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

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ClinicalTrials.gov Identifier: NCT04600505
Recruitment Status : Completed
First Posted : October 23, 2020
Last Update Posted : February 10, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE October 19, 2020
First Posted Date  ICMJE October 23, 2020
Last Update Posted Date February 10, 2021
Actual Study Start Date  ICMJE October 19, 2020
Actual Primary Completion Date January 18, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2020)
  • Maximum observed concentration (Cmax) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Evaluation of the relative bioavailability between the test formulations and the reference formulation for fixed dose combinations (FDCs) of BGF when delivered as BGF MDI with 3 different propellants by Cmax.
  • Area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUCinf.
  • Area under the plasma concentration- curve from time zero to the time of last quantifiable concentration (AUClast) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
  • Maximum observed concentration (Cmax) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    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 Cmax.
  • Area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUCinf.
  • Area under the plasma concentration- curve from time zero to the time of last quantifiable concentration (AUClast) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
  • Time to reach maximum observed concentration (tmax) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the pharmacokinetic (PK) parameters of BGF when administered as 3 different propellant formulations by tmax.
  • Terminal elimination half-life (t½λz) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by t½λz.
  • Mean residence time in the systemic circulation extrapolated to infinity (MRT) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by MRT.
  • Terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by λz.
  • Apparent total body clearance of drug after extravascular administration (CL/F) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by CL/F.
  • Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by Vz/F.
  • Treatment ratio for Cmax derived by dividing the Cmax of the test treatment by the reference treatment (TRCmax) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRCmax.
  • Treatment ratio for AUCinf, derived by dividing the AUCinf of the test treatment by the reference treatment (TRAUCinf) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRAUCinf.
  • Treatment ratio for AUClast derived by dividing the AUClast of the test treatment by the reference treatment (TRAUClast) of BGF MDI [ Time Frame: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose ]
    Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRAUClast.
  • Number of participants with serious adverse events (SAE) and non-serious adverse events [ Time Frame: Screening (Only SAE), Days -1, 1, and Day 2 until Follow-up visit (approximately 3 to 7 days post final dose) ]
    Assessment of the safety and tolerability of a combination of BGF when administered as single doses in 3 different propellant formulations in healthy participants.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess Drug Absorption of Fixed Dose Combinations of Budesonide, Glycopyrronium, and Formoterol
Official Title  ICMJE 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
Brief Summary The study will evaluate bioavailability, pharmacokinetics, safety, and tolerability of budesonide, glycopyrronium and formoterol (BGF) metered dose inhaler (MDI) formulated with 3 different propellants: Propellant 1 (Treatment A [test]), Propellant 2 (Treatment B [test]) and Hydrofluoroalkane (HFA) (Treatment C [reference]).
Detailed Description

The study will comprise:

  • Screening period: up to 28 days prior to first dosing;
  • Three treatment periods of maximum 3 days each: participants will be resident from the morning of the day before the first dosing with BGF MDI (Day -1) in Treatment Period 1, throughout all treatment and washout periods up to discharge on Day 2 of Treatment Period 3;
  • Follow-up: within 3 to 7 days after the last administration of BGF MDI. There will be a washout period of 3 to 7 days between each dose.

Each participant will receive 3 single-dose treatments of BGF MDI (1 dose Propellant 1 [Treatment A]; 1 dose Propellant 2 [Treatment B] and 1 dose HFA [Treatment C]), following an overnight fast of at least 8 hours. Each participant will be involved in the study for up to 53 days.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Masking Description:
This is a single blind study with regard to BGF MDI treatment, administered with 3 different propellants (Treatment A, B or C), in which the participants will remain blinded.
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease (COPD)
Intervention  ICMJE
  • Drug: Treatment A
    Participants will receive 2 inhalations of BGF MDI with propellant 1.
    Other Name: BGF MDI Propellant 1
  • Drug: Treatment B
    Participants will receive 2 inhalations of BGF MDI with propellant 2.
    Other Name: BGF MDI Propellant 2
  • Drug: Treatment C
    Participants will receive 2 inhalations of BGF MDI with HFA propellant.
    Other Name: BGF MDI HFA
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
  • 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.
    Interventions:
    • Drug: Treatment A
    • Drug: Treatment B
    • Drug: Treatment C
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 9, 2021)
23
Original Estimated Enrollment  ICMJE
 (submitted: October 19, 2020)
24
Actual Study Completion Date  ICMJE January 18, 2021
Actual Primary Completion Date January 18, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04600505
Other Study ID Numbers  ICMJE D5985C00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.

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

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

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Parexel
Investigators  ICMJE
Principal Investigator: David Han, Dr. PAREXEL Early Phase Clinical Unit-Los Angeles
PRS Account AstraZeneca
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP