A Safety, Tolerability and Efficacy Study With QBW251 in COPD Patients With QBW251

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02449018
• Collaborator: (none)
• Enrollment: 92
• Locations: 16
• Arms: 2
• Actual Duration (Months): 20.8
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To evaluate the efficacy, safety and tolerability of multiple doses of QBW251 vs placebo administered orally, on airway function, lung volume, and quality of life in patients with chronic obstructive pulmonary disease (COPD)

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease, COPD	Drug: QBW251; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Multiple Doses of QBW251 in Patients With COPD
• Actual Study Start Date: Apr 30, 2015
• Actual Primary Completion Date: Dec 27, 2016
• Actual Study Completion Date: Jan 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QBW251 QBW251 will be provided to participants during 70 days	Drug: QBW251; QBW251 capsule(s) taken orally twice per day
Placebo Comparator: Placebo Placebo will be provided to participants during 70 days	Drug: Placebo; Matching placebo capsule(s) taken orally twice per day

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Lung Clearance Index (LCI) [Baseline and Day 29]

   Change from baseline to Day 29 in LCI as measured by multiple breath nitrogen washout (MBNW) technique. MBNW is the time taken to wash out nitrogen while breathing 100% oxygen.

Secondary Outcome Measures

1. Change From Baseline in FEV1 Pre-bronchodilator [Day 29]

   Change From Baseline to Day 29 in FEV1 will be measured by spirometer before bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.

2. Change From Baseline in FEV1 Post-bronchodilator [Day 29]

   Change From Baseline to Day 29 in FEV1 will be measured by spirometer after bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.

3. Change From Baseline in FVC Pre Bronchodilator [Day 29]

   Change From Baseline to Day 29 in FVC will be measured by spirometer before bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured before bronchodilator

4. Change From Baseline in FVC Post- Bronchodilator [Day 29]

   Change From Baseline to Day 29 in FVC will be measured by spirometer after bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured after bronchodilator

5. Change From Baseline in TLC [Day 29]

   Change From Baseline to Day 29 in TLC will be measured by spirometry. Total lung capacity (TLC) is the volume in the lungs at maximal inflation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.

6. Change From Baseline in RV [Day 29]

   Change From Baseline to Day 29 in RV will be measured by spirometry. Residual volume (RV) is the volume of air remaining in the lungs after a maximal exhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.

7. Change From Baseline in FRC [Day 29]

   Change From Baseline to Day 29 in FRC will be measured by spirometry. Functional residual capacity (FRC) is the volume in the lungs at the end-expiratory position. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.

8. Change From Baseline in DLCO [Day 29]

   Diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the lung to the blood.

9. Plasma Concentration of QBW251 by TMax (0-8hours) [Day 1, Day 28]

   Tmax is the time to reach the maximum concentration after drug administration.

10. Plasma Concentration of QBW251 by CMax (0-8hours) [Day 1, Day 28]

    Cmax is the observed maximum plasma concentration following drug administration.

11. Plasma Concentration of QBW251 by AUClast (0-8hours) [Day 1, Day 28]

    AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration.

12. Plasma Concentration of QBW251 by AUC0-12h [Day 1, Day 28]

    AUC 0-12h is the area under the plasma concentration-time curve from time zero to 12 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Must have a diagnosis of GOLD II-III chronic obstructive pulmonary disease (COPD); Must have clinical diagnosis of chronic bronchitis; Must be either a current smoker (smoked ≤ 1 pack per day on average for the last 3 months with at least a 10 pack year smoking history) OR an ex-smoker with at least a 10 pack year smoking history; Exclusion Criteria: Must not be receiving chronic, daily, systemic steroids; Must not have severe emphysema (determined by HRCT); Must not have had a COPD exacerbation or respiratory tract infection requiring antibiotics or oral steroids or hospitalization within 6 weeks of screening; Must not be pregnant or nursing or a woman of child bearing potential; Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294
2	Novartis Investigative Site	Fullerton	California	United States	92835
3	Novartis Investigative Site	Waterbury	Connecticut	United States	06708
4	Novartis Investigative Site	Clearwater	Florida	United States	33765
5	Novartis Investigative Site	Port Orange	Florida	United States	32127
6	Novartis Investigative Site	Tampa	Florida	United States	33603
7	Novartis Investigative Site	Normal	Illinois	United States	61761
8	Novartis Investigative Site	Saint Louis	Missouri	United States	63141
9	Novartis Investigative Site	Huntersville	North Carolina	United States	28078
10	Novartis Investigative Site	Shelby	North Carolina	United States	28152
11	Novartis Investigative Site	Medford	Oregon	United States	97504
12	Novartis Investigative Site	Simpsonville	South Carolina	United States	29681
13	Novartis Investigative Site	Spartanburg	South Carolina	United States	29303
14	Novartis Investigative Site	Union	South Carolina	United States	29379
15	Novartis Investigative Site	Lodz		Poland	90-153
16	Novartis Investigative Site	Sobotka		Poland	55-050

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02449018
• Other Study ID Numbers: CQBW251X2201
• First Posted: May 20, 2015
• Last Update Posted: Jan 5, 2021
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: COPD,; chronic bronchitis,; inflammation,; airway,; LCI,; pulmonary function test,; lung function,; controlled clinical trial,; randomized,; airflow,; smoker
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Period Title: Overall Study
STARTED	64	28
COMPLETED	52	26
NOT COMPLETED	12	2

Baseline Characteristics

Arm/Group Title	QBW251	Placebo	Total
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)	Total of all reporting groups
Overall Participants	64	28	92
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.6 (6.61)	64.9 (7.55)	64.0 (6.89)
Sex: Female, Male (Count of Participants)
Female	31 48.4%	9 32.1%	40 43.5%
Male	33 51.6%	19 67.9%	52 56.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Lung Clearance Index (LCI)
Description	Change from baseline to Day 29 in LCI as measured by multiple breath nitrogen washout (MBNW) technique. MBNW is the time taken to wash out nitrogen while breathing 100% oxygen.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	50	24
Mean (Standard Deviation) [Days]	-0.03 (1.28)	-0.16 (1.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QBW251, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.130
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 90%; -0.24 to 0.79
	Parameter Dispersion	Type: Standard Deviation; Value: 0.31
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in FEV1 Pre-bronchodilator
Description	Change From Baseline to Day 29 in FEV1 will be measured by spirometer before bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	51	23
Mean (Standard Deviation) [Liters]	0.04 (0.24)	-0.02 (0.23)

3. Secondary Outcome

Title	Change From Baseline in FEV1 Post-bronchodilator
Description	Change From Baseline to Day 29 in FEV1 will be measured by spirometer after bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	51	24
Mean (Standard Deviation) [Liters]	0.05 (0.21)	-0.02 (0.16)

4. Secondary Outcome

Title	Change From Baseline in FVC Pre Bronchodilator
Description	Change From Baseline to Day 29 in FVC will be measured by spirometer before bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured before bronchodilator
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	51	23
Least Squares Mean (Standard Deviation) [Liters]	0.07 (0.05)	0.01 (0.07)

5. Secondary Outcome

Title	Change From Baseline in FVC Post- Bronchodilator
Description	Change From Baseline to Day 29 in FVC will be measured by spirometer after bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured after bronchodilator
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	51	24
Least Squares Mean (Standard Deviation) [Liters]	0.03 (0.04)	0.01 (0.05)

6. Secondary Outcome

Title	Change From Baseline in TLC
Description	Change From Baseline to Day 29 in TLC will be measured by spirometry. Total lung capacity (TLC) is the volume in the lungs at maximal inflation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	50	24
Least Squares Mean (Standard Deviation) [Liters]	0.01 (0.07)	-0.07 (0.10)

7. Secondary Outcome

Title	Change From Baseline in RV
Description	Change From Baseline to Day 29 in RV will be measured by spirometry. Residual volume (RV) is the volume of air remaining in the lungs after a maximal exhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	48	24
Least Squares Mean (Standard Deviation) [Liters]	0.03 (0.07)	-0.02 (0.10)

8. Secondary Outcome

Title	Change From Baseline in FRC
Description	Change From Baseline to Day 29 in FRC will be measured by spirometry. Functional residual capacity (FRC) is the volume in the lungs at the end-expiratory position. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	50	24
Least Squares Mean (Standard Deviation) [Liters]	0.01 (0.07)	-0.02 (0.09)

9. Secondary Outcome

Title	Change From Baseline in DLCO
Description	Diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the lung to the blood.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	42	22
Least Squares Mean (Standard Error) [ml/min/mmHg]	-0.91 (0.24)	-0.25 (0.34)

10. Secondary Outcome

Title	Plasma Concentration of QBW251 by TMax (0-8hours)
Description	Tmax is the time to reach the maximum concentration after drug administration.
Time Frame	Day 1, Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28

Arm/Group Title	QBW251
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)
Measure Participants	62
Day 1	1.27
Day 28	1.98

11. Secondary Outcome

Title	Plasma Concentration of QBW251 by CMax (0-8hours)
Description	Cmax is the observed maximum plasma concentration following drug administration.
Time Frame	Day 1, Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28

Arm/Group Title	QBW251
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)
Measure Participants	62
Day 1	1250 (840)
Day 28	1640 (916)

12. Secondary Outcome

Title	Plasma Concentration of QBW251 by AUClast (0-8hours)
Description	AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration.
Time Frame	Day 1, Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28

Arm/Group Title	QBW251
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)
Measure Participants	62
Day 1	3830 (3280)
Day 28	6840 (4490)

13. Secondary Outcome

Title	Plasma Concentration of QBW251 by AUC0-12h
Description	AUC 0-12h is the area under the plasma concentration-time curve from time zero to 12 hours.
Time Frame	Day 1, Day 28

Outcome Measure Data

Analysis Population Description

PK analysis set: included all patients with at least one available valid PK concentration measurement. Due to practicalities of study conduct PK samples were collected only up to 8 hours. As a result, from noncompartmental analysis AUClast was not calculated up to 12 hours after dosing So this data is not available.

Arm/Group Title	QBW251	Placebo
Arm/Group Description	QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods)	Placebo (70 days, run-in, treatment and wash-out periods)
Measure Participants	0	0

Adverse Events

Time Frame	Treatment-emergent adverse events
Arm/Group Title	Placebo		QBW251 300 mg Bid
Arm/Group Description	Placebo (70 days, run-in, treatment and wash-out periods)		QBW251 (28 day treatment period) and placebo (42 days, run-in and wash-out periods)
All Cause Mortality
	Placebo		QBW251 300 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/64 (0%)
Serious Adverse Events
	Placebo		QBW251 300 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		4/64 (6.3%)
Gastrointestinal disorders
Vomiting	0/28 (0%)		1/64 (1.6%)
Infections and infestations
Pneumonia	0/28 (0%)		1/64 (1.6%)
Metabolism and nutrition disorders
Hypokalaemia	0/28 (0%)		1/64 (1.6%)
Nervous system disorders
Cerebrovascular accident	0/28 (0%)		1/64 (1.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/28 (0%)		1/64 (1.6%)
Chronic obstructive pulmonary disease	0/28 (0%)		1/64 (1.6%)
Other (Not Including Serious) Adverse Events
	Placebo		QBW251 300 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/28 (17.9%)		6/64 (9.4%)
Gastrointestinal disorders
Diarrhoea	2/28 (7.1%)		2/64 (3.1%)
Nausea	2/28 (7.1%)		1/64 (1.6%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/28 (7.1%)		3/64 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 or disclosure of trial results in their entirety