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)

• 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: AstraZeneca
• 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

Tracking Information

• First Submitted Date: May 19, 2017
• First Posted Date: May 22, 2017
• Results First Submitted Date: April 30, 2019
• Results First Posted Date: May 22, 2019
• Last Update Posted Date: May 22, 2019
• Actual Study Start Date: May 25, 2017
• Actual Primary Completion Date: May 4, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 30, 2019)

• Mean Change From Baseline in Morning Pre-dose Trough Forced Expiratory Volume in 1 Second (FEV1) Over 24 Weeks [ Time Frame: From Baseline (Day 1) up to 24 weeks ]
  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.
• Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population [ Time Frame: From Baseline (Day 1) up to 24 weeks ]
  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).
• Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population [ Time Frame: From Baseline (Day 1) up to 24 weeks ]
  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).

Original Primary Outcome Measures (submitted: May 19, 2017)

Change from baseline in morning pre-dose trough FEV1 (volume of air forcibly exhaled in 1 second) [ Time Frame: over 24 weeks ]

To assess the effects of GFF relative to UV on lung function as measured by trough FEV1 in patients with moderate to very severe COPD

Current Secondary Outcome Measures (submitted: April 30, 2019)

• Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1 [ Time Frame: 5 minutes post-dose on Day 1 ]
  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.
• Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks [ Time Frame: From Baseline (Day 1) up to 24 weeks ]
  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).
• Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks [ Time Frame: From Baseline (Day -7 or 1) up to 24 weeks ]
  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).
• Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks [ Time Frame: From Baseline (Day -7) up to 24 weeks ]
  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.

Original Secondary Outcome Measures (submitted: May 19, 2017)

• Onset of action on day 1; proportion of patients with increase of FEV1 of ≥100 ml from baseline at 5 minutes [ Time Frame: 5 minutes on day 1 ]
  To further assess the effects of GFF relative to UV on lung function.
• Change from baseline in Peak FEV1 within 2 hours post-dosing [ Time Frame: over 24 weeks ]
  To further assess the effects of GFF relative to UV on lung function.
• Change from baseline in Peak Inspiratory Capacity (IC) within 2 hours post-dosing [ Time Frame: over 24 weeks ]
  To further assess the effects of GFF relative to UV on lung function.
• Transition Dyspnea Index (TDI) focal score [ Time Frame: over 24 weeks ]
  To assess the effects of GFF relative to UV on dyspnea
• Change from baseline in Early Morning Symptoms COPD Instrument (EMSCI) [ Time Frame: over 24 weeks ]
  To assess the effects of GFF relative to UV on symptoms of COPD

Current Other Pre-specified Outcome Measures (submitted: April 30, 2019)

• Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks [ Time Frame: From Baseline (Day -7) up to 24 weeks ]
  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).
• Mean Change From Baseline in Daily Rescue (Albuterol/Salbutamol MDI) Use Over 24 Weeks [ Time Frame: From Baseline (Day -7) up to 24 weeks ]
  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.
• Mean Change From Baseline in COPD Assessment Test (CAT) Score Over 24 Weeks [ Time Frame: From Baseline (Day -7 or 1) up to 24 weeks ]
  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).

Original Other Pre-specified Outcome Measures (submitted: May 19, 2017)

• Change from baseline in Night Time Symptoms COPD Instrument (NiSCI) [ Time Frame: over 24 weeks ]
  To assess the effects of GFF relative to UV on symptoms of COPD
• Change from baseline in daily rescue (albuterol/salbutamol MDI) use [ Time Frame: over 24 weeks ]
  To assess the effects of GFF relative to UV on symptoms of COPD
• Change from baseline in COPD Assessment Test (CAT) score [ Time Frame: over 24 weeks ]
  To assess the effects of GFF relative to UV on health-related quality of life

Descriptive Information

• Brief Title: 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
• Official Title: A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group Study to Assess the 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)
• Brief Summary: This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 week study to assess the efficacy and safety of Glycopyrronium/Formoterol Fumarate (GFF) fixed-dose combination 7.2/4.8 μg 2 inhalations twice daily compared to Umeclidinium/Vilanterol (UV) 62.5/25 μg fixed-dose combination 1 inhalation once daily in Patients with moderate to very severe COPD.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease COPD

Intervention

• Drug: Glycopyrronium/Formoterol Fumarate
  Metered dose inhaler (MDI), contains glycopyrronium/formoterol fumarate fixed-dose combination 7.2/4.8 μg per actuation
• Drug: umeclidinium/vilanterol
  Dry powder inhaler (DPI), Each metered dose contains umeclidinium/vilanterol 62.5/ 25μg fixed-dose combination per inhalation

Study Arms

• Experimental: Experimental
  glycopyrronium/formoterol fumarate 7.2/4.8 μg per actuation, twice daily
  Intervention: Drug: Glycopyrronium/Formoterol Fumarate
• Active Comparator: Active comparator
  umeclidinium/vilanterol 62.5/ 25μg per inhalation, once daily
  Intervention: Drug: umeclidinium/vilanterol

• Publications *: Maltais F, Ferguson GT, Feldman GJ, Deslee G, Bourdin A, Fjallbrant H, Siwek-Posluszna A, Jenkins MA, Martin UJ. A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD. Adv Ther. 2019 Sep;36(9):2434-2449. doi: 10.1007/s12325-019-01015-3. Epub 2019 Jul 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 4, 2017): 1119
• Original Estimated Enrollment (submitted: May 19, 2017): 1000
• Actual Study Completion Date: May 4, 2018
• Actual Primary Completion Date: May 4, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Age 40-95 years at screening
• Current or former smoker with a history of at least 10 pack-years of cigarette smoking
• Current clinical diagnosis of COPD, with COPD symptoms > 1 year prior to screening, as defined by GOLD criteria or other current guidelines
• COPD Severity defined by FEV1/FVC ratio <0.70 and FEV1 <80% of predicted normal value at screening and at randomisation
• COPD treatment with rescue medication only, or stable dose of maintenance monotherapy (LAMA, LABA or ICS), or stable dose of double maintenance therapy (LAMA/LABA or ICS/LABA), for one month prior to screening
• COPD Assessment Test (CAT) score ≥10 at randomisation
• Documentation of a chest x-ray (as per local practice) or computed tomography (CT) within 6 months prior to screening, with no clinically significant pulmonary abnormalities other than related to COPD

Exclusion criteria:

• Respiratory disease other than COPD, including:
• Current diagnosis of asthma
• Alpha-1 Antitrypsin Deficiency as the cause of COPD
• Other respiratory disorders and conditions as listed in the protocol
• Severe COPD exacerbation (resulting in hospitalisation) not resolved within 8 weeks prior to screening, or moderate exacerbation not resolved within 4 weeks, or during screening
• Pneumonia or lower respiratory tract infection that required antibiotics within 8 weeks prior to screening, or during screening.
• Significant diseases or conditions other than COPD which may put the patient at risk, or influence the results of the study or the patient's ability to participate, including cardiac disease, advanced renal disease, and cancer that has not been in complete remission for at least 5 years.
• Patients who have needed additions or alterations to their usual maintenance therapy for COPD due to worsening symptoms within 1 month prior to and during screening
• Treatment with depot corticosteroids within 6 weeks, or other systemic corticosteroids within 4 weeks, prior to screening. (Patients maintained on an equivalent of 5 mg prednisone per day for at least 3 months prior to screening are allowed.)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 95 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Canada, France, Hungary, Russian Federation, Ukraine, United States

Administrative Information

• NCT Number: NCT03162055
• Other Study ID Numbers: D5970C00002
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current

Collaborators

• Parexel International Ltd
• Cognizant Technology Solution
• Center for Information & Study on Clinical Research Participation (CISCRP)
• eResearchTechnology
• QuintilesIMS Limited
• Corporate Translations Inc

• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: April 2019