Efficacy and Safety of Inhaled AZD1402 Administered for Four Weeks in Adults With Asthma on Medium-to-High Dose Inhaled Corticosteroids

Phase 2

Terminated

Conditions: Asthma

Interventions: Drug: AZD1402
Drug: Placebo
Drug: Short acting beta agonist (SABA) (rescue medication)
Drug: Run-in medications (ICS-LABA combination)

Registration Number: NCT04643158

Lead Sponsor: AstraZeneca

Brief Summary: This is a randomised, placebo-controlled, double-blinded, multi-centre, 2-part study to assess the efficacy and safety of inhaled AZD1402. Part 1 will be performed in a Lead-in Cohort for each dose level to evaluate the safety and pharmacokinetics (PK) in a population with asthma controlled on medium dose inhaled corticosteroids (ICS)-long acting beta agonists (LABA) before progressing to dosing in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA in Part 2. The study will recruit participants receiving treatment with medium dose ICS with LABA for Part 1 and participants receiving treatment with medium-to-high dose ICS with LABA for Part 2 (separate inhalers or combination product).

Part 2 will be initiated following evaluation of safety and PK at the relevant dose level in Part 1a. The entire study period for each participant in both Parts 1 and 2, is approximately 3.5 months; a 2-week Screening Period, a 4 week Run-in Period, 4 weeks of Treatment Period, and 4 weeks of Follow-Up Period.

Detailed Description: Part 1 of the study will be randomised, double blind, placebo-controlled, and conducted in parallel for the 2 lower dose levels (Part 1a) followed by an unblinded safety review and escalation to the highest dose (Part 1b) dependent on the outcome of the safety review.

Part 1a will consist of 30 participants who will be randomised 1:1:1 to receive 1 of the 2 lower AZD1402 dry power inhaler (DPI) doses (Dose 1 or Dose 2) or placebo in parallel. Part 1b will consist of 15 participants who will be randomised 2:1 to receive the highest AZD1402 DPI dose (Dose 3) or placebo.

Part 1a Lead-in Cohort

* AZD1402 Dose 1

* AZD1402 Dose 2

* Placebo

Part 1b Lead-in Cohort

* AZD1402 Dose 3

* Placebo

Part 2 will be randomised, double blind, placebo controlled and will include approximately 165 participants randomised 2:1 (active to placebo) to evaluate 2 inhaled dose levels of AZD1402 versus placebo.

Part 2 will be started after the unblinded safety review for Part 1a. Part 2 will include:

* AZD1402 Dose 1

* AZD1402 Dose 2

* Placebo

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 72

Inclusion Criteria

Participants who have a documented clinical diagnosis of asthma for ≥ 12 months before Visit 1.
Participants who are able to perform acceptable pulmonary function testing for FEV1.
Participants who are able to demonstrate the ability to use the study inhalation device properly.
Male participants must be surgically sterile or agree to use highly-effective contraceptives.
All female participants must have a negative serum pregnancy test at Screening. Female participants of non-childbearing potential, Female participants of childbearing potential must have a negative urine pregnancy test before the administration of first dose of study intervention and must agree to use a highly-effective method of birth control.
Participant is a non smoker or an ex-smoker with a total smoking history of less than 10 pack-years.
Only for Part 1: Documented treatment with medium dose ICS with LABA for at least 6 months prior to Screening. ICS and LABA must be on a stable dose for at least 3 months prior to Screening, during Screening and Run-in Periods and may be contained in a combination product or separate inhaler. No asthma exacerbations in last 12 months requiring oral or intravenous (IV) steroids or hospitalisation/ emergency room visit due to asthma. Pre-bronchodilator FEV1 ≥ 70% predicted at Screening and start of Run-in. Asthma Control Questionnaire 6 score of ≤ 1.0 at Screening and start of Run-in.
Only for Part 2: Documented evidence of asthma. Documented treatment with medium-to-high dose ICS-LABA for at least 6 months prior to Screening. ICS and LABA must be on a stable dose for at least 4 weeks prior to Screening, during Screening and Run-in Periods. If on asthma maintenance controller medications in addition to ICS-LABA, the dose of the additional controller medications must be stable for at least 4 weeks prior to Screening, during Screening and Run-in Periods. Pre bronchodilator FEV1 of 40% to 85% (inclusive) predicted at Screening and start of Run-in. Blood eosinophil count of ≥ 150 cells/μL and FeNO ≥ 25 ppb at Screening. Asthma Control Questionnaire 6 score ≥ 1.5 at Screening.

Specific Randomisation Criteria at Visit 3

For Part 1: Pre-bronchodilator FEV1 ≥ 70% predicted. At least 70% compliance with usual asthma controller ICS-LABA during Run-in Period (from Visit 2 to Visit 3) based on daily electronic diary (e-Diary). Minimum 80% compliance with ePRO completion. Asthma Control Questionnaire 6 score of ≤ 1.0. C-reactive protein < 5 mg/L on Day -1.
For Part 2: Pre-bronchodilator FEV1 of 40% to 85% (inclusive) predicted. Asthma Control Questionnaire 6 score of ≥ 1.5. At least 70% compliance with usual asthma controller ICS-LABA during Run-in Period from (Visit 2 to Visit 3) based on daily e-Diary. Minimum 70% compliance with ePRO completion. C-reactive protein < 10 mg/L at Visit 2. A FeNO of ≥ 25 ppb.

Exclusion Criteria

Women who are pregnant or breastfeeding, or who are planning to become pregnant during the study.
Known or suspected hypersensitivity including anaphylaxis/anaphylactoid reaction following any biologic therapy, or known history of drug hypersensitivity to any component of the study intervention formulation.
Evidence of any active clinically important pulmonary disease other than asthma, within 5 years at screening.
History of pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
History or clinical suspicion of any clinically relevant or active disease or disorder.
History of severe COVID-19 infection requiring hospitalisation within the last 12 months or clinical history compatible with long COVID (symptoms beyond 12 weeks of acute infection).
Confirmed symptomatic COVID-19 infection during Screening, Run-in or prior to randomisation.
Current malignancy or history of malignancy.
Significant history of recurrent or ongoing 'dry eye'.
Diagnosis of Sjögren's syndrome.
High risk of infection suggesting abnormal immune function.
History of, or known significant infection or positivity at Screening period, including hepatitis B or C, or human immunodeficiency virus (HIV).
Evidence of active tuberculosis.
Clinically significant lower respiratory tract infection not resolved within 4 weeks prior to Screening and during Run-in.
Clinically significant upper respiratory tract infection at Screening and during Run-in.
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained.
Any clinically important ECG abnormalities.
Any clinically significant cardiac disease.
Uncontrolled hypertension.
History of life-threatening asthma attack or asthma attack requiring ventilation.
Part 2 only: History of 3 or more severe asthma exacerbations.
Daily rescue use of SABA ≥ 8 puffs for ≥ 3 consecutive days at any time during Run-in Period, before randomisation.
History of anaphylaxis.
Any clinically significant abnormalities in haematology.
Alanine aminotransferase or AST level ≥ 3 times the upper limit of normal (ULN), confirmed by repeated testing during Screening Period.
History of, drug or alcohol abuse within the past 2 years prior to Screening.
Planned in-patient surgery, major dental procedure or hospitalisation during the study.
Prior/Concomitant Therapy: Systemic corticosteroid use, AZD1402, marketed or investigational biologicals such as monoclonal antibodies or chimeric biomolecules, investigational nonbiologic drug within 60 days prior to Screening and during Run-in, any immunosuppressive therapy, Live or attenuated vaccine within 4 weeks of Screening and during Run-in, Receipt of COVID-19 vaccine (vaccine or booster dose) within 30 days prior to randomisation, Immunoglobulin or blood products within 4 weeks of Screening and during Run-in, Any immunotherapy within 3 months of Screening and during Run-in.
Part 1 only: Additional asthma maintenance controller medications in addition to ICS-LABA (eg, leukotriene receptor inhibitors, theophylline, LAMA, chromones) within 3 months of Screening period and during Run-in.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1 and Part 2: AZD1402 Dose 1	AZD1402	Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Part 1 and Part 2: AZD1402 Dose 1	Short acting beta agonist (SABA) (rescue medication)	Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Part 1 and Part 2: AZD1402 Dose 1	Run-in medications (ICS-LABA combination)	Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Part 1 and Part 2: AZD1402 Dose 2	AZD1402	Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Part 1 and Part 2: AZD1402 Dose 2	Short acting beta agonist (SABA) (rescue medication)	Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Part 1 and Part 2: AZD1402 Dose 2	Run-in medications (ICS-LABA combination)	Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Part 1: AZD1402 Dose 3	AZD1402	Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Part 1: AZD1402 Dose 3	Short acting beta agonist (SABA) (rescue medication)	Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Part 1: AZD1402 Dose 3	Run-in medications (ICS-LABA combination)	Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Part 1 and Part 2: Placebo	Placebo	Randomised participants will receive oral inhalation of matching placebo via DPI.
Part 1 and Part 2: Placebo	Short acting beta agonist (SABA) (rescue medication)	Randomised participants will receive oral inhalation of matching placebo via DPI.
Part 1 and Part 2: Placebo	Run-in medications (ICS-LABA combination)	Randomised participants will receive oral inhalation of matching placebo via DPI.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Adverse Events (AEs)	From Screening (Week -6) until Follow-up (Day 56)	The safety and tolerability of AZD1402 compared to placebo at different dose levels in adults with asthma controlled on medium dose ICS-LABA was evaluated.
Part 2: Change From Baseline in Pre-bronchodilator FEV1	Baseline and Week 4	The efficacy of inhaled AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was investigated.
Part 1: Change From Baseline in High-sensitivity C-reactive Protein (hsCRP)	Baseline, Day 12, Day 16, and Day 56	The safety and tolerability of AZD1402 compared to placebo at different dose levels in adults with asthma controlled on medium dose ICS-LABA was evaluated.
Part 1: Change From Baseline in FEV1 In-clinic Spirometry	Baseline, Day 1, Day 7, Day 14, Day 28, and Day 56	The safety and tolerability of AZD1402 compared to placebo at different dose levels in adults with asthma controlled on medium dose ICS-LABA was evaluated.
Part 1: Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) (In-clinic)	Baseline, Day 1, Day 7, Day 14, Day 28, and Day 56	The safety and tolerability of AZD1402 compared to placebo at different dose levels in adults with asthma controlled on medium dose ICS-LABA was evaluated.

Secondary Outcome Measures

Name	Time	Method
Part 1 and Part 2: Antidrug Antibodies (ADA) Titers	Day 1 until Day 56	ADA-positive samples were tested to investigate the immunogenicity of AZD1402.
Part 1 and Part 2: Maximum Observed Serum (Peak) Drug Concentration (Cmax)	Day 1 until Day 56	The pharmacokinetic (PK) profile of AZD1402 was investigated.
Part 1 and Part 2: Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t1/2λz)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Area Under Plasma Concentration-time Curve in the Dosing Interval τ (AUCτ)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Observed Lowest Drug Concentration Reached Before the Next Dose is Administered (Pre-dose) (Ctrough)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Time of Last Observed (Quantifiable) Concentration (Tlast)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Accumulation Ratio for AUCτ (Rac AUC)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 1 and Part 2: Accumulation Ratio for Cmax (Rac Cmax)	Day 1 until Day 56	The PK profile of AZD1402 was investigated.
Part 2: Change From Baseline in Asthma Control Questionnaire-6 (ACQ-6) at Week 4 and Average Over the Treatment Period	Baseline, Week 4	The efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA was further investigated. The ACQ was developed to measure asthma control. In the ACQ-6, participants were asked to recall how their asthma had been during the previous week by responding to one bronchodilation use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Higher scores indicated a worse outcome. The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.75 and ≤ 1.5 indicate partly controlled asthma, and scores \> 1.5 indicate not well-controlled asthma. Individual changes of at least 0.5 are considered clinically meaningful.
Part 2: Participants With a Decrease in ACQ 6 Score of ≥ 0.5 From Baseline to Week 4	Baseline, Week 4	The efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA was further investigated. The ACQ was developed to measure asthma control. In the ACQ-6, participants were asked to recall how their asthma had been during the previous week by responding to one bronchodilation use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Higher scores indicated a worse outcome. The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.75 and ≤ 1.5 indicate partly controlled asthma, and scores \> 1.5 indicate not well-controlled asthma. Individual changes of at least 0.5 are considered clinically meaningful.
Part 2: Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the Treatment Period	Baseline, 4 weeks	The efficacy of AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was further investigated. Peak expiratory flow was measured by the participants at home using a peak flow meter.
Part 2: Change From Baseline in Average Evening PEF Over the Treatment Period	Baseline, 4 weeks	The efficacy of AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was further investigated. Peak expiratory flow was measured by the participants at home using a peak flow meter.
Part 2: Change From Baseline in Daily Average Asthma Symptom Score (AM/PM) Over the Treatment Period	Baseline, 4 weeks	The efficacy of AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was further investigated. Severity scores for asthma symptoms were recorded twice daily in the morning and evening and documented in an e-Diary. Asthma symptom scores during night-time and day-time were assessed by the participant each morning and evening according to the following scoring system: 0: You have no asthma symptoms. 1: You are aware of your asthma symptoms but you can easily tolerate the symptoms. 2: Your asthma is causing you enough discomfort to cause problems with normal activities (or with sleep). 3: You are unable to do your normal activities (or to sleep) because of your asthma. Higher scores indicated worse outcome.
Part 2: Change From Baseline in Pre-bronchodilator FEV1 Average Over the 4-week Treatment Period	Baseline and Week 4	The efficacy of AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was further investigated.
Part 2: Change From Baseline in FeNO (In-clinic) at Week 4 and Average Over the Treatment Period	Baseline, Week 4	The effect of AZD1402 compared to placebo on airway inflammation in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was investigated. To investigate the effect of AZD1402 on airway inflammation, the measurement of FeNO was performed in accordance with ATS/ERS guidelines. Standardised conditions with regard to exhalation flow rate and duration of exhalation were followed such that plateau definition could be evaluated over a minimum of 3 seconds.
Part 2: Number of Participants With Adverse Events (AEs)	From Screening (Week -6) until Follow-up (Day 56)	The safety and tolerability of AZD1402 compared to placebo in adults with asthma uncontrolled on medium-to-high dose ICS-LABA was evaluated.