Chronic Obstructive Pulmonary Disease
Conditions
Keywords
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)
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.
Interventions
DRUGTreatment A (BGF MDI HFO with oral activated charcoal)
Subject will receive 4 inhalations as a single dose with oral activated charcoal - test formulation; administered during 1 Treatment Period.
DRUGTreatment B (BGF MDI HFA with oral activated charcoal)
Subject will received 4 inhalations as a single dose with oral activated charcoal - 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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hours (h), 2 h, 4 h, 8 h, 12h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | Bioequivalence (Cmax) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed. |
| Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | Bioequivalence (AUCinf) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed. |
| Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | Bioequivalence (AUClast) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The MRTinf PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
| Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The CL/F PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
| Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The tmax as PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
| Number of Participants With Adverse Events | From screening (Day -28 to Day -1) up to 55 days | The safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA with oral activated charcoal in healthy subjects was assessed. |
| Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The Vz/F PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
| Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The t½λz as PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
| Terminal Rate Constant (λz) | Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days) | The λz PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed. |
Countries
United States
Participant flow
Recruitment details
This study was conducted between 29 July 2022 to 11 April 2023 at a single study center - Parexel Early Phase Clinical Unit (Baltimore).
Pre-assignment details
The Screening period was up to 28 days. Informed Consent Form (ICF) was signed prior to screening procedures. All the study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence ABB Participant received 3 single dose treatment of Budesonide, Glycopyrronium, Formoterol (BGF) Metered Dose Inhaler (MDI) in 3 occasions.
Participant received BGF MDI Hydrofluoroolefin (HFO) (Treatment A); then BGF MDI Hydrofluoroalkane (HFA)(Treatment B); and then BGF MDI HFA (Treatment B) with oral activated charcoal prior and post dosing (A or B) on Day 1 with a washout period of 3 to 7 days between each dose. | 36 |
| Treatment Sequence BAB Participant received 3 single dose treatment of BGF MDI in 3 occasions. Participant received BGF MDI HFA (Treatment B); then BGF MDI HFO (Treatment A); and then BGF MDI HFA (Treatment B) with oral activated charcoal prior and post dosing (A or B) on Day 1 with a washout period of 3 to 7 days between each dose. | 36 |
| Treatment Sequence BBA Participant received 3 single dose treatment of BGF MDI in 3 occasions. Participant received BGF MDI HFA (Treatment B); then BGF MDI HFA (Treatment B); and then BGF MDI HFO (Treatment A) with oral activated charcoal prior and post dosing (A or B) on Day 1 with a washout period of 3 to 7 days between each dose. | 36 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Participants randomized, not treated | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | withdrawn from study | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment Sequence ABB | Treatment Sequence BAB | Treatment Sequence BBA | Total |
|---|---|---|---|---|
| Age, Continuous | 37.9 Years STANDARD_DEVIATION 10.5 | 37.8 Years STANDARD_DEVIATION 11.7 | 38.6 Years STANDARD_DEVIATION 11.1 | 38.1 Years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 24 Participants | 19 Participants | 64 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 10 Participants | 13 Participants | 35 Participants |
| Sex: Female, Male Female | 14 Participants | 15 Participants | 17 Participants | 46 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 19 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 103 | 0 / 105 | 0 / 104 |
| other Total, other adverse events | 12 / 103 | 19 / 105 | 4 / 104 |
| serious Total, serious adverse events | 0 / 103 | 0 / 105 | 0 / 104 |
Outcome results
Primary
Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf)
Bioequivalence (AUCinf) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Glycopyrronium | 45.66 hour (h)*pg/mL | Geometric Coefficient of Variation 245.3 |
| Treatment A | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Budesonide | 2533 hour (h)*pg/mL | Geometric Coefficient of Variation 61.57 |
| Treatment A | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Formoterol | 54.12 hour (h)*pg/mL | Geometric Coefficient of Variation 85.9 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Glycopyrronium | 33.60 hour (h)*pg/mL | Geometric Coefficient of Variation 223.9 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Budesonide | 2479 hour (h)*pg/mL | Geometric Coefficient of Variation 61.34 |
| Treatment B (Replicate 1) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Formoterol | 53.36 hour (h)*pg/mL | Geometric Coefficient of Variation 85.09 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Budesonide | 2507 hour (h)*pg/mL | Geometric Coefficient of Variation 76.08 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Formoterol | 53.70 hour (h)*pg/mL | Geometric Coefficient of Variation 111.9 |
| Treatment B (Replicate 2) | Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf) | Glycopyrronium | 64.50 hour (h)*pg/mL | Geometric Coefficient of Variation 271.8 |
Comparison: Statistical Comparison of Key Budesonide Pharmacokinetic Parameters (US approach)90% CI: [100.35, 115.72]
Comparison: Statistical Comparison of Key Glycopyrronium Pharmacokinetic Parameters (US approach)90% CI: [92.27, 136.49]
Comparison: Statistical Comparison of Key Formoterol Pharmacokinetic Parameters (US approach)90% CI: [91.76, 112.15]
Primary
Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast)
Bioequivalence (AUClast) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 25.11 hours (h)*pg/mL | Geometric Coefficient of Variation 182.1 |
| Treatment A | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 2460 hours (h)*pg/mL | Geometric Coefficient of Variation 63.25 |
| Treatment A | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 36.47 hours (h)*pg/mL | Geometric Coefficient of Variation 112.8 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 20.34 hours (h)*pg/mL | Geometric Coefficient of Variation 190.9 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 2398 hours (h)*pg/mL | Geometric Coefficient of Variation 62.89 |
| Treatment B (Replicate 1) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 35.68 hours (h)*pg/mL | Geometric Coefficient of Variation 117.6 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Budesonide | 2421 hours (h)*pg/mL | Geometric Coefficient of Variation 78.43 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Formoterol | 35.83 hours (h)*pg/mL | Geometric Coefficient of Variation 160.9 |
| Treatment B (Replicate 2) | Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast) | Glycopyrronium | 34.58 hours (h)*pg/mL | Geometric Coefficient of Variation 180.3 |
Comparison: Statistical Comparison of Key Budesonide Pharmacokinetic Parameters (US approach)90% CI: [99.3, 115.01]
Comparison: Statistical Comparison of Key Glycopyrronium Pharmacokinetic Parameters (US approach)90% CI: [89.12, 116.79]
Comparison: Statistical Comparison of Key Formoterol Pharmacokinetic Parameters (US approach)90% CI: [94.91, 122.36]
Comparison: Statistical Comparison of Key Budesonide Pharmacokinetic Parameters (EU approach)90% CI: [98.39, 114.41]
Comparison: Statistical Comparison of Key Glycopyrronium Pharmacokinetic Parameters (EU approach)90% CI: [84.18, 111.82]
Comparison: Statistical Comparison of Key Formoterol Pharmacokinetic Parameters (EU approach)90% CI: [92.59, 120.75]
Primary
Maximum Observed Plasma (Peak) Drug Concentration (Cmax )
Bioequivalence (Cmax) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hours (h), 2 h, 4 h, 8 h, 12h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Glycopyrronium | 14.31 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 98.78 |
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Budesonide | 1078 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 61.09 |
| Treatment A | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Formoterol | 18.82 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 75.45 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Glycopyrronium | 15.22 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 96.13 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Budesonide | 1111 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 63.42 |
| Treatment B (Replicate 1) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Formoterol | 19.31 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 74.53 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Budesonide | 1045 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 73.36 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Formoterol | 19.35 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 80.39 |
| Treatment B (Replicate 2) | Maximum Observed Plasma (Peak) Drug Concentration (Cmax ) | Glycopyrronium | 15.17 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 92.85 |
Comparison: Statistical Comparison of Key Budesonide Pharmacokinetic Parameters (US approach)90% CI: [95.78, 113.44]
Comparison: Statistical Comparison of Key Glycopyrronium Pharmacokinetic Parameters (US approach)90% CI: [84.31, 103.58]
Comparison: Statistical Comparison of Key Formoterol Pharmacokinetic Parameters (US approach)90% CI: [91.9, 109.11]
Comparison: Statistical Comparison of Key Budesonide Pharmacokinetic Parameters (EU approach)90% CI: [94.44, 112.6]
Comparison: Statistical Comparison of Key Glycopyrronium Pharmacokinetic Parameters (EU approach)90% CI: [85.29, 102.26]
Comparison: Statistical Comparison of Key Formoterol Pharmacokinetic Parameters (EU approach)90% CI: [91.44, 108.71]
Secondary
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)
The CL/F PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 630.7 Litre/hour (L/h) | Geometric Coefficient of Variation 245.3 |
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 250.7 Litre/hour (L/h) | Geometric Coefficient of Variation 61.57 |
| Treatment A | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 354.8 Litre/hour (L/h) | Geometric Coefficient of Variation 85.9 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 857.2 Litre/hour (L/h) | Geometric Coefficient of Variation 223.9 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 258.2 Litre/hour (L/h) | Geometric Coefficient of Variation 61.34 |
| Treatment B (Replicate 1) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 359.8 Litre/hour (L/h) | Geometric Coefficient of Variation 85.09 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Budesonide | 255.2 Litre/hour (L/h) | Geometric Coefficient of Variation 76.08 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Formoterol | 357.5 Litre/hour (L/h) | Geometric Coefficient of Variation 111.9 |
| Treatment B (Replicate 2) | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) | Glycopyrronium | 446.5 Litre/hour (L/h) | Geometric Coefficient of Variation 271.8 |
Secondary
Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz)
The t½λz as PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| 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 | 9.063 hours | Geometric Coefficient of Variation 300.9 |
| Treatment A | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Budesonide | 3.661 hours | Geometric Coefficient of Variation 32.13 |
| Treatment A | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Formoterol | 6.997 hours | Geometric Coefficient of Variation 53.32 |
| Treatment B (Replicate 1) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Glycopyrronium | 6.025 hours | Geometric Coefficient of Variation 308.2 |
| Treatment B (Replicate 1) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Budesonide | 3.304 hours | Geometric Coefficient of Variation 30.86 |
| Treatment B (Replicate 1) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Formoterol | 6.444 hours | Geometric Coefficient of Variation 64.95 |
| Treatment B (Replicate 2) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Budesonide | 3.656 hours | Geometric Coefficient of Variation 33.6 |
| Treatment B (Replicate 2) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Formoterol | 7.082 hours | Geometric Coefficient of Variation 77.98 |
| Treatment B (Replicate 2) | Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz) | Glycopyrronium | 13.30 hours | Geometric Coefficient of Variation 302.7 |
Secondary
Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf)
The MRTinf PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| 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) | Glycopyrronium | 12.04 hours | Geometric Coefficient of Variation 294.9 |
| Treatment A | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 3.893 hours | Geometric Coefficient of Variation 21.04 |
| Treatment A | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 9.139 hours | Geometric Coefficient of Variation 51.58 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Glycopyrronium | 7.991 hours | Geometric Coefficient of Variation 295 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 3.771 hours | Geometric Coefficient of Variation 23.43 |
| Treatment B (Replicate 1) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 8.497 hours | Geometric Coefficient of Variation 62.87 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Budesonide | 3.978 hours | Geometric Coefficient of Variation 22.85 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Formoterol | 9.254 hours | Geometric Coefficient of Variation 75.92 |
| Treatment B (Replicate 2) | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf) | Glycopyrronium | 18.30 hours | Geometric Coefficient of Variation 293 |
Secondary
Number of Participants With Adverse Events
The safety and tolerability of single doses of BGF MDI HFO and BGF MDI HFA with oral activated charcoal in healthy subjects was assessed.
Time frame: From screening (Day -28 to Day -1) up to 55 days
Population: The safety analysis set included all participants who received at least 1 inhalation of any BGF MDI.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A | Number of Participants With Adverse Events | Any AE | 12 Participants |
| Treatment A | Number of Participants With Adverse Events | Any SAE | 0 Participants |
| Treatment A | Number of Participants With Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment A | Number of Participants With Adverse Events | Any AE leading to discontinuation of study intervention | 0 Participants |
| Treatment A | Number of Participants With Adverse Events | Any possibly related AE | 4 Participants |
| Treatment A | Number of Participants With Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any AE | 19 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any AE leading to discontinuation of study intervention | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any possibly related AE | 6 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any SAE | 0 Participants |
| Treatment B (Replicate 1) | Number of Participants With Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any SAE | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any AE leading to discontinuation of study intervention | 0 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any AE | 4 Participants |
| Treatment B (Replicate 2) | Number of Participants With Adverse Events | Any possibly related AE | 2 Participants |
Secondary
Terminal Rate Constant (λz)
The λz PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Terminal Rate Constant (λz) | Glycopyrronium | 0.07648 1/hour | Geometric Coefficient of Variation 300.9 |
| Treatment A | Terminal Rate Constant (λz) | Budesonide | 0.1893 1/hour | Geometric Coefficient of Variation 32.13 |
| Treatment A | Terminal Rate Constant (λz) | Formoterol | 0.09907 1/hour | Geometric Coefficient of Variation 53.32 |
| Treatment B (Replicate 1) | Terminal Rate Constant (λz) | Glycopyrronium | 0.1151 1/hour | Geometric Coefficient of Variation 308.2 |
| Treatment B (Replicate 1) | Terminal Rate Constant (λz) | Budesonide | 0.2098 1/hour | Geometric Coefficient of Variation 30.86 |
| Treatment B (Replicate 1) | Terminal Rate Constant (λz) | Formoterol | 0.1076 1/hour | Geometric Coefficient of Variation 64.95 |
| Treatment B (Replicate 2) | Terminal Rate Constant (λz) | Budesonide | 0.1896 1/hour | Geometric Coefficient of Variation 33.6 |
| Treatment B (Replicate 2) | Terminal Rate Constant (λz) | Formoterol | 0.09787 1/hour | Geometric Coefficient of Variation 77.98 |
| Treatment B (Replicate 2) | Terminal Rate Constant (λz) | Glycopyrronium | 0.05213 1/hour | Geometric Coefficient of Variation 302.7 |
Secondary
Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)
The tmax as PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Glycopyrronium | 0.05 hours |
| Treatment A | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Budesonide | 0.33 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 | 0.07 hours |
| Treatment B (Replicate 1) | Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax) | Budesonide | 0.32 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 | 0.05 hours |
Secondary
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F)
The Vz/F PK profiles of BGF administered as BGF MDI HFO and BGF MDI HFA with oral activated charcoal was assessed.
Time frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Population: The PK analysis set consisted of all randomized participants who had at least 1 primary PK parameter that could be calculated, and who had no important protocol deviations thought to impact on the analysis of the PK data. Here, number of participants analyzed refers to number analyzed for each specific outcome measure.
| 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 | 8247 Litre (L) | Geometric Coefficient of Variation 41.09 |
| Treatment A | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1324 Litre (L) | Geometric Coefficient of Variation 57.12 |
| Treatment A | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 3581 Litre (L) | Geometric Coefficient of Variation 49.08 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Glycopyrronium | 7451 Litre (L) | Geometric Coefficient of Variation 53.3 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1231 Litre (L) | Geometric Coefficient of Variation 59.34 |
| Treatment B (Replicate 1) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 3345 Litre (L) | Geometric Coefficient of Variation 49.9 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Budesonide | 1346 Litre (L) | Geometric Coefficient of Variation 69.25 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Formoterol | 3653 Litre (L) | Geometric Coefficient of Variation 46.55 |
| Treatment B (Replicate 2) | Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F) | Glycopyrronium | 8566 Litre (L) | Geometric Coefficient of Variation 44.65 |