Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Chronic, obstructive, pulmonary, lung, respiratory disease, tolerability, placebo-controlled, pharmacokinetics, COPD
Brief summary
The purpose of this study is to assess the tolerability (effect of drug on body) and pharmacokinetics (effect of body on drug) of AZD9668 in patients with mild to moderate COPD
Interventions
DRUGAZD9668
30mg oral tablets twice daily (bid) for 14 days
DRUGPlacebo
Matched placebo to 30mg oral tablet twice daily (bid) for 14 days
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Mild to moderate COPD * Smokers or ex-smokers * post-menopausal females
Exclusion criteria
* Past history or current evidence of clinically significant heart disease * Lung disease other than COPD * Treatment with systemic steroids within 8 weeks of study visit 2 * Treatment with antibiotics within 4 weeks of study visit 1 or study visit 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Clearance of Drug From Plasma (CLR) | Pre-dose on day -1 to day 15 (end of dosing) | CLR following 14 days' dosing |
| Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose (AUC(0-12)) | Pre-dose on day -1 to day 15 (end of dosing) | AUC(0-12) following 14 days' dosing |
| Observed Peak or Maximum Plasma Concentration Following Drug Administration (Cmax) | Pre-dose on day -1 to day 15 (end of dosing) | Cmax following 14 days' dosing |
| Time to Reach Observed Peak or Maximum Concentration Following Oral Drug Administration (Tmax) | Pre-dose on day -1 to day 15 (end of dosing) | tmax following 14 days' dosing |
| Terminal Half-life of Drug in Plasma (t1/2) | Pre-dose on day -1 to day 15 (end of dosing) | t1/2 following 14 days' dosing |
| Alanine Aminotransferase (ALT) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | ALT level greater than 3 times the upper limit of normal |
| Aspartate Aminotransferase (AST) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | AST level greater than 3 times the upper limit of normal |
| Creatine Kinase (CK) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
| Total Bilirubin | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
| Creatinine | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Creatinine level greater than the upper limit of normal |
| Haemoglobin (Hb) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
| Reticulocytes | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
| Leucocytes | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
| QTcF (QT Interval Corrected for Heart Rate by Fridericia's Method) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | QTcF interval greater than 450 ms |
| QTcF | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | QTcF change from baseline greater than 60 ms |
| FEV1 (Forced Expiratory Volume in the First Second) | Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose) | Change from baseline to Day 14 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Differential Neutrophil Count | Pre-dose day -1 to post-dose on day 14 | Change from baseline to Day 14 in percentage neutrophil count |
| AZD9668 Sputum Concentrations | Pre-dose day -1 to post-dose on day 14 | — |
| Quantitative Sputum Bacteriology | Pre-dose day -1 to post-dose on day 15 | Number of patients with an increase in bacteriological count from Day -1 to Day 15 |
| Sputum Absolute Neutrophil Count | Pre-dose day -1 to post-dose on day 14 | Change from baseline to Day 14 in absolute neutrophil count |
Countries
Germany
Participant flow
Recruitment details
First patient enrolled: 11 June 2008. Last patient completed: 09 October 2008. Single-centre study performed at a Clinical Pharmacology Unit
Participants by arm
| Arm | Count |
|---|---|
| AZD9668 AZD9668 2x30mg oral tablets twice daily (bid) for 14 days | 12 |
| Placebo Matched placebo tablets twice daily (bid) for 14 days | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | AZD9668 | Placebo | Total |
|---|---|---|---|
| Age Continuous | 57.6 Years | 52.8 Years | 56 Years |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / — | 4 / — |
| serious Total, serious adverse events | 0 / 12 | 0 / 6 |
Outcome results
Primary
Alanine Aminotransferase (ALT)
ALT level greater than 3 times the upper limit of normal
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | Alanine Aminotransferase (ALT) | 0 Participants |
| Placebo | Alanine Aminotransferase (ALT) | 0 Participants |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose (AUC(0-12))
AUC(0-12) following 14 days' dosing
Time frame: Pre-dose on day -1 to day 15 (end of dosing)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9668 | Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose (AUC(0-12)) | 7560 nM.h |
Primary
Aspartate Aminotransferase (AST)
AST level greater than 3 times the upper limit of normal
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | Aspartate Aminotransferase (AST) | 0 Participants |
| Placebo | Aspartate Aminotransferase (AST) | 0 Participants |
Primary
Creatine Kinase (CK)
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | Creatine Kinase (CK) | 2.57 IU/L | Standard Deviation 19.26 |
| Placebo | Creatine Kinase (CK) | -69.57 IU/L | Standard Deviation 141.383 |
Primary
Creatinine
Creatinine level greater than the upper limit of normal
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | Creatinine | 1 Participants |
| Placebo | Creatinine | 1 Participants |
Primary
FEV1 (Forced Expiratory Volume in the First Second)
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | FEV1 (Forced Expiratory Volume in the First Second) | 0.039 L | Standard Deviation 0.2173 |
| Placebo | FEV1 (Forced Expiratory Volume in the First Second) | -0.110 L | Standard Deviation 0.3043 |
Primary
Haemoglobin (Hb)
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | Haemoglobin (Hb) | -2.0 g/L | Standard Deviation 4.73 |
| Placebo | Haemoglobin (Hb) | -0.2 g/L | Standard Deviation 6.18 |
Primary
Leucocytes
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | Leucocytes | -0.001 10**9/L | Standard Deviation 0.8816 |
| Placebo | Leucocytes | 0.265 10**9/L | Standard Deviation 0.4657 |
Primary
Observed Peak or Maximum Plasma Concentration Following Drug Administration (Cmax)
Cmax following 14 days' dosing
Time frame: Pre-dose on day -1 to day 15 (end of dosing)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9668 | Observed Peak or Maximum Plasma Concentration Following Drug Administration (Cmax) | 1420 nM |
Primary
QTcF
QTcF change from baseline greater than 60 ms
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | QTcF | 0 Participants |
| Placebo | QTcF | 0 Participants |
Primary
QTcF (QT Interval Corrected for Heart Rate by Fridericia's Method)
QTcF interval greater than 450 ms
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | QTcF (QT Interval Corrected for Heart Rate by Fridericia's Method) | 0 Participants |
| Placebo | QTcF (QT Interval Corrected for Heart Rate by Fridericia's Method) | 0 Participants |
Primary
Renal Clearance of Drug From Plasma (CLR)
CLR following 14 days' dosing
Time frame: Pre-dose on day -1 to day 15 (end of dosing)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9668 | Renal Clearance of Drug From Plasma (CLR) | 6.13 L/h |
Primary
Reticulocytes
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | Reticulocytes | -0.15 relative particle count (%) | Standard Deviation 2.851 |
| Placebo | Reticulocytes | 1.73 relative particle count (%) | Standard Deviation 1.605 |
Primary
Terminal Half-life of Drug in Plasma (t1/2)
t1/2 following 14 days' dosing
Time frame: Pre-dose on day -1 to day 15 (end of dosing)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9668 | Terminal Half-life of Drug in Plasma (t1/2) | 5.89 hours |
Primary
Time to Reach Observed Peak or Maximum Concentration Following Oral Drug Administration (Tmax)
tmax following 14 days' dosing
Time frame: Pre-dose on day -1 to day 15 (end of dosing)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9668 | Time to Reach Observed Peak or Maximum Concentration Following Oral Drug Administration (Tmax) | 1.01 hours |
Primary
Total Bilirubin
Change from baseline to Day 14
Time frame: Throughout the duration of the study (pre-dose, cmax, steady state, end of dosing and post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9668 | Total Bilirubin | 0.11 micromol/L | Standard Deviation 2.124 |
| Placebo | Total Bilirubin | -0.28 micromol/L | Standard Deviation 2.563 |
Secondary
AZD9668 Sputum Concentrations
Time frame: Pre-dose day -1 to post-dose on day 14
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9668 | AZD9668 Sputum Concentrations | 41.7 nM |
Secondary
Quantitative Sputum Bacteriology
Number of patients with an increase in bacteriological count from Day -1 to Day 15
Time frame: Pre-dose day -1 to post-dose on day 15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9668 | Quantitative Sputum Bacteriology | 3 Participants |
| Placebo | Quantitative Sputum Bacteriology | 2 Participants |
Secondary
Sputum Absolute Neutrophil Count
Change from baseline to Day 14 in absolute neutrophil count
Time frame: Pre-dose day -1 to post-dose on day 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9668 | Sputum Absolute Neutrophil Count | -0.4890 10**9/L |
| Placebo | Sputum Absolute Neutrophil Count | -2.5645 10**9/L |
Secondary
Sputum Differential Neutrophil Count
Change from baseline to Day 14 in percentage neutrophil count
Time frame: Pre-dose day -1 to post-dose on day 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9668 | Sputum Differential Neutrophil Count | 1.8 Percentage |
| Placebo | Sputum Differential Neutrophil Count | -4.25 Percentage |