Chronic Obstructive Pulmonary Disease
Conditions
Keywords
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)
Brief summary
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
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.
Interventions
Participants will receive 4 oral inhalations as a single dose - test formulation; administered during 1 treatment period.
Participants will receive 4 oral inhalations as a single dose - reference formulation; administered during 2 treatment periods.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The AUCinf of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The AUClast of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The Cmax of budesonide, glycopryrronium and formoterol in participants was evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The MRTinf of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The CL/F of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The tmax of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Screening up to Follow-up (3 to 7 days post final dose) [approximately 55 days] | The safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA was evaluated in healthy participants. |
| Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The Vz/F of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The λz of budesonide, glycopryrronium and formoterol in participants was evaluated. |
| Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The t½λz of budesonide, glycopryrronium and formoterol in participants was evaluated. |
Countries
United States
Participant flow
Recruitment details
This study was conducted in one study center in the US.
Pre-assignment details
The screening period was of 4 weeks. All the study assessments were performed as per the schedule of assessments. Participants who met the eligibility criteria were randomized to study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence ABB Participants received Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA, where Treatment A: BGF MDI HFO (test), Treatment B: BGF MDI HFA (reference). The reference formulation were administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. | 36 |
| Treatment Sequence BAB Participants received Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA, where Treatment A: BGF MDI HFO (test), Treatment B: BGF MDI HFA (reference). The reference formulation were administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. | 36 |
| Treatment Sequence BBA Participants received Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA, where Treatment A: BGF MDI HFO (test), Treatment B: BGF MDI HFA (reference). The reference formulation were administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. | 36 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence ABB | Treatment Sequence BAB | Treatment Sequence BBA | Total |
|---|---|---|---|---|
| Age, Continuous | 36.0 Years STANDARD_DEVIATION 10 | 35.8 Years STANDARD_DEVIATION 9.6 | 39.5 Years STANDARD_DEVIATION 11.2 | 37.1 Years STANDARD_DEVIATION 10.3 |
| Race/Ethnicity, Customized Asian | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 8 Participants | 10 Participants | 26 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 6 Participants | 4 Participants | 13 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 19 Participants | 20 Participants | 60 Participants |
| Sex: Female, Male Female | 14 Participants | 19 Participants | 16 Participants | 49 Participants |
| Sex: Female, Male Male | 22 Participants | 17 Participants | 20 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 108 | 0 / 107 | 0 / 107 |
| other Total, other adverse events | 16 / 108 | 21 / 107 | 9 / 107 |
| serious Total, serious adverse events | 0 / 108 | 0 / 107 | 0 / 107 |
Outcome results
Primary
Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf)
The AUCinf of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Glycopyronium | 85.62 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 94.55 |
| Treatment A | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Budesonide | 4047 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 46.71 |
| Treatment A | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Formoterol | 124.3 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 43.8 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Glycopyronium | 81.10 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 78.85 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Budesonide | 4112 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 40.78 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Formoterol | 121.3 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 41.19 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Budesonide | 4012 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 46.01 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Formoterol | 125.0 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 40.55 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) | Glycopyronium | 120.9 hour*picogram/milliliter (h*pg/mL) | Geometric Coefficient of Variation 83.4 |
Primary
Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast)
The AUClast of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 52.68 h*pg/mL | Geometric Coefficient of Variation 52.68 |
| Treatment A | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 3943 h*pg/mL | Geometric Coefficient of Variation 47.6 |
| Treatment A | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 102.5 h*pg/mL | Geometric Coefficient of Variation 48.47 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 49.31 h*pg/mL | Geometric Coefficient of Variation 84.38 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 4003 h*pg/mL | Geometric Coefficient of Variation 40.66 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 100.3 h*pg/mL | Geometric Coefficient of Variation 45.89 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 3905 h*pg/mL | Geometric Coefficient of Variation 46.82 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 103.9 h*pg/mL | Geometric Coefficient of Variation 42.47 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 63.29 h*pg/mL | Geometric Coefficient of Variation 72.9 |
Primary
Maximum Observed Plasma (Peak) Drug Concentration (Cmax)
The Cmax of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Glycopyrronium | 17.09 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 90.52 |
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Budesonide | 1124 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 65.67 |
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Formoterol | 23.48 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 60.12 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Glycopyrronium | 20.41 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 87.46 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Budesonide | 1143 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 60.79 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Formoterol | 24.54 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 62.22 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Budesonide | 1146 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 65.91 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Formoterol | 26.12 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 54.39 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax) | Glycopyrronium | 19.70 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 87.52 |
Secondary
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)
The CL/F of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 336.4 Liters/hour (L/h) | Geometric Coefficient of Variation 94.55 |
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 158.2 Liters/hour (L/h) | Geometric Coefficient of Variation 46.71 |
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 154.5 Liters/hour (L/h) | Geometric Coefficient of Variation 43.8 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 355.1 Liters/hour (L/h) | Geometric Coefficient of Variation 78.85 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 155.6 Liters/hour (L/h) | Geometric Coefficient of Variation 40.78 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 158.2 Liters/hour (L/h) | Geometric Coefficient of Variation 41.19 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 159.5 Liters/hour (L/h) | Geometric Coefficient of Variation 46.01 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 153.6 Liters/hour (L/h) | Geometric Coefficient of Variation 40.55 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 238.2 Liters/hour (L/h) | Geometric Coefficient of Variation 83.4 |
Secondary
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz)
The t½λz of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Glycopyrronium | 11.74 Hours | Geometric Coefficient of Variation 97.13 |
| Treatment A | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Budesonide | 4.596 Hours | Geometric Coefficient of Variation 25.19 |
| Treatment A | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Formoterol | 7.779 Hours | Geometric Coefficient of Variation 36.39 |
| Treatment B (Replicate 1) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Glycopyrronium | 11.53 Hours | Geometric Coefficient of Variation 92.16 |
| Treatment B (Replicate 1) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Budesonide | 4.506 Hours | Geometric Coefficient of Variation 25.24 |
| Treatment B (Replicate 1) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Formoterol | 7.766 Hours | Geometric Coefficient of Variation 36.5 |
| Treatment B (Replicate 2) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Budesonide | 4.622 Hours | Geometric Coefficient of Variation 24.99 |
| Treatment B (Replicate 2) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Formoterol | 8.037 Hours | Geometric Coefficient of Variation 39.39 |
| Treatment B (Replicate 2) | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) | Glycopyrronium | 17.99 Hours | Geometric Coefficient of Variation 100.5 |
Secondary
Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf)
The MRTinf of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 10.48 Hours | Geometric Coefficient of Variation 29.28 |
| Treatment A | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Glycopyrronium | 16.02 Hours | Geometric Coefficient of Variation 93.66 |
| Treatment A | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 4.855 Hours | Geometric Coefficient of Variation 21.37 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 10.38 Hours | Geometric Coefficient of Variation 30.42 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 4.893 Hours | Geometric Coefficient of Variation 24.3 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Glycopyrronium | 15.56 Hours | Geometric Coefficient of Variation 86.14 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 10.62 Hours | Geometric Coefficient of Variation 33.34 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Glycopyrronium | 24.50 Hours | Geometric Coefficient of Variation 96.84 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 4.924 Hours | Geometric Coefficient of Variation 19.98 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
The safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA was evaluated in healthy participants.
Time frame: From Screening up to Follow-up (3 to 7 days post final dose) [approximately 55 days]
Population: The safety analysis set included all participants who received at least one inhalation of any BGF MDI.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 16 Participants |
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE with outcome of death | 0 Participants |
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of Investigational Product (IP) | 0 Participants |
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related AE | 10 Participants |
| Treatment A | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 21 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of Investigational Product (IP) | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related AE | 12 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE with outcome of death | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE with outcome of death | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of Investigational Product (IP) | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 9 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any possibly related AE | 4 Participants |
Secondary
Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz)
The λz of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Glycopyrronium | 0.05906 1/hour | Geometric Coefficient of Variation 97.13 |
| Treatment A | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Budesonide | 0.1508 1/hour | Geometric Coefficient of Variation 25.19 |
| Treatment A | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Formoterol | 0.08911 1/hour | Geometric Coefficient of Variation 36.39 |
| Treatment B (Replicate 1) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Glycopyrronium | 0.06010 1/hour | Geometric Coefficient of Variation 92.16 |
| Treatment B (Replicate 1) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Budesonide | 0.1538 1/hour | Geometric Coefficient of Variation 25.24 |
| Treatment B (Replicate 1) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Formoterol | 0.08926 1/hour | Geometric Coefficient of Variation 36.5 |
| Treatment B (Replicate 2) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Budesonide | 0.1500 1/hour | Geometric Coefficient of Variation 24.99 |
| Treatment B (Replicate 2) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Formoterol | 0.08625 1/hour | Geometric Coefficient of Variation 39.39 |
| Treatment B (Replicate 2) | Terminal Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve (λz) | Glycopyrronium | 0.03853 1/hour | Geometric Coefficient of Variation 100.5 |
Secondary
Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)
The tmax of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Glycopyrronium | 0.03 Hours |
| Treatment A | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Budesonide | 0.35 Hours |
| Treatment A | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Formoterol | 0.08 Hours |
| Treatment B (Replicate 1) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Glycopyrronium | 0.03 Hours |
| Treatment B (Replicate 1) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Budesonide | 0.33 Hours |
| Treatment B (Replicate 1) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Formoterol | 0.08 Hours |
| Treatment B (Replicate 2) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Budesonide | 0.33 Hours |
| Treatment B (Replicate 2) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Formoterol | 0.08 Hours |
| Treatment B (Replicate 2) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Glycopyrronium | 0.03 Hours |
Secondary
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F)
The Vz/F of budesonide, glycopryrronium and formoterol in participants was evaluated.
Time frame: Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all participants in the safety analysis set for whom at least one primary PK parameter could be calculated and who had no IPDs or AEs thought to impact the analysis of the PK data. Here, N = number of participants analyzed refers to n = number analyzed for this outcome measure at specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Glycopyrronium | 5695 Liters (L) | Geometric Coefficient of Variation 43.16 |
| Treatment A | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1049 Liters (L) | Geometric Coefficient of Variation 47.84 |
| Treatment A | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 1734 Liters (L) | Geometric Coefficient of Variation 32.78 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Glycopyrronium | 5908 Liters (L) | Geometric Coefficient of Variation 46.44 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1012 Liters (L) | Geometric Coefficient of Variation 39.18 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 1773 Liters (L) | Geometric Coefficient of Variation 33.69 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1064 Liters (L) | Geometric Coefficient of Variation 45.06 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 1782 Liters (L) | Geometric Coefficient of Variation 36.52 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Glycopyrronium | 6182 Liters (L) | Geometric Coefficient of Variation 44.59 |