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Clinical Trial Results:
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.

Summary
EudraCT number	2015-001744-11
Trial protocol	BE
Global end of trial date	28 May 2018

Results information
Results version number	v1(current)
This version publication date	15 Jun 2019
First version publication date	15 Jun 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PT003019

ISRCTN number

US NCT number

NCT02937548

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

N/A, N/A, Sweden,

Public contact

Stephan Stenglein, MD, AstraZeneca, +46 031 776 1000, stephan.stenglein@astrazeneca.com

Scientific contact

Stephan Stenglein, MD, AstraZeneca, +46 031 776 1000, stephan.stenglein@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 May 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 May 2018

Global end of trial reached?

Yes

Global end of trial date

28 May 2018

Was the trial ended prematurely?

Main objective of the trial

Evaluate the Effects of PT001 and PT005 on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD.

Protection of trial subjects

For subjects that were on ICS LABA, the ICS LABA was discontinued, however, then prescribed an ICS Monotherapy at an equivalent dosing regimen for the duration of the study. For subjects that were on ICS Monotherapy, they were allowed to continue those medications at the same dose. Ventolin HFA was provided throughout the study for subjects to take as needed for relief of symptoms.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 23

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study randomized 23 subjects at 2 sites in Belgium from December 2016 to May 2018.

Screening details

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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Subject, Assessor

Overall Study

Arm description

All Subjects Randomized

Arm type

Experimental

Investigational medicinal product name

Glycopyrronium Metered Dose Inhalation

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Glycopyrronium Metered Dose Inhalation 14.4 μg

Investigational medicinal product name

Formoterol Fumarate Metered Dose Inhalation

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Formoterol Fumarate Metered Dose Inhalation 9.6 μg

Number of subjects in period 1	Overall Study
Started	23
Treated with GP MDI	20
Treated with FF MDI	22
Completed	19
Not completed	4
Adverse event, non-fatal	4

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	23	23
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	8	8
From 65-84 years	15	15
85 years and over	0	0
Age Continuous
Units: years
median (standard deviation)	64.6 ( 9.6 )	-
Sex: Female, Male
Units: Subjects
Female	6	6
Male	17	17
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	0	0
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	0	0
White	23	23
More than one race	0	0
Unknown or Not Reported	0	0

Subject analysis set title

GP MDI

Subject analysis set type

Intention-to-treat

Subject analysis set description

All Subjects Randomized

Subject analysis set title

FF MDI

Subject analysis set type

Intention-to-treat

Subject analysis set description

All Subjects Randomized

Subject analysis sets values	GP MDI	FF MDI
Number of subjects	20	22
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	7	8
From 65-84 years	13	14
85 years and over	0	0
Age Continuous
Units: years
median (standard deviation)	64.7 ( 9.4 )	64.0 ( 9.4 )
Sex: Female, Male
Units: Subjects
Female	4	5
Male	16	17
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	0	0
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	0	0
White	20	22
More than one race	0	0
Unknown or Not Reported	0	0

End points

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Reporting group title

Overall Study

Reporting group description

All Subjects Randomized

Subject analysis set title

GP MDI

Subject analysis set type

Intention-to-treat

Subject analysis set description

All Subjects Randomized

Subject analysis set title

FF MDI

Subject analysis set type

Intention-to-treat

Subject analysis set description

All Subjects Randomized

Primary: Specific Image-Based Airway Volume (siVaw)

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End point title

Specific Image-Based Airway Volume (siVaw) ^[1]

End point description

Specific image-based airway volume. Average across lobe, adjusted for lobe volume. Ratio to baseline

End point type

Primary

End point timeframe

Day 15

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data not available in compatible format to enter statistical analysis.

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	23	19	19
Units: mL/L
geometric mean (confidence interval 95%)	999999999 (999999999 to 999999999)	1.11 (1.02 to 1.22)	1.23 (1.14 to 1.33)

No statistical analyses for this end point

Primary: Specific image-based airway resistance (siRaw)

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End point title

Specific image-based airway resistance (siRaw) ^[2]

End point description

Specific image-based airway resistance (siRaw). Average across lobes, adjusted for lobe volume. Ratio to baseline.

End point type

Primary

End point timeframe

Day 15

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Data not available in compatible format to enter statistical analysis.

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	19	19	19
Units: kPa·s
geometric mean (confidence interval 95%)	999999999 (999999999 to 999999999)	0.75 (0.59 to 0.95)	0.56 (0.44 to 0.71)

No statistical analyses for this end point

Secondary: Image-based airway volume (iVaw)

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End point title

Image-based airway volume (iVaw)

End point description

Image-based airway volume (iVaw) without correction for lobe volume. Ratio to baseline.

End point type

Secondary

End point timeframe

Day 15

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	19	19	19
Units: mL
geometric mean (confidence interval 95%)	999999999 (999999999 to 999999999)	1.12 (1.01 to 1.24)	1.21 (1.12 to 1.31)

No statistical analyses for this end point

Secondary: Image-based airway resistance (iRaw)

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End point title

Image-based airway resistance (iRaw)

End point description

Image-based airway resistance (iRaw) without correction for lobe volume. Ratio to baseline.

End point type

Secondary

End point timeframe

Day 15

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	19	19	19
Units: kPa·s·L^-1
geometric mean (confidence interval 95%)	999999999 (999999999 to 999999999)	0.76 (0.59 to 0.97)	0.55 (0.41 to 0.72)

No statistical analyses for this end point

Secondary: FEV1

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End point title

FEV1

End point description

FEV1 Change from baseline in Forced Expiratory Volume at 1 second.

End point type

Secondary

End point timeframe

Day 15

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	19	19	19
Units: Liters
arithmetic mean (standard deviation)	999999999 ( 999999999 )	0.065 ( 0.193 )	0.151 ( 0.293 )

No statistical analyses for this end point

Secondary: Functional residual capacity (FRC)

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End point title

Functional residual capacity (FRC)

End point description

Functional residual capacity (FRC). Ratio to baseline.

End point type

Secondary

End point timeframe

Day 15

End point values	Overall Study	GP MDI	FF MDI
Number of subjects analysed	19	19	19
Units: Liter
geometric mean (confidence interval 95%)	999999999 (999999999 to 999999999)	0.978 (0.891 to 1.073)	0.938 (0.833 to 1.056)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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.

Adverse event reporting 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

GP MDI

Reporting group description

Glycopyrronium Metered Dose Inhalation

Reporting group title

FF MDI

Reporting group description

FF MDI Formoterol Fumarate Metered Dose Inhalation

Serious adverse events	GP MDI	FF MDI
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 20 (5.00%)	1 / 22 (4.55%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's Lymphoma
subjects affected / exposed	1 / 20 (5.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic Aneurysm
subjects affected / exposed	0 / 20 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	GP MDI	FF MDI
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 20 (15.00%)	3 / 22 (13.64%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 20 (5.00%)	3 / 22 (13.64%)
occurrences all number	1	3
Infections and infestations
Influenza
subjects affected / exposed	2 / 20 (10.00%)	1 / 22 (4.55%)
occurrences all number	2	1

More information

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Were there any global substantial amendments to the protocol? Yes

10 Aug 2016

Change from single center to multi-center Minor updates/clarifications to study design Revised to provide clarification on which FEV1 values at Visit 4 will be used to assess stability criteria Revised to provide clarification on the duration of each treatment period (15 days ± 5 days) and when baseline will be obtained. Revised to provide clarification of the prohibited COPD medications and the wash-out requirements of prohibited COPD medications prior to Visit 1 (Screening)

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Specific Image-Based Airway Volume (siVaw)

Primary: Specific Image-Based Airway Volume (siVaw)

Primary: Specific image-based airway resistance (siRaw)

Primary: Specific image-based airway resistance (siRaw)

Secondary: Image-based airway volume (iVaw)

Secondary: Image-based airway volume (iVaw)

Secondary: Image-based airway resistance (iRaw)

Secondary: Image-based airway resistance (iRaw)

Secondary: FEV1

Secondary: FEV1

Secondary: Functional residual capacity (FRC)

Secondary: Functional residual capacity (FRC)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: 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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Specific Image-Based Airway Volume (siVaw)

Primary: Specific Image-Based Airway Volume (siVaw)

Primary: Specific image-based airway resistance (siRaw)

Primary: Specific image-based airway resistance (siRaw)

Secondary: Image-based airway volume (iVaw)

Secondary: Image-based airway volume (iVaw)

Secondary: Image-based airway resistance (iRaw)

Secondary: Image-based airway resistance (iRaw)

Secondary: FEV1

Secondary: FEV1

Secondary: Functional residual capacity (FRC)

Secondary: Functional residual capacity (FRC)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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.