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

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

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)

The purpose of this study was to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in subjects with COPD would 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 provided 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.

This was 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 severe COPD (GOLD 2-3). The study consisted 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.

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on fibrinogen. The least-squares means for change from baseline in fibrinogen plasma concentrations after 12 weeks visits for each individual dose group were obtained from a linear mixed effects model for repeated measures (MMRM). A MMRM was fitted to the changes from baseline in fibrinogen for all time points until Day 84. A decrease in fibrinogen plasma concentration indicates improvement.

Change From Baseline in Total Bacteria Load of log10 Colony Forming Units (CFU) After 12 Weeks of Treatment

Change from baseline in total bacteria load of colony forming units of potentially pathogenic microorganisms in sputum. A decrease in airway bacterial colonization as detected in the sputum is considered improvement.

The COPD assessment test (CAT) is a short instrument which was used to quantify the symptom burden of COPD and disease severity of participants in this study. The CAT consists of 8 items, each presented as a semantic 6-point differential scale (0-5), providing a total range from 0 to 40. A higher score indicates a worse health status.

Change From Baseline in Euro Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire After 12 Weeks of Treatment

The EQ-5D-3L questionnaire is a general health status and health utility measure which captures 5 dimensions of health state: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and visual analog has a scale 0 to 100 (0=worst imaginable health state, 100=best imaginable health state).

Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total and Domain Scores After 12 Weeks of Treatment

The St. George's Respiratory questionnaire (SGRQ) was used to provide the health status measurements. The SGRQ contains 50 items divided into two parts covering three aspects of health related to COPD: Part I covers "Symptoms", Part II covers "Activity" and "Impacts". A score is calculated for each of these three subscales including the "Total" score. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.

Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment

The CASA-Q is a validated questionnaire used to measure cough and sputum production, and their impact in patients with COPD and/or chronic bronchitis. There are only domain scores and no overall score. The scores in each domain range from 0 to 100, with lower scores indicating more severe symptoms or a higher impact.

Pharmacokinetic blood samples were collected and evaluated in all participants exposed to QBW251. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification (LLOQ) was reported as zero.

FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The least-squares means for change from baseline in FEV1 to assess the effect of QBW251 compared to placebo after 12 weeks were obtained from a linear mixed effects model for repeated measures (MMRM). A positive change from baseline in pre-dose FEV1 is considered a favourable outcome.

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Vital Capacity). Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible.

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry. FEV1/FVC is the percent of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).

Cmax is the maximum (peak) observed plasma concentration of QBW251 after dose administration. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. Serial plasma PK concentrations were sampled on Day 1 and Day 28 up to 8 hours post dose in a subset of the patient population.

Cmax is the maximum (peak) observed plasma concentration of QBW251 after dose administration. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. On Day 56 and Day 84 pre-dose and 3 hour post dose sparse samples were collected from all participants.

Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of QBW251

Pharmacokinetic blood samples were collected and evaluated in all participants exposed to QBW251. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of QBW251.

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD exacerbations, exacerbations defined by EXACT-PRO questionnaire. The protocol defined that the time-to-event analyses were to be carried out only upon sufficient number of exacerbation events occur during the study to estimate the median in either of the treatment groups.

The EXACT-PRO is a validated 14-item electronic questionnaire designed to detect the frequency, severity, and duration of exacerbations in participants with COPD. Minimum score is 0 and Maximum score is 40 (higher scores indicate worsening indicative of an exacerbation). EXACT-PRO-defined exacerbations are defined as a persistent increase from baseline in total EXACT-PRO score of ≥9 points for 3 days or ≥12 points for 2 days.

From first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days

The Exacerbations of COPD Tool-Patient Reported Outcome (EXACT-PRO) is a validated 14-item electronic questionnaire designed to detect the frequency, severity, and duration of exacerbations in participants with COPD. Minimum score is 0 and Maximum score is 40 (higher scores indicate worsening indicative of an exacerbation). EXACT-PRO-defined exacerbations are defined as a persistent increase from baseline in total EXACT-PRO score of ≥9 points for 3 days or ≥12 points for 2 days. Annualized rate of exacerbations was analyzed using a generalized linear model assuming a negative binomial distribution.

From first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and function, measured by High Resolution Computed Tomography (HRCT).

To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and functions, measured by High Resolution Computed Tomography (HRCT). Air trapping is defined as the percentage of lung voxels with mean attenuation below -856 Hounsfield units (HU).

Inclusion Criteria: Patients who have signed an Informed Consent Form prior to initiation of any study-related procedure. Male and female adults aged ≥40 years at screening. Patients with stable COPD, stages GOLD 2-3, according to the current GOLD strategy (GOLD 2019) at screening. Patients with a post-bronchodilator FEV1/FVC < 0.70 at screening 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) between January 2019 to study screening. Patients with sputum positive (>0 CFU) for at least one strain of potentially pathogenic microorganism at screening (H influenzae, H parainfluenzae, P aeruginosa, S pneumoniae, S aureus, Moraxella catarrhalis, Enterobacteriaceae, Stenotrophomonas maltophilia, Burkholderia species, and Achromobacter species or any potential pathogenic bacteria measured by dilution/outgrowth. Any organism that is to be included and that is not included in the list of the protocol defined pathogens will be discussed case by case). Sputum samples may be re collected and re-tested once during the screening period. 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. Patients with plasma fibrinogen level ≥ 320 mg/dL at screening. Fibrinogen may be re-tested once during the screening period. A COPD Assessment Test (CAT) score of at least 10 at screening. 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. 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. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Exclusion Criteria: Patients with a history of long-QT syndrome or whose QTcF interval at screening (Fridericia method) 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). 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. 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. Patients with a history or current treatment for hepatic disease including but not limited to acute hepatitis, cirrhosis or hepatic failure. Patients with stable chronic hepatitis may be included in the study by agreement with Novartis Medical Expert on a case-by-case basis. 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. 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. 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). 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. Patients with history of asthma or any other clinically relevant lung diseases.. 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. Patients with pulmonary lobectomy, lung volume reduction surgery, bronchoscopic lung volume reductions, or lung transplantation. 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. Patients with a body mass index (BMI) of more than 40 kg/m2. Patients receiving any medications in the classes listed in Table 6-5. 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. 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. 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. 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. 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. 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.

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