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

Study Overview
=================
Brief Summary
-----------------
The study will assess the Pharmacokinetic (PK) and safety of BGF MDI [Budesonide/glycopyrronium/formoterol (BGF) metered dose inhaler (MDI)] formulated with 2 different propellants :Hydrofluoroolefin (HFO) and Hydrofluoroalkane (HFA) with oral activated charcoal in healthy subjects (male or female).

Detailed Description
-----------------
This is a Phase I, randomized, double-blind, single-dose, single-center, partial-replicate, 3 way cross-over study. The study will comprise: Screening period: up to 28 days prior to first dosing; Three treatment periods : Subject will be resident in the Clinical Unit from the morning on the day before dosing with BGF MDI (Day 1 of Treatment Period 1), until 24 hours following the final dose (Day 2 of Treatment Period 3 a washout period of 3 to 7 days between each dose; Follow-up: Within 3 to 7 days after the last administration of BGF MDI. Subjects will receive 3 single-dose treatments of BGF MDI [Test formulation Treatment A (BGF MDI HFO); Reference formulation Treatment B (BGF MDI HFA)] on Day 1 of each Treatment Period (1, 2, and 3) following an overnight fast of at least 8 hours. There will be a washout period of 3 to 7 days between each dose. Each subjects will be involved in the study for up to 55 days.

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

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: Treatment A (BGF MDI HFO with oral activated charcoal)
* Drug: Treatment B (BGF MDI HFA with oral activated charcoal)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy non-smoking male and/or female subjects aged 18 - 60 years with suitable veins for cannulation or repeated venipuncture. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating, confirmed at screening. 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 Forced expiratory volume in the first second (FEV1) ≥ 80% of the predicted normal value and an FEV1/FVC (Forced vital capacity) > 70% regarding age, height, and ethnicity at the screening visit. Subjects must demonstrate proper inhalation technique and have the ability to properly use an MDI device after training. Provision of signed and dated, written informed consent prior to any study specific procedures. 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. 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. Any clinically significant abnormal findings in physical examination, or vital signs at screening. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and HIV antibody. Subject has a positive RT-PCR test for SARS-CoV-2 prior to randomization. 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 COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated, Intensive Care Unit stay). Recent (within 14 days prior to admission to the Clinical Unit) exposure to someone who has COVID-19 symptoms or tested positive for SARS-CoV-2. Has a current occupation that involves routine exposure to potential COVID-19 patients or sources of SARS-CoV-2 infection (eg, healthcare worker). History of any respiratory disorders such as asthma, COPD, or idiopathic pulmonary fibrosis. Known or suspected history of 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 or history of hypersensitivity to drugs with a similar chemical structure or class to BGF. Current smokers or those who have smoked or used nicotine products (including e cigarettes) within 3 months prior to screening. Positive screen for drugs of abuse or cotinine at screening or on admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. 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
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

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 with oral activated charcoal<br>Subjects 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 with oral activated charcoal)<br>* Subject will receive 4 inhalations as a single dose with oral activated charcoal - test formulation; administered during 1 Treatment Period.<br>* Other names: Budesonide / Glycopyronium / Formoterol fumarate pressurized inhalation suspension, HFO;Drug: Treatment B (BGF MDI HFA with oral activated charcoal)<br>* Subject will received 4 inhalations as a single dose with oral activated charcoal - 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 with oral activated charcoal<br>Subjects 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 with oral activated charcoal)<br>* Subject will receive 4 inhalations as a single dose with oral activated charcoal - test formulation; administered during 1 Treatment Period.<br>* Other names: Budesonide / Glycopyronium / Formoterol fumarate pressurized inhalation suspension, HFO;Drug: Treatment B (BGF MDI HFA with oral activated charcoal)<br>* Subject will received 4 inhalations as a single dose with oral activated charcoal - reference formulation; administered during 2 Treatment Periods.<br>* Other names: Budesonide / Glycopyronium / Formoterol fumarate pressurized inhalation suspension, HFA;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma (peak) drug concentration (Cmax ) | To assess the bioequivalence (Cmax) of the lung 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 plasma concentration time curve from zero to infinity (AUCinf) | To assess the bioequivalence (AUCinf) of the lung 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 lung 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 profiles (tmax) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | 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 profiles (t½λz) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | 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 profiles (λz) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | 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 profiles (MRTinf) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | 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 profiles (CL/F) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | 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 profiles (Vz/F) of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal. | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | 
| Number of subjects with serious adverse events (SAE) and non-serious adverse events | To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA with oral activated charcoal in healthy subjects. | SAE: Screening (up to 28 days); AE: Screening, Day 1 and Day 2 until Follow-up visit (approximately 3 to 7 days post final dose) [approximately 55 days] | 
| Percentage of subjects with potentially clinically significant changes in laboratory values | To evaluate the percentage of subjects with clinically significant changes in Laboratory assessments (hematology, clinical chemistry, urinalysis). | Up to 55 days | 
| Percentage of subjects with abnormality in Physical examination | To assess the percentage of subjects with abnormality in full physical exams. | Up to 55 days | 
| Percentage of subjects with potentially clinically significant changes in ECGs | To evaluate the percentage of subjects with potentially clinically significant changes in 12-lead ECG recordings. | Up to 55 days | 
| Percentage of subjects with potentially clinically significant changes in Blood pressure | To evaluate the percentage of subjects with potentially clinically significant changes in systolic, diastolic Blood pressure. | Up to 55 days | 
| Percentage of subjects with potentially clinically significant changes in pulse rate | To evaluate the percentage of subjects with potentially clinically significant changes in pulse rate. | Up to 55 days | 
| Percentage of subjects with potentially clinically significant changes in body temperature | To evaluate the percentage of subjects with potentially clinically significant changes in body temperature. | Up to 55 days | 
| Percentage of subjects with potentially clinically significant changes in respiratory rate | To evaluate the percentage of subjects with potentially clinically significant changes in respiratory rate | Up to 55 days | 

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