A Study to Assess the Total Systemic Exposure Bioequivalence of of Budesonide, Glycopyrronium, and Formoterol Delivered by BGF MDI HFO Compared With BGF MDI HFA

Study Overview
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Brief Summary
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The study will evaluate bioequivalence, pharmacokinetics, safety, and tolerability of Budesonide, Glycopyrronium and Formoterol (BGF) metered dose inhaler (MDI) formulated with hydrofluoroolefin (HFO) [Test] and hydrofluoroalkane (HFA) [Reference] in healthy participants (male or female).

Detailed Description
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This is a Phase I, randomized, double-blind, single-dose, single-center, partial-replicate, 3 way cross-over study to assess pharmacokinetic and safety of BGF MDI when administered with different propellants, HFO (HFO-1234ze) - test and HFA (HFA-134a) - reference. The study will comprise of: A screening period up to 28 days prior to first dosing; Three Treatment Periods: Participants will be resident at the Clinical Unit from the morning on the day before dosing with BGF MDI on Day -1 of Treatment Period 1, until 24 hours following the final dose on Day 2 of Treatment Period 3, with a washout period of 3 to 7 days between each dose; and Follow-up: final safety Follow-up Phone Call within 3 to 7 days after the last administration of BGF MDI in Treatment Period 3. Each participant will receive 3 single dose treatments of BGF MDI (Treatment A: BGF MDI HFO [Test]; Treatment B: BGF MDI HFA [Reference]) following an overnight fast of at least 8 hours on Day 1 of each treatment period. The reference formulation will be administered during 2 of the 3 treatment periods. There will be a minimum of a 3 to 7 day washout between administration of each treatment. Each participant will be involved in the study for approximately 55 days.

Official Title
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A Phase I, Randomized, Double-blind, Single-dose, Partial-replicate, 3-way Cross-over Study to Assess the Total Systemic Exposure Bioequivalence of Budesonide, Glycopyrronium, and Formoterol Delivered by BGF MDI HFO Compared With BGF MDI HFA

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Treatment A: BGF MDI HFO
* Drug: Treatment B: BGF MDI HFA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures. Healthy male and female subjects aged 18 to 60 years with suitable veins for cannulation or repeated venepuncture. Females must have a negative pregnancy test, must not be lactating Have a Body Mass Index (BMI) between 18 and 35 kg/m2 inclusive and weigh at least 50 kg and no more than 120 kg inclusive. Subjects must have a FEV1 ≥ 80% of the predicted normal value and an FEV1/FVC > 70% regarding age, height, and ethnicity. Subjects must demonstrate proper inhalation technique and have the ability to properly use an MDI device after training. Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate. History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP). History of narrow angle glaucoma not adequately treated and/or change in vision that may be relevant. History of symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, in the opinion of the investigator, is clinically significant. Unresectable cancer that has not been in complete remission for at least 5 years. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results at screening, as judged by the investigator. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody. Subject has a positive Reverse transcriptase- Polymerase chain reaction (RT-PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Subject has clinical signs and symptoms consistent with SARS-CoV-2 infection, eg, fever, dry cough, dyspnea, sore throat, fatigue, or laboratory confirmed acute infection with SARS-CoV-2. Subject who had severe course of Corona virus disease of 2019 (COVID-19) (extracorporeal membrane oxygenation, mechanically ventilated, Intensive Care Unit stay). History of any respiratory disorders such as asthma, Chronic Obstructive Pulmonary Disorder (COPD), or idiopathic pulmonary fibrosis. Known or suspected history of alcohol or drug abuse. Receipt of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to randomization. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 3 months prior to screening. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins and minerals during the 2 weeks prior to the first administration of IMP. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol. Excessive intake of caffeine-containing drinks or food. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day or would likely be unable to refrain from the use of caffeine-containing beverages during confinement. Subjects who have previously received BGF MDI HFO.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: BGF MDI HFO 160/7.2/4.8 μg ex-actuator<br>Participants will receive Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. | Drug: Treatment A: BGF MDI HFO<br>* Participants will receive 4 oral inhalations as a single dose - test formulation; administered during 1 treatment period.<br>* Other names: Budesonide/Glycopyronium/Formoterol fumarate pressurized inhalation suspension, HFO;Drug: Treatment B: BGF MDI HFA<br>* Participants will receive 4 oral inhalations as a single dose - reference formulation; administered during 2 treatment periods.<br>* Other names: Budesonide/Glycopyronium/Formoterol fumarate pressurized inhalation suspension, HFA;|
| Experimental: Treatment B: BGF MDI HFA 160/7.2/4.8 μg ex-actuator<br>Participants will receive Reference formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. | Drug: Treatment A: BGF MDI HFO<br>* Participants will receive 4 oral inhalations as a single dose - test formulation; administered during 1 treatment period.<br>* Other names: Budesonide/Glycopyronium/Formoterol fumarate pressurized inhalation suspension, HFO;Drug: Treatment B: BGF MDI HFA<br>* Participants will receive 4 oral inhalations as a single dose - reference formulation; administered during 2 treatment periods.<br>* Other names: Budesonide/Glycopyronium/Formoterol fumarate pressurized inhalation suspension, HFA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve from zero to infinity (AUCinf) | To assess the bioequivalence (AUCinf) of the total systemic exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA. | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) | To assess the bioequivalence (AUClast) of the total systemic exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA. | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Maximum observed plasma (peak) drug concentration (Cmax) | To assess the bioequivalence (Cmax) of the total systemic exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA. | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach peak or maximum observed concentration or response following drug administration (tmax) | To characterize the PK profile (tmax) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) | To characterize the PK profile (λz) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) | To characterize the PK profile (t½λz) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRTinf) | To characterize the PK profile (MRTinf) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To characterize the PK profile (CL/F) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) | To characterize the PK profile (Vz/F) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | From Screening up to Follow-up Phone call (3 to 7 days post final dose) [approximately 55 days] | 
| Percentage of participants with potentially clinically significant changes in Blood Pressure | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with potentially clinically significant changes in laboratory values (hematology, clinical chemistry, and urinalysis) | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with potentially clinically significant changes in pulse rate | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with potentially clinically significant changes in body temperature | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with potentially clinically significant changes in respiratory rate | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with potentially clinically significant changes in electrocardiograms (ECGs) | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 
| Percentage of participants with abnormality in Physical examination | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA in healthy participants | Up to 55 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bioequivalence, Propellant, Corticosteroid, Long acting muscarine agonist (LAMA), Long acting beta agonist, Lung exposure, Healthy subjects, Inhaled corticosteroid (ICS), Long-acting β2 agonist (LABA), Next generation propellant (NGP)