Effect of Roflumilast at Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Phase 2

Terminated

• Conditions: Chronic Obstructive Pulmonary Disease With (Acute) Exacerbation
• Interventions: Drug: Roflumilast; Drug: Placebo

• Registration Number: NCT01473758
• Lead Sponsor: AstraZeneca

Brief Summary

The purpose of this trial is to investigate if roflumilast can reduce the neutrophilic inflammation at acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD). In addition, the potential benefit of roflumilast on severity and recovery periods of acute COPD exacerbations will be assessed using patient diaries and questionnaires.

Detailed Description

Participants will be asked whether they agree to participate in the measurements of arterial stiffness. Participants who agree will be included in the substudy, with the target of 60 patients with arterial stiffness measurements to complete the trial.

Study was terminated due to difficulty in identifying further eligible patients for this exploratory study within a reasonable time.

Study Timeline

• Study First Submitted: 2011-10-31
• Study First Submitted QC: 2011-11-14
• Study First Posted: 2011-11-17
• Study Start: 2012-02
• Primary Completion: 2014-03
• Study Completion: 2014-03
• Disposition First Submitted: 2015-02-20
• Disposition First Submitted QC: 2015-02-20
• Disposition First Posted: 2015-03-11
• Results First Submitted: 2015-07-23
• Status Verified: 2016-08
• Results First Submitted QC: 2016-08-31
• Results First Posted: 2016-10-24
• Last Update Submitted: 2016-12-22
• Last Update Posted: 2017-02-14

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 81

Inclusion Criteria

• Written informed consent (IC)
• Age ≥ 40 years
• History of COPD for at least 12 months prior to enrollment (Visit V0)
• Chronic productive cough for 3 months in each of the 2 years prior to enrollment (if other causes of productive cough have been excluded) and/or an exacerbation with predominantly bronchitic symptoms at enrollment
• Presentation of an acute exacerbation of COPD that will be associated with increased sputum volume or change in sputum colour
• Documented fixed airway obstruction determined by an FEV1/FVC ratio (post-bronchodilator) < 70% (if a pulmonary function test is not possible at Visit V0 a previous measurement can be taken which must not be older than 6 months)
• Former smoker (defined as: smoking cessation at least 1 year ago) or current smoker both with a smoking history of at least 10 pack years

Main

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Exclusion Criteria

• Diagnosis of asthma and/or other relevant lung disease
• Known alpha-1-antitrypsin deficiency
• Recurrent exacerbations (within 8 weeks of a preceding exacerbation)
• Treatment of current exacerbation with oral corticosteroids and/or antibiotics already started at enrollment
• Treatment with PDE4 inhibitors within 3 months prior to Visit V0
• Other protocol-defined exclusion criteria may apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Roflumilast	Roflumilast	added on to standard therapy for acute COPD exacerbations
Placebo	Placebo	added on to standard therapy for acute COPD exacerbations

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)	Baseline and Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects.
Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)	Baseline and Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)	Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) and were determined with a Neubauer hemocytometer.
Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)	Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) and were determined with a Neubauer hemocytometer.
Change From Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Total Cells (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. A negative change from Baseline indicates improvement.
Change From Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker IL-1β (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker C-reactive Protein (CRP) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in Sputum Marker Total Cells (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Fibrinogen (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker C-reactive Protein (CRP) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Fibrinogen (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Glucose (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Glucose (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in FEV1/FVC (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst).
Change From Baseline in Forced Vital Capacity (FVC) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in Forced Vital Capacity (FVC) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in FEV1/FVC (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction.
Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status.
Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status.
Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction.
Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst).
Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction.
Change From Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Treatment Score Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any changes in the participant's usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Symptom Score Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Symptom Score Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Treatment Score Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any changes in the participant's usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Hours Out of the Home Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Hours Out of the Home Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Exacerbation Length (Initial Approach)	8 Weeks	Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary.
Exacerbation Length (Extended Approach)	8 Weeks	Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary.
Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Baseline and Days 14 and 28	Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Baseline and Days 14 and 28	Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction.

Trial Locations

Locations (1)

Academic Unit of Respiratory Medicine, Royal Free Hospital, Jadwiga A. Wedzicha; 🇬🇧 London, United Kingdom