A Phase IIa Study to Investigate the Efficacy and Safety... | NCT02238483

ID	Type	Description	Link
2014-001053-16	EudraCT Number

Status Module

Label	Type	Description	Intervention Names
AZD7624	Experimental	Active treatment	Drug: AZD7624 1.0 mg
Placebo	Placebo Comparator	Placebo Comparator	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
AZD7624 1.0 mg	Drug	Inhaled AZD7624 solution, 11 mg/mL	AZD7624
Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time to First Moderate to Severe COPD Exacerbation or Early Drop-out Related to Worsening of COPD Symptoms		Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

Secondary Outcomes

Measure	Description	Time Frame
Annual Event Rate of Moderate and Severe COPD Exacerbations and Early Drop-outs Related to Worsening of COPD Symptoms (i.e. Composite Endpoint, ExDo)	For the production of summary statistics, the annual event rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Event Rate = No. of Events*365.25 / (Follow-up date - Date of randomization + 1).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of signed and dated written informed consent prior to any study specific procedures.
Male and females aged 40-85 years. Females must have a negative pregnancy test at Visit 1, must not be lactating and must be of non-childbearing potential. Males must be surgically sterile or agree to use an acceptable method of contraception for the duration of the study and for 3 months after the last dose of investigational product to prevent pregnancy in a partner.
A weight of ≥50 kg.
Diagnosis of COPD for more than 1 year at Visit 1, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014 guidelines.
COPD maintenance treatment with at least ICS/LABA for at least 2 months prior to enrolment to be continued unchanged during the study.
A post-bronchodilator FEV1/FVC <0.70 and a post-bronchodilator FEV1 ≤70% of the predicted normal value. Documented history of 2 or more moderate to severe COPD exacerbations within 12 months of randomisation, but not within the last 6 weeks before randomisation.
Current or ex-smokers with a smoking history of at least 10 pack-years.

Exclusion Criteria:

Involvement in the planning and conduct of the study.
Previous randomisation in the present study.
Participation in another clinical study with any investigational medicinal product within 3 months of randomisation. Previously intake of any p38 inhibitor.
Participation in, or scheduled for an intensive COPD rehabilitation programme at any time during the study.
Planned in-patient surgery or hospitalisation during the study.
Significant disease or disorder other than COPD which, may either put the patient at risk because of participation in the study, or influence the results of the study, or the patient's ability to participate in the study. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines (GINA 2013) or other accepted guidelines.
A clinically relevant abnormal findings in clinical chemistry, haematology and urinalysis.
Plasma myoglobin and CK above the upper reference range of the analysing laboratory at randomization.
A clinically relevant abnormal findings in physical examination, pulse or blood pressure.
A positive result on screening for serum hepatitis B hepatitis C and Human Immunodeficiency Virus (HIV).
History or family history of muscle diseases. Abnormal vital signs, defined as Systolic Blood Pressure (SBP) above 140 mmHg if <60 years of age and above 150 mmHg if ≥60 years of age; Diastolic Blood Pressure (DBP) above 90 mmHg; Pulse <50 or >100 bpm.
Prolonged QTcF >450 ms or family history of long QT syndrome or sudden death at young age. PR(PQ) interval of clinical significance, PR(PQ) > 250 ms.
Intermittent AV block of 2nd and 3rd degree or AV dissociation.
Patients with a QRS duration >120 ms.
Patients with persistent, and/or recurrent symptomatic tachyarrhythmias, as well as patients with an implantable cardioverter-defibrillator (ICD) or a permanent pacemaker.
Patients with recent Cardiovascular (CV) events or unstable CV disease or a myocardial infarction or stroke within 6 months of screening. History of hospitalization within 12 months caused by heart failure or a diagnosis of heart failure higher than New York Heart Association (NYHA) class II.
History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7624.
Any exacerbation or respiratory infection within 6 weeks of randomization.
Plasma donation within one month of Visit 1, or any blood donation/blood loss >500 mL during the 3 months prior to Visit 1.
History of, or current alcohol or drug abuse.
Treatment with any GCS (apart from prescribed steroids at run-in) within 6 weeks of Visit 3 regardless of indication.
Treatment with strong CYP3A inhibitors within 4 weeks prior to randomisation.

Name	Affiliation	Role
Naimish Patel, MD, PhD	AstraZeneca R&D Boston	Study Director
Barry Make, MD, FCCP, FACVPR	National Jewish Health, Denver, United States	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Los Angeles	California	90036	United States
Research Site

Results Section

Participant Flow Module

ID	Title	Description
FG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
FG001	Placebo	Matching placebo comparator

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Time to First Moderate to Severe COPD Exacerbation or Early Drop-out Related to Worsening of COPD Symptoms

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Median

Full Range

days

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000106 OG001105

Title

Denominators

Categories

Title	Measurements
	OG000NA(5 to NA)Too few events were observed in the treatment group for the estimation of median using Kaplan-Meier methodology. Too few events were observed for the estimation of the upper limit of the full range. OG001118.0(4 to NA)Too few events were observed for the estimation of the upper limit of the full range.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	H0: Hazard Ratio (AZD7624/placebo) equals 1 vs. H1: Hazard Ratio does not equal 1.	Regression, Cox		0.2371		Hazard Ratio (HR)	1.39			2-Sided	95	0.81	2.40			A hazard ratio greater than 1 indicates a higher rate of incidence in the AZD7624 group.		Superiority or Other

Secondary

Annual Event Rate of Moderate and Severe COPD Exacerbations and Early Drop-outs Related to Worsening of COPD Symptoms (i.e. Composite Endpoint, ExDo)

For the production of summary statistics, the annual event rate per subject is calculated, and standardized per a 52-week period according to the formula described below.

Annual Event Rate = No. of Events*365.25 / (Follow-up date - Date of randomization + 1).

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

Events / year

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants

Secondary

Time to First Event of Moderate or Severe COPD Exacerbations or Early Drop-out (Including Drop-outs Due to Any Cause)

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Median

Full Range

days

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Annual Event Rate of Moderate and Severe COPD Exacerbations and Early Drop-outs (Including Drop-outs Due to Any Cause)

For the production of summary statistics, the annual event rate per subject is calculated, and standardized per a 52-week period according to the formula described below.

Annual Event Rate = No. of Events*365.25 / (Follow-up date - Date of randomization + 1).

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

Events / year

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Time to First Moderate or Severe Exacerbation

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Median

Full Range

days

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Annual Exacerbation Rate of Moderate and Severe Exacerbations

For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below.

Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1).

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

Exacerbations / year

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Time to First Moderate or Severe Exacerbation (Where Worsening of COPD Symptoms is Defined as Anthonisens Criteria Fulfilled)

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Median

Full Range

days

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Annual Exacerbation Rate of Moderate and Severe Exacerbations (Where Worsening of COPD Symptoms is Defined as Anthonisens Criteria Fulfilled)

For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below.

Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1).

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

Exacerbations / year

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants

Secondary

Time to First Symptom Defined Exacerbation (as Defined by the Exacerbation of Chronic Pulmonary Disease Tool [EXACT] Daily Diary)

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Median

Full Range

days

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Annual Exacerbation Rate of Symptom Defined Exacerbations (as Defined by the EXACT Daily Diary)

For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below.

Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1).

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

Exacerbations / year

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Symptoms of COPD (Using the EXACT for Respiratory Symptoms [E-RS] Total Score, a Subset of Items From the EXACT Diary)

The EXACT for Respiratory Symptoms (E-RS) scale is a derivative instrument comprising a subset of 11 of the EXACT items to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. One further patient was not included in the analysis due to missing covariate data.

Posted

Least Squares Mean

Standard Error

scores on a scale

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants

Secondary

Health Related Quality of Life (as Assessed by St Georges Respiratory Questionnaire for COPD Patients [SGRQ-C])

The SGRQ-C is a modified version of the St. George's Respiratory Questionnaire, which has been developed to measure the impact of respiratory disease on health status. The SGRQ-C includes 14 questions in 3 domains: symptoms; activity; and impacts. Scores range from 0 to 100 with higher scores indicating benefit. Change in total score from pre study-treatment baseline to Week 12 end of treatment visit are reported.

Full Analysis Set excluding one patient due to lack of source data and GCP compliance issues.

Posted

Mean

Standard Deviation

scores on a scale

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants

Secondary

Dyspnea (Transitional Dyspnea Index (TDI) Score)

The Baseline/Transitional Dyspnea Index (BDI/TDI) provides a multidimensional measure of dyspnea in relation to activities of daily living. The BDI provides a measure of dyspnoea at a single state, the baseline, and the TDI evaluates changes in dyspnoea from the baseline state. The instrument consists of three components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these three components are rated in five grades from 0 (severe) to 4 (unimpaired), and are summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea are rated for each component by seven grades from -3 (major deterioration) to +3 (major improvement), and are added to form a total TDI score from -9 to +9. Positive scores indicate an improvement, and a change from the BDI or a difference between treatments of 1 point has been estimated to constitute the minimum clinically important difference.

The Full Analysis Set excluded one patient due to lack of source data and GCP compliance issues. Only patients with post-baseline TDI scores were included in the analysis.

Posted

Least Squares Mean

Standard Error

score on a scale

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo

Secondary

Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough Forced Expiratory Volume in 1 Second (FEV1)

Full Analysis Set excluding one patient due to lack of source data and GCP compliance issues.

Posted

Mean

Standard Deviation

Litres

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough Forced Vital Capacity (FVC)

Full Analysis Set excluding one patient due to lack of source data and GCP compliance issues.

Posted

Mean

Standard Deviation

Litres

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Secondary

Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough FEV1/FVC Ratio

Full Analysis Set excluding one patient due to lack of source data and GCP compliance issues.

Posted

Mean

Standard Deviation

L/L

Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days)

ID	Title	Description
OG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
OG001	Placebo	Matching placebo comparator

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG0007 affected108 at risk EG0016 affected105 at risk
Angina unstable	Cardiac disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk
Cardiac arrest	Cardiac disorders	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0010 affected105 at risk
Coronary artery occlusion	Cardiac disorders	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0010 affected105 at risk
Biliary colic	Hepatobiliary disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0010 affected105 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk
Nausea	Gastrointestinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0010 affected105 at risk
Urosepsis	Infections and infestations	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0010 affected105 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk
Syncope	Nervous system disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0011 affected105 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG00031 affected108 at risk EG00123 affected105 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG0008 affected108 at risk EG0012 affected105 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG0008 affected108 at risk EG0014 affected105 at risk
Dysgeusia	Nervous system disorders	MedDRA version 18.0	Non-systematic Assessment	EG0005 affected108 at risk EG0011 affected105 at risk
Influenza	Infections and infestations	MedDRA version 18.0	Non-systematic Assessment	EG0005 affected108 at risk EG0013 affected105 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 18.0	Non-systematic Assessment	EG0004 affected108 at risk EG0011 affected105 at risk
Bronchitis	Infections and infestations	MedDRA version 18.0	Non-systematic Assessment	EG0004 affected108 at risk EG0012 affected105 at risk
Nasopharyngitis	Infections and infestations	MedDRA version 18.0	Non-systematic Assessment	EG0004 affected108 at risk EG0014 affected105 at risk
Fatigue	General disorders	MedDRA version 18.0	Non-systematic Assessment	EG0003 affected108 at risk EG0010 affected105 at risk
Hypertension	Vascular disorders	MedDRA version 18.0	Non-systematic Assessment	EG0003 affected108 at risk EG0012 affected105 at risk
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 18.0	Non-systematic Assessment	EG0003 affected108 at risk EG0010 affected105 at risk
Asthenia	General disorders	MedDRA version 18.0	Non-systematic Assessment	EG0002 affected108 at risk EG0014 affected105 at risk
Sinusitis	Infections and infestations	MedDRA version 18.0	Non-systematic Assessment	EG0001 affected108 at risk EG0013 affected105 at risk
Oedema peripheral	General disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0013 affected105 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA version 18.0	Non-systematic Assessment	EG0000 affected108 at risk EG0013 affected105 at risk

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Title	Description
BG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd
BG001	Placebo	Matching placebo comparator
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	AZD7624	Active treatment 2 x 0.5mg inhalation qd			11	108	71	108
EG001	Placebo	Matching placebo comparator			11	105	48	105