaire. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on health status and quality of patients life.

  4. St. George's Respiratory Questionnaire (SGRQ) total and domain scores. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on changes in total and domain scores health-related quality of life.

  5. Cough and Sputum Assessment Questionnaire (CASA-Q). [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on domain scores which evaluate clinical symptoms, cough and sputum.

  6. Ctrough at pre-dose. [ Time Frame: Day 1, Day 28, Day 56 and Day 84. ]
    To assess the effect of QBW251 compared to placebo during and after 12 weeks of treatment on pharmacokinetics, assessing drug exposure.

  7. Trough FEV1. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Exploratory Volume in the first second).

  8. FVC. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Vital Capacity).

  9. FEV1/FVC. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry

  10. Cmax at post-dose. [ Time Frame: Post-dose (+3hr) at Day 1, Day 28, Day 56 and Day 84. ]
    To assess the effect of QBW251 compared to placebo during and after 12 weeks of treatment on pharmacokinetics, drug exposure.

  11. Cmax in a subset of patient population [ Time Frame: Post dose (+1hr, +2hr, +3hr, +4hr, +6hr, +8hr) at Day 1 and Day 28. ]
    To assess the effect of QBW251 compared to placebo during and after 12 weeks of treatment on pharmacokinetics, assessing drug exposure.

  12. AUC in a subset of patient population. [ Time Frame: Post-dose (+1hr, +2hr, +3hr, +4hr, +6hr, +8hr) at Day 1 and Day 28. ]
    To assess the effect of QBW251 compared to placebo during and after 12 weeks of treatment on pharmacokinetics, assessing drug exposure.

  13. Time to first COPD exacerbation. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD exacerbations, exacerbations defined by EXACT-PRO questionnaire.

  14. Proportion of patients (percentage) with exacerbations. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD exacerbations , exacerbations defined by EXACT-PRO questionnaire.

  15. Annualized rate of exacerbations. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD exacerbations, exacerbations defined by EXACT-PRO questionnaire.

  16. Airway wall. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and function, measured by HRCT.

  17. Airway extent of global and regional air trapping [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and functions, measured by HRCT.

  18. Airway lumen. [ Time Frame: Change from baseline at 12 weeks. ]
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and function measured by HRCT.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients who have signed an Informed Consent Form prior to initiation of any study-related procedure.
  2. Male and female adults aged ≥40 years at screening.
  3. Patients with stable COPD, stages GOLD 2-4, according to the current GOLD strategy (GOLD 2019) at screening.

    Patients with a post-bronchodilator FEV1/FVC < 0.70 at screening

  4. Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30% and FEV1 < 80% of the predicted normal at Screening who must have had at least 2 documented moderate or at least 1 documented severe exacerbation(s) in the 12 months prior to study entry.
  5. Patients with sputum bacterial load (log10≥105 CFU/mL) with at least one strain of potentially pathogenic microorganism at screening (H influenzae, H parainfluenzae, P aeruginosa, S pneumoniae, S aureus, Moraxella catarrhalis, Enterobacteriaceae).
  6. Patients who have been treated with a combination of LABA/LAMA or LABA/ICS or LABA/LAMA/ICS at a stable dose for the last 3 months prior to screening.

    COPD patients are allowed to stay on macrolides as background therapy if they have bronchiectasis as a secondary diagnosis and if they are treated with them at a stable dose 3 months before screening.

  7. Patients with plasma fibrinogen level ≥ 350 mg/dL at screening.
  8. A COPD Assessment Test (CAT) score of at least 10 at screening.
  9. Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack/day x 10 years, or 0.5 pack/day x 20 years) at screening.
  10. Patients featuring chronic bronchitis, defined as productive cough that occurs on most days (defined as >50% of days) during at least 3 consecutive months in the year prior to screening, as assessed by documentation of patient recollection (anamnesis) or documented in patients' records.
  11. Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion Criteria:

  1. Patients with a history of long-QT syndrome or whose QTcF interval at screening
  2. Patients who have a clinically significant ECG abnormality before randomization.
  3. Clinical laboratory values abnormalities (including Gamma GT, AST, ALT, total bilirubin or creatinine) considered as clinically significant in the opinion of the Investigator at screening. For additional guidance on hepatic parameters see exclusion criterion #5.
  4. 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 II diabetes.
  5. 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 AST/ALT of more than 1.5x ULN or abnormal PT/INR at screening.
  6. Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. 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.
  7. Patients who develop a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization during screening. Re-screening is permitted after a minimum of 2 weeks after the resolution of the COPD exacerbation (i.e 2 weeks after the stop of SOC therapy for exacerbation).
  8. Patients who have had a respiratory tract infection within 4 weeks prior to screening. If a respiratory tract infection occurs during screening, patients can be re-screened after a minimum of 2 weeks after resolution of the respiratory tract infection.
  9. Patients with history of asthma or any other clinically relevant lung diseases..
  10. Patients with suspected active pulmonary tuberculosis or currently being treatment for active pulmonary tuberculosis.

    Note: Patients with a history of pulmonary tuberculosis can be enrolled if they meet the following requirements: history of appropriate drug treatment followed by negative imaging results within 12 months prior to screening suggesting low probability of recurrent active tuberculosis.

  11. Patients with pulmonary lobectomy, lung volume reduction surgery, bronchoscopic lung volume reductions, or lung transplantation.
  12. Patients participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the trial. Participation in a maintenance program is permitted. Note: the supervised pulmonary rehabilitation program as a maintenance program has to be ongoing for at least 3 months at the time of enrollment.
  13. Patients with a body mass index (BMI) of more than 40 kg/m2.
  14. Patients receiving any medications in the classes listed in Table 6-5.
  15. Patients receiving any COPD related medications in the classes specified in Table 6-6, unless they undergo the required washout period prior to screening and follow the adjustment to treatment program.
  16. Patients receiving medications in the classes listed in Table 6-2 should be excluded unless the medication has been stabilized for the specified period and the stated conditions have been met.
  17. Use of other investigational drugs (approved or unapproved) within 30 days or 5 half-lives prior to screening, or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer; or longer if required by local regulations.
  18. Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
  19. 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.
  20. Patients who have not achieved an acceptable spirometry result at screening in accordance with American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria for acceptability and repeatability.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04268823


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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Germany
Novartis Investigative Site Recruiting
Heidelberg, Baden-Württemberg, Germany, 69126
Novartis Investigative Site Recruiting
Berlin, Germany, 10119
Novartis Investigative Site Recruiting
Essen, Germany, 45239
Novartis Investigative Site Recruiting
Frankfurt, Germany, 60596
Novartis Investigative Site Recruiting
Hannover, Germany, 30625
Novartis Investigative Site Recruiting
Leipzig, Germany, 04357
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04268823    
Other Study ID Numbers: CQBW251B2202
First Posted: February 13, 2020    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases