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Efficacy and Safety of Glycopyrronium/Formoterol Fumarate Fixed-dose Combination Relative to Umeclidinium/Vilanterol Fixed-dose Combination Over 24 Weeks in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (AERISTO)

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ClinicalTrials.gov Identifier: NCT03162055
Recruitment Status : Completed
First Posted : May 22, 2017
Results First Posted : May 22, 2019
Last Update Posted : May 22, 2019
Sponsor:
Collaborators:
Parexel International Ltd
Cognizant Technology Solution
Center for Information & Study on Clinical Research Participation (CISCRP)
eResearchTechnology
QuintilesIMS Limited
Corporate Translations Inc
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease COPD
Interventions Drug: Glycopyrronium/Formoterol Fumarate
Drug: umeclidinium/vilanterol
Enrollment 1119
Recruitment Details This study was conducted in 110 centers in 7 countries (Russia, Bulgaria, Ukraine, United States of America, Canada, Hungary and France) between 25 May 2017 and 04 May 2018. Participants with moderate to very severe chronic obstructive pulmonary disease (COPD) were recruited in this study.
Pre-assignment Details The study had a screening period, followed by a 24-week double-blind and double-dummy treatment period. A total of 1445 participants were screened. Of which, 1119 participants were enrolled and randomized to study treatment.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description Participants were randomized to receive 2 inhalations of glycopyrronium/formoterol fumarate (GFF) fixed-dose combination 7.2/4.8 micrograms (mcg) per actuation administered in the morning and evening by metered dose inhaler (MDI) for 24 weeks. Participants also received 1 inhalation of placebo matched to umeclidinium/vilanterol (UV) administered once daily in the morning by dry powder inhaler (DPI) for 24 weeks. Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Period Title: Overall Study
Started 559 560
Received Treatment 557 560
Safety Analysis Set 552 552
Full Analysis Set (FAS) 552 552
Per Protocol (PP) Analysis Set 506 510
Completed 497 517
Not Completed 62 43
Reason Not Completed
Adverse Event             6             5
Death             3             3
Lost to Follow-up             0             1
Study-specific withdrawal criteria             22             14
Withdrawal by Subject             17             2
Did not receive treatment             2             0
Incorrect randomization             4             3
Other             8             15
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol Total
Hide Arm/Group Description Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks. Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks. Total of all reporting groups
Overall Number of Baseline Participants 552 552 1104
Hide Baseline Analysis Population Description
The FAS included all randomized participants who received at least 1 inhalation of investigational product (IP) from the GFF or UV inhaler (active or placebo).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 552 participants 552 participants 1104 participants
64.3  (8.0) 63.8  (8.1) 64.1  (8.0)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 552 participants 552 participants 1104 participants
<65 years
273
  49.5%
292
  52.9%
565
  51.2%
65 - 74 years
223
  40.4%
214
  38.8%
437
  39.6%
75 - 84 years
53
   9.6%
43
   7.8%
96
   8.7%
>=85 years
3
   0.5%
3
   0.5%
6
   0.5%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 552 participants 552 participants 1104 participants
Female
142
  25.7%
160
  29.0%
302
  27.4%
Male
410
  74.3%
392
  71.0%
802
  72.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 552 participants 552 participants 1104 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
13
   2.4%
10
   1.8%
23
   2.1%
White
538
  97.5%
542
  98.2%
1080
  97.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Other
1
   0.2%
0
   0.0%
1
   0.1%
1.Primary Outcome
Title Mean Change From Baseline in Morning Pre-dose Trough Forced Expiratory Volume in 1 Second (FEV1) Over 24 Weeks
Hide Description To assess the effects of GFF relative to UV on lung function as measured by change from baseline in morning pre-dose trough FEV1 is defined as the average of the -60 and -30 minute pre-dose values at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). BR a/s = bronchodilator responsiveness to albuterol/salbutamol.
Time Frame From Baseline (Day 1) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: milliliter (mL)
82.4  (11.2) 169.6  (11.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis P-Value 0.9974
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -87.2
Confidence Interval (2-Sided) 97.5%
-117.0 to -57.4
Parameter Dispersion
Type: Standard Error of the Mean
Value: 13.3
Estimation Comments Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
2.Primary Outcome
Title Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population
Hide Description To assess the effects of GFF relative to UV on lung function in PP analysis set population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).
Time Frame From Baseline (Day 1) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: mL
293.5  (10.2) 296.9  (10.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -3.4
Confidence Interval (2-Sided) 97.5%
-32.8 to 25.9
Parameter Dispersion
Type: Standard Error of the Mean
Value: 13.1
Estimation Comments Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
3.Primary Outcome
Title Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population
Hide Description To assess the effects of GFF relative to UV on lung function in FAS population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).
Time Frame From Baseline (Day 1) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 552 552
Least Squares Mean (Standard Error)
Unit of Measure: mL
299.1  (9.9) 300.8  (9.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5516
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -1.7
Confidence Interval (2-Sided) 97.5%
-30.3 to 27.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 12.8
Estimation Comments Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
4.Secondary Outcome
Title Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1
Hide Description The percentage of participants with an increase in FEV1 of >=100 mL from baseline at 5 minutes post-dosing on Day 1 was determined to assess the early onset of action. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1). Only data assigned to the 5 minute window was used to determine response. Participants with missing data were considered non-responders for the analysis.
Time Frame 5 minutes post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS analysis set included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 552 552
Measure Type: Number
Unit of Measure: Percentage of participants
60.1 40.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments ln (1/(1-p))=Treatment+baseline FEV1+BR a/s MDI+stratification factor (prior treatment)+region.p=percentage of participants with increase of >=100 mL.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.30
Confidence Interval (2-Sided) 95%
1.79 to 2.95
Estimation Comments Estimate of the log odds of being a responder in the GFF treatment group compared to the UV treatment group using a logistic regression.
5.Secondary Outcome
Title Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks
Hide Description Peak change from baseline in IC is defined as the maximum of the IC assessments within the 2 hours post-dosing time windows at each visit minus baseline. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1).
Time Frame From Baseline (Day 1) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: mL
363.1  (15.5) 378.3  (15.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis P-Value 0.0371
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline IC + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -15.2
Confidence Interval (2-Sided) 95%
-53.4 to 22.9
Parameter Dispersion
Type: Standard Error of the Mean
Value: 19.4
Estimation Comments Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
6.Secondary Outcome
Title Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks
Hide Description The baseline dyspnea index (BDI) and TDI consist of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these 3 components were rated in 5 grades from 0 (very severe) to 4 (no impairment), and were summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea were rated for each component by 7 grades from -3 (major deterioration) to +3 (major improvement), and were added to form a TDI focal score from -9 to +9. Baseline is defined as the latest BDI assessment within 7 days before or at randomization (Day 1).
Time Frame From Baseline (Day -7 or 1) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
1.23  (0.10) 1.60  (0.10)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin -1.0 unit.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Repeated measures analysis
Comments TDI focal score = Treatment + Baseline Dyspnea Index + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -0.37
Confidence Interval (2-Sided) 95%
-0.59 to -0.14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.12
Estimation Comments Estimate of the mean TDI focal score over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
7.Secondary Outcome
Title Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks
Hide Description Change from baseline in the 6-item EMSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The EMSCI collected data about the frequency and severity of early morning symptoms and the impact of COPD symptoms on early morning activity in participants with COPD. Participants completed a daily electronic patient-reported outcome (ePRO) questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). TI = Time interval.
Time Frame From Baseline (Day -7) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-0.142  (0.018) -0.176  (0.018)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.
Statistical Test of Hypothesis P-Value 0.0017
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline EMSCI score + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.034
Confidence Interval (2-Sided) 95%
-0.011 to 0.078
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.023
Estimation Comments Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
8.Other Pre-specified Outcome
Title Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks
Hide Description Change from baseline in the 6-item NiSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The NiSCI collected data about the frequency and severity of night-time symptoms and the impact of COPD symptoms on night-time awakenings in participants with COPD. Participants completed a daily ePRO questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1).
Time Frame From Baseline (Day -7) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-0.165  (0.019) -0.207  (0.019)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.
Statistical Test of Hypothesis P-Value 0.0088
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline NiSCI score + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.042
Confidence Interval (2-Sided) 95%
-0.005 to 0.090
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.024
Estimation Comments Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
9.Other Pre-specified Outcome
Title Mean Change From Baseline in Daily Rescue (Albuterol/Salbutamol MDI) Use Over 24 Weeks
Hide Description The number of inhalations of rescue albuterol/salbutamol MDI was recorded in the participant ePRO in the morning and evening. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). a/s = albuterol/salbutamol.
Time Frame From Baseline (Day -7) up to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The rescue medication user analysis set included all participants in the FAS with average baseline rescue albuterol/salbutamol MDI use of >=1 inhalation/day. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 456 454
Least Squares Mean (Standard Error)
Unit of Measure: puffs/day
-1.70  (0.16) -2.35  (0.16)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9995
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline =Treatment + baseline rescue a/s MDI use + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.26 to 1.04
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.20
Estimation Comments Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
10.Other Pre-specified Outcome
Title Mean Change From Baseline in COPD Assessment Test (CAT) Score Over 24 Weeks
Hide Description The CAT is used to quantify the impact of COPD symptoms on health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of the 8 items is missing, the missing item was considered equal to the average of the 7 non-missing items for that participant. If more than 1 item is missing the score was considered missing. Baseline is defined as the latest assessment within 7 days before or at randomization (Day 1).
Time Frame From Baseline (Day -7 or 1) up to 24 weeks
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Hide Analysis Population Description
The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description:
Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.
Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Overall Number of Participants Analyzed 506 510
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-2.97  (0.21) -3.56  (0.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority p-value is calculated corresponding to the non-inferiority margin 2.0 unit.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Repeated measures analysis
Comments Change from baseline = Treatment + baseline CAT score + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.07 to 1.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.27
Estimation Comments Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
Time Frame From Baseline (Day 1) up to 14 days after last IP dose, approximately 26 weeks.
Adverse Event Reporting Description The safety analysis set included all participants who received at least 1 inhalation of the randomized active IP that they were assigned.
 
Arm/Group Title Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Hide Arm/Group Description Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks. Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
All-Cause Mortality
Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Affected / at Risk (%) Affected / at Risk (%)
Total   3/552 (0.54%)      3/552 (0.54%)    
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Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   32/552 (5.80%)      40/552 (7.25%)    
Blood and lymphatic system disorders     
Iron deficiency anaemia  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Cardiac disorders     
Acute myocardial infarction  1  1/552 (0.18%)  1 1/552 (0.18%)  1
Angina unstable  1  1/552 (0.18%)  1 2/552 (0.36%)  2
Arteriosclerosis coronary artery  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Cardiac failure  1  1/552 (0.18%)  1 1/552 (0.18%)  1
Cardiac failure acute  1  0/552 (0.00%)  0 2/552 (0.36%)  2
Myocardial infarction  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Congenital, familial and genetic disorders     
Hydrocele  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Eye disorders     
Cataract  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Gastrointestinal disorders     
Colitis  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Intestinal obstruction  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Mesenteric artery thrombosis  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Umbilical hernia  1  0/552 (0.00%)  0 1/552 (0.18%)  1
General disorders     
Death  1  1/552 (0.18%)  1 1/552 (0.18%)  1
Incarcerated hernia  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Non-cardiac chest pain  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Immune system disorders     
Anaphylactic shock  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Infections and infestations     
Erysipelas  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Gastroenteritis  1  1/552 (0.18%)  1 2/552 (0.36%)  2
Pneumonia  1  3/552 (0.54%)  3 3/552 (0.54%)  3
Pneumonia bacterial  1  1/552 (0.18%)  1 2/552 (0.36%)  2
Pneumonia staphylococcal  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Pneumonia streptococcal  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Pneumonia viral  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Sepsis  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Urosepsis  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Injury, poisoning and procedural complications     
Contusion  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Femur fracture  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Multiple fractures  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Pelvic fracture  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Metabolism and nutrition disorders     
Diabetic metabolic decompensation  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Musculoskeletal and connective tissue disorders     
Intervertebral disc protrusion  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Muscular weakness  1  0/552 (0.00%)  0 1/552 (0.18%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung adenocarcinoma  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Ovarian fibroma  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Small cell lung cancer  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Squamous cell carcinoma of lung  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  16/552 (2.90%)  17 10/552 (1.81%)  12
Pulmonary hypertension  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Pulmonary mass  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Respiratory failure  1  0/552 (0.00%)  0 2/552 (0.36%)  2
Skin and subcutaneous tissue disorders     
Diabetic foot  1  0/552 (0.00%)  0 2/552 (0.36%)  2
Vascular disorders     
Essential hypertension  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Hypertensive crisis  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Malignant hypertension  1  1/552 (0.18%)  1 0/552 (0.00%)  0
Post thrombotic syndrome  1  0/552 (0.00%)  0 1/552 (0.18%)  1
Thrombosis  1  0/552 (0.00%)  0 1/552 (0.18%)  1
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   129/552 (23.37%)      153/552 (27.72%)    
Ear and labyrinth disorders     
Vertigo  1  5/552 (0.91%)  6 6/552 (1.09%)  6
Gastrointestinal disorders     
Abdominal pain  1  4/552 (0.72%)  4 7/552 (1.27%)  8
Constipation  1  1/552 (0.18%)  1 7/552 (1.27%)  7
Diarrhoea  1  7/552 (1.27%)  8 13/552 (2.36%)  15
Dry mouth  1  2/552 (0.36%)  2 6/552 (1.09%)  6
Toothache  1  1/552 (0.18%)  1 6/552 (1.09%)  6
Infections and infestations     
Nasopharyngitis  1  30/552 (5.43%)  32 36/552 (6.52%)  42
Sinusitis  1  4/552 (0.72%)  4 6/552 (1.09%)  8
Upper respiratory tract infection  1  10/552 (1.81%)  13 10/552 (1.81%)  13
Viral upper respiratory tract infection  1  17/552 (3.08%)  18 26/552 (4.71%)  27
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/552 (0.18%)  1 6/552 (1.09%)  7
Back pain  1  12/552 (2.17%)  13 9/552 (1.63%)  9
Pain in extremity  1  1/552 (0.18%)  1 7/552 (1.27%)  7
Nervous system disorders     
Headache  1  34/552 (6.16%)  52 41/552 (7.43%)  55
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  20/552 (3.62%)  22 20/552 (3.62%)  22
Vascular disorders     
Hypertension  1  13/552 (2.36%)  16 7/552 (1.27%)  8
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
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.
Results Point of Contact
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Name/Title: Vice President, Inhalation and Oral Respiratory
Organization: AstraZeneca
Phone: +1 302 885 1180
EMail: ClinicalTrialTransparency@astrazeneca.com
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03162055    
Other Study ID Numbers: D5970C00002
First Submitted: May 19, 2017
First Posted: May 22, 2017
Results First Submitted: April 30, 2019
Results First Posted: May 22, 2019
Last Update Posted: May 22, 2019