Study to Assess PT010 in Adult and Adolescent Participants With Inadequately Controlled Asthma (KALOS)

Study Overview
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Brief Summary
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This is a variable length study to evaluate the efficacy and safety of budesonide/glycopyrronium/formoterol inhaler in adults and adolescents with severe asthma inadequately controlled with standard of care

Detailed Description
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This is a randomized, double-blind, double dummy, parallel group, multicenter 24 to 52 week variable length study to assess the efficacy and safety of budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler (MDI) relative to budesonide and formoterol fumarate MDI and Symbicort® pressurized MDI in adult and adolescent participants with inadequately controlled asthma. Approximately 2200 participants will be randomized globally.

Official Title
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A Randomized, Double-Blind, Double Dummy, Parallel Group, Multicenter Variable Length Study to Assess the Efficacy and Safety of PT010 Relative to PT009 and Symbicort® in Adult and Adolescent Participants With Inadequately Controlled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: BGF MDI 320/28.8/9.6 μg
* Drug: BGF MDI 320/14.4/9.6 μg
* Drug: BFF MDI 320/9.6 μg
* Drug: BFF pMDI 320/9 μg


Participation Criteria
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Eligibility Criteria
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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. Documented history of physician-diagnosed asthma > and/or = 1 year prior to V1. Regularly using a stable daily ICS/LABA regimen (including a stable ICS dose) with medium-to-high ICS doses for at least 4 weeks prior to V1. ACQ-7 total score ≥1.5 at Visits 1, 3, and 5 (pre-randomization). FEV1 % (assessed as an average of the 60 and 30 minute pre-dose assessments) predicted normal at V1, 2, 3, 4, and 5 (pre-randomization) Participants ≥ 18 years of age: < 80% Participants 12 to <18 years of age: < 90% FEV1 post-albuterol at V2 or V3 (if repeat needed). Participants > and/or = 18 years of age: Increase > and/or = 12% and > and/or = 200 mL. Participants 12 to <18 years of age: Increase =12% either in the 12 months prior to Visit 1 or at Visit 2, or at Visit 3. Note: Even if there is documented history of reversibility, all participants must be assessed for reversibility at Visit 2 (and Visit 3, if reversibility is not demonstrated at Visit 2) to provide reversibility baseline data for characterization. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol. Demonstrate acceptable MDI/pMDI administration technique. Received no asthma medication other than run-in BFF MDI BID and albuterol as needed during screening (except for allowed medications as defined in Table 9 and systemic corticosteroid or ICS for the treatment of an asthma exacerbation). eDiary 14-day compliance ≥70% during screening (defined as completing the daily eDiary for any 10 mornings and any 10 evenings and answering Yes to taking 2 puffs of run-in BFF MDI for any 10 mornings and 10 evenings in the last 14 days prior to randomization). No respiratory infection in the 4 weeks prior to randomization, or asthma exacerbation treated with systemic corticosteroid and/or additional ICS treatment in the 4 weeks prior to randomization. Exclusion Criteria: 1. Completed treatment for respiratory infection or asthma exacerbation with systemic corticosteroids within 4 weeks of V1. 2a. Participants where, in the opinion of the Investigator, treatment with biological therapy for asthma would be appropriate. 2b. Any marketed or investigational biologics within 3 months or 5 half-lives of V1, whichever is longer and must not be used during study duration. 3. Current smokers, former smokers with >10 pack-years history, or former smokers who stopped smoking <6 months prior to V1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana). 4. Current evidence of Chronic Obstructive Pulmonary Disease (COPD). 5a. Oral and IV corticosteroid use (any dose) within 4 weeks of V1. 5b. Use of systemic corticosteroids for any other reason except for the acute treatment of severe asthma exacerbation is prohibited for the duration of the study. 5c. Depot corticosteroid use for any reason within 3 months of V1. 6. Use of Long-Acting Muscarinic Antagonist (LAMA), either alone or as part of an inhaled combination therapy, in the 12 weeks prior to V1. 7. Use of oral beta2-agonist within 3 months of V1. 8. Use of any immunomodulators or immunosuppressive medication within 3 months or 5 half-lives, whichever is longer, and must not be used during the study duration. 9. Narrow angle glaucoma not adequately treated and/or change in vision that may be relevant, in the opinion of the Investigator, within 3 months of Visit 1. 10. Life-threatening asthma defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episode(s). 11. Hospitalization for asthma within 2 months of Visit 1. 12. Known history of drug or alcohol abuse within 12 months of Visit 1. 13. Regular use of a nebulizer or a home nebulizer for receiving asthma medications. 14. Using any herbal products by inhalation or nebulizer within 4 weeks of Visit 1 and does not agree to stop during the study duration. 15. Participation in another clinical study with a study intervention administered in the last 30 days or 5 half-lives, whichever is longer. Any other study intervention that is not identified in the protocol is prohibited for use during study duration. 16. Participants with a known hypersensitivity to beta2-agonists, corticosteroids, anticholinergics, or any component of the MDI or pMDI. 17. Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members. 18. For women only - currently pregnant (confirmed with positive highly sensitive pregnancy test), breast-feeding, or planned pregnancy during the study or not using acceptable contraception measures, as judged by the Investigator. Please refer to the study protocol for the complete inclusion and exclusion criteria list.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Budesonide, glycopyrronium, and formoterol fumarate (BGF) MDI 320/28.8/9.6 μg<br>BGF MDI 320/28.8/9.6 μg Budesonide, glycopyrronium, and formoterol fumarate (PT010) Metered Dose Inhaler (MDI) | Drug: BGF MDI 320/28.8/9.6 μg<br>* Budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler<br>* Other names: BGF;|
| Experimental: BGF MDI 320/14.4/9.6 μg<br>BGF MDI 320/14.4/9.6 μg Budesonide, glycopyrronium, and formoterol fumarate (PT010) Metered Dose Inhaler (MDI) | Drug: BGF MDI 320/14.4/9.6 μg<br>* Budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler<br>* Other names: BGF;|
| Active Comparator: Budesonide and formoterol fumarate (BFF) MDI 320/9.6 μg<br>BFF MDI 320/9.6 μg (Experimental/Comparator) Budesonide and formoterol fumarate (PT009) Metered Dose Inhaler (MDI) | Drug: BFF MDI 320/9.6 μg<br>* Budesonide and formoterol fumarate metered dose inhaler<br>* Other names: BFF;|
| Active Comparator: Symbicort®<br>Budesonide/ formoterol fumarate pressurized metered dose inhaler (pMDI) 320/9 μg | Drug: BFF pMDI 320/9 μg<br>* Budesonide/formoterol fumarate pressurized metered dose inhaler<br>* Other names: Symbicort®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 24 | Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 24 | 24 Weeks | 
| Rate of severe asthma exacerbations | Primary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Rate of severe asthma exacerbations | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in morning pre-dose trough FEV1 at Week 24 | Change from baseline in morning pre-dose trough FEV1 at Week 24 | 24 Weeks | 
| Percentage of responders in Asthma Control Questionnaire (ACQ)-7 (≥0.5 decrease equals response) at Week 24 | Percentage of responders in ACQ-7 (≥0.5 decrease equals response) at Week 24. Additional analysis will be conducted using pooled data from studies D5982C00007 and D5982C00008 | 24 weeks | 
| 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. Additional analysis will be conducted using pooled data from studies D5982C00007 and D5982C00008 | 24 Weeks | 
| Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ +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. Additional analysis will be conducted using pooled data from studies D5982C00007 and D5982C00008 | 24 weeks | 
| Percentage of responders in the St. George's Respiratory Questionnaire (SGRQ) (≥4.0 unit decrease equals response) at Week 24 | Percentage of responders in the St. George's Respiratory Questionnaire (SGRQ) (≥4.0 unit decrease equals response) at Week 24 | 24 Weeks | 
| 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 | 
| Time to first severe asthma exacerbation | Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Time to first severe asthma exacerbation | Up to 52 Weeks | 
| Rate of moderate/severe asthma exacerbations | Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Rate of moderate/severe asthma exacerbations | Up to 52 Weeks | 
| Time to first moderate/severe asthma exacerbation | Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Time to first moderate/severe asthma exacerbation | Up to 52 Weeks | 
| Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤ 55% at baseline. | Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤ 55% at baseline. | Up to 52 Weeks | 
| Rate of severe asthma exacerbations for participants with ≥ 1 severe exacerbation in the 12 months prior to Visit 1. | Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008: Rate of severe asthma exacerbations for participants with ≥ 1 severe exacerbation in the 12 months prior to Visit 1. | Up to 52 Weeks |