A 24-Week Efficacy and Safety Study to Assess Budesonide and Formoterol Fumarate Metered Dose Inhaler in Adult and Adolescent Participants With Inadequately Controlled Asthma (VATHOS)

Study Overview
=================
Brief Summary
-----------------
This is a 24 week study to evaluate the efficacy and safety of budesonide and formoterol fumarate metered dose inhaler in adults and adolescents with inadequately controlled asthma.

Detailed Description
-----------------
This is a Phase III randomized, double-blind, active comparison, parallel group, multicenter study comparing BFF MDI 320/9.6 μg to BD MDI 320 µg and open-label Symbicort TBH 320/9 μg in adult and adolescent participants who have asthma which remains inadequately controlled (ACQ-7 total score ≥ 1.5) despite treatment with medium dose ICS or ICS/LABA. Budesonide and Formoterol Fumarate MDI 160/9.6 μg is included in this study to evaluate dose response by comparing to BFF MDI 320/9.6 μg. All doses represent the sum of 2 actuations. All study interventions will be administered BID for 24 weeks. This study will be conducted at approximately 125 sites worldwide and will randomize approximately 630 adult and adolescent participants.

Official Title
-----------------
A Randomized, Double-Blind, Parallel Group, Multicenter 24 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler and Open-Label Symbicort® Turbuhaler® in Participants With Inadequately Controlled Asthma (VATHOS).

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

Intervention / Treatment
-----------------
* Drug: BFF MDI 320/9.6 μg
* Drug: BFF MDI 160/9.6 μg
* Drug: BD MDI 320 μg
* Drug: Open-label Symbicort TBH 320/9 μg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 12 to 80 years of age, male and female, BMI <40 kg/m2; females must be not of childbearing potential or using a form of 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 2020]. 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 the ICS doses, for at least 8 weeks prior to Visit 1. ACQ-7 total score ≥ 1.5 at Visits 1 and 4. 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. A pre-bronchodilator/pre-dose FEV1 at Visits 2, 3, and 4 that have not changed 20% or more (increase or decrease) from the pre-bronchodilator/pre-dose FEV1 recorded at the previous visit. 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. Use of a nebulizer or a home nebulizer for receiving asthma medications. 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). Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members. 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 320/9.6 μg<br>Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg | Drug: BFF MDI 320/9.6 μg<br>* Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg<br>* Other names: BFF;|
| Experimental: BFF MDI 160/9.6 μg<br>Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg | Drug: BFF MDI 160/9.6 μg<br>* Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg<br>* Other names: BFF;|
| Experimental: BD MDI 320 μg<br>Budesonide MDI (BD MDI), 320 μg | Drug: BD MDI 320 μg<br>* Budesonide MDI (BD MDI), 320 μg<br>* Other names: BD;|
| Active Comparator: Open-label Symbicort TBH 320/9 μg<br>Open-Label Comparator Symbicort Turbuhaler 320/9 μg | Drug: Open-label Symbicort TBH 320/9 μg<br>* Open-label Symbicort Turbuhaler 320/9 μg<br>* Other names: Symbicort TBH;|

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 24 | 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 24 | at week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| US (Key secondary): Change from baseline in morning pre-dose trough FEV1 at Week 24 | US (Key secondary): Change from baseline in morning pre-dose trough FEV1 at Week 24 | at week 24 | 
| Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks | Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks | over 24 weeks | 
| Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) at Week 24 | Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) at Week 24 | at week 24 | 
| Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) at Week 24 | Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) at Week 24 | at Week 24 | 
| 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 24 | 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 24 | at Week 24 | 
| 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 | Day 1 |