Duration of Effect of Biotene Spray in Patients With Symptomatic Dry Mouth
Phase: NA
Conditions: Dry Mouth
Sponsor: University of Rochester

Approved 5/22/2020
NCT03663231
DURATION OF EFFECT OF BIOTÈNE SPRAY 
IN PATIENTS WITH SYMPTOMATIC DRY MOUTH
Principal Investigator (P.I.)  Ralph Saunders, DDS, MS 
Sub-P.I. Christine Lung, DDS
Eastman Institute for Oral Health
625 Elmwood Avenue, Rochester, NY 14620
1. PURPOSE OF THE STUDY AND BACKGROUND
1.1. Purpose of the study
To determine the duration of effect of a single dose of Biotène Moisturizing Mouth 
Spray in subjects who complain of a clinically dry mouth. The effect of the product will 
be compared to a control spray (water).  A secondary objective is to assess how the 
perception of a dry mouth is related to the severity of actual hyposalivation.
1.2. Background
Xerostomia is a subjective feeling of a dry mouth which may or may not occur with 
decreased amounts of saliva in the mouth (Furness et al 2011, Sasportas et al. 2013, Jose 
et al. 2016).  Complaints of xerostomia are typically related to resting discomfort and 
difficulty with functions such as eating and speaking.  Xerostomia is commonly a 
permanent or temporary result of irradiation of salivary glands, autoimmune disease, 
smoking, alcohol use, and certain drug therapies.  Regardless of the cause, the complaint 
of xerostomia warrants an evaluation for hyposalivation.  Hyposalivation, which is a 
measurable decrease in saliva flow, is significant because of its destructive effects on 
oral tissues and reduced satisfaction with dentures.  However, even when occurring in 
the absence of hyposalivation, complaints of xerostomia need to be addressed.  
Currently, clinicians are recommending simple palliative therapies for xerostomia, which 
may include topical saliva substitutes, oral moisturizers, saliva stimulants in the forms of 
sprays, gels, gums, lozenges, mouth wash, and/or frequent sips of water.  Recent reviews 
have weak evidence in favor of any particular topical therapy (Shahdad, 2005; Sasportas, 
2013; Jose, 2016).
Biotène Moisturizing Mouth Spray is one such widely available over-the-counter (OTC) 
formulation which can be sprayed directly into the mouth for the relief of xerostomia.  
Although the spray is recommended empirically, its properties are not fully understood.  
One of the most important properties is its duration of effect in the mouth (Shahdad et al. 
2005; Sasportas et al 2013).  For example, how long a typical dose can be expected to 
last is not currently known. Manufacturers’ instructions for the use of Biotène  
Moisturizing Mouth Spray state, “Spray directly into the mouth, onto the tongue, and 
spread thoroughly throughout the mouth. Use as required.” For clinicians to effectively 

2
advise patients and institutions (e.g. nursing homes), information about expected 
duration of effect is needed.
2. STUDY DESIGN
2.1. Overview
This double blind controlled randomized crossover study is designed to determine the 
duration of effect of a single dose of Biotène Moisturizing Mouth Spray.  Because no 
detailed information about the duration of its effect is available now, a pilot study to 
determine sample size will be completed first. The spray consists of a mixture of starch, 
polymers, and plant oils which act as humectants to moisturize the oral tissues as well as 
flavorings that serve as salivary stimulants (Jose et al. 2016).  Subjects complaining of a 
dry mouth will be recruited from the Division of General Dentistry of the Eastman 
Institute for Oral Health.  Potential subjects will be scheduled for a screening 
appointment during which they will sign an informed consent form, complete a 
questionnaire about their experience with xerostomia, and then undergo a measurement 
of unstimulated whole saliva flow rate (UWSFR).  Those whose UWSFR is ≤ 
0.2mL/min. will be admitted to the study and will then be administered a dose of either 
the experimental or control (water) agents.  The unstimulated whole salivary flow rate of 
0.2 mL/min is selected because it is widely recognized as the level at which actual 
mouth dryness occurs (Coultard et al, 2008).  Statistical analysis will focus primarily on 
comparing the duration of action of the two agents but also collecting qualitative 
information about subjects’ experiences with xerostomia and the two agents.
2.2. Rationale for Study Design
Xerostomia is a common oral health problem, with up to 50% of the population affected 
(Furness et al, 2011).  A number of topical agents have been produced to help ameliorate 
the problem but evidence-based information about their indications and comparative 
effectiveness is sparse (Furness et al. 2011, Sasportas et al. 2013, Villa et al. 2015, Jose 
et al. 2016,).  This study aims to compare the duration of effect of one widely available 
topical product (Biotène Moisturizing Mouth Spray) to water for the management of 
xerostomia.  A pilot study is planned initially to determine the sample size for a 
definitive study. The double-blind design will avoid investigator bias after subjects are 
randomized to treatment groups.
2.3. Rationale for Dosage
The dosage selected for this investigation is three sprays (0.5 mL) from a primed 
metered-dose spray bottle identical to what is commercially available to patients.  This 
dose was selected because we feel it simulates the dose a patient with xerostomia would 

3
likely utilize. The spray will be administered by the investigator, Christine Lung, DDS,  
(CL) after priming the bottle twice prior to the providing the determined dose.
3. CHARACTERISTICS OF THE RESEARCH POPULATION
3.1. Subject Characteristics
Pilot Study
In order to establish adequate power at an acceptable level of significance for this study, 
an estimate of the duration of effect of the experimental and control is needed.  At this 
time no such information is available; therefore a pilot study will be completed, as 
suggested by the study statistician (C. Feng, PhD).  Results of the pilot will help 
determine the minimum number of subjects required for a definitive study.  The 
following describes the characteristics of the population for the pilot study:
a) Number of subjects:  A total of 20 subjects enrolled is suggested by the
biostatistician.  A subject is considered in the total count once informed consent has
been obtained and the inclusion criteria met.  To account for dropout and
disqualification of eligible subjects, 50 subjects will be recruited.
b) Gender and age of subjects:  Adults aged 18 years and over will be enrolled with
no regard to gender, although it is recognized that xerostomia in the general
population is more prevalent in older adults and in females (Fox et al. 1985).
c) Racial and ethnic origin:  Subjects will be recruited without regard to race or
ethnicity.
d) Vulnerable subjects:  Vulnerable subjects (as defined by University of Rochester
IRB Criteria) will not be enrolled.
3.2. Inclusion and Exclusion Criteria
a) Inclusion Criteria:

Adults who are in good general health and reply initially affirmatively to the
question, “Do you feel that your mouth is too dry and causes you discomfort at times
during the day other than on awakening from sleep?” This question is an adaptation
of the question used successfully by Jose and others (2016) to recruit study subjects.

Adults who are able to communicate easily in English and who are able to
demonstrate understanding of the study instructions.

Adults who are physically able to perform an unstimulated whole saliva flow rate
(UWSFR) test and who produce 0.2 mL/min or less of saliva.
b) Exclusion Criteria:

Adults under the care of a health professional specifically for xerostomia treatment,
including those taking prescription systemic parasympathetic medications.

4

Adults who regularly “self-medicate” their xerostomia with water or other agents or
products designed to treat their xerostomia and are unwilling or unable to cease use
of the agent for at least 48 hours prior to the two test visits.

Adults who are primarily mouth breathers (i.e. mouth breathing secondary to nasal
obstruction)

Adults who cannot consent for themselves or have physical/mental disabilities
requiring a caregiver.

Adults with a known allergy to any of the ingredients in Biotène Spray (eg. dairy
allergy)
3.3. Discussion of the Subject Population
The inclusion criteria target the large proportion of the adult population (up to 50%) 
(Furness et al, 2011) who are generally healthy but complain of a dry mouth.  This 
enrollment strategy focuses on a “real world” dry mouth population who might use these 
treatments for the daily management of their symptoms.  The exclusion criteria are 
aimed to eliminate factors and conditions that might artificially limit typical saliva flow.  
Subjects who have unstimulated whole salivary flow rates above the 0.2 mL/min 
threshold will be excluded to reduce the variation among subjects and minimize the 
possible participation of those who are unable to discriminate between lower and higher 
flow rates; this latter group may be studied further in another investigation.
4. SUBJECT IDENTIFICATION, RECRUITMENT, AND CONSENT
4.1. Method Of Subject Identification And Recruitment (See Appendices 1 and 2)
Subjects will be initially identified and recruited at all the dental clinics of the Eastman 
Institute for Oral Health (EIOH) at the University of Rochester, Rochester, NY, by the 
strategies described here. Those identified will be assured, from the outset, that neither 
their clinical care at EIOH nor their healthcare anywhere else in the University Medical 
Center will be affected by their decision whether or not to take part in the study.
1. Investigators’ patients. Both Drs. Lung and Saunders see EIOH patients regularly.
They will recruit patients directly from their patient pools by advising them of the
study and inclusion and exclusion criteria. They will pose the question regarding
discomfort from xerostomia detailed in section 3.2 a) above to any adult patients who
appear to meet the inclusion criteria; those who respond affirmatively will be
identified as potential subjects. Definitive qualification will follow as the subjects
complete the consent process and the UWSFR test.
2. Recruitment posters.  Posters will be placed in hallways, near elevators, and within
the dental operatories at the clinics and which will indicate that the study is
underway.  The posters will include the basic inclusion and exclusion criteria and the
information that those who are interested should contact Dr. Christine Lung by phone

5
or e-mail; her contact information will be included (Appendix 3).  Those who enter 
the study by this route will be considered to have “self-identified” themselves as 
potential study subjects.
3. Meetings with dental residents. Dr. Lung will meet with her fellow dental residents to
explain the study, provide posters, and request their assistance in recruiting potential
subjects from among their pool of regular patients.
Potential subjects will be asked to contact the investigator for a screening appointment at the 
study site and will be offered the consent form (please see next section 4.2 for details.), 
which includes details of the study to read and consider at their leisure and with others (e.g. 
family members, their personal dentists). They will be advised that, on completion of both 
sessions of the study, they will receive $75 plus parking in appreciation for their time and 
effort.  Persons who meet the inclusion criteria and sign the consent form will be considered 
recruited for the study.
As subjects qualify for the study, they will be placed, according to a randomization table 
(Appendix 4), in either one group (Group A) or the other (Group B).  If a patient being 
recruited is found not to meet the inclusion criteria, s/he will be dismissed and the next 
potential candidate will be evaluated for admission to the study.
Patients will be assured that their regular clinical care will not be affected by their decision to 
participate or not participate in the study.  Similarly, enrolled subjects who withdraw from 
the study will be assured that they will continue to receive their regular clinical care.
4.2. Process of Consent (Please see draft Consent Form) attached.)
After the initial discussion about the study, the investigator will provide the prospective 
subject with a paper consent form which describes the study in detail. The subject will be 
informed that they may undergo temporary discomfort during the study, and so this is a 
consideration whether or not to participate.  As previously described, potential subjects will 
be given every opportunity to discuss or ask questions of the investigators that occur to them. 
They will be advised of any anticipated risks and contact information for the investigators 
and others affiliated with the University who could assist with any problems which might 
develop and personnel who might carry responsibility for subjects’ safety.  The consent form 
will carry a statement to the effect that subjects may withdraw from the study at any time 
without affecting their eligibility for dental care or other care at the University and without 
any other penalty.  The subject must give her/his own consent without a caregiver, spouse, or 
legal guardian.  Signed consent forms will be paper documents stored in a locked file cabinet 
accessible only to the investigator on an electronically locked laboratory floor.
5. METHODS AND STUDY PROCEDURES
5.1.1. Treatment Dosage and Administration.

6
The methods and study procedures will consist of the following 11 parts which will be 
completed during a recruitment encounter and two testing visits. (See also Appendices 5 and 
6).
Recruitment Encounter
This will be brief and will occur at the time the potential subject volunteers to be 
considered for the study. (Please see below for details.)
Visit 1
1. Sign consent form (if not completed at Recruitment Encounter.)
2. Update of medical history and recording of blood pressure and pulse.
3. Questionnaire about subject’s xerostomia experience.
4. Determination of unstimulated whole saliva flow rate. 
The inclusion criteria for the study require that the rate be < 0.2 mL/min.  A 
subject’s participation will be terminated at this point if this inclusion criterion is 
not met.
5. Trial with randomly assigned alternative or experimental agent. 
6. Post-test study questionnaire about study agent.
Session 1 is complete at this point. An appointment will now be scheduled for Session 2.
Washout Period
As is usual in studies utilizing a crossover design a “washout period “will be employed in 
this investigation.  The retention time appears to be related to the viscosity of a topical agent 
for the relief of a dry mouth (Shahdad et al. 2005).  Therefore, a washout period of at least 48 
hours, to be utilized here, appears to be sufficient to eliminate the effects of a single 
application of Biotène.
Visit 2
1. Update of medical history and recording of blood pressure and pulse.
2. Determination of unstimulated whole saliva flow rate. Subjects will continue in the 
study regardless of their salivary flow rate at this point. The mean of the UWSFRs 
measured at Sessions 1 and 2 will be used in calculations comparing flow rates to 
duration of action of the two agents. This will be done as a matter of interest in the 
amount of variation that may exist between the 2 UWSFR measurements.
3. Trial with either control or experimental agent, whichever was not tested in Session 1.
      4. Post-study questionnaire about study agent, whichever was not tested in Session 1.
Each of the two testing visits is expected to utilize as much as three (3) hours but may be 
less, depending mainly on subjects’ responses to the test agents.  Both sessions will be 

7
scheduled in the time period 830am – 1230pm to control for known variations in daily flow 
rates.
Detailed descriptions of each part follow here.
Recruitment Encounter
This encounter would commonly occur during or after a routine clinic visit or otherwise after 
s/he learns of the study. At this time the investigator would read to the potential subject a 
scripted question plus a limited statement of eligibility.  If the investigator continues to feel 
that the subject may be eligible s/he will be encouraged to sign the consent form.  At the 
potential subject’s request s/he may take the consent form for the purpose of further 
consideration personally or with family, other health professionals, etc. and return it at the 
first experimental visit. (See Appendix 1 for Scripted Recruitment Statement).
Visit 1
1. Sign consent form if this was not done at the Recruitment Encounter.  Update of 
subject’s medical history and measurement of vital signs (blood pressure, pulse, 
respiration rate, presence and level of any pain.).
2. As also indicated previously, when subjects are initially contacted about the study they 
will be given a consent form to take with them and consider participation, possibly 
including discussions with family, health professionals, etc., and then return to the 
investigator. If any questions exist the investigator will respond and then require that the 
consent be signed by both the investigator and subject prior to proceeding. A copy of the 
signed form will be given to the subject and the original retained by the investigator in a 
locked file in a University facility accessible only to investigators.
3. Survey of Experience with Xerostomia. (Appendix 7)
A secondary aim of the study is to gather qualitative information about subjects’ 
experiences with xerostomia. A tested 6-item written questionnaire will be administered 
at this time.(Shahdad et al, 2005) for this purpose.  The time needed for completion of 
this brief questionnaire is estimated at 5 minutes.     
4. Determination of Unstimulated Whole Saliva Flow Rate. (UWSFR)  (See Appendix 8)
The purpose of this test is to determine whether or not potential subjects have a rate of 
not more than 0.2 mL/min. The UWSFR test will be completed in a quiet room with 
lighting generally at a low level but bright enough to allow for reading.  Subjects will be 
seated in a cushioned chair and encouraged to make themselves as relaxed and 
comfortable as possible. A pre-weighed plastic disposable drinking cup (+/- 0.01 g) will 
be given to the subject with instructions to cease the normal process of swallowing when 

8
saliva accumulates but rather allow it to accumulate in the mouth and then drain gently 
into the cup. The time will be noted by the investigator and, after 15 minutes, the 
investigator will advise the subject that the test has ended.  The investigator will again 
weigh the cup and saliva and record the weight.  One gram will be understood to be 
approximately equivalent to 1 mL of saliva and the new weight recorded.  The weight per 
minute will be calculated and understood to be the subject’s current unstimulated whole 
saliva flow rate (UWSFR). If the rate is < 0.2 mL/min the subject will be advised that the 
inclusion criteria for the remainder of the study have been met and that the study will 
continue. This level was selected as a “cut-off” both because it is the level at which 
existing literature recognizes genuine mouth dryness to likely exist and also because of 
our belief that subjects who perceive dryness in the presence of relatively ‘normal’ 
salivary flow rates, may be unreliable in their reports of beneficial effects of study agents.  
Subjects who do not meet the inclusion criteria will be given $25 in appreciation for their 
participation to this time and then dismissed.
6. First Test agent.
The subject will then be seated in a quiet dimly lit room and asked to refrain from 
speaking, including using phones, unless it is essential (e.g. they are feeling badly enough 
that their participation needs to be paused or stopped).  After not less than one (1) minute 
a visual analog scale (VAS) of dryness will be recorded in response to the question, 
“How much discomfort are you feeling from your dry mouth?.  (See Appendix 9).They 
will then be administered, by the investigator, a dose of 3 sprays (to the anterior dorsal of 
the tongue) of the randomly selected experimental or alternative agent with instructions 
to “spread it around in your mouth.” An electronic timer will be started by the 
investigator at that time. The investigator will be administering the agents after priming 
the spray bottle twice before aiming the first spray to the anterior dorsal of the subject's 
tongue. Neither the investigator nor the subject will know the identity of the administered 
agent.
One minute after the spray a second VAS will be recorded. For every 15 minutes elapsed, 
the investigator will repeat the question, "How much discomfort are you feeling from 
your dry mouth?"  Subjects' responses will be recorded each time. Subjects will be 
instructed to stop the timer when they feel that the effect of the administered agent has 
dissipated completely (Appendix 10).
Studies with other more viscous moisturizing agents have rarely found the duration of 
effect to be more than two (2) hours. Therefore, the maximum amount of time subjects in 
this study will be tested is two (2) hours (Jose et, 2016).  The endpoint for each subject, 
however, will occur the subject feels that the effect of the agent has dissipated; the 

9
duration of effect will be the time between starting the timer and the elapsed time to the 
endpoint.
6. Survey of Experience with First Test Agent.
A secondary objective of this study is to gather new information about subjects’ 
perceptions of the characteristics of agents designed to relieve xerostomia. However, a 
review of literature utilizing PubMed and references from other investigations did not 
reveal a standardized survey tool for this objective.  Therefore a new post-test 
questionnaire about agents designed to ameliorate xerostomia was designed by 
investigators and will be administered (Appendix 11).  This information could be useful 
in the subsequent full study to help determine whether or not further efforts are needed to 
mask any potentially noticeable differences between agents being tested. This is a 9-item 
survey of a variety of characteristics of potential agents.  A printed copy of the survey 
attached to a clipboard and also a black-ink pen will be handed to the subject.  The 
subject will be instructed to circle the best answers and then return.  The use here of this 
questionnaire will constitute a pilot study because it is new and has not yet been 
validated.
At this time the subject will be given a check for $25, an appointment for the second 
visit, and dismissed for the day.
Washout Period
A period of at least 48 hours will be required prior to Visit 2.
Visit 2
1. Update of medical history and recording of blood pressure and pulse.
2. Second sialometry to determine a second UWSFR.
3. Administration of second test agent (which ever was not used in Session 1).  
Recordings of VAS regarding the feeling of dryness will be made just before and after 
administration of the test agent and then every 15 minutes in a manner identical to that of 
Session 1. Subjects will be instructed to stop the timer when they feel the effect of the test 
agent has dissipated completely; this will mark the endpoint of the duration of effect, 
which will be recorded.
4. Survey of experience with second test agent.
   This will utilize the same survey form used in Session 1 (Appendix 11).
At this point, the subject has completed the required commitment to the study, and will be 
de-briefed, including being requested to verbally supply any comments they feel might be 
useful in future studies in which they might participate.  Subjects will be offered additional 

10
information and/or referrals to a dry mouth clinic as needed.  They will be compensated $50 
plus parking for their participation and dismissed.
(See also Appendices 4 and 5 for flow chart and schedule of activities.)
5.1.2. Amount of agent to be tested. And  5.1.3. Investigational drug/device.
The manufacturer of Biotène Moisturizing Mouth Spray has directions (Appendix 12) printed 
on the spray bottle stating, “Spray directly into the mouth, onto the tongue, and spread 
thoroughly inside the mouth.  Use as required. Safe to swallow when used as directed.” In an 
effort to minimize variation in the amount dispensed for this study but to remain essentially 
consistent with the manufacturer’s directions the investigator will assume the following 
calibration protocol for each subject:
1. Weigh the empty cup to be used for collection of whole saliva.
2. Prime the spray bottle by squeezing firmly at least twice, toward a sink or bucket.  
This “spray sample” will then be discarded.
3. Using the identical technique, three sprays will then be collected in a second empty 
cup and weighed. This will serve as a “calibration sample.”  This sample will then be 
discarded but the empty cup retained.
4.  The investigator will then direct three sprays to the anterior dorsal of the tongue. 
Utilizing a total of three sprays is intended to mimic what a xerostomic patient likely 
would do.  Having the investigator, instead of the subject, administer the agent is 
expected to make the amount of agent expressed be generally uniform among 
subjects.
5. The same cup will be handed to the subject and will be used for collection of the 
sample of whole saliva over a period of 15 minutes.
The organization and administration of the test agents will be completed in the laboratory of 
Stephen A. Bean, Pharm D, Manager of Investigational Drug Services (IDS) here at the 
University.  Each bottle of test agent (either Biotène Dry Mouth Moisturizing Spray or sterile 
water) will be appear in identical spray bottles.  The possibility exists that the investigator or 
subject may notice the scent and viscosity differences between the different agents, however 
this will unlikely impact the outcome measures. To assess the impact of these differences, the 
post-test questionnaire (Appendix 11) will ask subjects if they think they received the 
moisturizing spray or the alternative (sterile water). The spray bottles will be unlabelled 
except for a unique number which identifies the contents to IDS laboratory and the 
statistician. The true identities of the bottles will be unknown to the investigator and the 
subjects.  The contents of the test agent will be linked to each subject through a 
randomization process completed by IDS.

11
A recent study (Jose et al, 2016) sponsored by the manufacturer (GlaxoSmithKine) of 
Biotène spray investigated the comparative effect of 3 of its products with 2 hours as the 
primary endpoint. Since xerostomia lasting longer than 2 hours may be uncomfortable, 
demonstrating that an agent provides relief close to this time frame would have potential 
therapeutic and commercial value.  Although the study design was different, 49.5% of 
subjects reported that the spray was good, very good, or excellent at “relieving the discomfort 
of dry mouth” 2 hours after use of the spray.  A previous study (Shahdad et al. 2005) also 
discovered that most subjects achieved relief utilizing topical agents after 2 hours.  In this 
study involving a Biotène gel, it was found that the viscosity is positively correlated to the 
retention time of the agent (Shahdad et al. 2005).   Therefore, we expect the less viscous 
experimental spray to have a shorter retention time than the expected 2 hours.  Therefore, 2 
hours will be defined as the maximal endpoint in this study.  We expect that the crossover 
design and qualitative measures will aid  health care providers and patients to derive benefit 
from Biotène Moisturizing Mouth Spray or water.
This crossover study will employ a washout period of 48 or more hours.  The dose being 
administered to a subject is small, and the retention time is related to the viscosity of a topical 
agent for the relief of a dry mouth (Shahdad et al. 2005).  Therefore, a washout period of at 
least 48 hours appears to be sufficient to eliminate the effects of a single application of 
Biotène.
5.2. Efficacy Assessment
This pilot study was developed because estimated data regarding the duration of action of a 
single dose of Biotène Moisturizing Mouth Spray is not available.  The estimated duration is 
necessary for calculating the sample size for a definitive study.  At the completion of the 
pilot, the mean duration of action of both the experimental and control agents will be 
forwarded to the biostatistician (Changyong Feng, PhD) for calculation of the sample size for 
the definitive study. When the required sample size is returned to investigators, plans for the 
definitive efficacy assessment will be developed.  
5.3 Safety Assessments
During subject identification and recruitment comprehensive medical histories of potential 
subjects will be gathered. Persons whose histories suggest they are rated ASA III or higher 
will not be accepted in the study.  At the beginning of each visit subjects’ medical histories 
will be updated and their vital signs (blood pressure, pulse, respiration rate, presence and 
level of any pain) will be recorded by the investigator.  If the investigator, who is a dentist, 
feels that the subject would not be a safe candidate for a routine dental procedure that day, 
s/he will be re-scheduled to another day or discharged from the study.  
5.4. Assessment of Subject Compliance

12
Subjects will be under the direct supervision of the investigator during the observation period 
for up to 3 hours.
5.5  Data and Speciman Banking for Future Research Use
N/A
5.6  Genetic/Genomic Research Activities
N/A
5.7 Costs to the Subject
There are no costs for subjects nor for potential subjects.
      5.8 Payment for Participation
Potential subjects who are screened for the study will be compensated for parking in the 
ramp garage plus $25 for their first session.  Eligible subjects who return and complete the 
second session will be compensated for their parking plus an additional $50. 
      5.9 Return of Individual Research Results
In their second session subjects will be offered the results of their sialometry flow test and an 
interpretation by the investigator.  At their request, patients who have concerns about their 
test results will be given additional general information about managing their condition and 
also encouraged to see their own dentist or the EIOH Oral Medicine Clinic for further 
evaluation.
6. CONCOMITANT AND DISALLOWED MEDICATIONS
Subjects may take normal daily medications as usual.
7. SUBJECT WITHDRAWALS
Eligible subjects will be enrolled into the study on a rolling basis until a minimum number of 
subjects is attained.  If the withdrawal of a subject causes an insufficient number of subjects 
to be enrolled, the recruitment of another subject will be undertaken.
8. STUDY DRUG/DEVICE/BIOLOGIC ADMINISTRATION/ASSIGNMENT
Note:  The side of the box with the device information is included in Section 50 of the RSRB 
application. 
8.1.Biotène Dry Mouth Moisturizing Spray
Biotène Dry Mouth Moisturizing Spray (Appendix 12) contains water, polyglycitol, 
propylene glycol, sunflower oil, xylitol, milk protein extract, potassium sorbate, acesulfame 

13
K, potassium thiocyanate, lysozyme, lactoferrin, lactoperoxidase (45 mL).   No maximum 
dosage or interval for usage is specified. Product is to be used ad libitum.  The Investigation 
Drug Lab at the University of Rochester Strong Hospital, 601 Elmwood Ave, Rochester, NY 
will be supplying, packaging, and labeling the product as well as the placebo which will 
consist of distilled water.
The agent of interest is IND/IDE exempt for this clinical investigation as the product is 
lawfully marketed in the United States for the treatment of symptoms of dry mouth [FDA 21 
CFR 312.2(b)/FDA 21 CFR 812.2(c)].  
8.2.Dosage of Study Drug/Biologic
For the purpose of this study, 3 streams of the product (approximately 0.5 mL) administered 
by the investigator will be considered a dose. For consistent dosing, two sprays to prime the 
spray nozzle will be completed prior to administering a dose to the subject.
8.3.Subject Enrollment/Randomization
Subjects will be allocated to group A or group B using block randomization (Appendix 6).  
Subjects will be allocated to a group as they qualify for the study.  The subject and the 
investigator will be blinded to the group a subject is allocated to.  The products will be 
labeled identically except for a serial code on the bottle will correspond to the treatment or 
control.  The true identity of the products will be known only to the supplier (the 
Investigational Drug Lab, University of Rochester Strong Memorial Hospital), and unknown 
to the investigator and subjects until the completion of the study.  
8.4.Accountability of Investigational Supplies
The Investigational Drug Lab of the University of Rochester Strong Memorial Hospital, 601 
Elmwood Avenue, Rochester, NY will be responsible for the formulation and labeling of 
investigational supplies.  The Investigational Drug Lab will be the unblinded third party.  The 
investigator will handle the receipt, storage, dispensing, collection, accountability log, and 
disposal of the investigational supplies.
8.5.Subject Withdrawal of Study Drug
The agents under investigation have short-lasting and reversible effects that do not require 
the subject to be monitored following the study period.  Subjects may choose to withdraw 
from the study at any time without consequence and without side effects.  The effect of the 
agents under investigation can be reversed by rinsing out the mouth with warm water.
8.6.Emergency Drug Disclosure
Drug disclosure will be maintained electronically and in envelopes by the Investigational 
Drug Lab.  Drug disclosure should be accessed only in the case of a medical emergency.  If 

14
such action is necessary, the Investigational Drug Lab will provide the identity of the 
administered agent to the investigator and the appropriate medical team will be called.  Once 
the identity of the administered agent is revealed, the subject will be withdrawn from the 
entire study.
9. SAFETY AND REPORTABLE EVENTS
9.1. Adverse Event Definition
An adverse event is any symptom, sign, illness, or experience which develops or worsens 
during the course of the study, whether or not the event is considered related to study drug.
9.2. Serious Adverse Event
A serious adverse event is defined as any adverse medical experience that results in any of 
the following outcomes:
•
death;
•
is life-threatening;
•
requires inpatient hospitalization or prolongation of existing hospitalization;
•
results in persistent or significant disability/incapacity;
•
is a congenital anomaly/birth defect; or
•
requires medical or surgical intervention to prevent permanent impairment or damage.
9.3. Recording Adverse Events
At each subject visit the site study staff will assess adverse events by recording all voluntary 
complaints of the subject and by assessment of clinical and laboratory features.  After the 
study visit, the subject should be questioned directly regarding the occurrence of any adverse 
experience during his/her visit.  
All adverse events, whether observed by the investigator, elicited from or volunteered by the 
subject, will be documented.  Each adverse event will include a brief description of the 
experience, the date of onset, the date of resolution, the duration and type of experience, the 
severity, the relationship to investigational product (i.e., agent or control), contributing 
factors, and any action taken with respect to the study agent.
The timeframe that recording of adverse events will occur once the subject signs consent 
until subject completes the study or withdraws from participation. Follow up will occur until 
the adverse effect has resolved.  Follow up of adverse experiences after the subject concludes 
study participation should be with the investigator, who may decide to refer the subject to a 
primary care physician.
9.4. Responsibilities for Reporting Serious Adverse Events

15
The Investigator will record all serious adverse experiences that occur during the study 
period in the appropriate source documents and/or adverse event (AE) log as applicable.  The 
study period for reporting serious adverse events is from the time of signing consent to the 
end of the study participation.  The principal investigator and appropriate medical response 
teams will be notified immediately. The Investigator will comply with regulations and RSRB 
policy regarding the reporting of adverse events.
  
10. RISK/BENEFIT ASSESSMENT
10.1. Potential Risks 
As with all studies, there is a risk of breach of confidentiality.  Subjects may be exposed 
to substances that may elicit an allergic reaction.  Also, subjects may undergo temporary 
oral discomfort while their usual methods of moistening their mouths are forgone.
10.2. Protection Against Risks
The study design minimizes risk by administering a single dose of the agents being 
tested.  The subjects in the study will be under constant surveillance by the investigator.  
The investigator has a Basic Life Support Training.  Follow up of subjects who 
experience an adverse effect will be followed up by the investigator at no charge, 
otherwise referred to a primary care physician at the subject's expense.
10.3. Potential Benefits to Subjects
There are no benefits to participating in the study.
10.4. Alternatives to Participation
There is no alternative to participating in the study.
11. CONFIDENTIALITY OF DATA AND INFORMATION STORAGE
Confidentiality is the ethical and/or legal right that information, such as research data, will be 
held secret and safeguarded from disclosure unless consent is provided permitting disclosure.  
The subject data will be identified in the research data set using a unique random sequence of 
numbers.  The random unique code along with all data sets related to the study will be 
maintained by the investigator and will be destroyed 36 months following the completion of 
data analysis.
The research data will be stored on a password protected file on an encrypted flash drive 
using a subject ID number.  The flash drive will be stored in a cabinet in a locked office 
accessible only to the investigator.  Transfer of research data will only occur on a computer 
between flash drives.  Transfer of research data will not be done through email, cloud 
storage, or FTP or secure FTP.

16
12. RESEARCH INFORMATION IN MEDICAL RECORDS
Results of sialometry flow test will be recorded in the subject's dental chart.
13. DATA ANALYSIS AND MONITORING
13.1. Sample Size Determination
Because estimated durations of the test agents are not available, this pilot study is being 
undertaken. The number of subjects needed for this pilot study is 20, as recommended 
by the biostatistician.
13.2. Planned Statistical Analysis
After completion of the pilot study the number of subjects necessary for the definitive 
study will be calculated by the biostatistician.
13.3. Data and Safety Monitoring
Data and safety monitoring by the principal investigator is appropriate because the study 
is considered minimal risk and will be conducted at a single site.  Prompt reporting of 
reportable events and other study-related safety information will be made to the RSRB 
and sponsor.
14. REFERENCES
1. Coultard P. Saliva flow and its implications. Oral-maxillofacial surgery, radiology, pathology, and 
oral medicine (2nd ed/). 2008. Edinburgh: Churchill/Livingstone/Elsevier, 210-3.
2. Fox P, vander Ven, Sonies B, et al. Xerostomia: Evaluation of a symptom with increased 
significance. JADA 1985; 110: 519-25.
3. Furness S, Worthington H, Bryan G, et al. Interventions for the management of dry mouth: topical 
therapies. Cochrane Database System Reviews. 2011. www.ncbi.nlm.gov/pubmed/22161442.
4. Jose A, Siddiqi M, Cronin M, DiLauro TS, & Bosma ML. A randomized clinical trial in subjects 
with dry mouth evaluating subjective perceptions of an experimental oral gel, an oral rinse and a mouth 
spray compared to water. American Journal of Dentistry 2016; 29 :58-64. 
5. Sasportas LS, Hosford DN, Sodini MA, Waters DJ, Zambricki EA, Barral JK, et al. Cost-
effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and 
neck radiation therapy. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2013; 116: 
37-51.
6. Shahdad S, Taylor C, Barclay S, et al. A double-blind study of Biotene Oralbalance and BioXtra 
systems as salivary substitutes in patients with post-radiotherapy xerostomia. European J Cancer Care. 
2005: 15: 319-26.

17
7.The 
Vanderbilt 
Head 
and 
Neck 
Symptom 
Survey 
(version 
2.0) 
www.oralmedicinepacific.com/docs/head-and-neck-cancer-symptom-survey. Accessed 2-21-18.
8. Villa A, Connell CL, & Abati S. Diagnosis and management of xerostomia and hyposalivation. 
Therapeutics and Clinical Risk Management 2014;11:45-51.

18
Appendix 1 – Example script for screening subjects at the recruitment encounter
Investigator:
Hello, I understand you have heard of our study and may be interested in participating.  
Are you age 18 or older?
Potential subject:
Yes
No
Investigator: (If “yes”):
Do you frequently have the feeling of dryness of your mouth that gives you discomfort at 
times of the day in addition to when you first wake from sleep?
Potential subject:
Yes
No
Investigator: (If “yes”):
Do you regularly (at least daily) use any type of medication or product other than water 
to help relieve the feeling of dryness?
Potential subject: 
Yes
No
Investigator: (If “no”):
Proceed to next question
Investigator: (If “yes”)
Would you be willing and able to cease using the product for at least 48 hours (2 days) 
before each of the two test visits required by the study?
Investigator: (If “No”)
I’m sorry then you would not be a candidate for this study.  Thank you anyway.
Investigator: (If “Yes”)
If Yes
Fine, then let’s look for an appointment for your first test visit. Please know, however, 
that at this first visit, we must perform a test of your saliva for which you will be given $25 plus 
the cost of your parking.  If the results show a certain result, we will want you to return for a 
second and final visit.  If not, we must dismiss you from the study at that time.
If, however, we find that we do have the result required by the study, we will then 
schedule an appointment for the final visit, for which you will receive a payment of $50 plus the 
cost of your parking.
Do you have any questions?
Thank you for your interest in our study.

19
Appendix 2 – Flow diagram for screening subjects at the recruitment encounter
(1) Is the subject interested to enrol in the study and 18 
years or older?
NO
Subject is dismissed
YES
(2)  Ask: "Do you frequently have the feeling of dryness of 
your mouth that gives you discomfort at times of the day in 
addition to when you first wake from sleep?"
NO
Subject is disqualified
YES
(3)  Does subject currently use any palliative 
agent besides water for dry mouth relief?
NO
Proceed to question (4).
YES
(4)  Is subject willing to forgo use of any  
palliative agent besides water for 48 
hours ?
NO
Subject is disqualified
YES
Subject is eligible for 
enrolment

20
Appendix 3 – Recruitment poster for study

21
Appendix 4 – Six Block Randomization Table
 At enrollment, subjects will be randomly allocated to a number from 1-6 using the random 
blocks shown above.  The true identity of the products (Biotène or distilled water) will be 
known only to Investigational Drug Services, University of Rochester Strong Memorial 
Hospital.
523164   123465   521364   241563   435162   214653   
254163   345612   251634   246153   164325   436512
561234   134562   615342   432561   546132   642413

22
Appendix 5 – Flow diagram for subject recruitment, selection, and study design
Phase II 
(after 48 or more hours)
Phase I
Subject selection & 
randomization
Screening
Recruitment
Prospective 
subjects ages 18 
and over complain 
of a dry mouth.
Subject has generally good 
health (ASA I or II) and 
produce unstimulated 
whole saliva flow ≤0.2 
mL/min.
20 subjects 
randomized to 
Group A or B
Group A gets 
treatment 1
Group A gets 
treatment 2
Group B gets 
treatment 2
Group B gets 
treatment 1
Subject is under the care of a health 
professional specifically for the treatment of 
xerostomia,  is primarily a mouth breather 
(ie. mouth breathing 2° to nasal 
obstruction), cannot consent for self or has 
physical/mental disabilities where a 
caregiver is required, has known allergy to 
any of the ingredients in Biotène Spray (eg. 
dairy allergy), or produces unstimulated 
whole salivary flow rate >0.2 mL/min.
Subject is dismissed 
from study

23
Appendix 6 – Checklist for study procedures to be performed
Schedule of Activities
Session
1 
2
Obtain informed consent.
X
Confirm eligibility/enroll.
X
X
Medical history and vital signs.
X
X
Sialometry test
X
X
Test 1 (Biotene or Water)
X
Post-test Survey of First Product
X
Medical history and vital signs.
X
Test 2 (Biotene or Water)
X
Post-test Survey of Second 
Product
X
Post-test survey of xerostomia 
experience.
X

24
Appendix 7 - Patient Xerostomia Experience and Severity Questionnaire
Continuous variables recorded on a visual analogue scales (VAS)
Chart number:_____       Subject’s Initials:________               Date:___/___/____
Please respond to the following questions by placing a single mark on the line.  
The numbers below the scale are references only.
Acceptable:
 0             1            2            3            4             5            6             7            8            9           10
Not acceptable:
 0             1            2            3            4             5            6             7            8            9           10
1.
How dry is your mouth? (Extremes: 0 = 'not dry at all', 10 = 'worst imaginable dryness')
           0             1            2            3            4             5            6             7            8            9           10
2.
Do you have difficulty chewing because of your dry mouth? (Extremes: 0 ='no difficulties at all', 10 = 'very 
severe difficulties chewing')
           0             1            2            3            4             5            6             7            8            9           10
3.
Do you have difficulty swallowing because of your dry mouth? (Extremes: 0 = 'no difficulties at all', 10 ='very 
severe difficulties swallowing')
           0             1            2            3            4             5            6             7            8            9           10
4.
Is speech difficult because of your dry mouth? (Extremes: 0 = 'no difficulties at all', 10 = 'very severe 
difficulties with speech')
           0             1            2            3            4             5            6             7            8            9           10
5.
Is taste affected by your dry mouth? (Extremes: 0 = 'not affected at all', 10 = 'very severe alteration of taste')
           0             1            2            3            4             5            6             7            8            9           10
6.
Do you have a burning sensation in your mouth? (Extremes: 0 ='no burning at all', 10 ='very severe burning 
mouth')
           0             1            2            3            4             5            6             7            8            9           10

25
Appendix 8 – Sample data collection form for unstimulated whole saliva flow rates 
(mL/min)
Subject 
ID
Date
Subject 
Age
A -Wt of 
collected 
saliva (mg)
UWSFR 1 
(A / 15 
min)*
Date
B -Wt of 
collected 
saliva 
(mg)
UWSFR 2 
(B/ 15 
min)*
174
938
235
* Calculation based on specific gravity 1 mg = 1 mL

26
Appendix 9 - Level of discomfort a patient is feeling on a visual analog scale.
Chart number:_____       Subject’s Initials:________               Date:___/___/____
How much discomfort are you feeling from your dry mouth? (Extremes: 0 = 'no discomfort', 100 = 'worst 
imaginable discomfort/dryness')
 0             1            2            3            4             5            6             7            8            9           10

27
Appendix 10 – Sample data collection form for endpoint and VAS scores.
VAS scores on a 100 mm scale (t = time elapsed in minutes)
Subject 
ID
t=0*
t=1
t=15
t=30
t=45
t=60
t=75
t=90
t=105
t=120
End-
point 
(min)
1
VAS 
score at 
Endpoint 
(mm)
174
938
235
379
1The endpoint of the retention time is defined as when the subject has perceived that the 
effect of the agent has dissipated, or after 2 hours has elapsed.  The retention time will 
therefore be from the time the agent is administered to the endpoint.
* Timepoint before the test agent is administered

28
Appendix 11 - Subject evaluation of test agent
Chart number:_____       Subject’s Initials:________               Date:___/___/____
1. How quickly did the product provide relief of your dry mouth symptoms?
□
Immediately
□
In minutes
□
Did not provide relief
Please rate your responses to the following statements by circling the best answer:
2. The taste of the product was tolerable
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
3. The thickness of the product was acceptable
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
4. I would like to continue using this product
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
5. I would purchase this product to use on a regular basis
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
6. This product is easy to use
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
7. I would prefer using another product
    
Strongly disagree
Disagree
Not sure
Agree       Strongly agree
8. At today's visit, you sampled either a commercially available moisturizing spray or a 
standard therapy recommended by physicians. Which product do you think you 
received today?
□
Moisturizing spray
□
Standard therapy
□
Not sure
9. Can you name a preferred product ? ________________________
10. How long ago did you have anything to eat or drink today? Please choose the best 
response.
□
Less than 1 hour ago
□
Approximately 1 hour ago
□
Approximately 2 hours ago
□
Approximately 3 hours ago
□
I did not eat or drink anything this morning

29
Appendix 12 – Biotène product label/insert with directions for use

30
Appendix 13 – Phone script addendum for corrective action plan
Investigator:
Hi, my name is [state your name].  I am calling because you participated in a 
study titled “Duration of effect of moisturizing spray in patients with symptomatic 
dry mouth” at the University of Rochester’s Department of Dentistry.  Do you 
have a few minutes to discuss the study?

If yes, continue below.

If no, ask a better time to call back to discuss the study. 
We are calling to let you know that one of the inclusion criteria for the study was 
that subjects be between the age of 18 and 65 years of age. We wanted to make you 
aware that you were enrolled into the Biotène study despite your age being outside 
of the required range at the time of consent. There are no safety issues related to 
participation over the age of 65 and we are in the process of revising the inclusion 
criteria to include anyone 18 and older.
Because you were enrolled in error we are requesting your permission to continue 
to include data related to your participation in this study.  Choosing to provide your 
data, or exclude your data, from the study will not have any impact on your care at 
Eastman Dental or any other dental/medical setting.
We are only asking that you permit us to use your data that has already been 
collected for this study. You do not need to participate in any study procedures.
Would you be willing to let us continue to use the data collected for the study?  

If yes, thank them for their time and cooperation.

If no, thank them for their time and let them know the data will be 
securely discarded.