Trial Outcomes & Findings for AZD1419 Ph2a Study (NCT NCT02898662)

NCT ID: NCT02898662

Last Updated: 2019-11-06

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 81 participants
• Primary outcome timeframe: Baseline (Week 0) up to Week 52
• Results posted on: 2019-11-06

Participant Flow

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.

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.

Participant milestones

Measure	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.
Overall Study STARTED	40	41
Overall Study Completed Treatment	25	29
Overall Study COMPLETED	11	13
Overall Study NOT COMPLETED	29	28

Reasons for withdrawal

Measure	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.
Overall Study Adverse Event	1	0
Overall Study Loss of asthma control	23	24
Overall Study Withdrawal by Subject	4	1
Overall Study Technical issue	0	1
Overall Study Randomized in error	0	1
Overall Study Subject decision	1	0
Overall Study Other	0	1

Baseline Characteristics

AZD1419 Ph2a Study

Baseline characteristics by cohort

Measure	AZD1419 n=40 Participants 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 n=41 Participants 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.	Total n=81 Participants Total of all reporting groups
Age, Continuous	57.4 years STANDARD_DEVIATION 13.3 • n=5 Participants	53.3 years STANDARD_DEVIATION 15.4 • n=7 Participants	55.3 years STANDARD_DEVIATION 14.5 • n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	24 Participants n=7 Participants	46 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	40 Participants n=5 Participants	40 Participants n=7 Participants	80 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	40 Participants n=5 Participants	40 Participants n=7 Participants	80 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

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.

Outcome measures

Measure	AZD1419 n=40 Participants 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 n=41 Participants 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.
Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis	24 Participants	24 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

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.

Outcome measures

Measure	AZD1419 n=40 Participants 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 n=41 Participants 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.
Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis	24 Participants	24 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: 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.

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.

Outcome measures

Measure	AZD1419 n=37 Participants 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 n=41 Participants 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.
Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks	0.56 scores on a scale Standard Error 0.07	0.59 scores on a scale Standard Error 0.07

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: 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.

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.

Outcome measures

Measure	AZD1419 n=38 Participants 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 n=41 Participants 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.
LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks	0.79 scores on a scale Standard Error 0.10	0.82 scores on a scale Standard Error 0.10

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

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.

Outcome measures

Measure	AZD1419 n=40 Participants 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 n=41 Participants 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.
Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52	13 Participants	16 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: The FAS included all randomized participants who received any IP, irrespective of their protocol adherence and continued participation in the study.

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.

Outcome measures

Measure	AZD1419 n=40 Participants 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 n=41 Participants 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.
Percentage of Participants Using Reliever Medication up to Week 52	100 percentage of participants	100 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: 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.

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.

Outcome measures

Measure	AZD1419 n=37 Participants 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 n=39 Participants 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.
LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks post-BD FEV1	2.36 Liters Standard Error 0.05	2.39 Liters Standard Error 0.05
LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks pre-BD FEV1	2.24 Liters Standard Error 0.05	2.18 Liters Standard Error 0.05

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: 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.

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.

Outcome measures

Measure	AZD1419 n=38 Participants 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 n=41 Participants 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.
LS Mean Total PEF (Weekly) Over 52 Weeks	325.33 Liters/minute Standard Error 5.77	325.65 Liters/minute Standard Error 5.79

SECONDARY outcome

Timeframe: Baseline (Week 0) up to Week 52

Population: 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.

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.

Outcome measures

Measure	AZD1419 n=35 Participants 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 n=38 Participants 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.
LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks	33.26 parts per billion Standard Error 2.33	35.28 parts per billion Standard Error 2.33

Adverse Events

AZD1419

Serious events: 3 serious events

Other events: 22 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	AZD1419 n=40 participants at risk 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 n=41 participants at risk 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.
Musculoskeletal and connective tissue disorders Back pain	2.5% 1/40 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	0.00% 0/41 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Musculoskeletal and connective tissue disorders Trigger finger	2.5% 1/40 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	0.00% 0/41 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Renal and urinary disorders Calculus urinary	0.00% 0/40 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	2.4% 1/41 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Respiratory, thoracic and mediastinal disorders Pulmonary eosinophilia	2.5% 1/40 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	0.00% 0/41 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.

Other adverse events

Measure	AZD1419 n=40 participants at risk 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 n=41 participants at risk 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.
Gastrointestinal disorders Nausea	0.00% 0/40 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	7.3% 3/41 • Number of events 4 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
General disorders Chills	15.0% 6/40 • Number of events 13 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	2.4% 1/41 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
General disorders Pyrexia	25.0% 10/40 • Number of events 22 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	2.4% 1/41 • Number of events 1 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Infections and infestations Nasopharyngitis	12.5% 5/40 • Number of events 5 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	14.6% 6/41 • Number of events 8 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Musculoskeletal and connective tissue disorders Myalgia	15.0% 6/40 • Number of events 13 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	2.4% 1/41 • Number of events 2 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Nervous system disorders Headache	15.0% 6/40 • Number of events 9 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	9.8% 4/41 • Number of events 10 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.5% 5/40 • Number of events 9 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.	0.00% 0/41 • From first dose of IP (Week 0) up to Week 52. The safety analysis set included all participants who received any IP.

Additional Information

Global Clinical Lead

AstraZeneca

Phone: +1 302 885 1180

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place