Distribution of Neutrophils in Bronchial Mucosal Tissue in Asthma Patients Before and After 4 Weeks Treatment With AZD 5069

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01890148
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 5
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

Distribution of neutrophils in bronchial mucosal tissue in asthma patients before and after 4 wk treatment with AZD 5069

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: AZD5069	Phase 1

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: An Explorative Investigation to Study the Relationship and Distribution of Neutrophils in Bronchial Mucosal Tissue, Induced Sputum and Blood After Administration of 45 mg BD AZD 5069 for 4 Weeks to Patients With Moderate Persistent Neutrophilic Asthma
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 oral BD administration of 45 mg AZD5069	Drug: AZD5069; oral BD administration of 45 mg AZD5069

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. Number of Adverse Events [Up to 40 days]

   Summary of number of adverse events (safety set)

8. Number of Participants With Adverse Events [Up to 40 days]

   Summary of number of participants with adverse events (safety set)

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Grosshansdorf		Germany

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Kai Richter, MSD, Astrazeneca Sweden
• Principal Investigator: Klaus F Rabe, MD, Lung Clinic Grosshansdorf Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01890148
• Other Study ID Numbers: D3551C00003
• First Posted: Jul 1, 2013
• Last Update Posted: Feb 25, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by AstraZeneca: Asthma
• Additional relevant MeSH terms: Asthma

Study Results

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.

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Period Title: Overall Study
STARTED	5
COMPLETED	4
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Overall Participants	5
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	46.8 (10.3)
Sex: Female, Male (Count of Participants)
Female	1 20%
Male	4 80%

Outcome Measures

1. Primary Outcome

Title	Summary for Change From Baseline of Mean Global Semi-quantitative Score Values for Neutrophils in Bronchial Biopsies
Description	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

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
Mean (Standard Deviation) [Units on a scale]	-1.21 (0.54)

2. Primary Outcome

Title	Summary for Change From Baseline Neutrophils in Sputum
Description	Change from Baseline reflects the Day 8, Day22 and Day29 minus the baseline value.
Time Frame	Baseline, Day 8, Day 22 and Day29

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
Day 8	-4.294 (3.062)
Day 22	-6.670 (3.751)
Day 29	-3.849 (1.861)

3. Primary Outcome

Title	Summary for Change From Baseline Neutrophil Cell Counts in Blood
Description	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

Outcome Measure Data

Analysis Population Description

PD Analysis

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
Day 2	-2.517 (0.420)
Day 8	-1.494 (0.559)
Day 15	-1.985 (0.425)
Day 22	-1.658 (0.237)
Day 29	-1.178 (1.375)
Day 34	-0.306 (0.200)

4. Secondary Outcome

Title	Summary for Change From Baseline for IL-8 by Type of Sample
Description	Change from baseline reflects the Day 29 value minus the baseline value.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
IL-8 in Serum	46.88 (34.13)
IL-8 in Sputum	5780.75 (3763.83)

5. Secondary Outcome

Title	Summary for Change From Baseline for GRO-alpha by Type of Sample
Description	Change from baseline reflects the Day 29 value minus the baseline value.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

PD analysis set

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
GRO-alpha in Serum	179.75 (98.20)
GRO-alpha in Sputum	7352.50 (22373.99)

6. Secondary Outcome

Title	Summary for Change From Baseline for MMP-9 by Type of Sample
Description	Change from baseline reflects the Day 29 value minus the baseline value.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

PD analysis

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
MMP-9 in Serum	-157.75 (289.76)
MMP-9 in Sputum	-80.75 (178.55)

7. Secondary Outcome

Title	Summary Statistics for AUC0-4hrs on Day 29/ Visit T7 (PK Analysis Set)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	3
Geometric Mean (Standard Error) [h*nmol/L]	8571.72 (2421.99)

8. Secondary Outcome

Title	Summary Statistics for Cmin on Day 29/ Visit T7 (PK Analysis Set)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	4
Geometric Mean (Standard Error) [nmol/L]	466.92 (272.3)

9. Secondary Outcome

Title	Summary Statistics for Cmax on Day 29/ Visit T7 (PK Analysis Set)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	3
Geometric Mean (Standard Error) [nmol/L]	3565.76 (762.84)

10. Secondary Outcome

Title	Number of Adverse Events
Description	Summary of number of adverse events (safety set)
Time Frame	Up to 40 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	5
Total number of unique AEs	10
Total number of AEs	11
Total number of SAEs	0

11. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Summary of number of participants with adverse events (safety set)
Time Frame	Up to 40 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	5
Total number of subjects with at least one AE	4 80%
Number of subjects withdrawn from study due to AE	1 20%

12. Secondary Outcome

Title	Summary Statistics for Patient Diary Variables (Day Time)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	5
Measure Observation	197
Obs. with No asthma symptoms (Screening; n=55)	6
Obs. with No asthma symptoms (Period1; n=71)	7
Obs. with No asthma symptoms (Period2; n=71)	7

13. Secondary Outcome

Title	Summary Statistics for Patient Diary Variables (Night Time)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
Measure Participants	5
Measure observations	191
Obs. with No asthma symptoms (Screening; n=52)	9
Obs. with No asthma symptoms (Period1; n=69)	2
Obs. with No asthma symptoms (Period2; n=70)	10

Adverse Events

Arm/Group Title	AZD5069
Arm/Group Description	AZD5069 45mg oral twice daily (BID)
All Cause Mortality
	AZD5069
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AZD5069
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	AZD5069
	Affected / at Risk (%)	# Events
Total	4/5 (80%)
Gastrointestinal disorders
Toothache	1/5 (20%)
Investigations
Neutropil count decreased	1/5 (20%)
Musculoskeletal and connective tissue disorders
Back pain	2/5 (40%)
Nervous system disorders
Syncope	1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	1/5 (20%)	1
Dyspnoea	1/5 (20%)	1
Obstructive airways	1/5 (20%)	1
Oropharyngeal pain	1/5 (20%)	1
Vascular disorders
Hypertension	1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.