Clinical trial NCT02934607: A Study to Assess How Much Drug Reaches the Blood When Given From Symbicort pMDI With Spacer Compared to That of Symbicort pMDI Without Spacer in Healthy Volunteers
Official title: A Randomised, Open-Label, Single-Dose, Single-Centre, Crossover Study in Healthy Subjects to Assess the Relative Bioavailability of Symbicort pMDI 160/4.5µg Administered With a Spacer (With and Without Charcoal) and Symbicort pMDI 160/4.5µg Administered Without a Spacer (With and Without Charcoal)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Study is Being Conducted in Healthy Volunteers
Keywords: Asthma
Chronic obstructive pulmonary disease
Spacer device
Symbicort
Pressurized metered-dose inhaler
Relative bioavailability
Crossover
AstraZeneca
Safety
Activated charcoal
AeroChamber Plus Flow-Vu spacer device
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2016-10-17
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This study will be conducted to establish the relative bioavailability of budesonide and formoterol delivered via Symbicort pressurized metered-dose inhaler (pMDI) with and without a spacer device.

Administration under each condition will occur with the concomitant administration of activated charcoal to estimate exposure through the lung and without activated charcoal to estimate total systemic exposure.

Detailed description: Study Design:

This study will be a randomised, open-label, single-dose, crossover study in healthy subjects (males and females), performed at a single study centre.

The study will comprise:

* A screening period of maximum 28 days;
* Four treatment periods during which subjects will be resident from the afternoon before dosing with Symbicort until at least 24 hours after dosing; discharged on the morning of Day 2; and
* A final visit within 5 to 7 days after the last administration of Symbicort. There will be a minimum washout period of 3 days between each dose administration of Symbicort. Subjects will receive single doses of Symbicort on 4 occasions under fasted conditions. During screening, spirometry testing will be performed by a technologist or a qualified designee to ensure subjects perform adequate manoeuvres to achieve optimal lung function. Device and inhalation training will be conducted on admission to each treatment period, and prior to dosing on Day 1 of each treatment period.

Duration:

Approximately 7 weeks

Statistical Analysis:

* For total systemic exposure: Treatment B versus Treatment A
* For lung exposure: Treatment D versus Treatment C Treatment ratio will be assessed on the ratio of log-transformed Cmax, AUC0-t and AUC of budesonide and formoterol using a 2-sided 90% confidence interval (CI) approach based on a repeated measures analysis of variance (ANOVA) model including period and treatment as fixed effects, and subject as a random effect. The estimated treatment differences and the 90% CIs on the log scale will be back-transformed to obtain the Gmean ratios for each pair of treatments. The least squares means (and 95% CIs), Gmean ratios and 90% CIs will be tabulated for each comparison and analyte (budesonide and formoterol).

Sample Size:

The sample size is 56 to ensure adequate number of subjects are randomised and at least 44 evaluable subjects complete the study.

Assuming an intra-subject coefficient of variation (CV) of 33% (based on the variability of AUC0-12 for budesonide and AUC0-12 and Cmax for formoterol observed in a similarly designed crossover study in healthy adults), 44 evaluable subjects will give at least 80% power to show that the 90% CI for the treatment effects lies entirely within the range 0.8 to 1.25, i.e., would rule out a 20% change (on a log scale) in exposure to budesonide and formoterol.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy male and/or female subjects aged 18 years (inclusive) and older, with suitable veins for cannulation or repeated venipuncture.
3. Females must have a negative pregnancy test at screening and on first admission to the unit, must not be lactating.
4. Body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
5. Forced expiratory volume in 1 second (FEV1) ≥ 80% of predicted value and FEV1/Forced vital capacity (FVC) ratio ≥ 70%.
6. Non-smokers.

Exclusion Criteria:

1. 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 in the study.
2. History of diagnosed COPD or asthma. (Note: Subjects with a history of childhood asthma only will not be excluded from the study).
3. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
4. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
5. Any clinically significant abnormalities in clinical chemistry, 12-lead electrocardiogram (ECG) at screening, haematology, or urinalysis results at screening or vital signs at screening and first admission to the study unit.
6. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody.
7. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
8. Participation in another clinical study with a non-biologic investigational product or new formulation of a marketed non-biologic drug within 3 months prior to the screening visit.
9. Participation in another clinical trial with any marketed or investigational biologic within 4 months or 5 half-lives whichever is longer, prior to the screening visit.
10. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
11. History of severe or ongoing allergy/hypersensitivity (e.g., food allergy) or history of hypersensitivity to drugs with a similar chemical structure or class to Symbicort.
12. Positive screen for drugs of abuse, alcohol or cotinine at screening and on first admission to the study unit.
13. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
14. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. (Note: Hormonal contraception and hormonal replacement therapy are allowed for females, as applicable).
15. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
16. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
17. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Primary outcomes:
measure: Maximum observed plasma concentration (Cmax) of Symbicort pMDI administered with spacer device without charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC0-t) of Symbicort pMDI administered with spacer device without charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Cmax of Symbicort pMDI administered with spacer device with charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: AUC0-t of Symbicort pMDI administered with spacer device with charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Cmax of Symbicort pMDI administered without spacer device without charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: AUC0-t of Symbicort pMDI administered without spacer device without charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Cmax of Symbicort pMDI administered without spacer device with charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: AUC0-t of Symbicort pMDI administered without spacer device with charcoal
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
Secondary outcomes:
measure: AUC after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Tmax after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½,λz) after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Apparent volume of distribution during the terminal phase (extravascular administration) (Vz/F) after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Time of last quantifiable plasma concentration (tlast) after single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Terminal elimination rate constant (λz) after single doses of budesonide and formoterol delivered via Symbicort pMDI with space device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Percentage of subjects who experienced treatment-related adverse events (AEs) after administration of single doses of budesonide and formoterol delivered via Symbicort pMDI with spacer device
timeFrame: From signing the informed consent form until 5-7 days post final dose (approximately 7 weeks)
measure: AUC after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: tmax after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: t½,λz after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Vz/F after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: CL/F after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: tlast after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: λz after single doses of budesonide and formoterol delivered via Symbicort pMDI without spacer device
timeFrame: Pre-dose and at 5, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, 18 and 24 hours after Symbicort dosing
measure: Percentage of subjects who experienced treatment-related AEs after administration of single dose of budesonide and formoterol delivered via Symbicort pMDI without a spacer device
timeFrame: From signing the informed consent form until 5-7 days post final dose (approximately 7 weeks)
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit London, United Kingdom
name: Dr Rainard Fuhr, Dr. med
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gillen M, Forte P, Svensson JO, Lamarca R, Burke J, Rask K, Larsdotter Nilsson U, Eckerwall G. Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort(R) (budesonide/formoterol) pressurized metered dose inhaler. Pulm Pharmacol Ther. 2018 Oct;52:7-17. doi: 10.1016/j.pupt.2018.08.001. Epub 2018 Aug 2.