Evaluation of Two Mouth Sprays for Post-irradiation Xerostomia in Head and Neck Cancer Survivors: a Randomized, Double-blind Clinical Trial
Phase: NA
Conditions: Xerostomia, Head and Neck Cancer, Xerostomia Following Radiotherapy
Sponsor: Jonas Johnson

 
 Study Title: Evaluation of two mouth sprays for post-irradiation xerostomia in 
head and neck cancer survivors: a randomized, double-blind clinical trial  
 
 
NCT #: 04608773  
 
Document Type: Protocol and Statistical Analysis Plan 
Document Date: 10/3/2023 
 
 

Objective(s):  
The main objective of this study is to compare the efficacy of two FDA-approved 
mouth sprays (Biotene and Refresh) at relieving symptoms of xerostomia, or dry 
mouth, in patients who have received radiation for carcinoma of the head and neck. 
We aim to conduct a randomized, double-blinded, crossover study to demonstrate to 
what extent, two different FDA-approved mouth sprays are effective in relieving 
symptoms of xerostomia in patients who meet inclusion criteria for this study. We 
also want to determine to what extent, these mouth sprays are superior to water or to 
one another at relieving symptoms of xerostomia in this population. We will test the 
hypothesis that the use of either Biotene or Refresh mouth spray will be more 
effective at relieving symptoms of xerostomia than the use of water as mouth spray 
and that either Biotene or Refresh mouth spray will be more effective than the other at 
relieving symptoms of xerostomia in the included patients in this study. We also will 
test the hypothesis that both mouth sprays will increase the pH of patient mouths 
compared to water. 
 Study Design:  
This 6-week study will consist of two experimental phases lasting two weeks each. 
Both phases will be preceded by one-week washout periods. Patients will be 
randomized to receive test treatments of either Refresh mouth spray or Biotene mouth 
spray during the first experimental phase. They will receive the opposite mouth spray 
during the second experimental phase. Patients will be given a 1-month supply of both 
masked mouth sprays labeled as "Oral Hydrating Spray A" and "Oral Hydrating Spray 
B", as well as pH testing strips, prior to the initiation of the study. They will be given 
specific directions regarding the usage of the mouth sprays. They may use the mouth 
sprays as needed, every four hours, with 4 sprays per use at the start of both respective 
experimental phases. Additionally, subjects will be asked to measure mouth pH values 
at scheduled timepoints. Patients will be permitted to use water as a mouth spray 
during washout periods. The use of chewing gum, hard candy, and lozenges will be 
prohibited for the duration of the study, but liquid intake will not be limited. Patients 
will complete an xerostomia and demographics questionnaires at specified timepoints 
during the conduct of the trial. Participants can use 4 sprays every 4 hours. However, 
the frequency of usage is symptoms dependent. If participants are still experiencing 
relief after 4 hours, they may delay the next usage. 
Recruitment Methods:  
Patients will be recruited, in person, from the Head and Neck Survivorship clinic at 
the University of Pittsburgh Medical Center (UPMC). Patients will be screened for 

xerostomia at their regularly scheduled clinical visit and will be approached by 
clinical staff who are educated in this research to participate in this study if they meet 
participation criteria. For any patients other than those of Dr. Johnson's, a clinical care 
provider known to the patient will confirm that the potential subject has given 
permission for the research team to approach. 
 Stastical Analysis Plan: 
All statistical analyses were performed using STATA SE 17.0 for Mac OS. Descriptive 
statistics, including proportions, means, medians, standard deviations (SD), and interquartile 
ranges (IQR), were used to compare demographic and clinical features between treatment 
groups. The primary outcomes were reported dry mouth scores derived from the 100-mm VAS. 
Washout period scores were used as the baseline comparison for the mouth spray period that 
directly followed. Carryover effect was tested by unpaired t-test of the sum of primary outcomes 
after both treatments, with sequence as the grouping variable.9 Period effect was tested by 
unpaired t-test of the difference in primary outcomes between Biotène and HydraSmile after 
both treatments, with sequence as the grouping variable. To evaluate the treatment effect of 
Biotène and HydraSmile, we used paired t-test to compare the primary outcome after treatment 
compared to the corresponding baseline measurements. To investigate the treatment effect of 
HydraSmile vs Biotène, we followed the recent recommendation for analysis of 2*2 cross-over 
trials with two baseline measurements by Metcalfe and Mehrotra and implemented the analysis 
of covariance (ANCOVA) model to regress the difference in after-treatment measurement 
between HydraSmile and Biotène over the difference of baseline between HydraSmile and 
Biotène.10,11 The intercept term would be the treatment effect of HydraSmile compared to 
Biotène. In the exit survey, patients indicated which mouth spray (Biotène or HydraSmile) they 
preferred. Sub-group analysis was completed within each preference group to determine the 
effect of each mouth spray and the difference between them.