Study to Assess the Biochemical Similarity of Budesonide and Albuterol With an Alternate Propellant Compared to Current Propellant.

Study Overview
=================
Brief Summary
-----------------
This study will investigate the Pharmacokinetic (PK) and safety of Budesonide and albuterol (BDA) metered dose inhaler (MDI) HFO and BDA MDI HFA in healthy male and female participants.

Detailed Description
-----------------
Eligible participant will receive 3 single-dose treatments; 2 doses of BDA MDI HFA and 1 dose of BDA MDI HFO. Treatment A: 2 inhalations, single dose of BDA MDI HFO 80/90 μg (test formulation) Treatment B: 2 inhalations, single dose of BDA MDI HFA 80/90 μg (reference formulation) Participants will be randomly assigned to receive any 1 of the 3 treatment sequences of ABB, BBA or BAB. The study will comprise of: A screening period of maximum 28 days. Three Treatment periods will be up to approximately 22 days (including Follow-up). A final follow-up calls within 3-7 days after the last dose of study intervention. Each participant has to be involved in the study for up to 48 days.

Official Title
-----------------
A Phase 1, Randomized, Double-blind, Single-dose, Partial Replicate, 3-period Cross-over Study to Assess the Total Systemic Exposure Bioequivalence of Budesonide and Albuterol Delivered by BDA MDI Hydrofluoroolefin (HFO) Compared With BDA MDI (Hydrofluoroalkene) HFA.

Conditions
-----------------
Heathy Participants

Intervention / Treatment
-----------------
* Drug: Treatment A (BDA MDI HFO)
* Drug: Treatment B (BDA MDI HFA)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female participants (of non-childbearing potential) aged 18 to 60 years, inclusive, with suitable veins for cannulation or repeated venipuncture. Female participants must have a negative pregnancy test at screening and on admission and must not be lactating. Participants with Body mass index between 18 and 30 kg/m^2, inclusive, and weighing between 50 kg and no more than 120 kg inclusive. Participants must have a Forced expiratory volume (FEV)1 ≥ 80% of the predicted normal value and an FEV1/FVC> 70% regarding age, height, and ethnicity at the screening visit. Participants must demonstrate proper inhalation technique and is able to use an MDI properly after training. Exclusion Criteria: History or presence of gastrointestinal, hepatic or renal disease, or any other clinically significant disease or disorder. History of any clinically significant disease or disorder which may either put the participant at risk because of participation in the study or influence the results or the participant's ability to participate in the study. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study drug. Any clinically important abnormalities in clinical chemistry, haematology, or urinalysis results at the screening. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, or Human immunodeficiency virus (HIV). Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 lead ECG. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 3 months prior to screening. Known or suspected history of alcohol or drug abuse. Positive screen for drugs of abuse, alcohol, or cotinine at screening. History or presence of severe allergy/hypersensitivity. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of the study drug. Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks or 5 half-lives of the medication, whichever is longer, prior to the first administration of study drug. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening. Excessive intake of caffeine-containing drinks or food. Vulnerable participants.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a Partial-replicate, 3-period Cross-over study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence ABB<br>Participants will receive Treatment A, followed by Treatment B, followed by Treatment B, all treatments as a single dose, with a washout period of minimum 3 days, but no longer than 7 days, between each study dose administration. | Drug: Treatment A (BDA MDI HFO)<br>* Randomized participants will receive Treatment A (BDA MDI HFO) on Day 1 under fasted condition.<br>Drug: Treatment B (BDA MDI HFA)<br>* Randomized participants will receive Treatment B (BDA MDI HFA) on Day 1 under fasted condition.<br>|
| Experimental: Treatment sequence BBA<br>Participants will receive Treatment B, followed by Treatment B, followed by Treatment A, all treatments as a single dose, with a washout period of minimum 3 days, but no longer than 7 days, between each study dose administration. | Drug: Treatment A (BDA MDI HFO)<br>* Randomized participants will receive Treatment A (BDA MDI HFO) on Day 1 under fasted condition.<br>Drug: Treatment B (BDA MDI HFA)<br>* Randomized participants will receive Treatment B (BDA MDI HFA) on Day 1 under fasted condition.<br>|
| Experimental: Treatment sequence BAB<br>Participants will receive Treatment B, followed by Treatment A, followed by Treatment B, all treatments as a single dose, with a washout period of minimum 3 days, but no longer than 7 days, between each study dose administration. | Drug: Treatment A (BDA MDI HFO)<br>* Randomized participants will receive Treatment A (BDA MDI HFO) on Day 1 under fasted condition.<br>Drug: Treatment B (BDA MDI HFA)<br>* Randomized participants will receive Treatment B (BDA MDI HFA) on Day 1 under fasted condition.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) | The AUClast of budesonide and albuterol will be evaluated to assess the bioequivalence of the total systemic exposure of budesonide and albuterol administered. | Day 1, Day 2 (pre-dose and post-dose) | 
| Maximum plasma drug concentration (Cmax) | The Cmax of budesonide and albuterol will be evaluated to assess the bioequivalence of the total systemic exposure of budesonide and albuterol administered. | Day 1, Day 2 (pre-dose and post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve from time 0 to infinity (AUCinf) | The AUCinf after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Time to reach maximum observed concentration (Tmax) | The Tmax after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Terminal elimination half-life (T1/2λz) | The T1/2λz after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT) | The MRT after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Apparent total body clearance (CL/F) | The CL/F after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Apparent volume of distribution during the terminal phase (Vz/F) | The Vz/F after administration of budesonide and albuterol will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Ratio Maximum plasma drug concentration (Cmax) | The ratio of Treatment A (test formulation) and Treatment B (reference formulation) Cmax values will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Ratio Area under plasma concentration-time curve from time 0 to infinity (AUCinf) | The ratio of Treatment A (test formulation) and Treatment B (reference formulation) AUCinf values will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Ratio Are under plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) | The ratio of Treatment A (test formulation) and Treatment B (reference formulation) AUClast values will be evaluated. | Day 1, Day 2 (pre-dose and post-dose) | 
| Number of participants with Adverse Events | The safety and tolerability of single doses of BDA MDI HFO and BDA MDI HFA will be evaluated. | From Screening (≤ 28 days to Day -2) until Follow-up phone call (within 3 to 7 days post final dose) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Albuterol, Budesonide, Combination product, Hydrofluoralkene propellant, Hydrofluoroolefin propellant