A Study to Assess Drug Absorption of Fixed Dose Combinations of Budesonide, Glycopyrronium, and Formoterol

Study Overview
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Brief Summary
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The study will evaluate bioavailability, pharmacokinetics, safety, and tolerability of budesonide, glycopyrronium and formoterol (BGF) metered dose inhaler (MDI) formulated with 3 different propellants: Propellant 1 (Treatment A [test]), Propellant 2 (Treatment B [test]) and Hydrofluoroalkane (HFA) (Treatment C [reference]).

Detailed Description
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The study will comprise: Screening period: up to 28 days prior to first dosing; Three treatment periods of maximum 3 days each: participants will be resident from the morning of the day before the first dosing with BGF MDI (Day -1) in Treatment Period 1, throughout all treatment and washout periods up to discharge on Day 2 of Treatment Period 3; Follow-up: within 3 to 7 days after the last administration of BGF MDI. There will be a washout period of 3 to 7 days between each dose. Each participant will receive 3 single-dose treatments of BGF MDI (1 dose Propellant 1 [Treatment A]; 1 dose Propellant 2 [Treatment B] and 1 dose HFA [Treatment C]), following an overnight fast of at least 8 hours. Each participant will be involved in the study for up to 53 days.

Official Title
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A Randomized, Single Blind, 3-Period, 3-Treatment, Single-dose, Crossover Study to Assess the Relative Bioavailability of BGF Propellant 1 and BGF Propellant 2 Compared With BGF MDI HFA in Healthy Subjects

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: Treatment A
* Drug: Treatment B
* Drug: Treatment C


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. Non-smoking male participants with suitable veins for cannulation or repeated venipuncture. Participants must agree to follow the reproductive restrictions. Have a body mass index between 18 and 30 kg/m^2 and weigh at least 50 kg and no more than 100 kg. Participants must have a forced expiratory volume in one second ≥ 80% of the predicted value regarding age, height, and ethnicity at the screening visit. Exclusion Criteria: History or current evidence of a clinically significant (CS) disease or disorder (including but not limited to cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary). 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 CS illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP). Narrow angle glaucoma not adequately treated. All medications approved for control of intraocular pressures are allowed, including topical ophthalmic non-selective β-blockers. Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, in the opinion of the principal investigator (PI), is CS. Any cancer except squamous cell and basal cell carcinomas of the skin are allowed in the study. Any CS abnormalities in clinical chemistry, hematology, or urinalysis results, at screening and/or admission to the Clinical Unit: Systolic blood pressure (BP) < 90 mmHg or > 140 mmHg. Diastolic BP < 50 mmHg or > 90 mmHg. Heart rate < 45 or > 85 bpm. Any CS abnormal findings in vital signs, after 5 minutes supine rest, at screening and/or Day -1 of each Treatment Period, as judged by the PI. Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG as considered by the PI. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody. Known or suspected history of drug abuse. Participant has a positive reverse transcription polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prior to randomization. Participant has clinical signs and symptoms consistent with SARS-CoV-2 infection (e.g., fever, dry cough, dyspnea, sore throat, fatigue, or laboratory confirmed acute infection with SARS-CoV-2). Participant who had severe course of coronavirus disease 2019 (COVID-19). 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. Recent (within 14 days prior to admission to the Clinical Unit) visit to a healthcare facility where COVID-19 patients are being treated. Has a current occupation that involves routine exposure to potential COVID-19 patients or sources of SARS-CoV-2 infection. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. 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 the 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 at screening or 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, herbal remedies, megadose vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. Known or suspected history of alcohol abuse or excessive intake of alcohol. Participants who have previously received BGF. Judgment by the PI that the participant should not participate in the study if they have any ongoing or recent minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements. Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. History of any respiratory disorders such as asthma, COPD or idiopathic pulmonary fibrosis. Participants who cannot use an inhaler appropriately. Participants who cannot communicate reliably with the PI. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, eg vector, lipid nanoparticle) less than 7 days prior to the date of randomization (from last vaccination or booster dose).

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

Sexes Eligible for Study
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Male

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence ABC<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment A; Treatment B; Treatment C) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|
| Experimental: Treatment Sequence BCA<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment B; Treatment C; Treatment A) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|
| Experimental: Treatment Sequence CAB<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment C; Treatment A; Treatment B) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|
| Experimental: Treatment Sequence ACB<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment A; Treatment C; Treatment B) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|
| Experimental: Treatment Sequence BAC<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment B; Treatment A; Treatment C) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|
| Experimental: Treatment Sequence CBA<br>Participants will be randomized to one of the 6 different treatment sequences. Each participant will receive 3 single-dose treatments of BGF MDI (Treatment C; Treatment B; Treatment A) in 3 treatment periods, with first dose on Day -1 for all treatment periods. | Drug: Treatment A<br>* Participants will receive 2 inhalations of BGF MDI with propellant 1.<br>* Other names: BGF MDI Propellant 1;Drug: Treatment B<br>* Participants will receive 2 inhalations of BGF MDI with propellant 2.<br>* Other names: BGF MDI Propellant 2;Drug: Treatment C<br>* Participants will receive 2 inhalations of BGF MDI with HFA propellant.<br>* Other names: BGF MDI HFA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of BGF MDI | Evaluation of the relative bioavailability between the test formulations and the reference formulation for fixed dose combinations (FDCs) of BGF when delivered as BGF MDI with 3 different propellants by Cmax. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUCinf. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUClast. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Assessment of tmax of BGF when administered as 3 different propellant formulations. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Terminal Elimination Half-life (t½λz) of BGF MDI | Assessment of t½λz of BGF when administered as 3 different propellant formulations. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Assessment of CL/F of BGF when administered as 3 different propellant formulations. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Assessment of Vz/F of BGF when administered as 3 different propellant formulations. | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 
| Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Assessment of the safety and tolerability of a combination of BGF when administered as single doses in 3 different propellant formulations in healthy participants. | Screening, Day -1 until Follow-up visit, up to 53 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Budesonide, Glycopyrronium, Formoterol, Hydrofluoroalkane, Metered dose inhaler