Asthma
Conditions
Keywords
Asthma
Brief summary
Distribution of neutrophils in bronchial mucosal tissue in asthma patients before and after 4 wk treatment with AZD 5069
Detailed description
The purpose is to investigate the bronchial tissue neutrophil counts and distribution in asthma patients after 4 week oral treatment with AZD 5069
Interventions
DRUGAZD5069
oral BD administration of 45 mg AZD5069
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients of Caucasian origin, aged between 18 to 65 years, inclusive, at the time informed consent is obtained. 2. Physician based (according to GINA 2011) diagnosis of asthma for at least 6 months prior to the date informed consent is obtained and confirmed by 1 of the detailed respiratory criteria stated in the CSP 3. Morning prebronchodilator (ie, after abstinence from short-acting and long-acting ß-agonist treatment for ≥ 6 and ≥ 12 hours, respectively) FEV1 of ≥70% of predicted normal (PN) for age, sex and height at enrolment 4. Increased number of neutrophils in induced sputum samples at baseline, with a relative neutrophil count of ≥ 50% of total sputum cell count 5. Physician prescribed daily use of medium or high dose ICS (≥ fluticasone 250 μg to ≤ 1.000 µg or the equivalent daily, as defined in GINA 2011; see CSP Appendix E) plus LABA.
Exclusion criteria
1. History of clinically relevant allergies or idiosyncrasies to AZD5069 or other investigational CXCR2 antagonists, or any inactive ingredient(s) of the IMP, or tool-substances (eg, salbutamol, local anaesthetics) used for the purpose of this study 2. History of severe asthma exacerbation requiring hospitalization within the last 12 months before screening. 3. Asthma exacerbation requiring a treatment course of systemic (ie, oral or parenteral) corticosteroids within the 3 months before screening or ≥ 3 courses within the last 12 months before screening. 4. Moderate to severe airflow limitation (FEV1 \<70% PN) 5. Any chronic lower respiratory disease other than asthma (see CSP for details) that, as judged by the Investigator or Medical Monitor, would interfere with the evaluation of the IMP or interpretation of patient safety or study results. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary for Change From Baseline of Mean Global Semi-quantitative Score Values for Neutrophils in Bronchial Biopsies | Baseline and Week 4 | Change from baseline reflects the Week 4 value minus the baseline value. Baseline value is Day-14 measurement. For semi-quantitative scores, 1= few number of Neutrophils, 2= moderate number of Neutrophils, 3= abundant of Neutrophils. For this end point the reduction in mean of semi-quantitative (arbitrary) scores indicates better result, i.e. lower numbers of Neutrophils. The scores given for the biopsies taken at screening and end of treatment is the mean global semi-quantitative scores for the three compartments intraepithelial, subepithelial and submucosal. |
| Summary for Change From Baseline Neutrophils in Sputum | Baseline, Day 8, Day 22 and Day29 | Change from Baseline reflects the Day 8, Day22 and Day29 minus the baseline value. |
| Summary for Change From Baseline Neutrophil Cell Counts in Blood | Baseline, Day 2, Day 8, Day 15, Day 22, Day29 and Day 34 | Change from Baseline reflects the Day 2, Day 8, Day 15, Day 22, Day29 and Day 34 minus the baseline value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary Statistics for AUC0-4hrs on Day 29/ Visit T7 (PK Analysis Set) | At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7) | Summary statistics including geometric mean and standard error for AUC0-4hrs on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported. |
| Summary Statistics for Cmin on Day 29/ Visit T7 (PK Analysis Set) | At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7) | Summary statistics including geometric mean and standard error for Cmin on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported. |
| Summary Statistics for Cmax on Day 29/ Visit T7 (PK Analysis Set) | At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7) | Summary statistics including geometric mean and standard error for Cmax on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported. |
| Summary for Change From Baseline for IL-8 by Type of Sample | Baseline and Day 29 | Change from baseline reflects the Day 29 value minus the baseline value. |
| Number of Participants With Adverse Events | Up to 40 days | Summary of number of participants with adverse events (safety set) |
| Summary Statistics for Patient Diary Variables (Day Time) | Up to 44 days | Summary statistics for patient diary variable, observations with no asthma symptoms (day time), by period (safety set). The screening period was Day -14 to -1. Period 1 was the first half of treatment period, Day 1 to daytime record Day 15. Period 2 was the second half of treatment period, night-time record Day 15 to night-time record Day 29+1. One participant left the study on day 2, due to adverse event. |
| Summary Statistics for Patient Diary Variables (Night Time) | Up to 44 days | Summary statistics for patient diary variable, observations with no asthma symptoms (night time), by period (safety set). The screening period was Day -14 to -1. Period 1 was the first half of treatment period, Day 1 to daytime record Day 15. Period 2 was the second half of treatment period, night-time record Day 15 to night-time record Day 29+1. One participant left the study on day 2, due to adverse event. |
| Number of Adverse Events | Up to 40 days | Summary of number of adverse events (safety set) |
| Summary for Change From Baseline for GRO-alpha by Type of Sample | Baseline and Day 29 | Change from baseline reflects the Day 29 value minus the baseline value. |
| Summary for Change From Baseline for MMP-9 by Type of Sample | Baseline and Day 29 | Change from baseline reflects the Day 29 value minus the baseline value. |
Countries
Germany
Participant flow
Recruitment details
Thirteen patients were screened; 8 patients were screening failures, 5 patients were enrolled in the study and received treatment with AZD5069. First patient enrolled: 11 March 2014. Last patient completed: 18 August 2014.
Participants by arm
| Arm | Count |
|---|---|
| AZD5069 AZD5069 45mg oral twice daily (BID) | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | AZD5069 |
|---|---|
| Age, Continuous | 46.8 Years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Summary for Change From Baseline Neutrophil Cell Counts in Blood
Change from Baseline reflects the Day 2, Day 8, Day 15, Day 22, Day29 and Day 34 minus the baseline value
Time frame: Baseline, Day 2, Day 8, Day 15, Day 22, Day29 and Day 34
Population: PD Analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 2 | -2.517 10^9 cells/L | Standard Deviation 0.42 |
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 8 | -1.494 10^9 cells/L | Standard Deviation 0.559 |
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 15 | -1.985 10^9 cells/L | Standard Deviation 0.425 |
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 22 | -1.658 10^9 cells/L | Standard Deviation 0.237 |
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 29 | -1.178 10^9 cells/L | Standard Deviation 1.375 |
| AZD5069 | Summary for Change From Baseline Neutrophil Cell Counts in Blood | Day 34 | -0.306 10^9 cells/L | Standard Deviation 0.2 |
Primary
Summary for Change From Baseline Neutrophils in Sputum
Change from Baseline reflects the Day 8, Day22 and Day29 minus the baseline value.
Time frame: Baseline, Day 8, Day 22 and Day29
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5069 | Summary for Change From Baseline Neutrophils in Sputum | Day 8 | -4.294 10^9 cells/L | Standard Deviation 3.062 |
| AZD5069 | Summary for Change From Baseline Neutrophils in Sputum | Day 22 | -6.670 10^9 cells/L | Standard Deviation 3.751 |
| AZD5069 | Summary for Change From Baseline Neutrophils in Sputum | Day 29 | -3.849 10^9 cells/L | Standard Deviation 1.861 |
Primary
Summary for Change From Baseline of Mean Global Semi-quantitative Score Values for Neutrophils in Bronchial Biopsies
Change from baseline reflects the Week 4 value minus the baseline value. Baseline value is Day-14 measurement. For semi-quantitative scores, 1= few number of Neutrophils, 2= moderate number of Neutrophils, 3= abundant of Neutrophils. For this end point the reduction in mean of semi-quantitative (arbitrary) scores indicates better result, i.e. lower numbers of Neutrophils. The scores given for the biopsies taken at screening and end of treatment is the mean global semi-quantitative scores for the three compartments intraepithelial, subepithelial and submucosal.
Time frame: Baseline and Week 4
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5069 | Summary for Change From Baseline of Mean Global Semi-quantitative Score Values for Neutrophils in Bronchial Biopsies | -1.21 Units on a scale | Standard Deviation 0.54 |
Secondary
Number of Adverse Events
Summary of number of adverse events (safety set)
Time frame: Up to 40 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD5069 | Number of Adverse Events | Total number of unique AEs | 10 adverse events |
| AZD5069 | Number of Adverse Events | Total number of AEs | 11 adverse events |
| AZD5069 | Number of Adverse Events | Total number of SAEs | 0 adverse events |
Secondary
Number of Participants With Adverse Events
Summary of number of participants with adverse events (safety set)
Time frame: Up to 40 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD5069 | Number of Participants With Adverse Events | Total number of subjects with at least one AE | 4 Participants |
| AZD5069 | Number of Participants With Adverse Events | Number of subjects withdrawn from study due to AE | 1 Participants |
Secondary
Summary for Change From Baseline for GRO-alpha by Type of Sample
Change from baseline reflects the Day 29 value minus the baseline value.
Time frame: Baseline and Day 29
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5069 | Summary for Change From Baseline for GRO-alpha by Type of Sample | GRO-alpha in Serum | 179.75 pg/ml | Standard Deviation 98.2 |
| AZD5069 | Summary for Change From Baseline for GRO-alpha by Type of Sample | GRO-alpha in Sputum | 7352.50 pg/ml | Standard Deviation 22373.99 |
Secondary
Summary for Change From Baseline for IL-8 by Type of Sample
Change from baseline reflects the Day 29 value minus the baseline value.
Time frame: Baseline and Day 29
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5069 | Summary for Change From Baseline for IL-8 by Type of Sample | IL-8 in Serum | 46.88 pg/ml | Standard Deviation 34.13 |
| AZD5069 | Summary for Change From Baseline for IL-8 by Type of Sample | IL-8 in Sputum | 5780.75 pg/ml | Standard Deviation 3763.83 |
Secondary
Summary for Change From Baseline for MMP-9 by Type of Sample
Change from baseline reflects the Day 29 value minus the baseline value.
Time frame: Baseline and Day 29
Population: PD analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5069 | Summary for Change From Baseline for MMP-9 by Type of Sample | MMP-9 in Serum | -157.75 ng/ml | Standard Deviation 289.76 |
| AZD5069 | Summary for Change From Baseline for MMP-9 by Type of Sample | MMP-9 in Sputum | -80.75 ng/ml | Standard Deviation 178.55 |
Secondary
Summary Statistics for AUC0-4hrs on Day 29/ Visit T7 (PK Analysis Set)
Summary statistics including geometric mean and standard error for AUC0-4hrs on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported.
Time frame: At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5069 | Summary Statistics for AUC0-4hrs on Day 29/ Visit T7 (PK Analysis Set) | 8571.72 h*nmol/L | Standard Error 2421.99 |
Secondary
Summary Statistics for Cmax on Day 29/ Visit T7 (PK Analysis Set)
Summary statistics including geometric mean and standard error for Cmax on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported.
Time frame: At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5069 | Summary Statistics for Cmax on Day 29/ Visit T7 (PK Analysis Set) | 3565.76 nmol/L | Standard Error 762.84 |
Secondary
Summary Statistics for Cmin on Day 29/ Visit T7 (PK Analysis Set)
Summary statistics including geometric mean and standard error for Cmin on Day 29/ Visit T7 (PK analysis set). Plasma concentration data beyond 0.5 hrs post dose at Day 29 were missing for one patient. For this patient only Cmin value was reported and the AUC0-4hrs and Cmax values were not reported.
Time frame: At 0, 0.5, 1, 1.5, 2, 2.5, 3, 4 hours post dose on Day 29 (Visit T7)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5069 | Summary Statistics for Cmin on Day 29/ Visit T7 (PK Analysis Set) | 466.92 nmol/L | Standard Error 272.3 |
Secondary
Summary Statistics for Patient Diary Variables (Day Time)
Summary statistics for patient diary variable, observations with no asthma symptoms (day time), by period (safety set). The screening period was Day -14 to -1. Period 1 was the first half of treatment period, Day 1 to daytime record Day 15. Period 2 was the second half of treatment period, night-time record Day 15 to night-time record Day 29+1. One participant left the study on day 2, due to adverse event.
Time frame: Up to 44 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD5069 | Summary Statistics for Patient Diary Variables (Day Time) | Obs. with No asthma symptoms (Screening; n=55) | 6 Observations |
| AZD5069 | Summary Statistics for Patient Diary Variables (Day Time) | Obs. with No asthma symptoms (Period1; n=71) | 7 Observations |
| AZD5069 | Summary Statistics for Patient Diary Variables (Day Time) | Obs. with No asthma symptoms (Period2; n=71) | 7 Observations |
Secondary
Summary Statistics for Patient Diary Variables (Night Time)
Summary statistics for patient diary variable, observations with no asthma symptoms (night time), by period (safety set). The screening period was Day -14 to -1. Period 1 was the first half of treatment period, Day 1 to daytime record Day 15. Period 2 was the second half of treatment period, night-time record Day 15 to night-time record Day 29+1. One participant left the study on day 2, due to adverse event.
Time frame: Up to 44 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD5069 | Summary Statistics for Patient Diary Variables (Night Time) | Obs. with No asthma symptoms (Screening; n=52) | 9 Observations |
| AZD5069 | Summary Statistics for Patient Diary Variables (Night Time) | Obs. with No asthma symptoms (Period1; n=69) | 2 Observations |
| AZD5069 | Summary Statistics for Patient Diary Variables (Night Time) | Obs. with No asthma symptoms (Period2; n=70) | 10 Observations |