A Two-part Phase IIa Randomised, Double-blind, Placebo-controlled, Dose-ranging, Multi-centre Study to Assess Efficacy and Safety of Inhaled AZD1402 Administered as a Dry Powder for Four Weeks in Adults With Asthma on Medium-to-High Dose Inhaled Corticosteroids
Overview
- Phase
- Phase 2
- Intervention
- AZD1402
- Conditions
- Asthma
- Sponsor
- AstraZeneca
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- Part 1: Number of Participants With Adverse Events (AEs)
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants who have a documented clinical diagnosis of asthma for ≥ 12 months before Visit
- •Participants who are able to perform acceptable pulmonary function testing for FEV
- •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.
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.
Arms & Interventions
Part 1 and Part 2: AZD1402 Dose 1
Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Intervention: AZD1402
Part 1 and Part 2: AZD1402 Dose 1
Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Intervention: Short acting beta agonist (SABA) (rescue medication)
Part 1 and Part 2: AZD1402 Dose 1
Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI.
Intervention: Run-in medications (ICS-LABA combination)
Part 1 and Part 2: AZD1402 Dose 2
Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Intervention: AZD1402
Part 1 and Part 2: AZD1402 Dose 2
Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Intervention: Short acting beta agonist (SABA) (rescue medication)
Part 1 and Part 2: AZD1402 Dose 2
Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI.
Intervention: Run-in medications (ICS-LABA combination)
Part 1: AZD1402 Dose 3
Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Intervention: AZD1402
Part 1: AZD1402 Dose 3
Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Intervention: Short acting beta agonist (SABA) (rescue medication)
Part 1: AZD1402 Dose 3
Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI.
Intervention: Run-in medications (ICS-LABA combination)
Part 1 and Part 2: Placebo
Randomised participants will receive oral inhalation of matching placebo via DPI.
Intervention: Placebo
Part 1 and Part 2: Placebo
Randomised participants will receive oral inhalation of matching placebo via DPI.
Intervention: Short acting beta agonist (SABA) (rescue medication)
Part 1 and Part 2: Placebo
Randomised participants will receive oral inhalation of matching placebo via DPI.
Intervention: Run-in medications (ICS-LABA combination)
Outcomes
Primary Outcomes
Part 1: Number of Participants With Adverse Events (AEs)
Time Frame: 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
Time Frame: 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)
Time Frame: 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
Time Frame: 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)
Time Frame: 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 Outcomes
- Part 1 and Part 2: Antidrug Antibodies (ADA) Titers(Day 1 until Day 56)
- Part 1 and Part 2: Maximum Observed Serum (Peak) Drug Concentration (Cmax)(Day 1 until Day 56)
- 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)
- Part 1 and Part 2: Area Under Plasma Concentration-time Curve in the Dosing Interval τ (AUCτ)(Day 1 until Day 56)
- Part 1 and Part 2: Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast)(Day 1 until Day 56)
- Part 1 and Part 2: Observed Lowest Drug Concentration Reached Before the Next Dose is Administered (Pre-dose) (Ctrough)(Day 1 until Day 56)
- 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)
- 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)
- Part 1 and Part 2: Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)(Day 1 until Day 56)
- Part 1 and Part 2: Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)(Day 1 until Day 56)
- Part 1 and Part 2: Time of Last Observed (Quantifiable) Concentration (Tlast)(Day 1 until Day 56)
- Part 1 and Part 2: Accumulation Ratio for AUCτ (Rac AUC)(Day 1 until Day 56)
- Part 1 and Part 2: Accumulation Ratio for Cmax (Rac Cmax)(Day 1 until Day 56)
- Part 2: Change From Baseline in Asthma Control Questionnaire-6 (ACQ-6) at Week 4 and Average Over the Treatment Period(Baseline, Week 4)
- Part 2: Participants With a Decrease in ACQ 6 Score of ≥ 0.5 From Baseline to Week 4(Baseline, Week 4)
- Part 2: Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the Treatment Period(Baseline, 4 weeks)
- Part 2: Change From Baseline in Average Evening PEF Over the Treatment Period(Baseline, 4 weeks)
- Part 2: Change From Baseline in Daily Average Asthma Symptom Score (AM/PM) Over the Treatment Period(Baseline, 4 weeks)
- Part 2: Change From Baseline in Pre-bronchodilator FEV1 Average Over the 4-week Treatment Period(Baseline and Week 4)
- Part 2: Change From Baseline in FeNO (In-clinic) at Week 4 and Average Over the Treatment Period(Baseline, Week 4)
- Part 2: Number of Participants With Adverse Events (AEs)(From Screening (Week -6) until Follow-up (Day 56))