Clinical Evaluation of Clinpro™ 2.1% Sodium Fluoride Aqueous Solution in the Treatment of Dentin Hypersensitivity
Phase: NA
Conditions: Dentin Hypersensitivity
Sponsor: Solventum US LLC

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Page 1 of 68
Study Title
Clinical evaluation of Clinpro™  2.1% Sodium Fluoride Aqueous 
Solution in the treatment of dentin hypersensitivity
Study Number
EM-11-050084
Release Date
04/27/2023 10:23:21 AM CDT
Name of Device Under 
Investigation
Clinpro™  2.1% Sodium Fluoride Aqueous Solution 
Sponsor Address
3M Company
3M Center
St. Paul, MN  55144
Manufacturer Address
3M Company
3M Center
St. Paul, MN  55144
ELECTRONIC SIGNATURES:
Signer
Role
Date Signed
US113168:Morse Dan J
Clinical
April 27, 2023 06:16:33 AM CDT
ACQ6HZZ:Xu Xiaohui
Medical Monitor
April 27, 2023 10:23:19 AM CDT
A6T72ZZ:Han Helen
Clinical
April 26, 2023 01:37:28 PM CDT
A8R0XZZ:Parsram Cp
Regulatory 
and 
Compliance
April 26, 2023 01:39:54 PM CDT
3M Confidential
This document contains confidential information that is the property of 3M and is subject to 
all the restrictions on its use and disclosure contained in the study contract to which this is 
appended. Do not copy, disclose, circulate or use for benefit for any third party without 
written authorization from 3M.
NCT05768373

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Study Title
Clinical evaluation of Clinpro™  2.1% Sodium Fluoride 
Aqueous Solution in the treatment of dentin hypersensitivity
Study Number
EM-11-050084
Release Date
04/27/2023 10:23:21 AM CDT
Investigator Statements of Compliance 
This clinical investigation shall be conducted in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki.
This clinical investigation shall be conducted in accordance with ISO-14155, US FDA 21 
CFR parts 812, 50, 54, 56, and any regional or national regulations, as appropriate. 
The clinical investigation shall not begin until the required approval/favorable opinion from 
the Institutional Review Board (IRB)/Ethics Committee (EC) and regulatory authority (if 
applicable) has been obtained and permission to proceed has been received from the study 
Sponsor.  Any additional requirements imposed by the IRB/EC or regulatory authority shall 
be followed.  
I have read the Clinical Investigation Plan (CIP), including all appendices, as well as 
supporting study related documents and I agree that it contains all necessary details for me 
and my staff to conduct this study as described. I agree to record all adverse events/ 
deviations/product deficiencies or complaints and report those adverse events/ deviations to 
the Sponsor per this CIP and IRB/EC per local requirements.  I always agree to maintain 
product accountability and ensure security of study materials. I agree to comply with 
financial disclosure requirements.
All subjects will sign and date the approved Informed Consent before any study procedures 
are conducted, as applicable
I will ensure that all subjects meet inclusion criteria before enrolling them in the study.
I agree to maintain and retain records as required by this Clinical Investigation Plan.
Investigator’s Signature:
Investigator’s Name:
Institution:

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Study Title
Clinical evaluation of Clinpro™  2.1% Sodium Fluoride 
Aqueous Solution in the treatment of dentin hypersensitivity
Study Number
EM-11-050084
Release Date
04/27/2023 10:23:21 AM CDT
Date of Signature:

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ABBREVIATIONS/ACRONYMS
AE
adverse event
ADE
adverse device effect
CEJ
cementoenamel junction
CFR
code of federal regulations
CIP
Clinical Investigation Plan
cm
centimeter or centimeters
d
day(s)
DD
device deficiency
DHS
dentin hypersensitivity
ETAB
exposure time to air blast 
F-
fluoride
FDA
United States Food and Drug Administration
g
gram(s)
h
hour(s)
ICF
Informed Consent Form
IFU
instructions for use
IRB
Institutional Review Board
mm
millimeter or millimeters
OTC
over-the-counter
Q1
Quarter 1
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation

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SE
standard error
SR
Significant Risk
USADE
unanticipated serious adverse device effect
VAS
visual analog scale
VRS
verbal response scale

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TABLE OF CONTENTS
ABBREVIATIONS/ACRONYMS.............................................................................................4
1.
SUMMARY.....................................................................................................................11
2.
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION.........16
2.1.
Background
16
2.1.1.
Dentin Hypersensitivity ......................................................................................16
2.1.2.
Desensitizing F- containing Agents in the Treatment of DHS............................16
2.2.
Rationale for Studying the Specific Population/Condition
18
2.3.
Scientific Rationale for Design
19
3.
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE .19
3.1.1.
Control Device....................................................................................................20
3.2.
Device Regulatory Classification
20
3.3.
Intended Use of the Device/Indications for Use
21
4.
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE(S), CLINICAL 
PROCEDURE AND CLINICAL INVESTIGATION..............................................................21
4.1.
Benefits of the Device
21
4.2.
Risks of the Device
21
4.3.
Anticipated Adverse Device Effects
22
4.4.
Residual Risks
22
4.5.
Risk of Interactions with Concomitant Medical Treatments
22
4.6.
Mitigation of risk
23
4.7.
Risk to Benefit Rationale
23
5.
OBJECTIVES OF THE CLINICAL INVESTIGATION PLAN ....................................23
5.1.
Purpose of the Clinical Investigation
23
5.2.
Primary Objective(s)
23
5.3.
Study Endpoint(s)
23
5.3.1.
Primary Endpoint(s)............................................................................................23

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5.3.2.
Secondary Endpoint(s)........................................................................................24
5.3.3.
Additional/Exploratory Endpoints......................................................................24
5.3.4.
Safety Endpoint(s) ..............................................................................................24
6.
DESIGN OF CLINICAL INVESTIGATION .................................................................24
6.1.
Design
24
6.2.
Study Duration
25
6.3.
Minimization of Bias
25
6.4.
Investigational Use of Device and Comparator
25
6.5.
Subject Enrollment
25
6.5.1.
Enrollment Criteria .............................................................................................25
6.6.
Procedures and Assessments
27
6.6.1.
Obtaining Informed Consent...............................................................................27
6.6.2.
Laboratory Assessments to Determine Eligibility ..............................................28
6.6.3.
Demographics and Subject Characteristics.........................................................28
6.6.4.
Vital Signs...........................................................................................................28
6.6.5.
Randomization and Blinding ..............................................................................29
6.6.6.
Treatments...........................................................................................................29
6.6.7.
Post-Treatment Pain Assessments ......................................................................31
6.6.8.
Concomitant Medications...................................................................................31
6.6.9.
Adverse Events and Adverse Device Effects......................................................31
6.6.10.
Prohibited Procedures and On-Study Restrictions..........................................31
6.6.11.
End of Study Documentation..........................................................................32
6.7.
Visit Schedule and Description of Study Visits
32
6.7.1.
Point of Enrollment.............................................................................................32
6.7.2.
Visits ...................................................................................................................32
6.7.3.
Point of Exit........................................................................................................35
6.8.
Role of Sponsor Representative
36

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6.8.1.
Monitoring ..........................................................................................................36
6.8.2.
Other Sponsor Oversight.....................................................................................37
7.
DATA MANAGEMENT.................................................................................................37
7.1.
Data Collection and Management Responsibilities
37
7.2.
Study Records Retention
38
7.3.
Sponsor Oversight
38
8.
STATISTICAL CONSIDERATIONS.............................................................................38
8.1.
Pass/Fail Criteria
38
8.2.
Sample Size Determination
39
8.3.
Analysis Populations
39
8.4.
Statistical Analyses
39
8.4.1.
Demographic and Baseline Characteristics ........................................................39
8.4.2.
Analysis of Primary Endpoints...........................................................................39
8.4.3.
Analysis of Secondary Endpoints.......................................................................40
8.4.4.
Analysis of Additional/Exploratory Endpoints...................................................40
8.4.5.
Analysis of Safety Endpoints..............................................................................40
8.5.
Planned Interim Analyses and Criteria for Clinical Investigation
41
8.6.
Procedures for Reporting Deviations From Statistical Plan
41
8.7.
Procedures for Missing, Unused, or Spurious Data
41
8.8.
Validation Plan
41
9.
AMENDMENTS TO THE CIP .......................................................................................41
10.
DEVIATIONS FROM THE CIP .....................................................................................41
10.1.
Deviation Reporting Timelines
42
11.
DEVICE ACCOUNTABILITY.......................................................................................42
11.1.
Labeling for Device(s) Under Investigation
43
11.2.
Additional Study-specific Equipment/Device(s)
43
12.
STATEMENTS OF COMPLIANCE...............................................................................44

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12.1.
Ethical Considerations
44
12.2.
Periodic Reviews
44
12.3.
Participant Confidentiality
44
12.4.
Conflict of Interest
45
12.5.
Insurance
45
12.6.
Future Use of Stored Collected Specimens
45
13.
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES
46
13.1.
Safety and Event Reporting Definitions
46
13.2.
Classification of Events
47
13.2.1.
Severity Ratings ..............................................................................................47
13.2.2.
Relatedness to Study Device or Study Treatment...........................................48
13.3.
Details Concerning Safety Recording and Reporting Requirements
49
13.3.1.
Investigator Responsibilities ...........................................................................49
13.3.2.
Sponsor Responsibilities .................................................................................49
13.4.
Reporting Timelines
50
13.5.
Follow-up Period for Ongoing AEs
51
14.
VULNERABLE POPULATION.....................................................................................51
15.
SUSPENSION OR PREMATURE STUDY TERMINATION.......................................52
15.1.
By Sponsor
52
15.2.
By IRB
53
16.
REGISTRATION AND PUBLICATION POLICY........................................................53
16.1.
Public Registration
53
16.2.
Publications Resulting From Study/
53
17.
BIBLIOGRAPHY............................................................................................................53
18.
STUDY-SPECIFIC APPENDICES.................................................................................57
18.1.
Appendix A
57

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18.2.
Appendix B
64
18.3.
Appendix C
65

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1. SUMMARY
Study Title
Clinical evaluation of Clinpro™  2.1% Sodium Fluoride Aqueous 
Solution in the treatment of dentin hypersensitivity
Study Type
Pre-market
Principal 
Investigator (PI)
Name: Dr. Yiming Li, DDS, PhD, MSD
Title: Distinguished Professor
Site: Loma LindaUniversity Health 
Device under 
Investigation 
Summary
The investigational device for this study is 3M™ Clinpro™  2.1% 
Sodium Fluoride Aqueous Solution, which is a xylitol-sweetened 
aqueous fluoride coating that is applied topically to the tooth surfaces 
for the treatment of DHS.  3M™ Clinpro™  2.1% Sodium Fluoride 
Aqueous Solution contains 9,500 ppm fluoride as well as added 
calcium and phosphate. 
Sponsor
3M
Purpose
The purpose of this investigation is to generate data to support an 
indication for use of the Investigational product in treating dentin 
hypersensitivity (DHS) and to support global regulatory registration 
of the product.
Design
This is a prospective, randomized, single blinded, parallel, non-
inferiority trial, that will enroll Subjects requiring treatment for DHS.  
Subjects will be randomized in a 1:1 ratio with half of the Subjects 
treated with Clinpro™  2.1% Sodium Fluoride Aqueous Solution and 
the other half treated with Vanish™ 5% Sodium Fluoride White 
Varnish.  The study will be conducted at a single investigational site 
in the following location: Loma Linda University Health.
Selection of 
Subjects
A minimum of 96 enrolled Subjects that complete the treatment is 
planned for this study.  To achieve this minimum, the Investigator 
may enroll up to one hundred and twenty five (125) subjects.  
To be considered eligible for enrollment, Subjects must meet all the 
inclusion criteria and none of the exclusion criteria listed below.  

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Inclusion Criteria:
Subjects may be included that meet the following criteria:
1. Subject has at least one affected hypersensitive tooth upon air 
blast stimuli in the cervical area, and baseline pain score of 40 
mm and above as assessed by the 100 mm VAS.
2. Subject is at least 18 years old and have a minimum of 20 
natural teeth.
3. Subject is willing to withhold desensitizing treatment, 
including prescription, in-office or over the counter (OTC) 
desensitizing products, throughout the study period AND 
withhold during the washout period.
4. Subject agrees to only use the provided toothpaste, toothbrush, 
and follows all oral hygiene instructions throughout the study 
period AND follows all oral hygiene instructions during the 
washout period.
5. Subject is able to understand and willing to sign the Informed 
Consent, and is willing to return to the study facility for 
scheduled study visits and recalls
Exclusion Criteria:
Subjects may not be included that meet any of the following criteria:
1. Subject 
has 
medical 
(including 
psychiatric) 
and 
pharmacotherapeutic histories that may compromise the 
protocol – including the chronic use of anti-inflammatory, 
analgesic (pain), and mind-altering drugs; or analgesic (pain) 
medications within 48 hours prior to application of treatment. 
2. Subject is pregnant (self-reported) or breast feeding.
3. Subject has allergies to product ingredients, eg, rosin, mint 
flavoring.
4. Subject has systemic conditions that are etiologic or 
predisposing to dentin hypersensitivity (eg, chronic acid 
regurgitation).

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5. Subject has excessive dietary or environmental exposure to 
acids at time of screening.
6. Subject had periodontal treatment, bleaching treatments, or 
orthodontic treatments within previous 3 months or plans to 
have any other dental treatments during the study period.  
7. Subject is enrolled in another clinical trial at the time of 
screening that would interfere with this study.
8. Subject is, in the opinion of the investigator, unsuitable for 
enrollment in the study for reasons other than those specified 
in the above exclusion criteria.
Individual teeth may not be included that meet any of the following 
criteria:
9. Study tooth has periodontal probing depth of ≥ 4 mm.
10. Study tooth or the surrounding supporting tissue has any other 
painful pathology or defects.
11. Study tooth has been restored in the preceding 3 months.
12. Study tooth is an abutment for fixed or removable prostheses 
or suffers traumatic malocclusion.
13. Study tooth is crowned or extensively restored and the 
restorations extending into the test area.
14. The tooth has dentin hypersensitivity due to cracked enamel.
Device Regulatory 
Classification
Clinpro™  2.1% Sodium Fluoride Aqueous Solution is anticipated to 
be a class 2 medical device under FDA product code LBH (varnish, 
cavity per 21 CFR 872.3260) that will require FDA 510(k) ance. A 
510(k) Pre-market Notification is planned for the first quarter (Q1) of 
2023.  
Clinpro™  2.1% Sodium Fluoride Aqueous Solution is not expected 
to have 510(k) ance when the study begins.  For the purpose of this 
study, the product is not considered a Significant Risk(SR) 
investigational device under 21 CFR 812.3(m) because: 

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•
Is not intended as an implant and presents a potential for 
serious risk to the health, safety, or welfare of a subject;
•
Is not purported or represented to be for use supporting or 
sustaining human life and presents a potential for serious risk 
to the health, safety, or welfare of a subject;
•
Is not for a use of substantial importance in diagnosing, curing, 
mitigating, or treating disease, or otherwise preventing 
impairment of human health and presents a potential for 
serious risk to the health, safety, or welfare of a subject; and
•
Does not otherwise present a potential for serious risk to the 
health, safety, or welfare of a subject
Primary 
Objective(s)
The primary objective of this study is to evaluate the effect of 
Clinpro™  2.1% Sodium Fluoride Aqueous Solution (experimental) 
on DHS  in comparison to 3M™ Vanish™ 5% Sodium Fluoride 
White Varnish (commercialized, control), a well-known product in 
the market used for this purpose.
Endpoint(s)
Co-primary endpoints include:
1. the change in pain, using a 100-mm VAS from baseline to 
immediately after application (within 15 minutes post 
treatment) of test product or comparator.
2. the change in pain score from baseline to 24 ± 4 h post-
application, using VAS after exposure to air stimulus.
The secondary endpoints include:
1. change in pain score, using VAS, from baseline to 7 ± 2 days 
post-treatment, after exposure to air stimulus.
2. change in pain score, using VAS, from baseline to 21 ± 2 days 
post-treatment, after exposure to air stimulus. 
3. change in pain score, using VAS, from baseline to 30 ± 2 days 
post-treatment, after exposure to air stimulus.
The exploratory endpoints will include the reduction in pain (using a 
VAS) upon tactile testing with a periodontal probe, including:

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1. change from baseline to immediately post-treatment (within 15 
minutes post-treatment)
2. change from baseline to 24 ± 4 hours post-treatment
3. change from baseline to 7 ± 1 days post-treatment
4. change from baseline to 21 ± 2 days post-treatment
5. change from baseline to 30 ± 2 days post-treatment.
The safety endpoint will be the incidence of all AEs. 
Randomization 
and Blinding
Randomization should occur after obtaining informed consent and 
ensuring that the Subject meets all eligibility criteria; randomization 
should occur on the day of treatment before the initial application of 
the investigational device (Treatment arm) or control device (Control 
arm).  Due to the nature of the investigative device, the duration of 
treatment application, and the study design, Investigator blinding is 
not feasible for the study.  For Subjects with multiple eligible teeth, 
the PI will select the index tooth based on their experience and 
accessibility of the tooth for the stimuli; however, this selection must 
be made prior to randomization.  Randomization of the Subjects will 
be performed using a permuted block technique and will be 
centralized and electronic.  
Duration of the 
Study
The entire duration of the study is expected to last one year.  
Individual subject participation is expected to last 51 days, including 
a 3-week washout period before treatment. 
Sponsor Study 
Contact
Name: Helen Han, PhD
Address: 3M Center, Bldg 270
Telephone: 651-737-9234
Email.:  mhan3@mmm.com
Dental Monitor 
Contact
Name: Xiaohui Xu, Dr. med. Dent.
Address: Espe-Platz, 82229, Seefeld, Germany
Telephone: +4915120906206
Email:  xxu19@mmm.com

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2. JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION
2.1.
BACKGROUND
2.1.1.
Dentin Hypersensitivity
Dentin hypersensitivity (DHS) is characterized as exposed dentin in which brief, sharp pain 
occurs in response to stimuli (eg, thermal and/or tactile stimulus) and cannot be ascribed to any 
other form of dentin defect.1  DHS is a fairly common affliction for adults, with one study 
showing 21.3% of Subjects (163 of 767) with DHS in response to tactile stimulus and 38.6% 
of Subjects (296 of 767) with DHS in response to air-blast stimulus (ie, cold air exposure).2  
Not surprisingly, non-carious cervical lesions and gingival recession were significantly 
associated with DHS in response to both tactile and air stimulus (P ≤ 0.02) in the 
aforementioned population, and female sex was significantly associated with DHS in response 
to air-blast stimulus (P < 0.01).2  
There are currently two modes of action for agents used to manage DHS: (i) blocking pulpal 
nerve response or (ii) dentine tubule occlusion with resistance to removal by acidic challenges.3  
Fluoride (F-)-containing products, including those that are self-administered (eg, pastes and 
rinses) and those that are professionally applied (eg, varnishes and gels), have been shown to 
relieve DHS via the second mode of action through the formation of precipitates (eg, calcium-
phosphorous, calcium fluoride, and fluorapatite).4-6  The focus of this study is to compare two 
professionally applied F-containing products, one of which contains a hexane-based solvent 
and the other a novel aqueous solution (Clinpro™  2.1% Sodium Fluoride Aqueous 
Solution), on changes in DHS.     
2.1.2.
Desensitizing F- containing Agents in the Treatment of DHS
Previous publications reporting clinical trial results for the impact of professionally applied F--
containing products (with more than 1% F- in the product) on DHS in at least one arm of the 
trial date back to the early 1990s,7 with 22 clinical trials assessing DHS since that time.7-28  One 
publication had an inconsistent description of methods and study results, which made a 
meaningful interpretation of the data impractical.8  In addition, three other studies are not 
relevant for this trial since the F--containing products were used along with an adjunctive 
therapy (eg, subsequent laser treatment or iontophoresis)7,11 or citric acid was applied to teeth 
prior to assessing DHS.19  Lastly, eight of the previous studies did not evaluate the immediate 
impact of the F--containing product on DHS, which is the primary endpoint of this study, and 
fall outside of the main focus for this study.10,15-18,20,24,27  However, there have been 10 clinical 
studies assessing the immediate impact of a professionally applied F--containing product on 

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DHS.9,12-14,21-23,25,26,28  Of these 10 studies assessing the immediate impact of professionally 
applied F--containing products, half of the studies (5) examined 2% fluoride gels,14,21,23,26,28 and 
the other half examined the impact of 5% fluoride varnishes.9,12,13,22,25
2.1.2.1.
IMPACT OF 2% FLUORIDE GELS ON IMMEDIATE CHANGE IN DHS
Each of the 5 publications that assessed an immediate change in pain for study teeth with DHS 
used cold-air stimulus (ie, air blast stimulus) as part of the assessments.  In one of the studies, 
a verbal response scale (VRS) was used to assess pain, whereby a “0” indicated the absence of 
pain and a “4” indicated unbearable pain.23  Similar VRS scores were observed for 18 teeth 
before (2.5 ± 0.514) and immediately after (2.56 ± 0.511) application of the 2% F- gel.23  In the 
other four studies using 2% F-gels in one of the study arms, a visual analog scale (VAS) ranging 
from 0 to 10 cm (or 100 mm) was used to measure pain levels, whereby a “0” indicated no pain 
and a “10” (ie, 10 cm or 100 mm on the scale) indicated unbearable pain.14,21,26,28  In a study 
with a sample size of 27 teeth treated with 2% F-gel, Soares et al observed a mean (± standard 
deviation, or SD) reduction in the VAS score of 2.5 cm (± 1.86 cm) points immediately after 
product application when compared with the baseline score (P = 0.001).28  In a sample size of 
65 teeth treated with 2% F- gel, Femiano et al observed a change in the mean (range of single 
VAS values for the group) VAS score from 6.4 cm (±4 cm) at baseline to 3.2 cm (±5 cm) 
immediately after gel application (P < 0.001).14  Similarly, Lund et al described a reduction in 
the mean VAS score from 6.1 cm (variance or range not provided) at baseline to 4.1 cm when 
assessed 5 minutes after application of a 2% sodium fluoride gel (P < 0.05).21  In addition to 
VAS scores, Lund et al examined the exposure time to air blast (ETAB); for teeth treated with 
2% F- gel, there was an increased ETAB from 4.0 seconds at baseline to 9.3 seconds when 
measured 5 minutes after product application (P < 0.05).21  Lastly, Pamir et al observed a change 
in the mean (± standard error, or SE) VAS score (n = 30 teeth) from 5.0 cm (± 0.3 cm) at 
baseline to 1.7 cm (± 0.3 cm) immediately after application of the 2% sodium fluoride gel (P < 
0.05).26  In this study, the change in VAS scores in response to tactile stimulus was also 
examined, and a change in the mean (± SE) VAS score from 4.1 cm (± 0.2 cm) at baseline to 
1.1 cm (± 0.3 cm) immediately after application of the 2% sodium fluoride gel was observed 
(P < 0.05).26
2.1.2.2.
IMPACT OF 5% FLUORIDE VARNISHES ON IMMEDIATE CHANGE IN DHS
Previous clinical trials reporting on the immediate impact of 5% F- varnishes on DHS have 
assessed the response to cold-air stimulus and/or tactile stimulus.  Pain assessments were made 
using a VAS scale (described in Section 2.1.2.1), a calibrated Yeaple probe (for tactile stimulus) 
that was used to measure the amount of pressure in grams (g) until the Subject felt discomfort, 
or the Schiff scale, depending on the trial.  For the Schiff scale, scoring categories included: 

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“0”, indicating no response to the stimulus, “1”, indicating the Subject responded to the stimulus 
but did not request its discontinuation, “2”, indicating the Subject responded to the stimulus and 
requested its discontinuation or moved away from the stimulus, and “3”, indicating that the 
Subject considered the stimulus painful and requested its discontinuation.  
In 2003, Corona et al reported the number of Subjects (n = 30) within each Schiff category in 
response to air blast stimulus both before and immediately after application of a 5% F- varnish.  
Before treatment, there were no (0) Subjects with a score of “0”, 11 Subjects with a score of 
“1”, 13 Subjects with a score of “2”, and 6 with a score of “3”.  Immediately after treatment, 
11 Subjects had a score of “0”, 6 had a score of “1”, ten had a score of “2”, and 3 had a score 
of “3”.12  In 2018, Anderson et al analyzed the immediate impact of a 5% F- varnish on 
immediate changes in DHS by analyzing both the VAS and Schiff score upon air blast stimulus 
for 11 Subjects.  The mean (± SD) VAS was reduced from 58.18 mm (± 15.16 mm) at pre-
treatment to 30.5 mm (± 28.51 mm) after treatment, and the mean (± SD) Schiff score was 
reduced from 2.32 (± 0.72) at pre-treatment to 0.91 (± 1.0) after treatment (P < 0.05).9   In a 
study of 36 teeth treated with a 5% F- varnish, Eyüboğlu et al showed a significant reduction in 
VAS upon air blast stimulus (P < 0.001), changing from 56.39 mm (± 19.91) at baseline to 10 
mm (± 15.11 mm) immediately after treatment.13  Additionally, there was significant change in 
the amount of pressure (ie, tactile stimulus) before the Subject felt discomfort (P < 0.01), 
changing from 18.89 g (± 12.1 g) at baseline to 32.78 g (± 23.49 g) immediately after 
treatment.13  Finally, Machado et al observed a significant reduction in VAS (P < 0.05) in 
response to air blast stimulus, with a mean (± SD) VAS of 5.9 cm (± 1.5 cm) at baseline versus 
3.4 cm (± 2.4 cm) immediately after treatment.22  In this study, a significant reduction in VAS 
(p < 0.05) was also seen for teeth (n = 38) treated with a F--containing ionomeric sealant, with 
a mean (± SD) VAS of 6.7 cm (± 1.7 cm) at baseline and 3.4 cm (± 2.5 cm) immediately after 
treatment.22                 
2.2.
RATIONALE FOR STUDYING THE SPECIFIC POPULATION/CONDITION
Subjects with at least one tooth with DHS, defined as having a baseline VAS score of at least 
40 mm in response to air blast stimuli, were selected as the specific population/condition for 
this study since desensitizing agents are commonly used to treat DHS (see Section 2.1.1).  
Subjects with surrounding teeth or tissues with painful pathology or defects are being excluded 
in an effort to eliminate the potential for pain from an area other than the study tooth (ie, to not 
impact VAS scores from the study tooth itself).  Similarly, teeth with previous restorations or 
periodontal treatments are being excluded to limit other potential causes of tooth pain.

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2.3.
SCIENTIFIC RATIONALE FOR DESIGN
To have a high level of evidence, a prospective, randomized, single-blinded, parallel, non-
inferiority study was the design selected for this study.  A within-subject (ie, split-mouth) design 
was not included since the product compositions allow spreading to adjacent areas of the mouth.
Vanish™ 5% Sodium Fluoride White Varnish was selected as the comparator product (ie, 
Control device) for this study since it is a well-known fluoride varnish used as a desensitizing 
agent, with three previous publications describing its impact on the reduction of DHS when 
used in a clinical trial.13,20,22
The primary endpoint for this study will focus on the immediate reduction in DHS in response 
to a air blast stimulus (ie, the change from before product application to immediately after 
application), as measured using a VAS (see Section 5.3.1).  This timepoint was selected 
primarily due to the abundance of literature analyzing immediate changes in DHS in response 
to professionally applied F--containing desensitizing agents (see Section 2.1.2).  In addition,  
the baseline VAS and immediate post-application VAS will be assessed at the same visit, 
thereby limiting the number of Subjects that may be lost to follow-up prior to collection of data 
for the primary endpoint.
It is hypothesized that Clinpro™  2.1% Sodium Fluoride Aqueous Solution will be non-inferior 
to Vanish™ 5% Sodium Fluoride White Varnish in immediately reducing DHS.
3. IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
The investigational device for this study is Clinpro™  2.1% Sodium Fluoride Aqueous Solution, 
which is a xylitol-sweetened aqueous fluoride coating that is applied topically to the tooth 
surfaces for the treatment of DHS.  Clinpro™  2.1% Sodium Fluoride Aqueous Solution 
contains 9,500 ppm fluoride as well as added calcium and phosphate. 
This product is supplied in unit-dose packages containing 0.5 ml (0.5 grams) of the gel and is 
expected to be offered in a neutral, mint, and fruit (eg, melon) flavor.  Clinpro™  2.1% Sodium 
Fluoride Aqueous Solution will utilize the 3M L-Pop delivery system shown in Table 3-1, 
Figure A, along with a depiction of product application (Table 3-1, Figure B). 

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Table 3-1. Investigational Device
Name of Investigational Device
Depiction of the Investigational Device
A) Clinpro™  2.1% Sodium Fluoride 
Aqueous Solution
B)
Depiction of product application
3.1.1.
Control Device
The control device used in this study is Vanish™ 5% Sodium Fluoride White Varnish, which 
is a 22,600-ppm fluoride-containing varnish for application to enamel and dentin for the 
treatment of hypersensitive teeth.  This product is supplied in unit-dose packages containing 
0.5 ml (0.5 grams) of varnish coating and exhibits an extended-release formula that releases 
fluoride, calcium, and phosphate for 24 hours after application.
3.2.
DEVICE REGULATORY CLASSIFICATION
Clinpro™  2.1% Sodium Fluoride Aqueous Solution is anticipated to be a class 2 medical 
device under FDA product code LBH (varnish, cavity per 21 CFR 872.3260) that will require 
A
B

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FDA 510(k) ance. A 510(k) Pre-market Notification is planned for submission during the first 
quarter (Q1) of 2023.  
Clinpro™  2.1% Sodium Fluoride Aqueous Solution is not expected to have 510(k) clearance 
when the study begins.  For the purpose of this study, the product is not considered a Significant 
Risk(SR) investigational device under 21 CFR 812.3(m) because: 
•
Is not intended as an implant and presents a potential for serious risk to the health, safety, 
or welfare of a subject;
•
Is not purported or represented to be for use supporting or sustaining human life and 
presents a potential for serious risk to the health, safety, or welfare of a subject;
•
Is not for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a potential 
for serious risk to the health, safety, or welfare of a subject; and
•
Does not otherwise present a potential for serious risk to the health, safety, or welfare 
of a subject
3.3.
INTENDED USE OF THE DEVICE/INDICATIONS FOR USE 
The intended use of the device is the following:
Clinpro™  2.1% Sodium Fluoride Aqueous Solution is a fluoridated tooth coating. 
Data generated from this study is to support the indication for use in treating dentin 
hypersensitivity as well as support that the product is safe to use for the intended purpose. Data 
from this study will also be used for global regulatory registration.
4. BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE(S), CLINICAL 
PROCEDURE AND CLINICAL INVESTIGATION 
4.1.
BENEFITS OF THE DEVICE
Participants may benefit from a reduction in tooth hypersensitivity upon application of the 
investigational device or the comparator device.
4.2.
RISKS OF THE DEVICE
Fluoride varnishes and gels are considered to be low risk medical devices that are commonly 
used throughout dentistry.  Subjects participating in this clinical study may face the following 
potential risks, including but not limited to:

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•
Product contact with eye resulting in irritation
•
Skin irritation with possible blistering
•
Ingestion of excess product resulting in gastrointestinal upset, light headedness, 
dizziness, and/or presyncope 
•
Product aspiration.
•
Allergic reaction (eg, atopic dermatitis) 
4.3.
ANTICIPATED ADVERSE DEVICE EFFECTS
The anticipated Adverse Device Effects (ADEs) for Clinpro™  2.1% Sodium Fluoride Aqueous 
Solution include the following:
•
Ingestion of excess product resulting in gastrointestinal upset, light headedness, 
dizziness, and/or presyncope 
•
Allergic reaction
In addition to the anticipated ADEs for the investigational product, desensitizing agents that 
use organic solvents such as  Vanish™ 5% Sodium Fluoride White Varnish, also have the 
following anticipated ADEs:
•
Soft tissue erythema (redness)
•
Soft tissue edema (swelling)
•
Pruritus (itching), burning or other local sensations (eg, tingling or numbness)
Subjects with known allergies to components of the study devices are being excluded from 
participation in the study (see Section 6.5.1.2).  In addition, the anticipated ADEs listed above 
are being captured as safety data as part of this trial.
4.4.
RESIDUAL RISKS
The Subjects will undergo a single application of study product and are not expected to have 
long-term exposure to the material.  Therefore, residual risks are expected to be minimal for 
this study.
4.5.
RISK OF INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS
No specific risk of interaction with concomitant medical treatment is known for the tested 
devices.

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4.6.
MITIGATION OF RISK
Risk related to the device may be mitigated or controlled through appropriate selection of study 
subjects for inclusion into this study, adherence to this Clinical Investigation Plan (CIP), and 
reporting of Adverse Events (AEs), product deficiencies/complaints and deviations to the 
Sponsor.
4.7.
RISK TO BENEFIT RATIONALE
Based upon the risks and benefits listed above and adherence to this CIP, the study Subjects are 
at no greater risk of harm than individuals being treated for similar lesions who are not 
participating in this study.  The investigational device and the comparator device are being used 
in accordance with their intended use consistent with standard dental treatment plans for 
patients not participating in this study. Participants may benefit from a reduction in tooth 
hypersensitivity upon application of the investigational device or the comparator device.
5.  OBJECTIVES OF THE CLINICAL INVESTIGATION PLAN
5.1.
PURPOSE OF THE CLINICAL INVESTIGATION
The purpose of this investigation is to generate data to support an indication for use of the 
Investigational product in treating dentin hypersensitivity (DHS) and to support global 
regulatory registration of the product.
5.2.
PRIMARY OBJECTIVE(S)
The primary objective of this study is to evaluate the effect of Clinpro™  2.1% Sodium Fluoride 
Aqueous Solution (experimental) on DHS  in comparison to Vanish™ 5% Sodium Fluoride 
White Varnish (commercialized, control), a well-known product in the market used for this 
purpose.
5.3.
STUDY ENDPOINT(S)
5.3.1.
Primary Endpoint(s)
Co-primary endpoints include:
•
the change in pain, using a 100-mm VAS from baseline to immediately after application 
(within 15 minutes post treatment) of test product or comparator.
•
the change in pain score from baseline to 24 ± 4 h post-application, using VAS after 
exposure to air stimulus.

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Sensitivity will be assessed using VAS after exposure to air stimulus.
5.3.2.
Secondary Endpoint(s)
The secondary endpoints include:
1. change in pain score, using VAS, from baseline to 7 ± 2 days post-treatment, after 
exposure to air stimulus.
2. change in pain score, using VAS, from baseline to 21 ± 2 days post-treatment, after 
exposure to air stimulus. 
3. change in pain score, using VAS, from baseline to 30 ± 2 days post-treatment, after 
exposure to air stimulus.
5.3.3.
Additional/Exploratory Endpoints
The exploratory endpoints will include the reduction in pain (using a VAS) upon tactile testing 
with a periodontal probe, including:
1. Change from baseline to immediately post-treatment (within 15 minutes post-
treatment)
2. change from baseline to 24 ± 4 h post-treatment
3. change from baseline to 7 ± 2 days post-treatment
4. change from baseline to 21 ± 2 days post-treatment
5. change from baseline to 30 ± 2 days post-treatment.
5.3.4.
Safety Endpoint(s)
The safety endpoint will be the incidence of all AEs. 
6. DESIGN OF CLINICAL INVESTIGATION
6.1.
DESIGN
This is a prospective, randomized, single-blinded, parallel, non-inferiority study, that will enroll 
Subjects requiring treatment for DHS.  Subjects will be randomized in a 1:1 ratio with half of 
the Subjects treated with Clinpro™  2.1% Sodium Fluoride Aqueous Solution and the other 
half treated with  Vanish™ 5% Sodium Fluoride White Varnish. The study will be conducted 
at a single investigational site(s) in the following location(s): Loma Linda University Health.

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6.2.
STUDY DURATION
The entire duration of the study is expected to last one year.  Individual subject participation is 
expected to last up to 82 days, including a 3- to 6-week washout period before treatment. 
6.3.
MINIMIZATION OF BIAS
Due to the nature of the investigative device, the duration of treatment application, and the study 
design, Investigator blinding is not feasible for the study.  However, the following measures 
have been taken to minimize or avoid bias in this study:
•
Randomization in a permuted-block manner
•
Blinding of study Subject
•
Management of confounding factors – eg, exclusion of Subjects with other potential 
causes of tooth sensitivity (eg, previous restorations or periodontal treatments)
6.4.
INVESTIGATIONAL USE OF DEVICE AND COMPARATOR 
Clinpro™  2.1% Sodium Fluoride Aqueous Solution (Treatment arm) or  Vanish™ 5% Sodium 
Fluoride White Varnish (Control arm) will be used to treat DHS.  The investigational device is 
a new-to-market product, and at the time of this protocol, the product is not authorized for 
commercial sale or investigational use in any markets.  This investigation is being conducted 
prior to receiving formal market authorization in the country where the investigational site(s) 
is located; however, this study is considered a non-significant risk study, and appropriate 
approval from an IRB/ethics committee is required prior to the initiation of the study. The 
control device is being used in a manner consistent with the ed indication and IFU.  
6.5.
SUBJECT ENROLLMENT
A minimum of ninety six (96) enrolled Subjects that complete the treatment is planned for this 
study.  To achieve this minimum, the Investigator may enroll up to one hundred and twenty 
five (125) subjects.  
6.5.1.
Enrollment Criteria
To be considered eligible for enrollment, Subjects must meet all the inclusion listed in section 
6.5.1.1 and none of the exclusion criteria listed in Section 6.5.1.2.  Subjects are to be assessed 
for eligibility no more than 3-6 weeks prior (ie, at least 3 weeks but no more than 6 weeks) to 
the planned procedure and eligibility will be re-confirmed including the use of (IC4) on the day 
of the procedure.  Subjects who do not meet all the inclusion or meet any of the exclusion 

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criteria will not be eligible for randomization and will discontinue from the study.  They will 
be considered a screen failure.
6.5.1.1.
INCLUSION CRITERIA
Subjects may be included that meet the inclusion criteria in Table 6.5.1-1:
Table 6.5.1-1: Inclusion Criteria 
Number
Inclusion Criteria
1
Subject has at least one affected hypersensitive tooth upon air blast stimuli in the 
cervical area, and baseline pain score of 40 mm and above as assessed by the 100 
mm VAS.
2
Subject is at least 18 years old and have a minimum of 20 natural teeth.
3
Subject is willing to withhold desensitizing treatment, including prescription, in-
office or over the counter (OTC) desensitizing products, throughout the study 
period AND withhold during the washout period
4
Subject agrees to only use the provided toothpaste, toothbrush, and follows all 
oral hygiene instructions throughout the study period AND follows all oral 
hygiene instructions during the washout period.
5
Subject is able to understand and willing to sign the Informed Consent, and is 
willing to return to the study facility for scheduled study visits and recalls.
6.5.1.2.
EXCLUSION CRITERIA 
Subjects must be excluded from participating in this study if they meet any of the criteria in 
Table 6.5.1.2-1. 
Table 6.5.1.2-1: Exclusion Criteria 
Number
Exclusion Criteria
1
Subject has medical (including psychiatric) and pharmacotherapeutic histories 
that may compromise the protocol – including the chronic use of anti-
inflammatory, analgesic (pain), and mind-altering drugs; or analgesic (pain) 
medications within 48 hours prior to application of treatment. 
2
Subject is pregnant (self-reported) or breast feeding.

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Number
Exclusion Criteria
3
Subject has allergies to product ingredients, eg, rosin, mint flavoring.
4
Subject has systemic conditions that are etiologic or predisposing to dentin 
hypersensitivity (eg, chronic acid regurgitation).
5
Subject has excessive dietary or environmental exposure to acids at time of 
screening.
6
Subject had periodontal treatment, bleaching treatments, or orthodontic 
treatments within previous 3 months or plans to have any other dental treatments 
during the study period.  
7
Subject is enrolled in another clinical trial at the time of screening that would 
interfere with this study.
8
Subject is, in the opinion of the investigator, unsuitable for enrollment in the study 
for reasons other than those specified in the above exclusion criteria.
Number
Tooth Exclusion Criteria
9
Study tooth has periodontal probing depth of  ≥ 4 mm.
10
Study tooth or the surrounding supporting tissue has any other painful pathology 
or defects.
11
Study tooth has been restored in the preceding 3 months
12
Study tooth is an abutment for fixed or removable prostheses or suffers traumatic 
malocclusion.
13
Study tooth is crowned or extensively restored and the restorations extending into 
the test area.
14
The tooth has dentin hypersensitivity due to cracked enamel.
6.6.
PROCEDURES AND ASSESSMENTS
6.6.1.
Obtaining Informed Consent
Informed consent must be obtained for all Subjects prior to any study activities being performed 
or data being collected.  The Investigator or designee will review all relevant aspects of the 
study with the potential study Subject that are relevant to the Subject’s decision to participate 
throughout the study.  The Investigator or designee will provide ample time for the subject to 

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read and understand the Institutional Review Board (IRB)-approved Informed Consent Form 
(ICF) and to consider participation in the study.  
The study subject or legal authorized representative must sign and date the ICF.  The 
Investigator or designee must sign and date the ICF.  The ICF process must be documented by 
the Investigator or designee.  
The Informed Consent process includes documentation of the discussion regarding study 
procedures, subject concerns, that the subject was provided ample time to consider 
participation, and that all questions were answered prior to participation in any research activity.
The Investigator or designee must file the original ICF and provide the subject with a copy of 
the signed and dated Informed Consent and any other written documentation per local IRB 
requirements.
Subject privacy language, Health Insurance Portability and Accountability Act (HIPAA) or 
General Data Protection Regulation (GDPR), per local regulations may be added to the local 
Informed Consent by the Investigator.
6.6.2.
Laboratory Assessments to Determine Eligibility
No laboratory assessments will be performed as part of this study.
6.6.3.
Demographics and Subject Characteristics
After a Subject signs the ICF but before treatment, the following demographic data and Subject 
characteristics will be collected and documented:
•
Age
•
Sex
•
Baseline VAS upon air blast and tactile stimuli immediately before treatment 
•
Race
•
Ethnicity
•
Study tooth number 
6.6.4.
Vital Signs 
No vital signs will be captured as part of this study.

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6.6.5.
Randomization and Blinding
Randomization should occur after obtaining informed consent and ensuring that the Subject 
meets all eligibility criteria; randomization should occur on the day of treatment before the 
initial application of the investigational device (Treatment arm) or control device (Control arm).  
Due to the nature of the investigative device, the duration of treatment application, and the study 
design, Investigator blinding is not feasible for the study.  For Subjects with multiple eligible 
teeth, the PI will select the index tooth based on their experience and accessibility of the tooth 
for the stimuli; however, this selection must be made prior to randomization.  Randomization 
of the Subjects will be performed using a permuted block technique and will be centralized and 
electronic.  
6.6.6.
Treatments
6.6.6.1.
WASHOUT PERIOD
All Subjects will undergo a pre-treatment washout period for 3- to 6-weeks (± 4 days) post-
enrollment.  During this time, the Subject is to only use the oral hygiene products (Colgate 
Cavity Protection Fluoride Toothpaste - Great Regular Flavor 0.15% w/v Fluoride Ion, Colgate 
Company and Oral-B® Indicator™ Toothbrush, Sensitive 35 Extra Soft, Procter & Gamble 
Company) provided for the study, except for floss; beginning immediately after the consent 
visit.  The Subject should perform tooth brushing during this period with the sponsor-provided 
toothbrush and toothpaste as directed by the Investigator.  In addition, the Subject should refrain 
from taking prescription or OTC analgesic medications for 48 hours prior to the treatment visit 
and all post-treatment visits.  Any use of analgesics within 48 h prior to treatment visit should 
be documented on concomitant medications CRF.
6.6.6.2.
BASELINE PAIN ASSESSMENTS AND TREATMENT APPLICATIONS
The study tooth for Subjects in both arms of the study will be isolated from neighboring teeth 
according to standard dental practices (eg, VPS putty or cotton rolls)  and should remain isolated 
during pain assessment. Isolation materials may be removed during treatment application; 
however, the study tooth should remain clean and free of excess saliva for the application of 
the product. The method of isolation should be documented and should remain consistent for 
each study visit.  After isolation of the study tooth, a pain assessment will be performed (ie, a 
baseline pain score) in response to both an air-blast stimulus and tactile stimulus.  For the air-
blast stimulus, a pressure-calibrated air syringe should be placed perpendicular to the center 
cementoenamel junction (CEJ) of the study tooth.  With the tip of the syringe placed 
approximately 1 cm from the tooth, the syringe is to be fully activated for 1 second.    For the 

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tactile test, a periodontal probe will be moved from distal to mesial along the CEJ, with a 
continuous unidirectional stroke of  around 1 second duration.  After each stimulus, the Subject 
should score their pain by indicating their pain level on a 100-mm VAS that represents a 
continuum between “no pain”, indicated by 0 mm on the scale, and “worst pain”, indicated by 
100 mm on the scale.  A VAS score should be recorded for both the air-blast stimulus and tactile 
stimulus, with the VAS score for the air-blast stimulus occurring prior to initiating the tactile 
test, with a minimum of 3 minutes between tests.
After recording baseline pain scores, isolation should be maintained and excess saliva should 
be removed.  Immediately apply Clinpro™ 2.1% Sodium Fluoride Aqueous Solution 
(Treatment arm) or Vanish™ 5% Sodium Fluoride White Varnish (Control arm) as described 
in Sections 6.6.6.2.1 or 6.6.6.2.2, respectively.
6.6.6.2.1.
TREATMENT GROUP
After ensuring that the study tooth is clean and free of excess saliva, Clinpro™  2.1% Sodium 
Fluoride Aqueous Solution should be applied to the tooth using the applicator brush, according 
to the manufacturer’s IFU.  The product should be applied to the tooth in a thin layer, reloading 
the applicator brush as needed.  Only enough product should be used to form a thin coating on 
the desired treatment area, and it is not necessary to use all the product provided. After the 
application, any excess material or saliva may be suctioned from the mouth or the Subject may 
spit.  To achieve the maximum benefit, the Subject should avoid food, beverages, and oral rinses 
for 15 minutes after application.
6.6.6.2.2.
CONTROL GROUP
After ensuring that the study tooth of Subjects randomized to the Control group is clean and 
free of excess saliva, 3MTM Vanish™ 5% Sodium Fluoride White Solution should be applied 
to the tooth using the applicator brush, according to the IFU.  Before application, use the brush 
to thoroughly mix the varnish since components of all sodium fluoride varnishes can separate 
during storage.  The product should be applied to the study tooth in a thin layer, applying the 
varnish in sweeping horizontal brush strokes and avoiding excessive contact with soft tissue.  
Only enough varnish to form a thin coating should be used on the desired application area.  
After application, the Subject should close their mouth to allow the varnish to set and rinsing 
or suctioning immediately after application is not recommended.  To achieve the maximum 
benefit after application, the Subject should not brush or floss the teeth for at least 4 hours and 
preferably up to 24 hours after the application. The Subject should also eat soft foods and should 
not consume hot drinks or alcohol (mouth rinses) during the 24-hour period after application.  

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6.6.7.
Post-Treatment Pain Assessments
Post-treatment pain assessments will be performed for all Subjects in response to both an air-
blast stimulus and tactile stimulus with the VAS score for the air-blast stimulus occurring prior 
to initiating the tactile test, and waiting a minimum of 3 minutes between tests, as described in 
Section 6.6.6.2.
For post-treatment tactile (probe) testing, the same type of instrument that was used for the pre-
treatment test (ie, periodontal probe) should be used for the post-treatment test, taking care to 
use the similar force as before and not remove the coating on the tooth during the test performed 
immediately after treatment (whithin 15 minutes post-treatment).  All post-treatment VAS 
scores should be documented in the appropriate CRF.
6.6.8.
Concomitant Medications
Concomitant medications will be collected from the time of informed consent through the final 
study visit.  The medical name, start date, end date; end time or ongoing and indication reason 
will be reported.  
6.6.9.
Adverse Events and Adverse Device Effects
AEs and ADEs will be collected from the time of initial application of control or investigational 
treatment until end of study visit (30 days post-application).  AEs and ADEs will be reported 
according to Section 13.
6.6.10. Prohibited Procedures and On-Study Restrictions
No other treatments for the study tooth other than those described in Section 6.6.6 are permitted 
during the course of this study.  Any divergence from these treatment conditions will be 
captured as a protocol deviation (see Section 10) and the reason for selecting alternative 
treatments in the absence of an AE or device defect should be documented.  Study visits that 
occur outside of the study visit windows will also be documented as protocol deviations.  In 
addition, Subjects should avoid the following from the time of tooth treatment until completion 
of the study to ensure the oral hygiene activities and products used are controlled prior to and 
throughout the study:
•
Refrain from additional desensitizing treatments after application of the study product.
•
Refrain from activities that would impair the function of the products, including: 
o
acidic beverages
o
use of any tooth whitening/bleaching products for the entire study period. 

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•
Refrain from any non-emergency treatment for the entire study period.
Any deviation(s) from the CIP that diminishes the integrity of the data, results in non-adherence 
to the eligibility criteria, or impacts the Subject’s rights, safety, or welfare will be documented 
as major protocol deviation(s) (see Section 10).29
6.6.11. End of Study Documentation
Subjects may withdraw or be discontinued from this study at any time. The Investigator may 
discontinue a Subject’s study participation if the Investigator feels it is in the best interest of 
the Subject. 
The following information will be documented at the End of Study:
•
Last day of study participation
•
Completion status – Did the Subject complete the study (Yes/No)?
•
Reason for ending participation in the study 
6.7.
VISIT SCHEDULE AND DESCRIPTION OF STUDY VISITS
6.7.1.
Point of Enrollment
A Subject is considered enrolled in this study at time the Informed Consent process has been 
completed.  Since the subject will have signed the informed consent, if post-consent screening 
procedures or eligibility re-confirmation on the initial day of study procedures reveal that the 
subject does not meet eligibility criteria, the subject will be considered a Screen Fail and will 
not be assigned a treatment allocation number.  
6.7.2.
Visits
After Informed Consent has been obtained, each Subjects will be given Sponsor-supplied oral 
hygiene products (eg, toothbrush and toothpaste) to be used immediately after the consent visit 
and throughout the entire duration of the study.  All Subjects will return for a treatment visit 
(Day 0) and post-treatment follow-up visits at 24 hours (± 4 hours), 7 days (± 2 days), 21 days 
(± 2 days), and 30 days (± 2 days) after the treatment visit.  All applicable data are to be recorded 
in the applicable Case Report Form (CRF).
6.7.2.1.
SCHEDULE OF EVENTS
A schedule of events is in Tables 6.7.2.1-1 below:

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Table 6.7.2.1-1: Schedule
Consenting Visit & 
pre-treatment 
washout
Treatment 
Visit
24-hour 
follow 
up
Day 7
follow-
up
Day 21 
follow-up
30 Day 
follow-up
Unscheduled 
Visit
Visit Number 
1
2
3
4
5
6
Visit Window
3-6 weeks
Day 0
24 ± 4 h
7 d ± 2 d
21 d ± 2 d
30 d ± 2 d
Screening
X
Informed Consent signed
X
Concomitant meds
X
X
X
X
X
X
X
Eligibility confirmation
X
X*
Enrollment
X
Randomization
X
DHS Treatment
X
Pain assessments to air-blast stimulus 
and tactile stimulus
X
X**
X
X
X
X
X
AEs / SAEs / ADEs / DDs
X
X
X
X
X
X
End-of-Study
X
X***
* Before treatment
**Before treatment (baseline) and after treatment 
***if applicable

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6.7.2.2.
STUDY VISIT 1 (CONSENTING AND QUALIFICATION VISIT)
1. The following procedures and assessments will be completed at Visit 1: Assessment of 
eligibility, including assessment of self-reported pregnancy/breastfeeding status for 
female Subjects, as described in Section 6.5.1.
2. Obtain informed consent, as described in Section 6.6.1.
3. Document Subject demographics and characteristics, as described in Section 6.6.3.
4. Document concomitant medications, as described in Section 6.6.8.
5. Provide Subjects with Sponsor-supplied study products for oral hygiene (eg, toothbrush, 
toothpaste). 
6.7.2.3.
STUDY VISIT 2 (DAY 0 – TREATMENT VISIT)
The following procedures and assessments will be completed at Visit 2:
1. Confirmation that Subject meets eligibility criteria (see Section 6.5.1) and update 
concomitant medications (see Section 6.6.8) as Visit 2 occurs on a different day than 
Visit 1.  If Visit 1 and Visit 2 are  > 6 weeks apart, Subject should be re-screened.
2. Baseline pain assessments and DHS treatment, as described in Section 6.6.6.
3. Post-treatment pain assessments after application (within 15 minutes post-treatment), as 
described in Section 6.6.7.
4. Assessment and documentation of AEs, ADEs, and DDs, as described in Section 6.6.9.
6.7.2.4.
STUDY VISIT 3 (24 ±4 H POST-TREATMENT)
The following procedures and assessments will be completed at Visit 3:
1. Pain assessments, as described in Section 6.6.7
2. Document concomitant medications, as described in Section 6.6.8.
3. Assessment and documentation of AEs, ADEs, and DDs, as described in Section 6.6. 9.
6.7.2.5.
STUDY VISIT 4 (DAY 7 ± 1 D POST-TREATMENT)
1. Pain assessments, as described in Section 6.6.7
2. Document concomitant medications, as described in Section 6.6.8.
3. Assessment and documentation of AEs, ADEs, and DDs, as described in section 6.6.9.

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6.7.2.6.
STUDY VISIT 5 (DAY 21 ± 2 D POST-TREATMENT)
1. Pain assessments, as described in Section 6.6.7
2. Document concomitant medications, as described in Section 6.6.8.
3. Assessment and documentation of AEs, ADEs, and DDs, as described in section 6.6.9.
6.7.2.7.
STUDY VISIT 6 (END OF STUDY – DAY 30 ± 2 D POST-TREATMENT)
1. Pain assessments, as described in Section 6.6.7
2. Document concomitant medications, as described in Section 6.6.8.
3. Assessment and documentation of AEs, ADEs, and DDs, as described in section 6.6.9.
4. Documentation of end of study (see Section 6.6.11).
6.7.2.8.
UNSCHEDULED VISIT
1. Pain assessments, as described in Section 6.6.7
2. Document concomitant medications, as described in Section 6.6.8.
3. Assessment and documentation of AEs, ADEs, and DDs, as described in section 6.6.9.
4. Documentation of end of study, as described in Section 6.6.11, if applicable.
6.7.3.
Point of Exit
Study Subjects may exit the study for a variety of reasons. The Investigator shall record the 
reason for ending participation in the study in the applicable Case Report Form.  These reasons 
include, but are not limited to:
•
Study completion (all study related visit(s) are completed)
•
Withdrawal by the Subject
•
Withdrawal by Investigator
•
Lost to follow-up
•
Death
•
Study Termination
In the event of subject withdrawal or discontinuation prior to treatment visit (screen fail), study 
Subjects will be replaced until the desired enrollment is reached.  In the event of subject 
withdrawal or discontinuation post treatment visit, Subject will not be replaced.

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Data collected until the last known contact of study subject may be used in the analysis of study 
data.  For study subjects lost to follow-up, the Investigator shall make 3 documented attempts 
before confirming the subject is lost to follow-up.  If the study subject withdraws from the study 
for any reason and there is an ongoing safety event, additional safety event information may 
need to be collected by the Investigator and shared with Sponsor. 
6.8.
ROLE OF SPONSOR REPRESENTATIVE
6.8.1.
Monitoring 
Study monitoring is conducted to ensure that (i) the rights, safety, and well-being of study 
participants are protected, (ii) the reported study data are accurate, complete, and verifiable, 
and (iii) the conduct of the study is in compliance with the currently approved CIP, with good 
clinical practice (GCP) principles, and with applicable regulatory requirement(s).  3M, as 
Sponsor of this clinical investigation, is responsible for study oversight and for providing the 
Principal Investigators (PIs) and study staff with training regarding the proper conduct of the 
clinical investigation with regard to CIP adherence and validity of the data recorded on the 
CRFs.  3M has therefore assigned study monitor(s) to this clinical investigation.  The progress 
of the clinical investigation will be monitored by:
•
Periodic and/or remote review
•
Telephone communications 
•
Review of CRFs and source documents (eg subject records)
The study monitor(s), other authorized representatives of the Sponsor, representatives of the 
IRB, or regulatory authorities may inspect all documents and records required to be maintained 
by the Investigator, including but not limited to Subject records (office, clinic, or hospital) for 
the participants in this study.  The clinical study site personnel will permit access to such 
records.  The Investigator will give 3M study monitor(s) direct access to source documents that 
support data on the CRFs, including any electronic records.  If site policies restrict access to 
Subjects’ files to site personnel, the PI will designate a staff member to work with the Sponsor’s 
monitor to verify source documents on an as-needed basis.  This verification will be conducted 
in a way that will ensure that only study-related information is examined.
Details of clinical site monitoring are documented in a Monitoring Plan (MP).  The MP 
describes who will conduct the monitoring, the planned frequency of monitoring visits, records 
to be reviewed, and the distribution of monitoring reports.

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Independent audits may be conducted by 3M personnel or an independent party to ensure 
monitoring practices are performed consistently across all participating sites and that monitors 
are following the MP.
6.8.2.
Other Sponsor Oversight
In addition to study monitoring, the Sponsor, or their representatives may conduct the following 
tasks during this study:
•
Audits of the Investigator
•
Provision of technical support/product specific training for the study device
7. DATA MANAGEMENT
Data collected for this study will be analyzed and stored at 3M or an approved supplier for use 
by researchers including those outside of the study.  Permission to transmit, store and use data 
outside of the study will be included in the informed consent.  Details of data management for 
this investigation are documented in a Data Management Plan (DMP).  The DMP describes the 
procedures used for CRF tracking, data review, database cleaning, query management, coding 
and data reconciliation.
7.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the site Investigator.  The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.
All source documents should be completed in a neat, legible, permanent and un-editable manner 
to ensure accurate interpretation of data.  Data recorded in the electronic case report form 
(eCRF) derived from source documents must be consistent with the data recorded on the source 
documents. 
All data, including AEs and expected AE data, will be entered into a 21 CFR Part 11-compliant 
data capture system provided by the Sponsor.  The data system includes password protection 
and internal quality checks (eg, automatic range checks) to identify data that appear 
inconsistent, incomplete, or inaccurate.
The Sponsor is responsible for compilation and verification of the clinical study data, retention 
of the clinical study database, performance of statistical analysis, and preparation of the clinical 
study report.

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7.2.
STUDY RECORDS RETENTION
Information for each study participant will be securely stored at each clinical site for internal 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
location in accordance with policies from the reviewing IRBs, Institutions, regulatory 
authorities, and Sponsor requirements.
No records will be destroyed without the written consent of the Sponsor.  It is the responsibility 
of the Sponsor to inform the Investigator when study documents no longer need to be retained.
7.3.
SPONSOR OVERSIGHT
The Investigator will allow access to clinical study records for periodic on-site or remote 
monitoring visits by a designated 3M representative, with the understanding that the 
representative is bound by professional secrecy and will not disclose the identity of any 
Subject or personal medical information.  The representative will review eCRFs for 
completeness during monitoring visits and after the eCRFs are submitted; any discrepancies 
will be resolved with the Investigator or designee, as appropriate.  The data will be entered 
into the clinical study database and verified for accuracy.
In addition to on-site or remote monitoring, routine review of submitted study information 
will be conducted by the Sponsor to ensure compliance with the CIP.  Items reviewed include 
but are not limited to AEs, deviations, number of withdrawn/terminated Subjects, which all 
may impact the completion of the study.  Appropriate measures may be taken to ensure 
Investigator compliance with the CIP.
8. STATISTICAL CONSIDERATIONS
8.1.
PASS/FAIL CRITERIA
The null hypotheses that we seek to reject are that Vanish™ 5% Sodium Fluoride White Varnish 
has a 15.0 mm higher change from baseline VAS than Clinpro™ 2% Sodium Fluoride Aqueous 
Solution when measured immediately after application (within 15 minutes post-treatment) or at 
24-hours after treatment (±4 hours).  The null and alternate hypotheses are described below.
H0:
Vanish™ Varnish changed from baseline – Clinpro™ 2.1% Sodium Fluoride Aqueous 
Solution change from baseline >15 mm.
Ha:
Vanish™ Varnish changed from baseline – Clinpro™ 2.1% Sodium Fluoride Aqueous 
Solution change from baseline  ≤15 mm.

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8.2.
SAMPLE SIZE DETERMINATION
Twenty-eight hypersensitivity studies were reviewed for difference in treatment effect (change 
from baseline) of actives and several reported differences between actives in VAS change from 
baseline of greater than 20 mm.  Even with these notable differences, the authors routinely 
declare all actives effective in treatment of hypersensitivity. This study will use a more 
conservative non-inferiority margin of 15 mm. A standard deviation for change from baseline 
at immediately after treatment (within 15 minutes post-treatment) and 24-hours of 20 mm will 
be used.  There is uncertainty in the efficacy difference between treatments as well as the error 
term.  An interim analysis will be conducted at approximately 50% of subject treatment to 
reassess sample size with no alpha spending required.  Ninety-six (96; 48 per arm) total subjects 
will provide 80% power allowing for a 2 mm difference in efficacy difference between 
treatments and 2 co-primary endpoints tested.  No subjects will be lost to follow-up for the 
primary time point of immediate hypersensitivity relief, but there may be loss to follow-up for 
co-primary endpoint of hypersensitivity relief at 24-hours after treatment.  
8.3.
ANALYSIS POPULATIONS
All dosed subjects without a major protocol deviation will be included in the analysis dataset 
for the co-primary endpoints of change in hypersensitivity immediately after product 
application and change in hypersensitivity 24-hours after application.   For the secondary and 
exploratory endpoints, all dosed subjects without a major protocol deviation occurring up to the 
evaluation time for each endpoint will be included in the analysis dataset for that endpoint.  All 
treated subjects will be included in the safety analysis dataset. Major protocol deviation(s) for 
exclusion from the analysis dataset will be defined and documented in a blinded fashion prior 
to interim and final analyses (eg, inadequate washout).
8.4.
STATISTICAL ANALYSES
8.4.1.
Demographic and Baseline Characteristics
Demographic and baseline characteristics for the study will be generated and displayed by 
treatment arm and overall.  Key baseline characteristics variables may include but are not 
limited to general health status, baseline pain, and any specific factors that may affect the 
change in pain after treatment.  
8.4.2.
Analysis of Primary Endpoints
At the final analysis, multiplicity will be controlled through a Hochberg procedure.  Ninety-
five- percent (95%) confidence intervals will be generated for the difference between treatments 

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in change from baseline immediately after application and separately for the difference between 
treatments in change from baseline 24-hours after application using Student’s t distribution.  
Scenario 1:  Neither of the 95% confidence intervals contain 15 mm.
Result: Non-inferiority for both co-primary endpoints will be declared 
Scenario 2:  Both of the 95% confidence intervals contain 15 mm.
Result:  No non-inferiority for either co-primary endpoints will be declared, and all analyses 
will be informational only.
Scenario 3:  One confidence interval contains 15 mm, and the other confidence interval does 
not contain 15 mm.
The endpoint that does not contain 15 mm has the potential to be declared non-inferior.  For 
this endpoint, as part of the Hochberg procedure, a 97.5% confidence interval will be generated.  
Non-inferiority for this endpoint will be declared if the new confidence interval does not contain 
15 mm.
8.4.3.
Analysis of Secondary Endpoints
If the null hypotheses are rejected for both co-primary endpoints, the alpha will be passed to 
test for non-inferiority of Clinpro™ 2.1% Sodium Fluoride Aqueous Solution to Vanish™ 
Varnish for the various secondary endpoints.  Ninety five percent (95%) confidence intervals 
will be generated for the difference between treatments in change from baseline using the 
Student’s t distribution at each evaluation time.  Non-inferiority will be declared if Vanish™ 
Varnish changed from baseline minus Clinpro™ 2.1% Sodium Fluoride Aqueous Solution 
change from baseline is less than or equal to 15 mm for each secondary endpoint. There are 3 
secondary endpoints.  The alpha will be passed sequentially in the order listed in section 5.3.2.
8.4.4.
Analysis of Additional/Exploratory Endpoints
Ninety five percent (95%) confidence intervals will be generated for the difference between 
treatments in change from baseline using a Student’s distribution at each evaluation time.  No 
non-inferiority will be declared.
8.4.5.
Analysis of Safety Endpoints
Adverse events will be summarized by treatment.

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8.5.
PLANNED INTERIM ANALYSES AND CRITERIA FOR CLINICAL INVESTIGATION
An interim analysis will be conducted after treating approximately 50% of the planned sample 
size for the purpose of sample size re-estimation.  No alpha will need to be spent because of 
this sample size re-estimation.  The parameter estimates from the interim data will be used and 
the sample size necessary for 80% power will be calculated.
8.6.
PROCEDURES FOR REPORTING DEVIATIONS FROM STATISTICAL PLAN
Any deviations from the original plan will be described and justified in the final report.
8.7.
PROCEDURES FOR MISSING, UNUSED, OR SPURIOUS DATA 
If a subject withdraws, only the data up to withdrawal will be used.  There will be no imputation 
of missing outcome data.  Any non-use of data will be explained and justified in the final report. 
8.8.
VALIDATION PLAN
The results of this study will be used for registration, therefore level 2 validation of the statistical 
programs and output will be performed.  Level 2 validation entails independent review of logs, 
output, program code, and report results.
9. AMENDMENTS TO THE CIP
If modifications to this CIP are necessary (eg, to protect the safety of the Subjects and/or the 
integrity of the data), the CIP will be amended and approved by the Sponsor.  All changes will 
be evaluated for impact per the standard operating procedures of the Sponsor.  In collaboration 
with the Investigator(s), the CIP modifications will then be documented and submitted for 
ethical and regulatory approval (as required) before implementation.  Modifications will be 
considered implemented after all ethical and regulatory approvals (as required) are received and 
all key Sponsor personnel, Investigators, and Investigator designees, including key site staff, 
have been trained regarding the modified CIP. 
10. DEVIATIONS FROM THE CIP
The Investigator is not allowed to deviate from the CIP except as specified in Section 5.6.4 of 
the International Standard, ISO/FDIS 14155.  Briefly, deviations from the CIP to protect the 
rights, safety, and well-being of human Subjects under emergency circumstances may proceed 
without prior approval of the Sponsor and the IRB; however, such deviations shall be 
documented and reported to the Sponsor and the IRB in accordance with IRB requirements.  
All deviations shall be documented on a deviation report form or appropriate CRF, and a 
deviation report form shall be completed for each event per individual Subject.  The Investigator 

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is responsible for reporting all deviations to the Sponsor and reviewing IRB, per local 
requirements.
10.1. DEVIATION REPORTING TIMELINES
The timelines and methods for reporting the different types of deviations to the Sponsor are 
provided in Table 10.1-1.
Table 10.1-1.  Deviation reporting timelines and methods
Type of Deviation
Report to Sponsor
Method
Major
Subject safety, rights or welfare; OR
Compromise the data integrity or 
statistical analysis of the study; OR 
Non-adherence to Inclusion/Exclusion 
criteria
Within 24 hours of 
study staff becoming 
aware of event
Initial: Phone/Email to 
Sponsor
Complete CRF
All other protocol deviations
Per CIP-designated 
visits
Complete CRF
11. DEVICE ACCOUNTABILITY
The device(s) under investigation and additional study-specific equipment to be used in both 
arms of the study (listed in Table 11-1) will not be distributed to the investigational site until 
all agreements between the site and 3M are finalized and IRB approval has been obtained.  3M 
requires that Investigator maintains device accountability and security of the devices at all 
times. The Investigator or designee will keep records documenting the following: 
•
Maintain and account for devices at the Investigator site, including:
o
the name(s) of person(s) who received, used, returned, or disposed of the device;
o
the date of receipt, identification, and quantity of each investigational device 
(batch number/serial number or unique code);
o
the expiration date of the device, if applicable.
•
Keep devices in a secure storage area, accessible only to authorized individuals.

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•
Dispense devices only to Subjects properly enrolled in and eligible for the study, 
including the following:
o
Subject identification;
o
the date or dates of use.
•
Return all unused investigational materials to the Sponsor at the end of the study or 
dispose of as agreed upon, including:
o
the date of return of unused, expired, or malfunctioning investigational 
devices, if applicable;
o
the date and documentation of disposal of the investigational devices as per 
instructions of the Sponsor, if applicable.
The Sponsor shall have instructions in place and make packaging materials available, if 
applicable, for the safe return or disposal of investigational devices.
Table 11-1: Additional Study-specific Device Information
Device Name
Manufacturer
Vanish™ 5% Sodium Fluoride White 
Varnish
3M™ Company
Colgate Cavity Protection Fluoride 
Toothpaste - Great Regular Flavor 
0.15% w/v Fluoride Ion  
Colgate
Oral-B® 
Indicator™ 
Toothbrush, 
Sensitive 35 Extra Soft
Procter & Gamble Company
11.1. LABELING FOR DEVICE(S) UNDER INVESTIGATION
The devices under investigation will be labeled according to applicable regulations.  A 
sample label will be retained, along with other study-related documents, at the site (eg, in the 
Investigator Site File).
11.2. ADDITIONAL STUDY-SPECIFIC EQUIPMENT/DEVICE(S)
Additional study-specific equipment/devices used in this study shall be maintained, calibrated 
(if applicable) and ensured to be functioning correctly during the study, in accordance with this 

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study CIP or applicable site policy and regulatory requirements.  The Sponsor should be notified 
of any anticipated or known issues with the device functionality that may impact the study 
conduct or outcome.
12. STATEMENTS OF COMPLIANCE
12.1. ETHICAL CONSIDERATIONS
This study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki.  In addition, this clinical investigation shall be conducted in accordance with ISO-
14155, US FDA 21 CFR parts 812, 50, 54, 56, and any regional or national regulations, as 
appropriate.  
Approving IRBs will be provided all relevant study documentation to safeguard the rights, 
safety, and well-being of Subjects as mandated.  The participating Investigator will obtain IRB 
approval of the study prior to initiation of the study at the site.  The protocol, IFU, ICF, written 
information given to Subjects, safety updates, and any revisions to these documents will be 
provided to the IRB by the Investigator.
12.2. PERIODIC REVIEWS
Ongoing reviews by IRB are required for the duration of the clinical study.  The Investigator 
will comply with local IRB requirements for ongoing reviews, at a minimum annually.  The 
Sponsor may provide an annual study report to participating Investigators.
12.3. PARTICIPANT CONFIDENTIALITY
Participant confidentiality and privacy is strictly held in trust by the participating Investigators, 
their staff, and the Sponsor(s) and their authorized representatives.  Information collected about 
Subjects during the study will be kept confidential and managed according to the requirements 
of the IRB and HIPAA of 1996.  This confidentiality is extended to cover the testing of 
biological samples and other clinical information relating to participants (eg, images related to 
the study wound).  Therefore, the CIP, documentation, data, and all other information generated 
will be held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized third party without the prior written approval of the Sponsor. 
In the event that a Subject revokes authorization to collect or use personal health information 
(PHI), the Investigator retains the ability to use all information collected prior to the revocation 
of Subject authorization.

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Study data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at 3M or an approved supplier.  This data will not include the 
participant’s contact or identifying information.  Rather, individual participants and their 
research data will be identified by a unique study identification number (see Section 6.6.5).  The 
electronic data capture system used by clinical sites and by 3M research staff will be secured 
and password protected.  At the end of the study, all study databases will be archived at 3M or 
an approved supplier.  
12.4. CONFLICT OF INTEREST
The independence of this study from any actual or perceived influence, such as by the medical 
device industry, is critical.  Therefore, any actual conflict of interest of persons who have a role 
in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed.  Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  The Sponsor has established procedures for all Investigators to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
12.5. INSURANCE
The Sponsor shall provide clinical study related insurance covering the reasonable, and 
necessary costs of diagnostic, therapeutic and medical treatment including hospitalization costs 
(treatment costs) for such participant injuries following the administration or use of the study 
device(s) in accordance with this CIP and in accordance with the national regulations.  The 
Sponsor may reimburse the institution and/or study participants for treatment costs depending 
on who incurred such treatment costs.  The Sponsor will not be responsible for paying for or 
reimbursing treatment costs if (i) the injury is attributable to the negligence or misconduct of 
any agent or employee of the institution or Investigator, or the failure of such persons to comply 
with a study protocol, (ii) the treatment costs are covered by the study participant’s medical or 
hospital insurance coverage, or (iii) the treatment costs arose as a result of the treatment of 
normal progression of the study participant’s disease or injuries resulting from interventions 
that the study participants would have incurred had they not participated in the study. 
12.6. FUTURE USE OF STORED COLLECTED SPECIMENS
No biological specimens are being collected as part of this study.

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13. ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES
Subject safety and event reporting are important in this study.  Investigators are responsible for 
ensuring that all safety events are recorded in the subject record(s). Events defined in Section 
13.1 will be reported to the Sponsor, as applicable, per the timelines in Section 13.3.
13.1. SAFETY AND EVENT REPORTING DEFINITIONS
This study utilizes the following definitions, as listed in Table 13.1-1 below.
Table 13.1-1: Definitions
Term
Definition
Adverse Event 
(AE)
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device.  This includes, but is not limited to, 
events related to the investigational device or the comparator and to 
procedures involved in this study.
Adverse Device 
Effect (ADE) 
An adverse event related to the use of an investigational medical 
device. This includes any adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational medical device. 
This includes any event that is a result of a user error or intentional 
misuse of the investigational device. 
Serious Adverse 
Event (SAE)
Any adverse event that:
•
Led to death
•
Led to serious deterioration in the health of the subject, users, or 
other persons as defined by one of more of the following: 
o
a life-threatening illness or injury, or
o
a permanent impairment of a body structure or a body function 
including chronic diseases, or
o
in-patient or prolonged hospitalization, or

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Term
Definition
o
medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure 
or a body function
o
Led to fetal distress, fetal death or a congenital anomaly or 
birth defect including physical or mental impairment.
NOTE: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP without serious deterioration in health, 
is not considered a SAE
Serious Adverse 
Device Effect 
(SADE) 
An adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
A serious adverse device effect, which by its nature, incidence, 
severity, or outcome has not been identified in the current version of 
the risk analysis report
Device Deficiency 
(DD) 
An inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance, such as malfunctions, use 
errors, and inadequate labelling.
Complaint 
Any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device after it is released for 
distribution.   Note: Device-related adverse events would meet this 
definition.
13.2. CLASSIFICATION OF EVENTS
13.2.1. Severity Ratings
The severity ratings for events are defined in Table 13.2.1-1.   The Investigator shall ensure 
rating of reportable events on the applicable Case Report Form.

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Table 13.2.1-1: Severity Ratings Definitions
Term 
Definition
Mild
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities
Moderate
An event that is sufficiently discomforting to interfere with normal 
everyday activities
Severe
An event that prevents normal everyday activities
13.2.2. Relatedness to Study Device or Study Treatment
Table 13.2.2-1 defines the relatedness definitions for events.  The Investigator shall ensure 
rating of reportable events on the applicable Case Report Form.
Table 13.2.2-1: Relatedness Definitions
Term 
Definition
Not Related
Relationship to the device or procedure can be excluded
Possible
Relationship with the use of the study device is weak but cannot be 
ruled out completely.
Causal
The event is associated with the study device or with the procedures 
beyond a reasonable doubt when:
•
The event is a known side effect of the device
•
The event has a temporal relationship with the study 
device/application procedures
•
The event involves a body/site or organ that
o
The device or procedures are applied to;
o
The device or procedures have an effect on
•
The event follows a known response pattern to the device

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13.3. DETAILS CONCERNING SAFETY RECORDING AND REPORTING REQUIREMENTS
13.3.1. Investigator Responsibilities
It is the responsibility of each participating Investigator to ensure all safety events (eg, AEs, 
SAEs, device effects, or DDs) are recorded in the Subject’s record.  The collection/reporting 
period for safety events will begin from the time of randomization through the end of the 
study.  Investigators should assess for AEs at each visit after randomization, and study 
Subjects should be instructed to report any AE that they experience to the Investigator.  All 
AEs, regardless of perceived relationship to study product, will be documented in a timely 
manner and reported according to the methods and timelines in Section 13.4.  In addition, 
the worsening of an underlying medical condition should also be recorded as an AE.  The 
AE description will include the nature of the experience (AE term), the start date, the end 
date, the severity of each sign or symptom, the seriousness of the event or experience, the 
relationship to study treatment, the course of action taken, and the outcome of the experience.  
It will be indicated if the AE caused the Subject to be discontinued from the study.
USADEs must be reported by the Investigator to the Sponsor and the reviewing IRB 
according to their reporting requirements within 24 hours of becoming aware of the event 
(see Table 13.4-1).  In addition to submitting UADEs to the IRB, the Investigators will, along 
with the Sponsor, decide to continue, suspend, or terminate the study.
13.3.2. Sponsor Responsibilities
Safety oversight will be under the direction of the Medical Monitor and Safety Monitor of 
3M, which both have appropriate expertise.  The Clinical Trial Safety Officer and Senior 
Medical Director will routinely review and assesses the safety data of the study.  Emergency 
contact information for reporting SAEs or SADEs will be provided to the Investigator or 
Investigator designee, as well as the IRB, before initiating the study.
The Sponsor will evaluate the received AEs/SAEs and if an event is confirmed to be an 
SAE/USADE, will then immediately conduct an evaluation of a USADE and report the 
results of the evaluation to the FDA and participating Investigators within 5 working days 
after the Sponsor first receives notice of the event (21 CFR 812.46(b), 812.150).  If the 
Sponsor determines that the event presents an unreasonable risk to the study Subjects, the 
Sponsor will terminate all clinical studies or parts of studies presenting risk as soon as 
possible.

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13.4. REPORTING TIMELINES
Table  13.4-1 below indicates the reporting timelines for events to the Sponsor.  The 
Investigator shall report to local IRB and local regulatory authorities, per local requirements.  
Reporting to Sponsor begins when study staff are aware of the event.  For any event listed in 
the table below, the study Sponsor may request additional information from the Investigator, 
including but not limited to, medical records, laboratory testing, radiological results, etc. 
regarding the event.
Table 13.4-1. Reporting Timelines for safety events
Type of event
Report to Sponsor
Method
Adverse Events (AE) 
deemed by the Investigator 
to be related to participation 
in the study and considered 
to be due to the study 
intervention or comparator 
product.
Per protocol visits
Complete CRF
Adverse Device Effects 
(ADE)/Unanticipated 
Adverse Device Effect 
(UADE)
Per protocol visits
Complete CRF
Serious Adverse Event 
(SAE)/Serious Adverse 
Device Effect (SADE)
Within 24 hours of study 
staff becoming aware of 
event
Initial: Phone/Email to Dental 
Monitor
Followed by: Complete CRF 
and complete 3M SAE Report 
Form.  This form should be 
completed by the Investigator, 
or designee, and submitted (e-
mail) to saereport@mmm.com
Unanticipated Serious 
Adverse Device Effect 
(USADE)
Within 24 hours of study 
staff becoming aware of 
event
Initial: Phone/Email to Dental 
Monitor
Followed by: Complete CRF

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Type of event
Report to Sponsor
Method
Device Deficiency (DD)
Within 3 business days of 
becoming aware of event
Complete CRF
Product Complaints on 3M 
Marketed Product
Within 3 business days of 
becoming aware of event
Complete CRF
13.5. FOLLOW-UP PERIOD FOR ONGOING AES
Any AEs that are not device-related and are ongoing at the end of the study should be marked 
as “persistent” per the eCRF.  Any AEs that are device-related and ongoing at the end of the 
study may be followed for an additional 30 calendar days, as medically necessary.  Any Events 
ongoing at the end of this 30-day period should be marked as “persistent” per the eCRF.  Events 
reported by Subjects after the last study visit may be reported to the Sponsor up to 30 calendar 
days from the date of the last visit.  All unrelated AEs will be considered closed at the time the 
Subject completes participation in the study.
14. VULNERABLE POPULATION
This study is intended to be conducted using a non-vulnerable adult population (ie, 18 years of 
age or older) with no expectations of benefits associated with participation or of a retaliatory 
response from senior hierarchical members in case of refusal to participate.  In addition, the 
study includes only Subjects that are capable of and can provide informed consent.  However, 
the study does not exclude economically or educationally disadvantaged persons.  The 
protection of rights, well-being, and safety of vulnerable populations is the most important 
consideration and should take precedent over the interests of the study.  In addition, the 
protection of rights, well-being, and safety of vulnerable populations, and ascertaining 
appended safeguards, are the prerogative of the IRB, and the Investigator should comply with 
all institutional guidelines related to vulnerable populations.
In the recruitment process, the Investigator will ensure that Subject recruitment is free from 
pressure and will respect the Subject’s expectations of privacy.  Participation will be presented 
as a voluntary option.  In addition, the screening process will contain procedures to assess the 
pregnancy status of females of childbearing age (self-reported) as well as the decisional 
capacity of potential study Subjects.  The study will be described to all potential Subjects by 
the Investigator in non-technical terms, and the ICF will be written in an essentially non-
technical manner to suit the solicited community.  The study will be presented in a manner that 
permits ample time for consideration of participation, with no undue pressure related to the 
timing of the request.

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15. SUSPENSION OR PREMATURE STUDY TERMINATION
Both the Sponsor and the Principal Investigator (PI) reserve the right to terminate the clinical 
investigation at any time. Should this be necessary, the procedures will be arranged on an 
individual basis after review and consultation by both parties. If the study is terminated 
prematurely or suspended, study Subjects and the IRB will be informed promptly and provided 
with the reason(s) for the termination or suspension by the Sponsor or by the Investigator. If 
applicable, regulatory authorities and the personal dentist of the Subjects will also be informed.  
In terminating the clinical investigation, the 3M study team personnel and the PI will assure 
that adequate consideration is given to the protection of the Subjects' interests.
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
participating Investigators, IRB and regulatory authorities.  If the study is prematurely 
terminated or suspended, the PI will promptly inform study participants, the IRBs, and Sponsor, 
and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Determination of early efficacy that would warrant stoppage – defined in section 8.5
•
Determination of futility – defined in section 8.5
•
Insufficient compliance to CIP requirements
•
Data that are not sufficiently complete and/or evaluable
Suspended studies may resume once concerns about safety, CIP compliance, and data quality 
are addressed, and satisfy the Sponsor, IRB, and regulatory authorities.
15.1. BY SPONSOR
The Sponsor reserves the right to discontinue the clinical study for business or ethical reasons 
at any time, such as, but not limited to:
•
Information regarding the study product causes doubt as to the benefit/risk ratio.
•
Changes in medical practice limit utility of the data obtained from the study.
•
Investigator(s) lack of compliance with the approved CIP, lack of oversight, and/or not 
following applicable regulatory or IRB/EC guidelines in conducting the study

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•
Incidence or severity of AEs indicates a potential health hazard or poses an unreasonable 
risk to the study participants
•
Subject enrollment is unsatisfactory
•
Fraud or misconduct
15.2. BY IRB
The IRB may choose to discontinue the study at the site for which they granted approval. If the 
IRB discontinues the study, the Investigator will report a withdrawal of IRB approval to the 
study Sponsor within five (5) working days.
16. REGISTRATION AND PUBLICATION POLICY
16.1. PUBLIC REGISTRATION 
The Sponsor shall ensure that the study is conducted in accordance with applicable publication 
and data sharing policies and complies with any national registration requirements.  A 
description 
of 
this 
study 
will 
be 
publicly 
available 
at 
the 
website, 
http://www.ClinicalTrials.gov, as required by U.S. law.  The online study description will 
include a summary of the study results but will not include information that identifies Subjects.
16.2. PUBLICATIONS RESULTING FROM STUDY/
When applicable, attempts will be made to publish the results of the study.  Details regarding 
publication policies, including publication rights and timing, will be addressed in the study 
contracts between the Sponsor and the study sites if applicable.
17. BIBLIOGRAPHY
1.
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design and conduct of clinical trials on dentine hypersensitivity. J Clin Periodontol. Nov 
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Rahiotis C, Polychronopoulou A, Tsiklakis K, Kakaboura A. Cervical dentin 
hypersensitivity: a cross-sectional investigation in Athens, Greece. J Oral Rehabil. Dec 
2013;40(12):948-57. doi:10.1111/joor.12109
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Sanz M, Baumer A, Buduneli N, et al. Effect of professional mechanical plaque removal 
on secondary prevention of periodontitis and the complications of gingival and periodontal 
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Periodontology on effective prevention of periodontal and peri-implant diseases. J Clin 
Periodontol. Apr 2015;42 Suppl 16:S214-20. doi:10.1111/jcpe.12367
4.
Petersson LG. The role of fluoride in the preventive management of dentin 
hypersensitivity and root caries. Clin Oral Investig. Mar 2013;17 Suppl 1:S63-71. 
doi:10.1007/s00784-012-0916-9
5.
Twetman S. The evidence base for professional and self-care prevention--caries, erosion 
and sensitivity. BMC Oral Health. 2015;15 Suppl 1:S4. doi:10.1186/1472-6831-15-S1-S4
6.
West NX, Seong J, Davies M. Management of dentine hypersensitivity: efficacy of 
professionally and self-administered agents. J Clin Periodontol. Apr 2015;42 Suppl 16:S256-
302. doi:10.1111/jcpe.12336
7.
McBride MA, Gilpatrick RO, Fowler WL. The effectiveness of sodium fluoride 
iontophoresis in patients with sensitive teeth. Quintessence Int. Aug 1991;22(8):637-40. 
8.
Abuzinadah SH, Alhaddad AJ. A randomized clinical trial of dentin hypersensitivity 
reduction over one month after a single topical application of comparable materials. Sci Rep. 
Mar 24 2021;11(1):6793. doi:10.1038/s41598-021-86258-3
9.
Anderson CJ, Kugel G, Gerlach R. A randomized, controlled comparison of two 
professional dentin desensitizing agents immediately post-treatment and 2 months post-
treatment. Am J Dent. Dec 2018;31(6):297-302. 
10.
Antoniazzi RP, Machado ME, Grellmann AP, Santos RC, Zanatta FB. Effectiveness of 
a desensitizing agent for topical and home use for dentin hypersensitivity: a randomized clinical 
trial. Am J Dent. Oct 2014;27(5):251-7. 
11.
Ashari MA, Berijani A, Anbari F, Yazdani Z, Zandian A. Comparison of the 
Effectiveness of Combined Diode Laser and GLUMA Bonding Therapy With Combined Diode 
Laser and 5% Sodium Fluoride Varnish in Patients With Dentin Hypersensitivity. Journal of 
Lasers in Medical Sciences. 2021;12
12.
Corona SA, Nascimento TN, Catirse AB, Lizarelli RF, Dinelli W, Palma-Dibb RG. 
Clinical evaluation of low-level laser therapy and fluoride varnish for treating cervical dentinal 
hypersensitivity. 
J 
Oral 
Rehabil. 
Dec 
2003;30(12):1183-9. 
doi:10.1111/j.1365-
2842.2003.01185.x
13.
Eyuboglu GB, Naiboglu P. Clinical Efficacy of Different Dentin Desensitizers. Oper 
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14.
Femiano F, Femiano R, Lanza A, Festa MV, Rullo R, Perillo L. Efficacy of diode laser 
in association to sodium fluoride vs Gluma desensitizer on treatment of cervical dentin 
hypersensitivity. A double blind controlled trial. Am J Dent. Aug 2013;26(4):214-8. 
15.
Hansen EK. Dentin hypersensitivity treated with a fluoride-containing varnish or a 
light-cured glass-ionomer liner. Scand J Dent Res. Dec 1992;100(6):305-9. doi:10.1111/j.1600-
0722.1992.tb01076.x
16.
Jalaluddin M, Almalki SA. Evaluation of the Efficacy of Three Different Treatment 
Modalities in the Management of Dentinal Hypersensitivity: A Comparative Study. World. 
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17.
Kara C, Orbak R. Comparative evaluation of Nd:YAG laser and fluoride varnish for the 
treatment 
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hypersensitivity. 
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2009;35(7):971-4. 
doi:10.1016/j.joen.2009.04.004
18.
Kishore A, Mehrotra KK, Saimbi CS. Effectiveness of desensitizing agents. J Endod. 
Jan 2002;28(1):34-5. doi:10.1097/00004770-200201000-00008
19.
Kumar NG, Mehta DS. Short-term assessment of the Nd:YAG laser with and without 
sodium fluoride varnish in the treatment of dentin hypersensitivity--a clinical and scanning 
electron 
microscopy 
study. 
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Periodontol. 
Jul 
2005;76(7):1140-7. 
doi:10.1902/jop.2005.76.7.1140
20.
Lee SH, Lee NY, Lee IH. Clinical evaluation of the efficacy of fluoride adhesive tape 
(F-PVA) in reducing dentin hypersensitivity. Am J Dent. Jun 2013;26(3):143-8. 
21.
Lund RG, Silva AF, Piva E, Da Rosa WL, Heckmann SS, Demarco FF. Clinical 
evaluation of two desensitizing treatments in southern Brazil: A 3-month follow-up. Acta 
Odontol Scand. Nov 2013;71(6):1469-74. doi:10.3109/00016357.2013.770919
22.
Machado AC, Maximiano V, Yoshida ML, et al. Efficacy of a calcium-
phosphate/fluoride varnish and ionomeric sealant on cervical dentin hypersensitivity: A 
randomized, double-blind, placebo-controlled clinical study. J Oral Rehabil. Jan 
2022;49(1):62-70. doi:10.1111/joor.13270
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Miron M, Lungeanu D, Ciora E, Ogodescu E, Todea C. Using Laser-Doppler 
Flowmetry to Evaluate the Therapeutic Response in Dentin Hypersensitivity. Int J Environ Res 
Public Health. Nov 26 2020;17(23)doi:10.3390/ijerph17238787
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Olusile AO, Bamise CT, Oginni AO, Dosumu OO. Short-term clinical evaluation of 
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Osmari D, Fraga S, Ferreira ACO, Eduardo CP, Marquezan M, Silveira BLD. In-office 
Treatments for Dentin Hypersensitivity: A Randomized Split-mouth Clinical Trial. Oral Health 
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Pamir T, Ozyazici M, Baloglu E, Onal B. The efficacy of three desensitizing agents in 
treatment of dentine hypersensitivity. J Clin Pharm Ther. Feb 2005;30(1):73-6. 
doi:10.1111/j.1365-2710.2004.00613.x
27.
Ritter AV, de LDW, Miguez P, Caplan DJ, Swift EJ, Jr. Treating cervical dentin 
hypersensitivity with fluoride varnish: a randomized clinical study. J Am Dent Assoc. Jul 
2006;137(7):1013-20; quiz 1029. doi:10.14219/jada.archive.2006.0324
28.
Soares ML, Porciuncula GB, Lucena MI, Gueiros LA, Leao JC, Carvalho AA. Efficacy 
of Nd:YAG and GaAlAs lasers in comparison to 2% fluoride gel for the treatment of dentinal 
hypersensitivity. Gen Dent. Nov-Dec 2016;64(6):66-70. 
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Bhatt A. Protocol deviation and violation. Perspect Clin Res. Jul 2012;3(3):117. 
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18. STUDY-SPECIFIC APPENDICES
18.1. APPENDIX A
REVISION HISTORY
The purpose of this appendix is to describe modifications made to this document, in detail, 
when moving from Version 1.0 to Version 2.0.
Overall summary of changes
Version 2
Added a Co-primary endpoint by moving the first secondary endpoint (24-hour time point) 
to the primary endpoint. This change resulted in the following changes:
1. Sample size: the minimum number of the subjects changed from 80 to 96. The 
maximum number of the subjects was also changed from 90 to 125.
2. Statistical Considerations (Sections 8.1-8.5) were modified to reflect the changes of 
primary endpoints.
Section modified
Original text
Updated text
Summary
Endpoints
Section 5.3.1
Primary Endpoint(s)
The primary endpoint for this 
study is the change in pain, using 
a 100-mm VAS from baseline to 
immediately after application 
(within 15 minutes post-
treatment) of test product or 
comparator.  Sensitivity will be 
assessed using VAS after 
exposure to air stimulus.
Co-primary endpoints 
include:
•
the change in pain, 
using a 100-mm 
VAS from baseline 
to immediately after 
application (within 
15 minutes post 
treatment) of test 
product or 
comparator.
•
the change in pain 
score from baseline 
to 24 ± 4 h post-
application, using 
VAS after exposure 
to air stimulus.

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Summary Endpoint
Section 5.3.2
Secodary Endpoint(s)
The secondary endpoints 
include:
1.
the change in pain score 
from baseline to 24 ± 4 h 
post-application, using 
VAS after exposure to air 
stimulus.
2. change in pain score, 
using VAS, from 
baseline to 7 ± 2 days 
post-treatment, after 
exposure to air stimulus.
3. change in pain score, 
using VAS, from 
baseline to 21 ± 2 days 
post-treatment, after 
exposure to air stimulus. 
4. change in pain score, 
using VAS, from 
baseline to 30 ± 2 days 
post-treatment, after 
exposure to air stimulus.
The secondary endpoints 
include:
1. change in pain score, 
using VAS, from 
baseline to 7 ± 2 
days post-treatment, 
after exposure to air 
stimulus.
2. change in pain score, 
using VAS, from 
baseline to 21 ± 2 
days post-treatment, 
after exposure to air 
stimulus. 
3. change in pain score, 
using VAS, from 
baseline to 30 ± 2 
days post-treatment, 
after exposure to air 
stimulus.
Summary 
Selection of Subjects
Section 6.5
Subject Enrollment
A minimum of 80 enrolled 
Subjects that complete the study 
period is planned for this study.  
To achieve this minimum, the 
Investigator may enroll up to 
ninety (90) subjects.  
A minimum of 96 enrolled 
Subjects that complete the 
treatment is planned for this 
study.  To achieve this 
minimum, the Investigator 
may enroll up to one 
hundred and twenty five 
(125) subjects.  
Section 8.1
The null hypothesis that we seek 
to reject is that Clinpro™ 2% 
Sodium Fluoride Aqueous 
The null hypotheses that we 
seek to reject are that 
Vanish™ 5% Sodium 

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Solution has a 15.0 mm lower 
change from baseline VAS than 
Vanish™ 5% Sodium Fluoride 
White Varnish measured 
immediately after application 
(within 15 minutes post-
treatment).  The null and 
alternate hypotheses are 
described below.
Fluoride White Varnish has 
a 15.0 mm higher change 
from baseline VAS than 
Clinpro™ 2% Sodium 
Fluoride Aqueous Solution 
when measured immediately 
after application (within 15 
minutes post-treatment) or at 
24-hours after treatment (±4 
hours).  The null and 
alternate hypotheses are 
described below.
Section 8.2 Sample Size 
Determination
A standard deviation of 20.0 mm 
for the change between baseline 
and immediately after treatment 
(within 15 minutes post-
treatment) will be used.  There is 
uncertainty in the efficacy 
difference between treatments as 
well as the error term.  An 
interim analysis will be 
conducted at approximately 50% 
of enrollment.  Based on the 
O’Brien-Fleming alpha spending 
function for group sequential 
design, the interim analysis will 
use an alpha of 0.002 (1-sided) 
and the final analysis will use an 
alpha of 0.023 (1-sided).   Eighty 
(80; 40 per arm) total subjects 
will provide 92% power if there 
is no efficacy difference between 
treatments and 83% power if 
Clinpro™ 2% Sodium Fluoride 
Aqueous Solution has a 0.2 cm 
lower change from baseline then 
A standard deviation for 
change from baseline at 
immediately after treatment 
(within 15 minutes post-
treatment) and 24-hours of 
20 mm will be used.  There 
is uncertainty in the efficacy 
difference between 
treatments as well as the 
error term.  An interim 
analysis will be conducted at 
approximately 50% of 
subject treatment to reassess 
sample size with no alpha 
spending required.  Ninety-
six (96; 48 per arm) total 
subjects will provide 80% 
power allowing for a 2 mm 
difference in efficacy 
difference between 
treatments and 2 co-primary 
endpoints tested.  No 
subjects will be lost to 
follow-up for the primary 

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the control. No subjects will be 
lost to follow-up for the primary 
time point of immediate 
hypersensitivity relief, but there 
may be loss to follow-up for the 
secondary time points
time point of immediate 
hypersensitivity relief, but 
there may be loss to follow-
up for co-primary endpoint 
of hypersensitivity relief at 
24-hours after treatment.  
Section 8.3 Analysis 
Populations
All dosed subjects without a 
major protocol deviation will be 
included in the analysis dataset 
for the primary endpoint of 
change in pain immediately after 
product application.   
All dosed subjects without a 
major protocol deviation 
will be included in the 
analysis dataset for the co-
primary endpoints of change 
in hypersensitivity 
immediately after product 
application and change in 
hypersensitivity 24-hours 
after application. Major 
protocol deviation(s) for 
exclusion from the analysis 
dataset will be defined and 
documented in a blinded 
fashion prior to interim and 
final analyses (eg, 
inadequate washout).   
Section 8.4.2 
Analysis of Primary 
Endpoints
A ninety five percent (95%) 
confidence interval will be 
generated for the difference 
between treatments in change 
from baseline immediately after 
application using a Student’s t-
test.  Non-inferiority will be 
declared if Vanish™ Varnish 
changed from baseline minus 
Clinpro™  2.1% Sodium 
Fluoride Aqueous Solution 
At the final analysis, 
multiplicity will be 
controlled through a 
Hochberg procedure.  
Ninety-five- percent (95%) 
confidence intervals will be 
generated for the difference 
between treatments in 
change from baseline 
immediately after 
application and separately 

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change from baseline is less than 
or equal to 15.0 mm.
for the difference between 
treatments in change from 
baseline 24-hours after 
application using Student’s t 
distribution.  
Scenario 1:  Neither of the 
95% confidence intervals 
contain 15 mm.
Result: Non-inferiority for 
both co-primary endpoints 
will be declared 
Scenario 2:  Both of the 95% 
confidence intervals contain 
15 mm.
Result:  No non-inferiority 
for either co-primary 
endpoints will be declared, 
and all analyses will be 
informational only.
Scenario 3:  One confidence 
interval contains 15 mm, and 
the other confidence interval 
does not contain 15 mm.
The endpoint that does not 
contain 15 mm has the 
potential to be declared non-
inferior.  For this endpoint, 
as part of the Hochberg 
procedure, a 97.5% 
confidence interval will be 
generated.  Non-inferiority 
for this endpoint will be 
declared if the new 

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confidence interval does not 
contain 15 mm.
Section 8.4.3 Analysis 
of Secondary Endpoints
If the null hypothesis is rejected 
for the primary endpoint, the 
alpha will be passed to test for 
non-inferiority of Clinpro™  
2.1% Sodium Fluoride Aqueous 
Solution to Vanish™ Varnish for 
the various secondary endpoints.  
Ninety five percent (95%) 
confidence intervals will be 
generated for the difference 
between treatments in change 
from baseline using a Student’s 
t-test at each evaluation time.  
Non-inferiority will be declared 
if Vanish™ Varnish changed 
from baseline minus Clinpro™  
2.1% Sodium Fluoride Aqueous 
Solution change from baseline is 
less than or equal to 15.0 mm for 
each secondary endpoint. There 
are 4 secondary endpoints.  The 
alpha will be passed sequentially 
in the order listed in section 
5.3.2.
If the null hypotheses are 
rejected for both co-primary 
endpoints, the alpha will be 
passed to test for non-
inferiority of Clinpro™ 
2.1% Sodium Fluoride 
Aqueous Solution to 
Vanish™ Varnish for the 
various secondary endpoints.  
Ninety five percent (95%) 
confidence intervals will be 
generated for the difference 
between treatments in 
change from baseline using 
the Student’s t distribution at 
each evaluation time.  Non-
inferiority will be declared if 
Vanish™ Varnish changed 
from baseline minus 
Clinpro™ 2.1% Sodium 
Fluoride Aqueous Solution 
change from baseline is less 
than or equal to 15 mm for 
each secondary endpoint. 
There are 3 secondary 
endpoints.  The alpha will be 
passed sequentially in the 
order listed in section 5.3.2.
Section 8.5
Planned Interim 
Analysis and Criteria for 
Clinical Investigation
An interim analysis will be 
conducted at approximately 50% 
of enrollment.  Based on the 
O’Brien-Fleming alpha spending 
An interim analysis will be 
conducted after treating 
approximately 50% of the 
planned sample size for the 

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function for group sequential 
design, the interim analysis will 
use an alpha of 0.002 (1-sided) 
and the final analysis will use an 
alpha of 0.023 (1-sided).  The 
study may be stopped if the 
conditional power is <50%, but 
the study will not be required to 
be stopped.  In addition, sample 
size re-estimation will be carried 
out if condition power falls 
between 50 and 80%.
purpose of sample size re-
estimation.  No alpha will 
need to be spent because of 
this sample size re-
estimation.  The parameter 
estimates from the interim 
data will be used and the 
sample size necessary for 
80% power will be 
calculated.

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18.2. APPENDIX B
LISTING OF SITES AND INVESTIGATORS
Site 
No.
Name of Site
Name of Principal 
Investigator
Professional 
Title
Contact 
information
01
Loma Linda 
University Health
Dr. Yiming Li
Distinguished 
Professor
yli@llu.edu

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18.3. APPENDIX C 
Example of Visual Analogue Scale (VAS)
Subject Pain Assessment during Air Blast
Subject # _______
Instructions: Using a pen, draw a vertical mark on the colorful line that best represents the level of pain 
experienced during the sensitivity tesing.  Pain score is calculated by measuring the distance or length of the 
mark from the left edge of the bar (0 mm).  Scale will be printed to ensure the line maintains a length of 100mm 
for the study.
Pain scoring:   
   mm
Baseline  
Pain scoring: 
mm
Immediately Post-treatment
Pain scoring: 
 mm
24 h post-treatment

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Pain scoring: 
 mm 
 7 d post-treatment
Pain scoring: 
 mm 
 21 d post-treatment
Pain scoring: 
 mm 
30 d post-treatment

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Subject Pain Assessment during Tactile Test
Subject # _______
Instructions:  Using a pen, draw a vertical mark on the colorful line that best represents the level of pain 
experienced during the sensitiity testing.  Pain score is calculated by measuring the distance or length of the mark 
from the left edge of the bar (0 mm).  Scale will be printed to ensure the line maintains a length of 100mm for the 
study.
Pain scoring:   
   mm
Baseline  
Pain scoring: 
mm
Immediately Post-treatment
Pain scoring: 
 mm
24 h post-treatment
Pain scoring: 
 mm 
 7 d post-treatment

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Pain scoring: 
 mm 
 21 d post-treatment
Pain scoring: 
 mm 
30 d post-treatment