NCT04268823

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

Terminated Phase 2 Results posted Last updated 20 June 2024

What this trial tests

Phase 2 trial testing QBW251 in Chronic Obstructive Pulmonary Disease in 54 participants. Terminated before completion.

Timeline

10 September 2020

Primary endpoint
13 September 2022

20 September 2022

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	54
Start date	10 September 2020
Primary completion	13 September 2022
Estimated completion	20 September 2022
Sites	12 locations across Austria, United Kingdom, Switzerland, Germany

Drugs / interventions tested

• QBW251 — full drug profile →
• Placebo

Conditions studied

• Chronic Obstructive Pulmonary Disease — all drugs for Chronic Obstructive Pulmonary Disease →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

40 and older, any sex, with Chronic Obstructive Pulmonary Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Fibrinogen Plasma Concentrations After 12 Weeks of Treatment Primary · Baseline, week 12.

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.

Group	Value	95% CI
QBW251 300mg	-0.086	± 0.1374
Placebo	0.117	± 0.1365

Change From Baseline in Total Bacteria Load of log10 Colony Forming Units (CFU) After 12 Weeks of Treatment Secondary · Baseline, week 12.

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.

Group	Value	95% CI
QBW251 300mg	-0.2	± 0.30
Placebo	0.0	± 0.32

Change From Baseline in COPD Assessment Test (CAT) Questionnaire After 12 Weeks of Treatment Secondary · Baseline, week 12.

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.

Group	Value	95% CI
QBW251 300mg	-3.55	± 0.947
Placebo	-2.16	± 0.874

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

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).

Group	Value	95% CI
QBW251 300mg	7.63	± 3.116
Placebo	3.43	± 2.854

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

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.

Week 12- total score

Group	Value	95% CI
QBW251 300mg	-2.99	± 2.297
Placebo	-2.17	± 2.111

Week 12- Symptoms score

Group	Value	95% CI
QBW251 300mg	-0.98	± 3.052
Placebo	-6.73	± 2.806

Week 12- Activity score

Group	Value	95% CI
QBW251 300mg	-1.96	± 2.388
Placebo	-1.35	± 2.194

Week 12- Impact score

Group	Value	95% CI
QBW251 300mg	-3.72	± 2.944
Placebo	-1.65	± 2.705

Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment Secondary · Baseline, week 12.

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.

Week 12 - cough symptom score

Group	Value	95% CI
QBW251 300mg	4.36	± 3.339
Placebo	4.11	± 3.083

Week 12 - sputum symptom score

Group	Value	95% CI
QBW251 300mg	5.00	± 3.401
Placebo	0.78	± 3.121

Week 12 - cough impact score

Group	Value	95% CI
QBW251 300mg	4.64	± 2.936
Placebo	2.60	± 2.697

Week 12 - sputum impact score

Group	Value	95% CI
QBW251 300mg	3.22	± 3.298
Placebo	2.28	± 3.017

Pre-dose Trough Concentration (Ctrough) of QBW251 Secondary · Day 1, Day 28, Day 56 and Day 84

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.

Day 1

Group	Value	95% CI
QBW251 300mg	0.00	± 0.00

Day 28

Group	Value	95% CI
QBW251 300mg	526	± 735

Day 56

Group	Value	95% CI
QBW251 300mg	489	± 540

Day 84

Group	Value	95% CI
QBW251 300mg	567	± 883

Change From Baseline in Trough FEV1 After 12 Weeks of Treatment Secondary · Baseline, week 12.

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.

Group	Value	95% CI
QBW251 300mg	0.0	± 0.03
Placebo	-0.1	± 0.03

Change From Baseline in FVC After 12 Weeks of Treatment Secondary · Baseline, week 12

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.

Group	Value	95% CI
QBW251 300mg	-0.1	± 0.05
Placebo	-0.1	± 0.05

Change From Baseline in FEV1/FVC After 12 Weeks of Treatment Secondary · Baseline, week 12.

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).

Group	Value	95% CI
QBW251 300mg	1.7	± 0.58
Placebo	-0.3	± 0.55

Maximum Observed Plasma Concentrations (Cmax) of QBW251 in a Subset of Patient Population Secondary · Pre dose, Post dose (1, 2, 3, 4, 6, and 8 hours) at Day 1 and Day 28.

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.

Day 1

Group	Value	95% CI
QBW251 300mg	1000	± 608

Day 28

Group	Value	95% CI
QBW251 300mg	1580	± 866

Maximum Observed Plasma Concentrations (Cmax) of QBW251 Secondary · Post-dose (3 hours) at Day 56 and Day 84.

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.

Day 56

Group	Value	95% CI
QBW251 300mg	903	± 648

Day 84

Group	Value	95% CI
QBW251 300mg	997	± 497

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were reported from first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

QBW251 300 mg b.i.d

Serious: 2/26 (8%)

Deaths: 0/26

Placebo

Serious: 0/28 (0%)

Deaths: 0/28

Total

Serious: 2/54 (4%)

Deaths: 0/54

Serious adverse events (3 terms)

Reaction	System	QBW251 300 mg b.i.d	Placebo	Total
Arrhythmia supraventricular	Cardiac disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—

Other adverse events (5 terms — click to expand)

Reaction	System	QBW251 300 mg b.i.d	Placebo	Total
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Pulmonary mass	Respiratory, thoracic and mediastinal disorders	—	—	—
COVID-19	Infections and infestations	—	—	—

Most-reported serious reactions: Arrhythmia supraventricular, Pneumonia, Lung neoplasm malignant.

Data from ClinicalTrials.gov NCT04268823 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease.
   Rodrigues SO, Cunha CMCD, Soares GMV, Silva PL, et al · · 2021 · cited 61× · PMID 34681202 · DOI 10.3390/ph14100979