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
Condition: Study is Being Conducted in Healthy Volunteers
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Symbicort pMDI with spacer device; Symbicort pMDI without spacer device
Intervention type(s): Drug; Drug
Intervention description(s): Relative bioavailability of budesonide and formoterol delivered via Symbicort pressurized metered-dose inhaler (pMDI) with a spacer device (test); Relative bioavailability of budesonide and formoterol delivered via Symbicort pMDI without a spacer device (reference)
Intervention MeSH terms: Budesonide, Formoterol Fumarate Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
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