Laymen Terminology Chronic Bronchitis and Emphysema, Scientific Terminology Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, Neutrophil, Respiratory Disease
Brief summary
The purpose of this study is the evaluate the safety and tolerability of AZD5069 in patients with Chronic Obstructive Pulmonary Disease
Interventions
DRUGPlacebo
Oral dose bid
DRUGAZD5069 50mg
Oral dose bid
DRUGAZD5069 80mg
Oral dose bid
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of COPD with symptoms for more than one year before screening * Body mass index of 18-30 kg/m2 and weight of 50-100kg * Current or ex-smokers with a smoking history of at least 10 pack years (1 pack year = tobacco consumption corresponding to 20 cigarettes smoked per day for one year) at screening * FEV1 of 30% or above and less than 80% of the predicted normal value post-bronchodilator at screening * FEV1/FVC less than 70% post-bronchodilator at screening
Exclusion criteria
* Any clinically significant disease or disorder * Exacerbation of COPD which was not resolved within 30 days of first dosing * Patients who have received live or live-attenuated vaccine in the 2 weeks prior to first dosing * Asthma and any current respiratory tract disorder other than COPD which is considered to be clinically significant * Disease history suggesting reduced or abnormal immune function other than that related to COPD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Treatment for Total Protein (Urinalysis) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in total protein in urine is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for Diastolic Blood Pressure (Vital Signs) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in diastolic blood pressure (Vital Sign) is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for Pulse Rate (Vital Signs) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in pulse rate (Vital Sign) is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for FEV1 Pre-bronchodilator (Lung Function Test) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in FEV1 Pre-bronchodilator is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for FEV1 Post-bronchodilator (Lung Function Test) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in FEV1 Post-bronchodilator is calculated as the End of Treatment value minus the Baseline value. |
| Number of Participants Who Developed High Transaminase Values (Clinical Chemistry) | Up to Follow-up Visit (3 to 18 days after End of Treatment [Day 28]) | High Transaminase Values are defined as a measurment of ALT (alanine aminotransferase) or AST (aspartate aminotransferase) greater than or equal to 3 times the upper limit of normal (ALT ULN = 36 IU/L, AST ULN = 33 IU/L). |
| Patients Who Experienced at Least One Adverse Events(s) | From start of treatment (Day 0) up to 28 days (End of Treatment) | Adverse event (AE) data, both serious and non-serious. An AE is the development of an undesirable medical condition (eg, nausea, chest pain, tachycardia, laboratory findings) or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. |
| Number of Participants With Abnormal Physical Examination Findings | Last Observation on Treatment (up to Day 28) | Physical examination includes assessment of general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, musculo-skeletal (including spine and extremities), cardiovascular, lungs and abdomen. The findings were deemed to be normal/abnormal based on the clinical judgment of the investigator. |
| Number of Participants With Abnormal Electrocardiogram (ECG) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | ECGs were recorded in the supine position after the patient has rested for 10 minutes. Heart rate, QRS duration, PR, RR and QT intervals were recorded. Overall evaluation of the ECG is classified as normal, abnormal or borderline. Only participants with ECG at baseline classified as normal are reported (ie, only changes from normal to abnormal). |
| Change From Baseline to End of Treatment for Leucocytes Count in Blood (Safety Blood Sample) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in circulating leucocyte counts (including neutrophils) is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for Body Temperature | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in body temperature (oral) is calculated as the End of Treatment value minus the Baseline value. |
| Change From Baseline to End of Treatment for Systolic Blood Preassure (Vital Signs) | Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28) | The change in systolic blood pressure (Vital Sign) is calculated as the End of Treatment value minus the Baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Curve of AZD5069 | End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing | The area under the plasma concentration curve is estimated from time 0 (dosing) to 24 hours after dosing. |
| Maximum Plasma Concentration for AZD5069 | End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing | The maximum plasma concentration (Cmax) is the highest level of drug in plasma. |
| Time to Maximum Plasma Concentration for AZD5069 | End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing | Time (in relation to dosing) at which the maximum plasma concentration is observed. |
| Maximum Reduction of Circulating Neutrophils in Blood, From Baseline | Baseline (last non-missing assessment prior to first dose of study medication), weeks 1, 2 and 3, and End of Treatment (Day 28) | The change in circulating neutrophils in blood is calculated as the visit value minus the Baseline value. Only participants with reduction are considered. |
| Plasma Concentration of AZD5069 After 1 Hour of Dosing | End of Treatment (Day 28), 1 hour after dosing | At this visit, approximately 1 hour after dosing (at the clinic), a blood sample was collected for determination of drug concentration in plasma. |
Countries
Bulgaria, Germany, Hungary, Ukraine
Participant flow
Recruitment details
First patient enrolled: 22 November 2010. Last patient completed: 22 March 2011. Fifteen centres across 4 countries participated in this study: Bulgaria (4), Germany (4), Hungary (4) and Ukraine (3)
Pre-assignment details
22 patients enrolled were not randomized due to eligibility not fulfilled (17 patients) and voluntary discontinuation (5 patients)
Participants by arm
| Arm | Count |
|---|---|
| Placebo 4 x placebo capsules, twice daily (bid) | 29 |
| AZD5069 50 mg 1 x 50 mg AZD5069 capsule and 3 x placebo capsules, bid | 30 |
| AZD5069 80 mg 4 x 20 AZD5069 mg capsules, bid | 28 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Voluntary Discontinuation by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | AZD5069 50 mg | AZD5069 80 mg |
|---|---|---|---|---|
| Age, Continuous | 64 Years STANDARD_DEVIATION 7.4 | 62 Years STANDARD_DEVIATION 7.9 | 65 Years STANDARD_DEVIATION 6.9 | 65 Years STANDARD_DEVIATION 7.4 |
| Body Mass Index | 26.118 kg/m^2 STANDARD_DEVIATION 3.14 | 24.842 kg/m^2 STANDARD_DEVIATION 2.77 | 27.645 kg/m^2 STANDARD_DEVIATION 2.89 | 25.803 kg/m^2 STANDARD_DEVIATION 3.18 |
| FEV1/FVC at screening | 52.91 % STANDARD_DEVIATION 10.58 | 52.54 % STANDARD_DEVIATION 9.62 | 51.75 % STANDARD_DEVIATION 11.65 | 54.52 % STANDARD_DEVIATION 10.51 |
| GOLD classification III Severe | 34 Participants | 12 Participants | 10 Participants | 12 Participants |
| GOLD classification II Moderate | 53 Participants | 17 Participants | 20 Participants | 16 Participants |
| Nicotine pack years | 37 Pack Year STANDARD_DEVIATION 20.4 | 38 Pack Year STANDARD_DEVIATION 21.4 | 39 Pack Year STANDARD_DEVIATION 22 | 34 Pack Year STANDARD_DEVIATION 17.9 |
| % Predicted FEV1 at screening | 56 % STANDARD_DEVIATION 13.2 | 56 % STANDARD_DEVIATION 13.9 | 57 % STANDARD_DEVIATION 13.6 | 54 % STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 27 Participants | 9 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Male | 60 Participants | 20 Participants | 18 Participants | 22 Participants |
| Weight | 76 Kg STANDARD_DEVIATION 11.59 | 73.7 Kg STANDARD_DEVIATION 14.02 | 78.9 Kg STANDARD_DEVIATION 9.18 | 75.4 Kg STANDARD_DEVIATION 10.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 29 | 8 / 30 | 1 / 28 |
| serious Total, serious adverse events | 0 / 29 | 1 / 30 | 1 / 28 |
Outcome results
Primary
Change From Baseline to End of Treatment for Body Temperature
The change in body temperature (oral) is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Body Temperature | -0.1 degrees C | Standard Deviation 0.43 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Body Temperature | 0.0 degrees C | Standard Deviation 0.57 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Body Temperature | -0.0 degrees C | Standard Deviation 0.39 |
Primary
Change From Baseline to End of Treatment for Diastolic Blood Pressure (Vital Signs)
The change in diastolic blood pressure (Vital Sign) is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Diastolic Blood Pressure (Vital Signs) | 2.0 mmHg | Standard Deviation 7.2 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Diastolic Blood Pressure (Vital Signs) | -2.0 mmHg | Standard Deviation 7.9 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Diastolic Blood Pressure (Vital Signs) | -1.0 mmHg | Standard Deviation 8.2 |
Primary
Change From Baseline to End of Treatment for FEV1 Post-bronchodilator (Lung Function Test)
The change in FEV1 Post-bronchodilator is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for FEV1 Post-bronchodilator (Lung Function Test) | -0.02 L | Standard Deviation 0.23 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for FEV1 Post-bronchodilator (Lung Function Test) | 0.10 L | Standard Deviation 0.256 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for FEV1 Post-bronchodilator (Lung Function Test) | 0.02 L | Standard Deviation 0.194 |
Primary
Change From Baseline to End of Treatment for FEV1 Pre-bronchodilator (Lung Function Test)
The change in FEV1 Pre-bronchodilator is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for FEV1 Pre-bronchodilator (Lung Function Test) | -0.03 L | Standard Deviation 0.238 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for FEV1 Pre-bronchodilator (Lung Function Test) | 0.05 L | Standard Deviation 0.238 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for FEV1 Pre-bronchodilator (Lung Function Test) | -0.01 L | Standard Deviation 0.218 |
Primary
Change From Baseline to End of Treatment for Leucocytes Count in Blood (Safety Blood Sample)
The change in circulating leucocyte counts (including neutrophils) is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Leucocytes Count in Blood (Safety Blood Sample) | -0.12 10^9/L cells/L | Standard Deviation 1.974 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Leucocytes Count in Blood (Safety Blood Sample) | -1.55 10^9/L cells/L | Standard Deviation 2.059 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Leucocytes Count in Blood (Safety Blood Sample) | -1.08 10^9/L cells/L | Standard Deviation 2.404 |
Primary
Change From Baseline to End of Treatment for Pulse Rate (Vital Signs)
The change in pulse rate (Vital Sign) is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Pulse Rate (Vital Signs) | 1 beats/minute | Standard Deviation 6.2 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Pulse Rate (Vital Signs) | -1 beats/minute | Standard Deviation 6.9 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Pulse Rate (Vital Signs) | 3 beats/minute | Standard Deviation 7.9 |
Primary
Change From Baseline to End of Treatment for Systolic Blood Preassure (Vital Signs)
The change in systolic blood pressure (Vital Sign) is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Systolic Blood Preassure (Vital Signs) | 3.0 mmHg | Standard Deviation 11 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Systolic Blood Preassure (Vital Signs) | -0.0 mmHg | Standard Deviation 12.1 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Systolic Blood Preassure (Vital Signs) | -3.0 mmHg | Standard Deviation 15.7 |
Primary
Change From Baseline to End of Treatment for Total Protein (Urinalysis)
The change in total protein in urine is calculated as the End of Treatment value minus the Baseline value.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Change From Baseline to End of Treatment for Total Protein (Urinalysis) | -0.02 g/L | Standard Deviation 0.034 |
| Arm 2 - AZD5069 50 mg | Change From Baseline to End of Treatment for Total Protein (Urinalysis) | -0.01 g/L | Standard Deviation 0.022 |
| Arm 3 - AZD5069 80 mg | Change From Baseline to End of Treatment for Total Protein (Urinalysis) | -0.01 g/L | — |
Primary
Number of Participants Who Developed High Transaminase Values (Clinical Chemistry)
High Transaminase Values are defined as a measurment of ALT (alanine aminotransferase) or AST (aspartate aminotransferase) greater than or equal to 3 times the upper limit of normal (ALT ULN = 36 IU/L, AST ULN = 33 IU/L).
Time frame: Up to Follow-up Visit (3 to 18 days after End of Treatment [Day 28])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Placebo | Number of Participants Who Developed High Transaminase Values (Clinical Chemistry) | 0 Participants |
| Arm 2 - AZD5069 50 mg | Number of Participants Who Developed High Transaminase Values (Clinical Chemistry) | 0 Participants |
| Arm 3 - AZD5069 80 mg | Number of Participants Who Developed High Transaminase Values (Clinical Chemistry) | 0 Participants |
Primary
Number of Participants With Abnormal Electrocardiogram (ECG)
ECGs were recorded in the supine position after the patient has rested for 10 minutes. Heart rate, QRS duration, PR, RR and QT intervals were recorded. Overall evaluation of the ECG is classified as normal, abnormal or borderline. Only participants with ECG at baseline classified as normal are reported (ie, only changes from normal to abnormal).
Time frame: Baseline (last non-missing assessment prior to first dose of study medication) and End of Treatment (Day 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) | 0 Participants |
| Arm 2 - AZD5069 50 mg | Number of Participants With Abnormal Electrocardiogram (ECG) | 0 Participants |
| Arm 3 - AZD5069 80 mg | Number of Participants With Abnormal Electrocardiogram (ECG) | 0 Participants |
Primary
Number of Participants With Abnormal Physical Examination Findings
Physical examination includes assessment of general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, musculo-skeletal (including spine and extremities), cardiovascular, lungs and abdomen. The findings were deemed to be normal/abnormal based on the clinical judgment of the investigator.
Time frame: Last Observation on Treatment (up to Day 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Placebo | Number of Participants With Abnormal Physical Examination Findings | 0 Participants |
| Arm 2 - AZD5069 50 mg | Number of Participants With Abnormal Physical Examination Findings | 0 Participants |
| Arm 3 - AZD5069 80 mg | Number of Participants With Abnormal Physical Examination Findings | 1 Participants |
Primary
Patients Who Experienced at Least One Adverse Events(s)
Adverse event (AE) data, both serious and non-serious. An AE is the development of an undesirable medical condition (eg, nausea, chest pain, tachycardia, laboratory findings) or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
Time frame: From start of treatment (Day 0) up to 28 days (End of Treatment)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Placebo | Patients Who Experienced at Least One Adverse Events(s) | 9 Participants |
| Arm 2 - AZD5069 50 mg | Patients Who Experienced at Least One Adverse Events(s) | 10 Participants |
| Arm 3 - AZD5069 80 mg | Patients Who Experienced at Least One Adverse Events(s) | 6 Participants |
Secondary
Area Under the Plasma Concentration Curve of AZD5069
The area under the plasma concentration curve is estimated from time 0 (dosing) to 24 hours after dosing.
Time frame: End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Area Under the Plasma Concentration Curve of AZD5069 | 29600 nmol*h/L | Geometric Coefficient of Variation 108 |
| Arm 2 - AZD5069 50 mg | Area Under the Plasma Concentration Curve of AZD5069 | 38800 nmol*h/L | Geometric Coefficient of Variation 95.6 |
Secondary
Maximum Plasma Concentration for AZD5069
The maximum plasma concentration (Cmax) is the highest level of drug in plasma.
Time frame: End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Maximum Plasma Concentration for AZD5069 | 2550 nmol/L | Geometric Coefficient of Variation 107 |
| Arm 2 - AZD5069 50 mg | Maximum Plasma Concentration for AZD5069 | 3340 nmol/L | Geometric Coefficient of Variation 95.6 |
Secondary
Maximum Reduction of Circulating Neutrophils in Blood, From Baseline
The change in circulating neutrophils in blood is calculated as the visit value minus the Baseline value. Only participants with reduction are considered.
Time frame: Baseline (last non-missing assessment prior to first dose of study medication), weeks 1, 2 and 3, and End of Treatment (Day 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Placebo | Maximum Reduction of Circulating Neutrophils in Blood, From Baseline | 1.324 10^9/L cells/L | Standard Deviation 1.2152 |
| Arm 2 - AZD5069 50 mg | Maximum Reduction of Circulating Neutrophils in Blood, From Baseline | 2.759 10^9/L cells/L | Standard Deviation 1.4422 |
| Arm 3 - AZD5069 80 mg | Maximum Reduction of Circulating Neutrophils in Blood, From Baseline | 2.678 10^9/L cells/L | Standard Deviation 2.071 |
Secondary
Plasma Concentration of AZD5069 After 1 Hour of Dosing
At this visit, approximately 1 hour after dosing (at the clinic), a blood sample was collected for determination of drug concentration in plasma.
Time frame: End of Treatment (Day 28), 1 hour after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 2 - AZD5069 50 mg | Plasma Concentration of AZD5069 After 1 Hour of Dosing | 2599.551 nmol/L | Standard Deviation 2085.601 |
| Arm 3 - AZD5069 80 mg | Plasma Concentration of AZD5069 After 1 Hour of Dosing | 5433.611 nmol/L | Standard Deviation 4622.932 |
Secondary
Time to Maximum Plasma Concentration for AZD5069
Time (in relation to dosing) at which the maximum plasma concentration is observed.
Time frame: End of Treatment (Day 28); pre-dose, 1, 2, 3, and 5 hours after dosing
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 - Placebo | Time to Maximum Plasma Concentration for AZD5069 | 1.56 hours |
| Arm 2 - AZD5069 50 mg | Time to Maximum Plasma Concentration for AZD5069 | 1.56 hours |