AZD1419 Ph2a study - INCONTRO

Study identifier:D2500C00003

ClinicalTrials.gov identifier:NCT02898662

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 2 Placebo-Controlled, Randomized, Double Blind, Adaptive Dose Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With Eosinophilic, Moderate to Severe Asthma

Medical condition

asthma

Phase

Phase 2

Healthy volunteers

Study drug

AZD1419, Placebo

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 99 Years

Date

Study Start Date: 12 Oct 2016

Primary Completion Date: 25 Sept 2018

Study Completion Date: 25 Sept 2018

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Oct 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

-Male and female patients 18 years and above
- Physician-diagnosed asthma requiring treatment with ICS and a long-acting beta agonist (LABA). Patients must have taken ICS plus LABA controller medication for at least 3 months prior to screening
- Pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% predicted
- Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception
- Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from the first dose of the IMP and until 1 month after the last dose of the IMP to prevent pregnancy in a partner
- Blood eosinophil levels ≥ 250 cells/μL at screening OR a history of blood eosinophil levels ≥ 250 cells/μL at any time in the preceding 2 years AND blood eosinophil levels ≥ 150 cells /μL at screening. The eosinophilia must be believed to be due to asthma and not have other known causes, e.g. helminth infection
- ACQ-5 score ≤1.5 at screening
- ACQ-5 score ≤0.75 at randomization
- Documentation of any of the following within 5 years prior to Visit 1:
• Proof of post-bronchodilator reversibility in FEV1 of ≥12% and ≥200 mL
• Proof of a positive response to a methacholine or histamine challenge (a decrease in FEV1 by 20% [PC20] at ≤8 mg/mL)
• Proof of positive response to mannitol challenge (a decrease in FEV1 by 15% [PD15] at ≤635 mg or a >10% decrease in FEV1 between consecutive doses)
• Proof of diurnal variability in PEF >20% over the course of 24 hours in at least
4 out of 7 consecutive days
If historical documentation is not available, proof of reversibility or a positive response to a methacholine, histamine or mannitol challenge or diurnal variation must be demonstrated according to above and documented during Visit 1

Exclusion Criteria

- Clinically significant lung disease other than asthma (eg, chronic obstructive pulmonary disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, active tuberculosis).
- History of autoimmune disease including but not limited to Wegener’s granulomatosis, system lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, multiple sclerosis, autoimmune thrombocytopenia, primary biliary cirrhosis or any other autoimmune disease considered clinically relevant by the investigator
- Ongoing allergen immunotherapy or plans to begin such therapy during the study period
- DLco ≤ 60% of the lower limit of normal
- Breast feeding, pregnancy or intention to become pregnant during the course of the study
- Changes in chest X-ray suggesting clinically significant parenchymal disease other than asthma

Location

Research Site

København NV, Denmark, 2400

Location

Research Site

Edelény, Hungary, 3780

Location

Research Site

Balassagyarmat, Hungary, 2660

Location

Research Site

Miskolc, Hungary, 3529

Location

Research Site

Farkasgyepü, Hungary, 8582

Location

Research Site

Odense C, Denmark, 5000

Location

Research Site

Hvidovre, Denmark, 2650

Location

Research Site

Naestved, Denmark, 4700

Arms	Assigned Interventions
Experimental: AZD1419 Dose adaption of AZD1419, 4 mg or 8 mg or 1 mg based on occurence of AE's	Drug: AZD1419 Inhaled AZD1419 administered at the clinic as once weekly inhalations with the I-neb® device. Start dose is 4 mg and dose adaptation is applied (downtitration to 1mg or uptitration to 8 mg or remain on 4 mg) based on appearance of flu like adverse events Other Name: NA
Placebo Comparator: Placebo Matching placebo	Drug: Placebo Inhaled Placebo administered at the clinic as once weekly inhalations with the I-neb® device. Start dose is Placebo 4 mg and dose adaptation is applied (downtitration to 1mg or uptitration to 8 mg or remain on 4 mg) based on appearance of flu like adverse events Other Name: NA

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted at 16 centers in 4 countries (Hungary, Poland, Denmark and Sweden) between 12 October 2016 and 25 September 2018. Participants with eosinophilic moderate to severe asthma on a maintenance treatment of controller inhaled corticosteroids (ICS) + long-acting β2 agonists (LABA) and no other controller medication were recruited.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study had a screening period (2-4 weeks), a 12-week dosing period and an observation period (up to 40 weeks). A total of 81 participants were randomized in this study to test the hypothesis that AZD1419 provided sustained asthma control in eosinophilic asthma participants after removal of ICS and LABA medication.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 milligrams (mg) AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 milligrams (mg) AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.

Placebo

Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Participant Flow: Overall Study

	AZD1419	Placebo
STARTED	40	41
Completed Treatment	25	29
COMPLETED	11	13
NOT COMPLETED	29	28
Adverse Event	1	0
Loss of asthma control	23	24
Withdrawal by Subject	4	1
Technical issue	0	1
Randomized in error	0	1
Subject decision	1	0
Unspecified	0	1

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The full analysis set (FAS) included all randomized participants who received any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.

Placebo

Baseline Measures

	AZD1419	Placebo	Total
Number of Participants [units: Participants]	40	41	81
Age Continuous [units: years] Mean ± Standard Deviation	57.4 ± 13.3	53.3 ± 15.4	55.3 ± 14.5
Sex: Female, Male [units: ]
Female	22	24	46
Male	18	17	35
Race/Ethnicity, Customized [units: ]
White	40	40	80
Other	0	1	1
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	0	1	1
Not Hispanic or Latino	40	40	80
Unknown or Not Reported	0	0	0

Outcome Measures

1. Primary Outcome Measure: Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Primary
Measure Name	Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis
Measure Description	LOAC was defined as any of the following: • Increase of asthma control questionnaire-5 (ACQ-5) to ≥ 1.5. • ≥ 30% reduction in morning peak expiratory flow (PEF) from baseline on 2 consecutive days. • ≥ 6 additional reliever inhalations of short-acting β agonist (SABA) in a 24-hour period relative to baseline on 2 consecutive days. • Exacerbation requiring systemic corticosteroids as decided by Investigator. Time to LOAC was calculated as start date of first LOAC – date of randomization + 1. Start date of LOAC was latest date that 1 of the 4 criteria were satisfied immediately prior to the exacerbation start date, provided no more than 7 days between LOAC and exacerbation start date. Time to LOAC was displayed using a Kaplan-Meier plot and the outcome measure is presented as number of participants with events. Cox regression analysis was used to compare treatments.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	40	41
Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis [units: participants]	24	24

Statistical Analysis 1 for Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis

Groups^[1]	All groups
Method^[3]	Regression, Cox
P-Value^[4]	0.5722
Hazard Ratio (HR)^[5]	1.05
95% Confidence Interval	( 0.59 to 1.87 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for time to LOAC. Cox regression model analysis with age and gender included as covariates.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	1-sided p-value
[5]	Other relevant estimation information:
	Hazard ratio < 1 favours AZD1419 over placebo.

2. Secondary Outcome Measure: Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis
Measure Description	LOAC was defined as any of the following: • Increase of ACQ-5 to ≥ 1.5. • ≥ 30% reduction in morning PEF from baseline on 2 consecutive days. • ≥ 6 additional reliever inhalations of SABA in a 24-hour period relative to baseline on 2 consecutive days. • Exacerbation requiring systemic corticosteroids. Number of participants experiencing LOAC up to Week 52 is presented. A generalized linear model based on a generalized estimating equation was used to compare treatments.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	40	41
Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis [units: participants]	24	24

Statistical Analysis 1 for Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis

Groups^[1]	All groups
Method^[3]	Other [Generalized estimating equation analysis]
P-Value^[4]	0.2006
Odds Ratio (OR)^[5]	1.86
95% Confidence Interval	( 0.72 to 4.79 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for participants experiencing LOAC. Odds ratio was estimated using a generalized linear model based on a generalized estimating equation approach fitting treatment, visit and age and gender as covariates.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks
Measure Description	In the ACQ-5 questionnaire, participants were asked to recall the status of their asthma during the previous week with regards to symptoms. The questionnaire included the items: • Awoken at night by asthma symptoms. • Severity of asthma symptoms in the morning. • Limitation of daily activities due to asthma. • Shortness of breath. • Wheeze. The ACQ-5 score was computed as the un-weighted mean of responses to the 5 items, measured on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). A lower score indicated a better outcome. If ACQ-5 reached a value of 1.5 or more, the participant was reported as having LOAC. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline ACQ-5, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study. Only participants with data available for analysis are presented.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	37	41
Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks [units: scores on a scale] Least Squares Mean (Standard Error)	0.56 (0.07)	0.59 (0.07)

Statistical Analysis 1 for Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.8166
Other^[5]	-0.02
95% Confidence Interval	( -0.22 to 0.17 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for ACQ-5 score. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks
Measure Description	Asthma symptoms during night-time and daytime were recorded by the participant each morning and evening in the Asthma Daily Diary. Symptoms were recorded using a 4-point response scale, which ranged from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in the evening), night-time score (recorded in the morning), and total score were calculated separately. The daily asthma symptom total score was calculated by taking the sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline asthma daily diary weekly average, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study. Only participants with data available for analysis are presented.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	38	41
LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks [units: scores on a scale] Least Squares Mean (Standard Error)	0.79 (0.10)	0.82 (0.10)

Statistical Analysis 1 for LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.8412
Other^[5]	-0.03
95% Confidence Interval	( -0.32 to 0.26 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for asthma daily diary score. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52 [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52
Measure Description	Moderate exacerbation was defined as a temporary increase in maintenance therapy to prevent a severe event supported by sustained (≥ 2 day) worsening in at least 1 key control metric ie, asthma score, reliever medication use, night time awakening or morning PEF. Severe exacerbation was defined as a worsening in asthma symptoms and: • Use of systemic corticosteroids for at least 3 days and/or • An unscheduled or emergency room visit due to asthma symptoms requiring systemic corticosteroids and/or • An in-patient hospitalization due to asthma requiring systemic corticosteroids. Time to moderate or severe asthma exacerbation was calculated as start date of first moderate or severe exacerbation – date of randomization + 1. Time to moderate or severe asthma exacerbation was displayed using a Kaplan-Meier plot and the outcome measure is presented as number of participants with events.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	40	41
Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52 [units: participants]	13	16

Statistical Analysis 1 for Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52

Groups^[1]	All groups
Method^[3]	Regression, Cox
P-Value^[4]	0.5477
Hazard Ratio (HR)^[5]	0.80
95% Confidence Interval	( 0.38 to 1.67 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for time to moderate or severe asthma exacerbation. Cox regression model analysis with age and gender included as covariates.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	Hazard ratio < 1 favours AZD1419 over placebo.

Statistical Analysis 2 for Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52

Groups^[1]	All groups
Method^[3]	Other [Generalized estimating equation analysis]
P-Value^[4]	0.7294
Odds Ratio (OR)^[5]	0.88
95% Confidence Interval	( 0.41 to 1.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for participants with moderate or severe asthma exacerbation. Odds ratio was estimated using a generalized linear model based on a generalized estimating equation approach fitting treatment and visit as covariates.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Percentage of Participants Using Reliever Medication up to Week 52 [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	Percentage of Participants Using Reliever Medication up to Week 52
Measure Description	The use of SABAs was allowed as rescue medication (reliever bronchodilator) throughout the study. Reliever medication use was captured in the Asthma Daily Diary twice daily (morning and evening), recorded as the number of inhaler puffs. The number of inhalations (puffs) per day was calculated as: number of night inhaler puffs + number of day inhaler puffs. Percentage of participants using reliever medication (SABA) up to Week 52 is presented.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	40	41
Percentage of Participants Using Reliever Medication up to Week 52 [units: percentage of participants]	100	100

No statistical analysis provided for Percentage of Participants Using Reliever Medication up to Week 52

7. Secondary Outcome Measure: LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks
Measure Description	Lung function was assessed by pre- and post-BD FEV1 which was measured by spirometry. To ensure quality control, all spirometry measurements were reviewed to ensure that they met American Thoracic Society / European Respiratory Society criteria for acceptability. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline FEV1 (pre- or post-BD, as applicable), visit and treatment-by-visit with participant as random effects, and age and gender as covariates. Baseline was the last non-missing measurement recorded prior to randomization.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study. Only participants with data available for analysis are presented.

Reporting Groups

	Description
AZD1419	Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
Placebo	Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	37	39
LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks [units: Liters] Least Squares Mean (Standard Error)
pre-BD FEV1	2.24 (0.05)	2.18 (0.05)
post-BD FEV1	2.36 (0.05)	2.39 (0.05)

Statistical Analysis 1 for LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.3764
Other^[5]	0.06
95% Confidence Interval	( -0.08 to 0.20 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for pre-BD FEV1. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.7013
Other^[5]	-0.03
95% Confidence Interval	( -0.17 to 0.11 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for post-BD FEV1. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: LS Mean Total PEF (Weekly) Over 52 Weeks [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	LS Mean Total PEF (Weekly) Over 52 Weeks
Measure Description	Morning and evening PEF measurements were recorded by the participant on a daily basis and then averaged over the week. The weekly average total PEF was calculated by taking the sum of the average of the weekly morning mean and weekly evening mean. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline PEF, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study. Only participants with data available for analysis are presented.

Reporting Groups

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	38	41
LS Mean Total PEF (Weekly) Over 52 Weeks [units: Liters/minute] Least Squares Mean (Standard Error)	325.33 (5.77)	325.65 (5.79)

Statistical Analysis 1 for LS Mean Total PEF (Weekly) Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.9686
Other^[5]	-0.32
95% Confidence Interval	( -16.54 to 15.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for PEF. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks [ Time Frame: Baseline (Week 0) up to Week 52 ]

Measure Type	Secondary
Measure Name	LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks
Measure Description	FeNO measurements were taken at home by participants every second day. The weekly average FeNO was based on the average of measurements taken at home for a specific week. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline FeNO, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization.
Time Frame	Baseline (Week 0) up to Week 52
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study. Only participants with data available for analysis are presented.

Reporting Groups

Description

AZD1419

Placebo

Measured Values

	AZD1419	Placebo
Number of Participants Analyzed [units:participants]	35	38
LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks [units: parts per billion] Least Squares Mean (Standard Error)	33.26 (2.33)	35.28 (2.33)

Statistical Analysis 1 for LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks

Groups^[1]	All groups
Method^[3]	Other [Repeated measures analysis]
P-Value^[4]	0.5403
Other^[5]	-2.02
95% Confidence Interval	( -8.55 to 4.52 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between groups for FeNO. Repeated measures analysis.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	2-sided p-value
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	From first dose of IP (Week 0) up to Week 52.
Additional Description	The safety analysis set included all participants who received any IP.

Reporting Groups

Description

AZD1419

Placebo

Serious Adverse Events

AZD1419

Placebo

Total, serious adverse events

# participants affected / at risk

3/40 (7.50%)

1/41 (2.44%)

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/40 (2.50%)

0/41 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Trigger finger¹,^†

# participants affected / at risk

1/40 (2.50%)

0/41 (0.00%)

# events

Renal and urinary disorders

Calculus urinary¹,^†

# participants affected / at risk

0/40 (0.00%)

1/41 (2.44%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary eosinophilia¹,^†

# participants affected / at risk

1/40 (2.50%)

0/41 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.0

Other Adverse Events

Time Frame	From first dose of IP (Week 0) up to Week 52.
Additional Description	The safety analysis set included all participants who received any IP.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

Description

AZD1419

Placebo

Other Adverse Events

AZD1419

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

22/40 (55.00%)

11/41 (26.83%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

0/40 (0.00%)

3/41 (7.32%)

# events

General disorders and administration site conditions

Chills¹,^†

# participants affected / at risk

6/40 (15.00%)

1/41 (2.44%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

10/40 (25.00%)

1/41 (2.44%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

5/40 (12.50%)

6/41 (14.63%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

6/40 (15.00%)

1/41 (2.44%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

6/40 (15.00%)

4/41 (9.76%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

5/40 (12.50%)

0/41 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.0

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	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.
	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 more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+1 302 885 1180
E-mail:	[email protected]

Documents available

Protocol
Download
Statistical Analysis Plan (SAP)
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Protocol

Statistical Analysis Plan (SAP)

Trial Results Summaries