Explorative Clinical Investigation to Investigate the Ability of PreciseInhale to Direct Regional Lung Targeting and Reduce the Degree of Throat Deposition and Subsequent Gastrointestinal Absorption in Healthy Volunteers After Inhalation of Test Drug Substances Via the PreciseInhale System

Intended use The PreciseInhale system is a benchtop aerosol generation and dispensation system set up for extracting aerosol from clinical inhalers. The PreciseInhale system is classified as a Class IIa device according to MDD Annex IX, Rule 11.

PreciseInhale is intended to administer test drug substances in precise doses by producing exact amounts of inhalable aerosols from a clinical inhaler.

Extraction of the aerosol and exposure to humans must comply with operator and test subject safety regulations and only conducted in accordance with permits from the Swedish Medical Products Agency (MPA) and Swedish Ethical Review Authority (SERA) if necessary.

Indication PreciseInhale is not intended to treat any specific condition that requires medical attention. The purpose of the clinical investigation is to prove that the principle of operation of PreciseInhale is useful for administration of aerosols to humans.

Methodology Screening (Visit 1) will take place from Day -35 to Day 1 and will include general health assessments and an eligibility check.

At Visits 2 to 9, subjects will be admitted to the research clinic on Day -1 and will remain at the research clinic for PK and safety assessments until at least 12 hours after a single dose fluticasone propionate/salmeterol 250/25 µg is administered on the morning of Day 1 (Visit 2, 4, 6 and 8). The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs and ECG will be checked at pre-determined timepoints. There is immediate access to equipment and qualified staff in case of an emergency.

Fluticasone propionate/salmeterol will be administered to each subject via the Evohaler or the PreciseInhale system, in the morning of Day 1 of each treatment period.

The 4 treatment periods will include these 4 inhalation sessions (up to 5 minutes/per session):

• Single dose inhalation of fluticasone propionate/salmeterol 250 µg/25 µg administered via the Evohaler in accordance with instruction in the SmPC for Seretide Evohaler forte.
• Single dose of fluticasone propionate/salmeterol 250 µg/25 µg administered via the PreciseInhale system set up for whole lung exposure. The entire 300 mL aerosol volume produced by the single dose from the inhaler will be inhaled at a flow rate in accordance with instructions for the Evohaler.
• A subdivided dose of fluticasone propionate/salmeterol 250 µg/25 µg administered via the PreciseInhale system set up for six repetitive 70 mL Alveolar bolus/ Breath hold exposures. Each 70 mL bolus will be extracted from a freshly generated volume of 300 mL aerosol produced by actuation of a single dose from the inhaler.
• A subdivided dose of fluticasone propionate/salmeterol 250 µg/25 µg administered via the PreciseInhale system set up for six repetitive 70 mL Bronchial bolus/ Breath hold exposures. Each 70 mL bolus will be extracted from a freshly generated volume of 300 mL aerosol produced by actuation of a single dose from the inhaler.

Inhalations will be administered by trained study personnel and the subjects will receive inhalation training before each inhalation session.

Subjects will be served a light breakfast before each treatment administration. After 1 hour post dose, the meal intake is unrestricted within the meal selection available at the research clinic. Lunch, Snack, dinner and evening snack (optional) will be served approximately 4, 6, 9 and 12 hours post-dose, respectively. Fluids will be restricted 1 hour prior to dosing until 1 hour after dosing. An optional breakfast may be served in the morning of Day 2 before the subject leaves the clinic.

PK samples will be collected at 17 time points in each treatment period: pre-dose, 2, 4, 6, 15, 30, 45 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after treatment.

The subjects will be discharged from the research clinic in the evening of Day 1 (12 hours post treatment) and return to the research clinic in the morning (Visits 3, 5, 7 and 9; 24 hours post treatment) of Day 2 for PK sampling (and follow up safety assessments on the last Day 2).

There will be a wash-out period of at least 1 week between treatments. A follow-up telephone call (Visit 10, end-of-study) will be made 3-5 days after the last inhalation to follow-up on adverse events and device deficiencies.

A device user experience questionnaire will be completed by the study subject and PreciseInhale operator after all inhalation sessions with the PreciseInhale have been completed, i.e after the fourth inhalation session.

Inclusion criteria

• Willing and able to give written informed consent for participation in the study.
• Healthy male or female subject aged ≥18 and ≤30 years inclusive.
• Body Mass Index (BMI) ≥18 and ≤30 kg/m2 and weight ≥50 kg to ≤100 kg at screening.
• Clinically normal medical history, physical findings, vital signs and laboratory values at the time of screening, as judged by the Investigator.

Exclusion criteria

• History of any clinically significant disease or disorder (including clinically significant disease affecting the respiratory tract, thoracic deformities affecting lung function and/or lung volumes, muscle diseases affecting lung function and/or lung volumes and any known mouth or nasal passage deformities) which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• Any clinically significant illness, medical/surgical procedure or trauma within two weeks prior to the first inhalation with the investigational device, which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV).
• After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges:

• Systolic blood pressure > 140 mm Hg
• Diastolic blood pressure > 90 mm Hg
• Pulse < 40 or > 85 beats per minute
• Former regular daily smoker.
• Current smokers or users of nicotine products (including vaping/e-cigarettes). Irregular use of nicotine (e.g. smoking, snuffing, chewing tobacco, vaping) less than three times per week is allowed before the screening visit.
• FVC or FEV1 outside of normal ranges (depending on subject's gender, height and age) at screening.
• Female subjects who are pregnant or who are currently breast feeding.
• Administration of a new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment with less than one month before the first inhalation session.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity (including pollen allergy), as judged by the Investigator.
• History of hypersensitivity to drugs with a similar chemical structure or class to fluticasone or salmeterol, as judged by the Investigator.
• Positive screen for drugs of abuse or alcohol at screening or on admission to the research unit prior to any of the inhalation sessions.
• Current or history of alcohol abuse and/or use of anabolic steroids or drugs of abuse.
• Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening.
• Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.