A 12-week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants With Inadequately Controlled Asthma (LITHOS)

Study Overview
=================
Brief Summary
-----------------
This is a 12-week study to evaluate the efficacy and safety of budesonide and formoterol fumarate metered dose inhaler relative to budesonide metered dose inhaler in adults and adolescents with inadequately controlled asthma.

Detailed Description
-----------------
This is a Phase III, randomized, double-blind, parallel group, multicenter study comparing Budesonide and Formoterol Fumarate Metered Dose Inhaler (BFF MDI) 160/9.6 μg twice daily (BID) to Budesonide MDI 160 μg (BD MDI), over 12 weeks. The study population will consist of adult and adolescent participants with asthma who remain inadequately controlled, as demonstrated by an Asthma Control Questionnaire (ACQ)-7 total score ≥1.5, despite treatment with low dose inhaled corticosteroid (ICS) or ICS/long-acting beta2-agonist (LABA). This study is to assess the benefits and safety of BFF MDI on lung function and asthma health-related quality of life. This study will be conducted at approximately 90 sites worldwide and will randomize approximately 340 adult and adolescent participants.

Official Title
-----------------
A Randomized, Double-Blind, Parallel Group, Multicenter 12 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants With Inadequately Controlled Asthma (LITHOS)

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: BFF MDI 160/9.6 μg BID (320/19.2μg/day)
* Drug: BD MDI 160 μg BID (320 μg/day)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria 12 to 80 years of age, male and female, BMI <40 kg/m2; females of childbearing potential should be using highly effective birth control. Participants who have a documented history of physician-diagnosed asthma ≥ 6 months prior to Visit 1, according to GINA guidelines [GINA 2021]. Healthcare records for 1 year prior to Visit 1 must be provided for adolescent participants (12 to < 18 years of age) to ensure consistent evaluation and follow-up of treatment in those participants. Participants who have been regularly using a stable daily ICS or an ICS/LABA regimen (including a stable ICS dose), with allowed ICS doses, for at least 8 weeks prior to Visit 1. ACQ-7 total score ≥ 1.5 at Visits 1 and 4. A pre-bronchodilator/pre-dose FEV1 < 90% predicted normal value at Visits 1, 2, and 3 and a pre-dose FEV1 of 50% to 90% at Visit 4 (pre-randomization). Reversibility to albuterol, defined as a post-albuterol increase in FEV1 of ≥ 12% and ≥ 200 mL for participants ≥ 18 years of age OR a post-albuterol increase of FEV1 of ≥ 12% for participants 12 to < 18 years of age either in the 12 months prior to Visit 1 or at Visit 2 or Visit 3, if repeat testing is necessary. A pre-bronchodilator/pre-dose FEV1 at Visits 2, 3, and 4 that has not changed 20% or more (increase or decrease) from the pre-bronchodilator/pre-dose FEV1 recorded at the previous visit. Asthma stability during run-in based on Investigator discretion using the symptom worsening assessment defined in Section 8.1.2.8 as a guideline. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol. Demonstrate acceptable MDI administration technique. eDiary compliance ≥ 70% during screening, defined as completing the daily eDiary and answering Yes to taking 2 puffs of run-in BD MDI for any 10 mornings and 10 evenings in the last 14 days prior to randomization. Exclusion criteria Life-threatening asthma as defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s). Any respiratory infection or asthma exacerbation treated with systemic corticosteroids and/or additional ICS treatment in the 8 weeks prior to Visit 1 and throughout the Screening Period. Hospitalization for asthma within 8 weeks of Visit 1. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (eg, active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, and COPD). Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through participation, or that could affect the efficacy or safety analysis. Known history of drug or alcohol abuse within 12 months of Visit 1. Unresectable cancer that has not been in complete remission for at least 5 years prior to Visit 1. Note: Squamous cell and basal cell carcinomas of the skin are not exclusionary. Participation in another clinical study with an Investigational Product administered in the last 30 days or 5 half-lives, whichever is longer. Any other Investigational Product that is not identified in this protocol is prohibited for use during study duration. Previous or current randomization in any budesonide and formoterol fumarate or budesonide, glycopyrronium, and formoterol fumarate studies (PT009 or PT010). Use of a nebulizer or a home nebulizer for receiving asthma medications. Note: Acute use of a nebulizer for an asthma exacerbation during hospitalization is allowed as long as there is no occurrence within 8 weeks of Visit 1. Do not meet the stable dosing period prior to Visit 1 or unable to abstain from protocol-defined prohibited medications during Screening and Treatment Periods. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid nanoparticle) ≤7 days prior to Visit 1 (from last vaccination or booster dose). Participants with known hypersensitivity to beta2-agonists, corticosteroids, or any component of the MDI. Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or electrocardiogram (ECG), which in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study. Current smokers, former smokers with > 10 pack-years history, or former smokers who stopped smoking < 6 months prior to Visit 1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana). Planned hospitalization during the study. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members. Judgment by the Investigator that the participant is unlikely to comply with study procedures, restrictions and requirements. For women only - currently pregnant (confirmed with positive highly sensitive urine pregnancy test), breast-feeding, or planned pregnancy during the study or not using acceptable contraception measures, as judged by the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BFF MDI 160/9.6 μg BID (320/19.2μg/day)<br>Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), BDI (320/19.2μg/day) | Drug: BFF MDI 160/9.6 μg BID (320/19.2μg/day)<br>* Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg BID (320/19.2μg/day)<br>* Other names: BFF;|
| Active Comparator: BD MDI 160 μg BID (320 μg/day)<br>Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day) | Drug: BD MDI 160 μg BID (320 μg/day)<br>* Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day)<br>* Other names: BD;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| United States (US): Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 12 | United States (US): Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 12 | at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| US (Key secondary): Change from baseline in morning pre-dose trough FEV1 at Week 12 | US (Key secondary): Change from baseline in morning pre-dose trough FEV1 at Week 12 | at week 12 | 
| Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 12 Weeks | Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 12 Weeks | over 12 Weeks | 
| Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) at Week 12 | Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) at Week 12 | at Week 12 | 
| Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) at Week 12 | Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) at Week 12 | at Week 12 | 
| Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) at Week 12 | Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12)(≥ 0.5 increase equals response) at Week 12 | at Week 12 | 
| Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1 | Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1 (within group comparison) | on Day 1 |