A study to assess the effects of PT003 and Placebo MDI on specific image based airway volumes and resistance in subjects with moderate to severe COPD

Study identifier:PT003018

ClinicalTrials.gov identifier:NCT02643082

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, Single-Center Study to Evaluate the Effects of PT003 and Placebo MDI on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD

Medical condition

COPD

Phase

Phase 3

Healthy volunteers

Study drug

GFF MDI (PT003) 14.4/9.6μg, Placebo MDI

Sex

All

Actual Enrollment

Study type

Interventional

Age

40 Years - 80 Years

Date

Study Start Date: 23 Dec 2015

Primary Completion Date: 26 Jan 2017

Study Completion Date: 26 Jan 2017

Study design

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

Verification:

Verified 01 Apr 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 an acceptable method of contraception
-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 FEV1/FVC ratio of <70% and FEV1 must be 30% to 80% before predicted normal value, calculated using 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.
Please refer to the study protocol for the complete inclusion criteria list.

Location

Research Site

Edegem, Belgium, 2650

Arms	Assigned Interventions
Experimental: GFF MDI, 14.4/9.6μg Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI)	Drug: GFF MDI (PT003) 14.4/9.6μg Glycopyrronium and Formoterol Fumarate Other Name: GFF
Placebo Comparator: Placebo MDI Placebo Metered Dose Inhaler (MDI)	Drug: Placebo MDI Comparator: Placebo MDI which contains no active ingredients Other Name: Placebo

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 was conducted at 1 site in Antwerp Belgium from January 2016 to December 2016.The study was anticipated to run for approximately 9 months but not to expected to exceed 12 months. The study period was duration was expected to run approximately 13 weeks for each subject.

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: subjects in Sequence 1 received GFF MDI in Treatment Period 1 followed by Placebo MDI in Treatment Period 2, and subjects in Sequence 2 received Placebo MDI in Treatment Period 1 followed by GFF MDI in Treatment Period 2. There was a a washout of 5-21 days,in between treatment periods.

Reporting Groups

	Description
GFF MDI/Placebo MDI	Treatment Sequence of Glycopyrronium Formoterol Fumarate Metered Dose Inhalation/Placebo Metered Dose Inhalation
Placebo MDI/GFF MDI	Treatment Sequence of Placebo Metered Dose Inhalation/Glycopyrronium Formoterol Fumarate Metered Dose Inhalation

Participant Flow for 3 periods

Period 1: Period 1

	GFF MDI/Placebo MDI	Placebo MDI/GFF MDI
STARTED	10	10
COMPLETED	9	10
NOT COMPLETED	1	0
Adverse Event	1	0

Period 2: Washout

	GFF MDI/Placebo MDI	Placebo MDI/GFF MDI
STARTED	9	10
COMPLETED	9	10
NOT COMPLETED	0	0

Period 3: Period 2

	GFF MDI/Placebo MDI	Placebo MDI/GFF MDI
STARTED	9	10
COMPLETED	9	10
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	All Randomized Patients

Baseline Measures

	Overall Study
Number of Participants [units: Participants]	20
Sex: Female, Male [units: ]
Female	5
Male	15
Age Continuous [units: Years] Mean ± Standard Deviation	64.8 ± 8.7
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	0
White	20
More than one race	0
Unknown or Not Reported	0

Outcome Measures

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

Measure Type	Primary
Measure Name	Specific Airway Volume (siVaw)
Measure Description	Specific image-based airway volume. Average across lobe, adjusted for lobe volume
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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Specific Airway Volume (siVaw) [units: mL/L] Geometric Least Squares Mean (95% Confidence Interval)	1.79 (1.48 to 2.16)	1.02 (0.85 to 1.24)

Statistical Analysis 1 for Specific Airway Volume (siVaw)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	1.75
95% Confidence Interval	( 1.65 to 1.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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2. Primary Outcome Measure: Specific Airway Resistance (siRaw) [ Time Frame: Day 15 ]

Measure Type	Primary
Measure Name	Specific Airway Resistance (siRaw)
Measure Description	Specific image-based airway resistance. Average across lobes, adjusted for lobe volume
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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Specific Airway Resistance (siRaw) [units: kPa s] Geometric Least Squares Mean (95% Confidence Interval)	0.09 (0.07 to 0.11)	0.30 (0.23 to 0.40)

Statistical Analysis 1 for Specific Airway Resistance (siRaw)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.29
95% Confidence Interval	( 0.25 to 0.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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3. Secondary Outcome Measure: Airway Resistance (iRaw) [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	Airway Resistance (iRaw)
Measure Description	iRaw represents the airway resistance, averaged across lobes, without correction for lung lobe volume
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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Airway Resistance (iRaw) [units: kPa s/L] Geometric Least Squares Mean (95% Confidence Interval)	0.07 (0.06 to 0.10)	0.25 (0.19 to 0.33)

Statistical Analysis 1 for Airway Resistance (iRaw)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.29
95% Confidence Interval	( 0.26 to 0.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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[3]	Other relevant information, such as adjustments or degrees of freedom:
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[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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4. Secondary Outcome Measure: Airway Volume (iVaw) [ Time Frame: Day 15 ]

Measure Type	Secondary
Measure Name	Airway Volume (iVaw)
Measure Description	iVaw represents the airway Volume, averaged across lobes, without correction for lung lobe volume
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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Airway Volume (iVaw) [units: mL] Geometric Least Squares Mean (95% Confidence Interval)	2.11 (1.73 to 2.58)	1.18 (0.97 to 1.44)

Statistical Analysis 1 for Airway Volume (iVaw)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	1.79
95% Confidence Interval	( 1.67 to 1.92 )

[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:
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[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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5. Secondary Outcome Measure: Change From Baseline in FEV1 (L) at Day 15 [ Time Frame: Baseline and Day 15 ]

Measure Type	Secondary
Measure Name	Change From Baseline in FEV1 (L) at Day 15
Measure Description	Change from baseline in Forced Expiratory Volume at 1 second
Time Frame	Baseline and 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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Change From Baseline in FEV1 (L) at Day 15 [units: Liters] Least Squares Mean (95% Confidence Interval)	0.334 (0.245 to 0.422)	-0.110 (-0.198 to -0.022)

Statistical Analysis 1 for Change From Baseline in FEV1 (L) at Day 15

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.443
95% Confidence Interval	( 0.318 to 0.569 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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[3]	Other relevant information, such as adjustments or degrees of freedom:
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[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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6. Secondary Outcome Measure: Change from baseline in FRC (L) at Day 15 [ Time Frame: Baseline and Day 15 ]

Measure Type	Secondary
Measure Name	Change from baseline in FRC (L) at Day 15
Measure Description	Change from baseline in Functional Residual Capacity
Time Frame	Baseline and 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
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Measured Values

	GFF MDI 14.4/9.6 µg	Placebo MDI
Number of Participants Analyzed [units:participants]	20	19
Change from baseline in FRC (L) at Day 15 [units: Liters] Geometric Least Squares Mean (95% Confidence Interval)	0.90 (0.86 to 0.93)	1.03 (0.99 to 1.07)

Statistical Analysis 1 for Change from baseline in FRC (L) at Day 15

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.87
95% Confidence Interval	( 0.82 to 0.92 )

[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:
	No text entered.
[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:
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Serious Adverse Events

Time Frame	Adverse events were collected from the time the subject signed consent throughout the two treatment periods and washout period (approximately 49 days) and up to 10 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
Overall Study	All Randomized Patients
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Serious Adverse Events

Overall Study

GFF MDI 14.4/9.6 µg

Placebo MDI

Total, serious adverse events

# participants affected / at risk

2/20 (10.00%)

1/20 (5.00%)

1/19 (5.26%)

Cardiac disorders

Acute Coronary Syndrome¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Cardiac disorders

Acute Myocardial Infarction¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# 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 consent throughout the two treatment periods and washout period (approximately 49 days) and up to 10 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	5%

Reporting Groups

	Description
Overall Study	All Randomized Patients
GFF MDI 14.4/9.6 µg	GFF MDI
Placebo MDI	Placebo

Other Adverse Events

Overall Study

GFF MDI 14.4/9.6 µg

Placebo MDI

Total, other (not including serious) adverse events

# participants affected / at risk

15/20 (75.00%)

12/20 (60.00%)

8/19 (42.11%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea exertional¹,^†

# participants affected / at risk

3/20 (15.00%)

0/20 (0.00%)

3/19 (15.79%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

2/20 (10.00%)

0/19 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Obstructive Airway Disorder¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary Mass¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Rales¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

2/20 (10.00%)

0/19 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

2/20 (10.00%)

1/19 (5.26%)

# events

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

2/20 (10.00%)

1/19 (5.26%)

# events

Nervous system disorders

Dysgeusia¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Cardiac disorders

Acute Coronary Syndrome¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Cardiac disorders

Acute Myocardial Infarction¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Cardiac disorders

Bradycardia¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Infections and infestations

Respiratory Tract Infection¹,^†

# participants affected / at risk

2/20 (10.00%)

0/19 (0.00%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

1/20 (5.00%)

1/19 (5.26%)

# events

Gastrointestinal disorders

Toothache¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

General disorders

Oedema¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# events

Metabolism and nutrition disorders

Iron Defficiency¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal Pain¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Renal and urinary disorders

Renal Mass¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Renal and urinary disorders

Renal Pain¹,^†

# participants affected / at risk

1/20 (5.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

1/20 (5.00%)

0/19 (0.00%)

# 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:	Pearl Therapeutics, Inc.
Organization:	Pearl Therapeutics, Inc.
Phone	650-305-2600
E-mail:	[email protected]

Documents available

Protocol with updated PDFA coverpage
Download
Updated version per comments from CT.gov
Download
Updated version per CT.gov comments
Download
Updated version per CT.gov comments
Download
Updated version per comments from CT.gov
Download
Updated version per CT.gov comments
Download
Updated version per comments from CT.gov
Download
Updated version per comments from CT.gov
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Chad Orevillo

Pearl Therapeutics

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Protocol with updated PDFA coverpage

Updated version per comments from CT.gov

Updated version per CT.gov comments

Updated version per CT.gov comments

Updated version per comments from CT.gov

Updated version per CT.gov comments

Updated version per comments from CT.gov

Updated version per comments from CT.gov

Trial Results Summaries