Trial Outcomes & Findings for Clinical Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT04268823)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

54 participants

Primary outcome timeframe

Baseline, week 12.

Results posted on

2024-06-20

Participant Flow

Participants took part in 12 investigative sites in 4 countries.

Informed consent was obtained from each participant in writing at screening before any study specific procedure was performed. The study was explained to the participant by the investigator or designee, who answered any questions, and written information was also provided.

Participant milestones

Participant milestones
Measure	QBW251 300mg QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Overall Study STARTED	26	28
Overall Study COMPLETED	24	28
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	QBW251 300mg QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Overall Study Adverse Event	1	0
Overall Study Participant Decision	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily	Total n=54 Participants Total of all reporting groups
Age, Continuous	65.7 years STANDARD_DEVIATION 7.13 • n=5 Participants	67.3 years STANDARD_DEVIATION 8.37 • n=7 Participants	66.5 years STANDARD_DEVIATION 7.77 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	11 Participants n=7 Participants	27 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	17 Participants n=7 Participants	27 Participants n=5 Participants
Race/Ethnicity, Customized White	26 Participants n=5 Participants	28 Participants n=7 Participants	54 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in Fibrinogen Plasma Concentrations After 12 Weeks of Treatment	-0.086 g/L Standard Error 0.1374	0.117 g/L Standard Error 0.1365

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in Total Bacteria Load of log10 Colony Forming Units (CFU) After 12 Weeks of Treatment	-0.2 log10 CFU/mL Standard Error 0.30	0.0 log10 CFU/mL Standard Error 0.32

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in COPD Assessment Test (CAT) Questionnaire After 12 Weeks of Treatment	-3.55 Score on a scale Standard Error 0.947	-2.16 Score on a scale Standard Error 0.874

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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).

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in Euro Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire After 12 Weeks of Treatment	7.63 Score on a scale Standard Error 3.116	3.43 Score on a scale Standard Error 2.854

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total and Domain Scores After 12 Weeks of Treatment Week 12- total score	-2.99 Score on a scale Standard Error 2.297	-2.17 Score on a scale Standard Error 2.111
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total and Domain Scores After 12 Weeks of Treatment Week 12- Symptoms score	-0.98 Score on a scale Standard Error 3.052	-6.73 Score on a scale Standard Error 2.806
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total and Domain Scores After 12 Weeks of Treatment Week 12- Activity score	-1.96 Score on a scale Standard Error 2.388	-1.35 Score on a scale Standard Error 2.194
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total and Domain Scores After 12 Weeks of Treatment Week 12- Impact score	-3.72 Score on a scale Standard Error 2.944	-1.65 Score on a scale Standard Error 2.705

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment Week 12 - cough symptom score	4.36 Score on a scale Standard Error 3.339	4.11 Score on a scale Standard Error 3.083
Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment Week 12 - sputum symptom score	5.00 Score on a scale Standard Error 3.401	0.78 Score on a scale Standard Error 3.121
Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment Week 12 - cough impact score	4.64 Score on a scale Standard Error 2.936	2.60 Score on a scale Standard Error 2.697
Change From Baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) After 12 Weeks of Treatment Week 12 - sputum impact score	3.22 Score on a scale Standard Error 3.298	2.28 Score on a scale Standard Error 3.017

SECONDARY outcome

Timeframe: Day 1, Day 28, Day 56 and Day 84

Population: The PK analysis set included all participants with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received QBW251 and experienced no protocol deviations with relevant impact on PK data.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Pre-dose Trough Concentration (Ctrough) of QBW251 Day 1	0.00 ng/mL Standard Deviation 0.00	—
Pre-dose Trough Concentration (Ctrough) of QBW251 Day 28	526 ng/mL Standard Deviation 735	—
Pre-dose Trough Concentration (Ctrough) of QBW251 Day 56	489 ng/mL Standard Deviation 540	—
Pre-dose Trough Concentration (Ctrough) of QBW251 Day 84	567 ng/mL Standard Deviation 883	—

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in Trough FEV1 After 12 Weeks of Treatment	0.0 liters (L) Standard Error 0.03	-0.1 liters (L) Standard Error 0.03

SECONDARY outcome

Timeframe: Baseline, week 12

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in FVC After 12 Weeks of Treatment	-0.1 liters (L) Standard Error 0.05	-0.1 liters (L) Standard Error 0.05

SECONDARY outcome

Timeframe: Baseline, week 12.

Population: Pharmacodynamic (PD) analysis set. Participants were analyzed according to the study treatment received. The PD analysis set included all participants with PD data at both baseline and at least one post-baseline assessment which were not affected by any protocol deviations.

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).

Outcome measures

Outcome measures
Measure	QBW251 300mg n=26 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo n=28 Participants Placebo oral dose, one capsule twice daily
Change From Baseline in FEV1/FVC After 12 Weeks of Treatment	1.7 percent Standard Error 0.58	-0.3 percent Standard Error 0.55

SECONDARY outcome

Timeframe: Pre dose, Post dose (1, 2, 3, 4, 6, and 8 hours) at Day 1 and Day 28.

Population: The PK analysis set included all participants with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received QBW251 and experienced no protocol deviations with relevant impact on PK data. The analysis was performed on a subset of the PK analysis set for participants where serial plasma PK concentrations were sampled.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=12 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Maximum Observed Plasma Concentrations (Cmax) of QBW251 in a Subset of Patient Population Day 1	1000 ng/mL Standard Deviation 608	—
Maximum Observed Plasma Concentrations (Cmax) of QBW251 in a Subset of Patient Population Day 28	1580 ng/mL Standard Deviation 866	—

SECONDARY outcome

Timeframe: Post-dose (3 hours) at Day 56 and Day 84.

Population: The PK analysis set included all participants with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received QBW251 and experienced no protocol deviations with relevant impact on PK data.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=21 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Maximum Observed Plasma Concentrations (Cmax) of QBW251 Day 56	903 ng/mL Standard Deviation 648	—
Maximum Observed Plasma Concentrations (Cmax) of QBW251 Day 84	997 ng/mL Standard Deviation 497	—

SECONDARY outcome

Timeframe: Pre dose, Post dose (1, 2, 3, 4, 6, and 8 hours) at Day 1 and Day 28

Population: The PK analysis set included all participants with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received QBW251 and experienced no protocol deviations with relevant impact on PK data.

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.

Outcome measures

Outcome measures
Measure	QBW251 300mg n=12 Participants QBW251 300 mg oral dose, one capsule twice daily	Placebo Placebo oral dose, one capsule twice daily
Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of QBW251 Day 1	4290 h*ng/mL Standard Deviation 3630	—
Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of QBW251 Day 28	7320 h*ng/mL Standard Deviation 5950	—

Adverse Events

QBW251 300 mg b.i.d

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Total

Serious events: 2 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	QBW251 300 mg b.i.d n=26 participants at risk QBW251 300 mg b.i.d	Placebo n=28 participants at risk Placebo	Total n=54 participants at risk Total
Cardiac disorders Arrhythmia supraventricular	3.8% 1/26 • 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.	0.00% 0/28 • 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.	1.9% 1/54 • 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.
Infections and infestations Pneumonia	3.8% 1/26 • 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.	0.00% 0/28 • 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.	1.9% 1/54 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	3.8% 1/26 • 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.	0.00% 0/28 • 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.	1.9% 1/54 • 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.

Other adverse events

Other adverse events
Measure	QBW251 300 mg b.i.d n=26 participants at risk QBW251 300 mg b.i.d	Placebo n=28 participants at risk Placebo	Total n=54 participants at risk Total
Gastrointestinal disorders Diarrhoea	15.4% 4/26 • 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.	0.00% 0/28 • 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.	7.4% 4/54 • 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.
Infections and infestations COVID-19	3.8% 1/26 • 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.	7.1% 2/28 • 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.	5.6% 3/54 • 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.
Infections and infestations Nasopharyngitis	11.5% 3/26 • 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.	3.6% 1/28 • 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.	7.4% 4/54 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	15.4% 4/26 • 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.	10.7% 3/28 • 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.	13.0% 7/54 • 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.
Respiratory, thoracic and mediastinal disorders Pulmonary mass	11.5% 3/26 • 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.	3.6% 1/28 • 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.	7.4% 4/54 • 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.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER