Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Budesonide, Glycopyrronium, Formoterol, Hydrofluoroalkane, Metered dose inhaler
Brief summary
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
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.
Interventions
DRUGTreatment A
Participants will receive 2 inhalations of BGF MDI with propellant 1.
DRUGTreatment B
Participants will receive 2 inhalations of BGF MDI with propellant 2.
DRUGTreatment C
Participants will receive 2 inhalations of BGF MDI with HFA propellant.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
This is a single blind study with regard to BGF MDI treatment, administered with 3 different propellants (Treatment A, B or C), in which the participants will remain blinded.
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
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: 1. Systolic blood pressure (BP) \< 90 mmHg or \> 140 mmHg. 2. Diastolic BP \< 50 mmHg or \> 90 mmHg. 3. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 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. |
| Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 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. |
| Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | Assessment of tmax of BGF when administered as 3 different propellant formulations. |
| Terminal Elimination Half-life (t½λz) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | Assessment of t½λz of BGF when administered as 3 different propellant formulations. |
| Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | Assessment of CL/F of BGF when administered as 3 different propellant formulations. |
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose | Assessment of Vz/F of BGF when administered as 3 different propellant formulations. |
| Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Screening, Day -1 until Follow-up visit, up to 53 days | Assessment of the safety and tolerability of a combination of BGF when administered as single doses in 3 different propellant formulations in healthy participants. |
Countries
United States
Participant flow
Recruitment details
This study was conducted between 19 Oct 2020 to 17 May 2021 at a single study center - Parexel Early Phase Clinical Unit (Los Angeles).
Pre-assignment details
This study consisted of a Screening Period of 28 days. There were three treatment periods of maximum three days each, with washout period of 3 to 7 days between each study dose administration. The assessments were done as per the schedule of assessment in the clinical study protocol.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence ABC Randomized participants received 3 single-dose treatments of BGF MDI (1 dose Propellant 1 \[Treatment A\]; 1 dose Propellant 2 \[Treatment B\] and 1 dose HFA propellant \[Treatment C\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 8 |
| Treatment Sequence BCA Randomized participants received 3 single-dose treatments of BGF MDI (1 dose Propellant 2 \[Treatment B\]; 1 dose HFA propellant \[Treatment C\] and 1 dose Propellant 1 \[Treatment A\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 8 |
| Treatment Sequence CAB Randomized participants received 3 single-dose treatments of BGF MDI (1 dose HFA propellant \[Treatment C\]; 1 dose Propellant 1 \[Treatment A\] and 1 dose Propellant 2 \[Treatment B\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 8 |
| Treatment Sequence ACB Randomized participants received 3 single-dose treatments of BGF MDI (1 dose Propellant 1 \[Treatment A\]; 1 dose HFA propellant \[Treatment C\] and 1 dose Propellant 2 \[Treatment B\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 8 |
| Treatment Sequence BAC Randomized participants received 3 single-dose treatments of BGF MDI (1 dose Propellant 2 \[Treatment B\]; 1 dose Propellant 1 \[Treatment A\] and 1 dose HFA propellant \[Treatment C\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 7 |
| Treatment Sequence CBA Randomized participants received 3 single-dose treatments of BGF MDI (1 dose HFA propellant \[Treatment C\]; 1 dose Propellant 2 \[Treatment B\] and 1 dose Propellant 1 \[Treatment A\]) in 3 treatment periods, with wash-out periods of 3 - 7 days between each study dose administration under fasted conditions. | 8 |
| Total | 47 |
Baseline characteristics
| Characteristic | Treatment Sequence ABC | Treatment Sequence BCA | Treatment Sequence CAB | Treatment Sequence ACB | Treatment Sequence BAC | Treatment Sequence CBA | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.0 Years STANDARD_DEVIATION 7.56 | 38.5 Years STANDARD_DEVIATION 7.67 | 36.6 Years STANDARD_DEVIATION 6.63 | 34.4 Years STANDARD_DEVIATION 8.33 | 34.7 Years STANDARD_DEVIATION 11.63 | 39.1 Years STANDARD_DEVIATION 11.89 | 36.6 Years STANDARD_DEVIATION 8.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 7 Participants | 7 Participants | 5 Participants | 6 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 3 Participants | 22 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 7 Participants | 8 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 47 | 0 / 47 |
| other Total, other adverse events | 9 / 47 | 10 / 47 | 10 / 47 |
| serious Total, serious adverse events | 0 / 47 | 0 / 47 | 0 / 47 |
Outcome results
Primary
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.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Glycopyrronium | 30.32 h*pg/mL | Geometric Coefficient of Variation 39.74 |
| Treatment A | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Budesonide | 2454 h*pg/mL | Geometric Coefficient of Variation 36.76 |
| Treatment A | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Formoterol | 93.68 h*pg/mL | Geometric Coefficient of Variation 35.71 |
| Treatment B | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Glycopyrronium | 27.23 h*pg/mL | Geometric Coefficient of Variation 30.67 |
| Treatment B | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Budesonide | 2262 h*pg/mL | Geometric Coefficient of Variation 32.27 |
| Treatment B | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Formoterol | 115.1 h*pg/mL | Geometric Coefficient of Variation 30.99 |
| Treatment C | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Budesonide | 2314 h*pg/mL | Geometric Coefficient of Variation 45.6 |
| Treatment C | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Formoterol | 92.84 h*pg/mL | Geometric Coefficient of Variation 30.45 |
| Treatment C | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUCinf) of BGF MDI | Glycopyrronium | NA h*pg/mL | — |
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [91.95, 119.2]
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [83.33, 115.3]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [70.33, 131]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [86.31, 157.8]
Primary
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.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Glycopyrronium | 29.87 h*pg/mL | Geometric Coefficient of Variation 88.09 |
| Treatment A | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Budesonide | 2391 h*pg/mL | Geometric Coefficient of Variation 36.77 |
| Treatment A | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Formoterol | 66.17 h*pg/mL | Geometric Coefficient of Variation 50.54 |
| Treatment B | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Glycopyrronium | 28.63 h*pg/mL | Geometric Coefficient of Variation 53.9 |
| Treatment B | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Budesonide | 2197 h*pg/mL | Geometric Coefficient of Variation 32.81 |
| Treatment B | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Formoterol | 74.34 h*pg/mL | Geometric Coefficient of Variation 41.35 |
| Treatment C | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Budesonide | 2232 h*pg/mL | Geometric Coefficient of Variation 44.14 |
| Treatment C | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Formoterol | 67.82 h*pg/mL | Geometric Coefficient of Variation 55.58 |
| Treatment C | Area Under the Plasma Concentration- Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of BGF MDI | Glycopyrronium | 29.20 h*pg/mL | Geometric Coefficient of Variation 82.24 |
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [94.53, 121.9]
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [84.59, 115.4]
Comparison: Statistical Comparison of Glycopyrronium PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [86.18, 130.6]
Comparison: Statistical Comparison of Glycopyrronium PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [80.84, 123]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [86.44, 111.4]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [88.82, 128.9]
Primary
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.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Maximum Observed Concentration (Cmax) of BGF MDI | Formoterol | 12.70 pg/mL | Geometric Coefficient of Variation 50.52 |
| Treatment A | Maximum Observed Concentration (Cmax) of BGF MDI | Budesonide | 552.2 pg/mL | Geometric Coefficient of Variation 54.74 |
| Treatment A | Maximum Observed Concentration (Cmax) of BGF MDI | Glycopyrronium | 11.74 pg/mL | Geometric Coefficient of Variation 72.16 |
| Treatment B | Maximum Observed Concentration (Cmax) of BGF MDI | Glycopyrronium | 10.19 pg/mL | Geometric Coefficient of Variation 58.42 |
| Treatment B | Maximum Observed Concentration (Cmax) of BGF MDI | Formoterol | 11.68 pg/mL | Geometric Coefficient of Variation 47.22 |
| Treatment B | Maximum Observed Concentration (Cmax) of BGF MDI | Budesonide | 483.2 pg/mL | Geometric Coefficient of Variation 48.43 |
| Treatment C | Maximum Observed Concentration (Cmax) of BGF MDI | Budesonide | 489.4 pg/mL | Geometric Coefficient of Variation 61.61 |
| Treatment C | Maximum Observed Concentration (Cmax) of BGF MDI | Formoterol | 11.48 pg/mL | Geometric Coefficient of Variation 52.95 |
| Treatment C | Maximum Observed Concentration (Cmax) of BGF MDI | Glycopyrronium | 10.76 pg/mL | Geometric Coefficient of Variation 70.78 |
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [91.01, 137.1]
Comparison: Statistical Comparison of Budesonide PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [78.67, 124]
Comparison: Statistical Comparison of Glycopyrronium PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [85.5, 137.3]
Comparison: Statistical Comparison of Glycopyrronium PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [74.69, 120.5]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment A (test) versus Treatment C (reference)90% CI: [97.02, 122.7]
Comparison: Statistical Comparison of Formoterol PK Parameters for Treatment B (test) versus Treatment C (reference)90% CI: [83.78, 119.5]
Secondary
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.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Glycopyrronium | 502.6 Litre/hour | Standard Deviation 201.8 |
| Treatment A | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Budesonide | 137.9 Litre/hour | Standard Deviation 43.28 |
| Treatment A | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Formoterol | 108.8 Litre/hour | Standard Deviation 43.64 |
| Treatment B | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Glycopyrronium | 544.5 Litre/hour | Standard Deviation 158.1 |
| Treatment B | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Budesonide | 148.6 Litre/hour | Standard Deviation 50.91 |
| Treatment B | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Formoterol | 87.14 Litre/hour | Standard Deviation 32.16 |
| Treatment C | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Budesonide | 155.3 Litre/hour | Standard Deviation 105.4 |
| Treatment C | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Formoterol | 108.3 Litre/hour | Standard Deviation 38.41 |
| Treatment C | Apparent Total Body Clearance of Drug After Extravascular Administration (CL/F) of BGF MDI | Glycopyrronium | NA Litre/hour | — |
Secondary
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.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Glycopyrronium | 1992 Litre | Standard Deviation 200.5 |
| Treatment A | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Budesonide | 941.9 Litre | Standard Deviation 328.6 |
| Treatment A | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Formoterol | 1171 Litre | Standard Deviation 281.2 |
| Treatment B | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Glycopyrronium | 2079 Litre | Standard Deviation 638.9 |
| Treatment B | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Budesonide | 1023 Litre | Standard Deviation 330.4 |
| Treatment B | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Formoterol | 1007 Litre | Standard Deviation 211.3 |
| Treatment C | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Budesonide | 1142 Litre | Standard Deviation 1005 |
| Treatment C | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Formoterol | 1167 Litre | Standard Deviation 180.9 |
| Treatment C | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of BGF MDI | Glycopyrronium | NA Litre | — |
Secondary
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.
Time frame: Screening, Day -1 until Follow-up visit, up to 53 days
Population: The Safety Analysis Set included all participants who received at least 1 inhalation of any BGF MDI formulated treatment. This included all original and replacement participants where the 1 inhalation criterion was met.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to discontinuation of IMP | 0 Participants |
| Treatment A | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any serious AE (including events with outcome = death) | 0 Participants |
| Treatment A | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE | 9 Participants |
| Treatment A | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE with outcome = death | 0 Participants |
| Treatment A | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Treatment B | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any serious AE (including events with outcome = death) | 0 Participants |
| Treatment B | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE | 10 Participants |
| Treatment B | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE with outcome = death | 0 Participants |
| Treatment B | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to discontinuation of IMP | 0 Participants |
| Treatment B | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Treatment C | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Treatment C | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE leading to discontinuation of IMP | 0 Participants |
| Treatment C | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE | 10 Participants |
| Treatment C | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any serious AE (including events with outcome = death) | 0 Participants |
| Treatment C | Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events | Any AE with outcome = death | 0 Participants |
Secondary
Terminal Elimination Half-life (t½λz) of BGF MDI
Assessment of t½λz of BGF when administered as 3 different propellant formulations.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Terminal Elimination Half-life (t½λz) of BGF MDI | Budesonide | 4.420 hours | Standard Deviation 0.4003 |
| Treatment A | Terminal Elimination Half-life (t½λz) of BGF MDI | Formoterol | NA hours | — |
| Treatment B | Terminal Elimination Half-life (t½λz) of BGF MDI | Budesonide | 4.438 hours | Standard Deviation 0.7886 |
| Treatment C | Terminal Elimination Half-life (t½λz) of BGF MDI | Budesonide | 4.574 hours | Standard Deviation 0.4267 |
| Treatment C | Terminal Elimination Half-life (t½λz) of BGF MDI | Formoterol | NA hours | — |
Secondary
Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI
Assessment of tmax of BGF when administered as 3 different propellant formulations.
Time frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose
Population: The PK Analysis Set consisted of all participants in the Safety Analysis Set for whom at least 1 of the primary PK parameters could have been calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Number Analyzed in each row signifies only the participants with available data that were analyzed for BGF MDI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Glycopyrronium | 0.08 hours |
| Treatment A | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Budesonide | 0.50 hours |
| Treatment A | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Formoterol | 0.17 hours |
| Treatment B | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Glycopyrronium | 0.08 hours |
| Treatment B | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Budesonide | 0.75 hours |
| Treatment B | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Formoterol | 0.50 hours |
| Treatment C | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Budesonide | 0.52 hours |
| Treatment C | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Formoterol | 0.17 hours |
| Treatment C | Time to Reach Maximum Observed Concentration (Tmax) of BGF MDI | Glycopyrronium | 0.08 hours |