A Study to Assess the Effects of PT001 and PT005 MDI on Specific Image Based Parameters in Subjects with Moderate to Severe COPD

Study identifier:PT003019

ClinicalTrials.gov identifier:NCT02937584

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Randomized, Double-Blind, Two Treatment, Two Period, Chronic Dosing (2 Weeks), Cross-Over, Multi-Center Study to Evaluate the Effects of PT001 and PT005 on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD.

Medical condition

COPD, Chronic Obstructive Pulmonary Disease

Phase

Phase 3

Healthy volunteers

Study drug

GP MDI (PT001) 14.4 μg, FF MDI (PT005) 9.6 μg

Sex

All

Actual Enrollment

Study type

Interventional

Age

40 Years - 80 Years

Date

Study Start Date: 29 Dec 2016

Primary Completion Date: 28 May 2018

Study Completion Date: 28 May 2018

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 May 2019 by Pearl Therapeutics, Inc.

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

-Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative urine pregnancy test at Visit 1, and agrees to use acceptable contraceptive methods used consistently and correctly
-Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS)
-Current or former smokers with a history of at least 10 pack-years of cigarette smoking.
− At Visit 1, FEV1/FVC ratio must be <0.70
− At Visit 1, post-bronchodilator FEV1must be >30% and <80% predicted normal value,
calculated using The Third National Health and Nutrition Examination Survey
(NHANES III) reference equations.

Exclusion Criteria

-Significant diseases other than COPD, i.e., disease or condition which, in the opinion of the Investigator, may put the subject at risk because of participation in the study or may influence either the results of the study or the subject’s ability to participate in the study.
-Women who are pregnant or lactating, or are planning to become pregnant during the course of the study, or women of childbearing potential who are not using an acceptable method of contraception.
-Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma.
-Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening) or during the run-in period (Visit 1 to Visit 2).
-Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening) or during the run-in period (Visit 1 to Visit 2).
-Subjects with a diagnosis of angle closure glaucoma will be excluded, regardless of whether or not they have been treated.
-Subjects who have a history of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, or any component of the MDI.

Location

Research Site

Edegem, Belgium, 2650

Location

Research Site

Erpent, Belgium, 5101

Arms	Assigned Interventions
Experimental: GP MDI (PT001) 14.4 μg Glycopyrronium	Drug: GP MDI (PT001) 14.4 μg Glycopyrronium
Experimental: FF MDI (PT005) 9.6 μg Formoterol Fumarate	Drug: FF MDI (PT005) 9.6 μg Formoterol Fumarate

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study randomized 23 subjects at 2 sites in Belgium from December 2016 to May 2018.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were randomized into 1 of 2 treatment sequences. Sequence 1 received GP MDI in Period 1 followed by FF MDI in Period 2. Sequence 2 received FF MDI in Period 1 followed by GP MDI in Period 2.

Reporting Groups

	Description
GP MDI/ FF MDI	Glycopyrronium Metered Dose Inhalation /Formoterol Fumarate Metered Dose Inhalation
FF MDI/GP MDI	Formoterol Fumarate Metered Dose Inhalation / Glycopyrronium Metered Dose Inhalation

Participant Flow for 3 periods

Period 1: Period 1

	GP MDI/ FF MDI	FF MDI/GP MDI
STARTED	11	12
COMPLETED	10	10
NOT COMPLETED	1	2
Adverse Event	1	2

Period 2: Washout

	GP MDI/ FF MDI	FF MDI/GP MDI
STARTED	10	10
COMPLETED	10	9
NOT COMPLETED	0	1
Adverse Event	0	1

Period 3: Period 2

	GP MDI/ FF MDI	FF MDI/GP MDI
STARTED	10	9
COMPLETED	10	9
NOT COMPLETED	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

ITT Population - all subjects who were randomized to treatment. Treatment was assigned as randomized regardless of the treatment actually received.

Reporting Groups

	Description
Overall Study	ITT Population

Baseline Measures

	Overall Study
Number of Participants [units: Participants]	23
Age Continuous [units: Years] Mean ± Standard Deviation	64.6 ± 9.6
Sex: Female, Male [units: Participants]
Female	6
Male	17
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	0
White	23
More than one race	0
Unknown or Not Reported	0

Outcome Measures

1. Primary Outcome Measure: Specific Image-Based Airway Volume (siVaw) [ Time Frame: Day 15 ]

Measure Type	Primary
Measure Name	Specific Image-Based Airway Volume (siVaw)
Measure Description	Specific image-based airway volume. Average across lobe, adjusted for lobe volume. Ratio to baseline
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
Specific Image-Based Airway Volume (siVaw) [units: Unit free ratio to baseline] Geometric Mean (95% Confidence Interval)	1.11 (1.02 to 1.22)	1.23 (1.14 to 1.33)

Statistical Analysis 1 for Specific Image-Based Airway Volume (siVaw)

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0187
Other^[5]	1.11
95% Confidence Interval	( 1.02 to 1.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant according to Hochberg’s procedure applied across primary endpoints within each treatment
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Specific Image-Based Airway Volume (siVaw)

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	<0.0001
Other^[5]	1.23
95% Confidence Interval	( 1.14 to 1.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant according to Hochberg’s procedure applied across primary endpoints within each treatment
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Specific image-based airway resistance (siRaw) [ Time Frame: Day 15 ]

Measure Type	Primary
Measure Name	Specific image-based airway resistance (siRaw)
Measure Description	Specific image-based airway resistance (siRaw). Average across lobes, adjusted for lobe volume. Ratio to baseline.
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
Specific image-based airway resistance (siRaw) [units: Unit free ratio to baseline] Geometric Mean (95% Confidence Interval)	0.75 (0.59 to 0.95)	0.56 (0.44 to 0.71)

Statistical Analysis 1 for Specific image-based airway resistance (siRaw)

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0219
Other^[5]	0.75
95% Confidence Interval	( 0.59 to 0.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant according to Hochberg’s procedure applied across primary endpoints within each treatment
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Specific image-based airway resistance (siRaw)

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	<0.0001
Other^[5]	0.56
95% Confidence Interval	( 0.44 to 0.71 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant according to Hochberg’s procedure applied across primary endpoints within each treatment
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Image-based airway volume (iVaw) [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	Image-based airway volume (iVaw)
Measure Description	Image-based airway volume (iVaw) without correction for lobe volume. Ratio to baseline.
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
Image-based airway volume (iVaw) [units: Unit free ratio to baseline] Geometric Mean (95% Confidence Interval)	1.12 (1.01 to 1.24)	1.21 (1.12 to 1.31)

Statistical Analysis 1 for Image-based airway volume (iVaw)

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0283
Other^[5]	1.12
95% Confidence Interval	( 1.01 to 1.24 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Image-based airway volume (iVaw)

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	<0.0001
Other^[5]	1.21
95% Confidence Interval	( 1.12 to 1.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Image-based airway resistance (iRaw) [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	Image-based airway resistance (iRaw)
Measure Description	Image-based airway resistance (iRaw) without correction for lobe volume. Ratio to baseline.
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
Image-based airway resistance (iRaw) [units: Unit free ratio to baseline] Geometric Mean (95% Confidence Interval)	0.76 (0.59 to 0.97)	0.55 (0.41 to 0.72)

Statistical Analysis 1 for Image-based airway resistance (iRaw)

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0304
Other^[5]	0.76
95% Confidence Interval	( 0.59 to 0.97 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Image-based airway resistance (iRaw)

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0003
Other^[5]	0.55
95% Confidence Interval	( 0.41 to 0.72 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: FEV1 [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	FEV1
Measure Description	FEV1 Change from baseline in Forced Expiratory Volume at 1 second.
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
FEV1 [units: L] Mean (Standard Deviation)	0.065 (0.193)	0.151 (0.293)

Statistical Analysis 1 for FEV1

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.1582
Other^[5]	0.065
95% Confidence Interval	( -0.028 to 0.158 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for FEV1

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.0375
Other^[5]	0.151
95% Confidence Interval	( 0.010 to 0.292 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Functional residual capacity (FRC) [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	Functional residual capacity (FRC)
Measure Description	Functional residual capacity (FRC). Ratio to baseline.
Time Frame	Day 15
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Measured Values

	GP MDI	FF MDI
Number of Participants Analyzed [units:participants]	19	19
Functional residual capacity (FRC) [units: L] Geometric Mean (95% Confidence Interval)	0.978 (0.891 to 1.073)	0.938 (0.833 to 1.056)

Statistical Analysis 1 for Functional residual capacity (FRC)

Groups^[1]	GP MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.6176
Other^[5]	0.978
95% Confidence Interval	( 0.891 to 1.073 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Functional residual capacity (FRC)

Groups^[1]	FF MDI
Method^[3]	t-test, 2 sided
P-Value^[4]	0.2699
Other^[5]	0.938
95% Confidence Interval	( 0.833 to 1.056 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Within-group comparison to baseline using paired test
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug.
Additional Description	The Safety Population was defined as all subjects who were randomized to treatment regardless and received at least one dose of study treatment. Serious adverse events collected from the time the subject signed consent up to 14 days following the last dose of study drug.

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Serious Adverse Events

GP MDI

FF MDI

Total, serious adverse events

# participants affected / at risk

1/20 (5.00%)

1/22 (4.55%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Non-Hodgkin's Lymphoma¹,^†

# participants affected / at risk

1/20 (5.00%)

0/22 (0.00%)

# events

Vascular disorders

Aortic Aneurysm¹,^†

# participants affected / at risk

0/20 (0.00%)

1/22 (4.55%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Other Adverse Events

Time Frame	Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug.
Additional Description	The Safety Population was defined as all subjects who were randomized to treatment regardless and received at least one dose of study treatment. Serious adverse events collected from the time the subject signed consent up to 14 days following the last dose of study drug.

Frequency Threshold

Threshold above which other adverse events are reported	2%

Reporting Groups

	Description
GP MDI	Glycopyrronium Metered Dose Inhalation
FF MDI	FF MDI Formoterol Fumarate Metered Dose Inhalation

Other Adverse Events

GP MDI

FF MDI

Total, other (not including serious) adverse events

# participants affected / at risk

3/20 (15.00%)

3/22 (13.64%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

1/20 (5.00%)

3/22 (13.64%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

2/20 (10.00%)

1/22 (4.55%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Drafts of any and all publications or presentations of this study must be submitted at least 30 days prior to submission for publication or presentation to Pearl Therapeutics for review, approval, and to ensure consistency. Pearl Therapeutics has the right to request appropriate modification to correct facts and to represent it's opinions, or the opinions of the publication committee, if these differ with the proposed publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Stephan Stenglein, MD
Organization:	AstraZeneca
Phone	+46 (0)31 776 1000
E-mail:	[email protected]

Documents available

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Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

Jane Fitzpatrick

973.975.0333

Investigators

Principal Investigator

Chad Orevillo

Pearl Therapeutics

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

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Trial Results Summaries