Comparison of Esophageal Clearance Times of Oral Budesonide Preparations
Condition: Eosinophilic Esophagitis
MeSH terms: Esophagitis; Eosinophilic Esophagitis
Study type: Interventional

Summary: 
      The purpose of this study is to determine if a xanthan gum or honey based budesonide slurry
      exhibit comparable mucosal contact time to a budesonide/sucralose slurry in healthy adult
      subjects.
    

Detailed description: 
      This study will be a blinded randomized cross over trial study, comparing one of two
      alternative slurries (xanthan gum or honey) against the current standard sucralose slurry in
      each subject and determining esophageal clearance for each.

      A total of 24, up to 30 healthy adult subjects will be enrolled and randomized to their
      treatment group by sequentially numbered, opaque, sealed envelopes (SNOSE) prepared by an
      uninvolved third party. These envelopes will be labeled numerically "Subject 1" through
      "Subject 24", and will randomly contain which treatment will be administered, and in what
      order. If additional subjects are recruited, 6 additional SNOSE will be prepared in a similar
      manner. There will be 4 types envelopes prepared- Sucralose-Xanthan Gum, Xanthan
      Gum-sucralose, Sucralose-Honey and Honey-Sucralose. One of these regimens will be randomly
      inserted into an opaque envelope as described previously and sealed. The envelope will be
      given to the subject after enrollment and consent, and will be opened by the nuclear medicine
      pharmacist to determine the assigned preparation that will be compounded and administered.
      Subjects will be randomized in a 1:1:1:1 ratio using a computer program based on random
      number generation.

      The sucralose slurry will consist of 10 grams of sucralose mixed with 4ml of 0.5mg/2ml
      nebulized budesonide solution (for a total budesonide dose of 1mg) and 1mCi (1ml) of Tc99
      sulfur colloid for a total volume of approximately 10ml.

      The honey slurry will consist of 5ml of honey mixed with 4ml of 0.5mg/2ml nebulized
      budesonide solution (for a total budesonide dose of 1mg) and 1mCi (1ml) of Tc99 sulfur
      colloid for a total volume of approximately 10ml.

      The xanthan gum slurry will consist of 50mg xanthan gum powder mixed with 4ml of a 0.5mg/2ml
      nebulized budesonide solution (for a total budesonide dose of 1mg), along with a flavoring
      packet of cold pressed crystallized orange flavor and 1mCi (1ml) of Tc99 sulfur colloid and
      5ml of distilled water for a total volume of approximately 10ml.

      The study technician, interpreting radiologist and study coordinators will be blinded to the
      type of slurry ingested. Each subject will be asked to guess which of the three slurries
      he/she received following consumption of each slurry. In addition, the subject will complete
      the hedonic general labeled magnitude scale (h-gLMS) following consumption of each slurry.

      Data will be collected at initial entry (age, sex, race, height, complete blood cell count )
      and recorded on a data spreadsheet. The first swallow study will be recorded as a time
      interval (1 second intervals from initial swallow until 10 minutes have elapsed) as a count
      of tracer in the esophagus, from which an area under the curve of total esophageal contact
      time will be calculated. After a 1 hour "washout" period and two 8 oz glasses of water are
      ingested the second slurry will be administered and the data from the same time points will
      be collected. This data will be obtained from the nuclear medicine department. The same
      individual will denote the areas of interest on the nuclear medicine study (upper to lower
      esophagus) as well as obtain, record, and calculate clearances to eliminate inter-operator
      variability. This technique is validated and is currently utilized to determine esophageal
      clearance for the diagnosis of achalasia in adults and will utilize the same camera and
      protocol (NM 250- Esophageal Transit Study). Data results will be plotted as quantity of
      tracer remaining (y axis) vs time (x axis) to calculate a total Area Under the Curve (amount
      remaining at each time point summed until all tracer has cleared).

      In a previous study comparing nebulized and viscous topical corticosteroid treatments (Dellon
      et al, Gastroenterology 2012;143:321-324), the mucosal medication contact time measured by
      scintigraphy and represented by the area under the curve (AUC) for the overall esophagus. The
      AUC was higher for the oral viscous slurry group (median=48,900) compared to the
      nebulized/swallowing group (median=19,200), p=0.005.

      The measurement units, range and standard deviation for these contact time AUCs were not
      provided. There is also no data provided on within subject changes for any outcomes.

      Attempting to extrapolate the expected variability in the AUCs in this study, standard
      deviations of ~29000 for the oral viscous slurry group and ~11400 for the
      nebulized/swallowing group would result in a similar P value. Both of these theoretical
      standard deviations are ~60% of the medians.

      1. Assumptions for sample size estimation for the comparisons of the standard oral viscous
      slurry to an experimental slurry):

        1. The mean AUC for the oral viscous slurry treatment (the 'standard') will be 48,900, with
           a standard deviation of 29,000.

        2. For each group of subjects (xanthan gum and honey), the probability of a Type I error is
           controlled at α=0.05.

        3. There will be no crossover or carryover effect.

      If the study design was not a crossover and two separate groups were studied (one receiving
      the standard slurry and the other receiving the experimental slurry), a sample of 13 subjects
      per group would have 80% power to detect a difference of 24450 in AUC (i.e. a 50% change from
      the standard oral viscous slurry).

      Given that this study design has each subject measured for both the standard and experimental
      slurries, we assume that there will be a correlation between studies (r=0.70, within subject
      standard deviation of 22,460) and we anticipate that a sample of 12 subjects will have 80%
      power to detect a change of 20000 between oral viscous slurry and the experimental slurry
      (either honey or gum).

      To allow for dropouts, up to 30 subjects will be recruited for this within-subject comparison
      in the study.

      Data Analysis Plan:

        1. Demographic characteristics of the study groups will be presented using means with
           standard deviations and counts with percentages.

        2. A patient flow diagram will be presented to describe the recruitment process (i.e.
           number of subjects consented, number of withdrawals), randomization and completion
           rates.

        3. The primary outcome is the the mucosal medication contact time measured by scintigraphy
           and represented by the area under the curve (AUC) for the overall esophagus. A secondary
           outcome will be the number of total seconds until 100% clearance.

        4. Two separate experiments will be analyzed: Comparison of xanthan gum to budesonide and
           comparison of honey to budesonide. With the AUC as the dependent variable, repeated
           measures analysis of variance for the crossover design will be used to compare slurries
           and the order of testing.

        5. Secondary outcomes will be the number of seconds until clearance and the taste of the
           substance as measured by gLMS. Repeated measures analysis of variance for the crossover
           design will be used to compare slurries and the order of testing.

        6. Differences in AUC and taste between honey and xanthan gum will be explored using a two
           sample t-test or Wilcoxon rank sum test as appropriate
    

Intervention name(s): Xanthan Gum; Honey
Intervention type(s): Other; Other
Intervention description(s): esophageal mucosal contact time vs sucralose slurry; esophageal mucosal contact time of honey vs sucralose slurry
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Keywords: slurry; splenda; sucralose; budesonide; mucosal contact time