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

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

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]).

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: Treatment A; Drug: Treatment B; Drug: Treatment C

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: David Han, Dr., PAREXEL Early Phase Clinical Unit-Los Angeles

Publications and helpful links

Helpful Links

• CSR Synopsis
• CSP & SAP

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Actual): May 17, 2021
• Study Completion (Actual): May 17, 2021

Study Registration Dates

• First Submitted: October 19, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (Actual): October 23, 2020

Study Record Updates

• Last Update Posted (Actual): January 23, 2023
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Hydrofluoroalkane; Formoterol; Budesonide; Metered dose inhaler; Glycopyrronium
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: D5985C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No