Phase 2 Efficacy & Safety Evaluation of Advantage Anti-Caries Varnish for Primary Prevention
Phase: PHASE2
Conditions: Dental Caries in Children
Sponsor: Advantage Silver Dental Arrest, LLC

Phase 2 Efficacy & Safety Evaluation of Advantage Anti-Caries Varnish for Primary Prevention 
 
 
      
Protocol # 2019-10-19 
 
Version 2.4 / July 1, 2022 
 
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PHASE 2 EFFICACY & SAFETY EVALUATION OF ADVANTAGE ANTI-CARIES VARNISH 
FOR PRIMARY PREVENTION 
 
 
Study Acronym: NGIHN SERI MWAHU 
 
Advantage Protocol Number: 2019-10-19 
 
Clinical Trial Registration Number: NCT04947527 
 
IND #128835 
 
IND Sponsor: Advantage Silver Dental Arrest, LLC 
PO Box 12746 
Salem, OR 97309-0746 
 
Sponsor Contact: Peter Milgrom, DDS 
 
Principal Investigator: Ohnmar Tut, BDS MPhil 
 
Medical Monitor: John Hedson, MD 
 
Regulatory Monitors:  Douglas Bierer, PhD 
 
 
Version Number: 2.4   
 
Version Date: 07/01/2022  
 
 
 
 
 
 
 
 
 
 

Phase 2 Efficacy & Safety Evaluation of Advantage Anti-Caries Varnish for Primary Prevention 
 
 
      
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PROTOCOL APPROVAL 
 
 
 
 
 
Phase 2 Efficacy & Safety Evaluation of Advantage Anti-Caries Varnish for Primary Prevention 
 
STUDY ACRONYM: NGIHN SERI MWAHU 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ohnmar K. Tut, BDS MPhil 
        
 
          Date 
Principal Investigator 
 
 
 
 
 
 
 
       
 
Peter Milgrom, DDS 
 
 
 
 
Date 
Sub-Investigator 
 
 
 
 
 
 
 
 
 
 
 
 

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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312)  
 
• 
ICH E6; 62 Federal Register 25691 (May 9, 1997)  
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 
 

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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
I have carefully read this protocol, and agree that it contains all the necessary information for 
conducting the study safely. 
 
I will conduct this study in strict accordance with this protocol and according to the current Good 
Clinical Practice (GCP) regulations and guidelines [21 CFR (Code of Federal Regulations) Parts 11, 
50, 54 and 56 and ICH (International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use) Topic E6 (R1)], and local regulatory requirements. 
Any changes in procedure will only be made if necessary to eliminate immediate hazards and/or to 
protect the safety, rights or welfare of subjects.  
 
I will provide copies of the protocol and all other information relating to the pre-clinical and prior 
clinical experience, which were furnished to me, to all physicians and other study personnel 
responsible to me who participate in this study. I will discuss this information with them to assure 
that they are adequately informed regarding the study drug and conduct of the study. 
 
I will ensure that the drugs supplied to me for this study will be used only for administration to 
subjects enrolled in this study protocol and for no other purpose. 
 
I agree to keep records on all subject information (case report forms, informed consent statements, 
drug accountability records, and all other information collected during the study) in accordance with 
the current GCP, local and national regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ohnmar Tut 
 
Printed Principal Investigator Name  
 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 

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SUMMARY OF CHANGES 
 
Protocol Amendments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL ................................................................................................... 2 
STATEMENT OF COMPLIANCE ....................................................................................... 3 
SIGNATURE PAGE ............................................................................................................ 4 
SUMMARY OF CHANGES ................................................................................................. 5 
Protocol Amendments .........................................................................................................5 
LIST OF ABBREVIATIONS .............................................................................................. 10 
PROTOCOL SUMMARY .................................................................................................. 11 
Alignment with ICH Topic E 5 (R1) [Ethnic Factors in the Acceptability of Foreign 
Clinical Data] .................................................................................................................... 13 
SCHEMATIC OF STUDY DESIGN................................................................................... 14 
1.  Key Roles .................................................................................................................... 15 
2.  Introduction: Background Information and Scientific Rationale ......................... 16 
2.1 Background Information ........................................................................................... 16 
2.2 Potential Risks and Benefits .................................................................................... 18 
2.2.1  
Potential Risks ............................................................................................................................ 18 
2.2.2  
Known Potential Benefits .......................................................................................................... 18 
3.  Objectives .................................................................................................................... 19 
3.1 Study Objectives ........................................................................................................ 19 
3.2 Study Outcome Measures......................................................................................... 19 
3.2.1  
Primary Outcome Measures ..................................................................................................... 19 
3.2.2  
Secondary Outcome Measures ................................................................................................ 19 
4.  Study Design ............................................................................................................... 19 
4.1 Rationale for Study Design ....................................................................................... 19 
4.2  Rationale for Dosage ................................................................................................. 20 
5.  Study Enrollment and Withdrawal ........................................................................... 20 
5.1 Subject Numbers .......................................................................................................... 20 
5.2 Subject Inclusion Criteria ......................................................................................... 20 
5.3 Subject Exclusion Criteria ........................................................................................ 20 
5.4   Discussion of Subject Characteristics .................................................................... 21 
5.5   Strategies for Recruitment and Retention .............................................................. 21 

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5.6 Treatment Assignment Procedures ......................................................................... 22 
5.6.1   Subject Identification Numbers ................................................................................................... 22 
5.6.2  
Randomization Procedures ....................................................................................................... 22 
5.7  Masking Procedures .................................................................................................. 22 
5.8  Reasons for Withdrawal ............................................................................................ 23 
5.8.1 
 Handling of Withdrawals ........................................................................................................... 23 
5.9  Termination of Study ................................................................................................. 23 
6.  Investigational Product ............................................................................................. 24 
6.1 Investigational Product Description ........................................................................ 24 
6.1.1  
Acquisition .................................................................................................................................... 24 
6.1.2  
Formulation, Packaging, and Labeling .................................................................................... 24 
6.1.3  
Product Storage and Stability ................................................................................................... 25 
6.2 Dosage, Preparation and Administration of Study Investigational Products .... 25 
6.3 Accountability Procedures for the Investigational Product(s) ............................. 25 
6.4 Assessment of Subject Compliance with Investigational Product ..................... 25 
6.5 Coding/Emergency Treatment Disclosure .............................................................. 25 
6.6 Concomitant Medications/Treatments .................................................................... 26 
7.  Study Schedule/Procedures and Evaluations ........................................................ 26 
7.1   Subject recruitment procedures: ............................................................................. 26 
7.2   Baseline Visit .............................................................................................................. 27 
7.3   Visits 2-8 Treatment Visit .......................................................................................... 27 
7.4 Visit 9 Year 2 Exam Visit ........................................................................................... 28 
7.5 Premature Withdrawal ............................................................................................... 28 
7.6 Unscheduled Visit ...................................................................................................... 28 
8.  Assessments .............................................................................................................. 29 
8.1  Primary and Secondary Outcome Variables .......................................................... 29 
8.2  Efficacy Assessments ............................................................................................... 29 
8.2.1 
Caries Examination .................................................................................................................... 29 
8.3  Safety Assessments .................................................................................................. 29 
8.3.1. 
General Health (Medical History and Physical Examination) .............................................. 29 
9.  Assessment of Safety ................................................................................................ 30 
9.1 Specification of Safety Parameters ......................................................................... 30 
9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ................................................................................................................................ 30 

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9.3 Adverse Events .......................................................................................................... 30 
9.4 Expected Adverse Reactions ................................................................................... 31 
9.5 Serious Adverse Events............................................................................................ 31 
9.5.1 
Unanticipated Problems ............................................................................................................ 31 
9.5.2 
Procedures to be Followed in the Event of Abnormal Clinical Findings ............................ 32 
9.6 Reporting Procedures ............................................................................................... 32 
9.6.1  
Reportable Events ...................................................................................................................... 32 
9.6.2 
Serious Adverse Events ............................................................................................................ 32 
9.6.3 
Adverse Event Causality Definitions........................................................................................ 33 
9.6.4 
Adverse Event Severity Definitions ......................................................................................... 34 
9.7  Responsibilities of Investigator/Sponsor for Reporting SAEs ............................ 34 
9.7.1 
Regulatory Reporting for Studies Conducted Under an IND ............................................... 34 
9.7.2 
Other Unanticipated Problems ................................................................................................. 34 
9.8 Type and Duration of Follow-up of Subjects after Adverse Events .................... 35 
9.9 Halting Rules .............................................................................................................. 35 
10.  Site Monitoring ......................................................................................................... 35 
10.1 Clinical Site Monitoring ............................................................................................. 35 
10.2 Regulatory Inspections ............................................................................................. 36 
11.  Statistical Considerations ....................................................................................... 36 
11.1 Study Hypotheses ...................................................................................................... 36 
11.2 Sample Size Considerations ..................................................................................... 36 
11.3 Statistical Analysis Plan............................................................................................ 37 
11.3.1 Primary Statistical Analysis. ........................................................................................................ 37 
11.3.2 Analysis of Safety Data. ............................................................................................................... 38 
11.3.3 Participant Disposition. ................................................................................................................. 38 
12.  Source Documents and Access to Source Data/Documents ............................. 38 
12.1 Primary Source Documents ...................................................................................... 38 
12.2 CRF Worksheets ........................................................................................................ 38 
13.  Ethics/Protection of Human Subjects ................................................................... 39 
13.1 Ethical Standard ......................................................................................................... 39 
13.2 Institutional Review Board ........................................................................................ 39 
13.3 Amendments .............................................................................................................. 39 
13.4 Informed Consent Process ....................................................................................... 39 
13.5 Exclusion of Women, Minorities, and Children (Special Populations)................ 40 

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13.6 Subject Confidentiality .............................................................................................. 40 
13.7 Study Discontinuation ............................................................................................... 40 
14.  Data Handling and Record Keeping ...................................................................... 40 
14.1 Data Management Responsibilities ......................................................................... 40 
14.2 Data Capture Methods ............................................................................................... 41 
14.3 Types of Data .............................................................................................................. 41 
14.4 Timing/Reports ........................................................................................................... 41 
14.5 Study Records ............................................................................................................ 42 
14.5.1 Study File and Site Documents .................................................................................................. 42 
14.5.2 Maintenance and Retention of Records .................................................................................... 43 
14.6 Protocol Deviations ................................................................................................... 44 
14.7 Protocol Violations.................................................................................................. 44 
15.  Publication Policy .................................................................................................... 45 
16.  Literature References .............................................................................................. 45 
17.  Addendum ................................................................................................................. 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ADA 
American Dental Association 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NDA 
New Drug Application 
OHRP 
Office for Human Research Protections 
PCP 
Primary Care Physician 
PHI 
Protected Health Information 
PI 
Principal Investigator 
10% PVPI 
10% Povidone/1.0% Iodine 
SAE 
Serious Adverse Event 
S-ECC 
Severe Early Childhood Caries 
SOP 
Standard Operating Procedure 
WIRB 
Western Institutional Review Board 
WCG IRB  
WIRB-Copernicus Group Institutional Review Board 
 
 
           
 

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PROTOCOL SUMMARY 
 
Title 
Phase 2 Efficacy & Safety Evaluation of Advantage Anti-Caries 
Varnish for Primary Prevention 
Acronym Title: NGIHN SERI MWAHU 
Précis 
The purpose of the study is to determine the efficacy & safety of 
Advantage Anti-Caries Varnish for primary prevention 
Objectives 
Primary 
To determine if Advantage Anti-Caries Varnish (test varnish) is 
superior to an active control varnish (5% NaF, no PVP-I) in the 
prevention of caries lesions in the primary dentition. Specifically, 
prevention of caries lesions in primary teeth that either are sound, 
have only d1 (white spots) lesions or unerupted at baseline. 
 
Secondary 
To document the safety of the test varnish. 
 
Study Population  
Children 6 to 24 months at time of entry, approximately 50% male, 50% 
female 
Phase 
2 
Number of Sites 
One: Pohnpei State, Federated States of Micronesia 
Study Duration 
The entire study duration will be about 3 years, allowing for start-up, 
training, the active phase, and close out. 
Subject 
Participation 
Duration 
The total duration of subject participation is 24 months. 
Description of 
Agent or 
Intervention 
Single-center, double-blind, controlled Phase 2 study with parallel 
groups of children. Subjects will be randomized to receive either test 
varnish or control varnish topically to the teeth. Treatment will be 
administered quarterly for up to 24 months. 
Estimated Time to 
Complete 
Enrollment 
3 months 
Number of Subjects Total number of subjects planned is: 254 
Inclusion Criteria 
1. The subject’s parent or legal guardian must provide signed and 
dated informed consent (parent permission form). 
2. The subject’s parent or legal guardian must be willing and able to 
comply with study requirements. 
3. The subject is aged 6 to 24 months at the time of the enrollment. 
4. The subject must be in good general health as evidenced by patient 
report. 

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5. The subject will have at least 1 erupted tooth that is either sound or 
has only a d1 (white spots) lesion. 
Exclusion Criteria 
 
1. Previous treatment with fluoride varnish  
2. Known allergy to iodine 
3. Diagnosis of thyroid disease 
4. Chronic, prophylactic use of antibiotics   
5. Treatment with another investigational drug or other intervention 
within 30 days preceding the Baseline Visit.  
6. Visible cavities (d2-4) in the erupted primary teeth 
7. Presence of intraoral soft tissue pathology 
8. Parent anticipates the child will move from Pohnpei during the 
next 2 years. 
 
Route and Dosage 
Form 
Treatment applied to teeth topically (0.2 mL test or control) 
 
Primary Outcome 
Measures 
Efficacy: 
Primary: New surface-level primary caries (d2-4mfs) at 24-months 
post baseline 
Secondary: Presence/Absence of new caries (d2-4mfs) at 12-
months post baseline 
 
Secondary 
Outcome Measures 
Safety: Adverse event occurrence 
 
 
 

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Alignment with ICH Topic E 5 (R1) [Ethnic Factors in the Acceptability of Foreign 
Clinical Data]  
 
Alignment with ICH Topic E 5 (R1) [Ethnic Factors in the Acceptability of Foreign 
Clinical Data]:  The study site is Pohnpei State, Federated States of Micronesia (FSM). Under 
US law and the Compact of Free Association between the US and FSM, this site is considered 
to be part of the US.  There are no intrinsic (genetic or physiologic) or extrinsic (cultural or 
environmental) characteristics of the population that would influence the safety, efficacy, dosage 
or dose regiment of the drug. Children consume a diet largely of processed foods from the US 
mainland and the main pathogenic organism in the etiology of tooth decay has been shown to 
be Streptococcus mutans, as it is among children in the US proper. These children also use 
toothpastes produced in the US and regulated by FDA. In addition, this trial will be supervised 
by a regulatory monitor based in the US and familiar with US regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
254 Subjects 
Obtain Informed consent (parent/guardian) 
Screen subjects by clinical criteria 
       Review eligibility 
Randomization 
Initial application 
of varnish 
Initial application 
of varnish 
224-48 hr 
Safety check 
24-48 hr 
Safety check 
Application of 
varnish  
Application of 
varnish 
Application of 
varnish 
   One Year post-baseline dental examinations  
Two Years post-baseline dental examinations 
Baseline 
Visit 1 
Visit 2-4 
Visit 5-8 
127 subjects  
      Arm 1 
127 subjects  
      Arm 2 
24-48 hr 
Safety check 
224-48 hr 
Safety check 
24-48 hr 
Safety check 
24-48 hr 
Safety check 
Application of 
varnish 
Screening 

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1.  Key Roles 
Individuals: 
Principal Investigator:  
 
Dr. Ohnmar Tut 
Department of Oral Health Sciences 
University of Washington, Seattle 
Email: Ohnmar@uw.edu 
Sponsor/Investigator: 
Peter Milgrom, DDS 
Member 
Advantage Silver Dental Arrest, LLC 
Email: drmilgrom@silverarrest.com 
 
Medical Monitor 
Johnny Hedson, MD 
Pohnpei State Hospital 
Pohnpei, FSM 
Regulatory Monitors:  
 
 
Douglas Bierer, PhD (primary) 
Douglas Bierer Consulting, LLC 
7415 Graves Rd 
Cincinnati, OH 45243 
 
William Cooley, PhD (secondary) 
Cooley Consulting, Inc. 
531 Chisholm Trail 
Wyoming, OH 45215 
 
 
Site Director 
Marcelle Gallen, BDS 
Chief of Dental Division 
Pohnpei State Department of Health Services 
Pohnpei, FSM 
Institution and Locations: 
Pohnpei State Department of Health Services 
Pohnpei, FSM 
Biostatistician 
Lloyd Mancl, PhD 
Research Associate Professor of Oral Health Sciences 
University of Washington 
Seattle, WA 
Email: llman@uw.edu 
Coordination Center 
Regional Clinical Dental Research Center 
Institute of Translational Health Sciences 
1959 NE Pacific St., Box 357480, Seattle, WA 98195 
206-685-8132 / FAX: 206-685-9654 
 
 
 
 
 

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2.  Introduction: Background Information and Scientific Rationale 
 
2.1 Background Information 
 
Background: Topical fluorides have been the mainstay in the prevention of dental caries for 
decades. There are abundant data on sodium fluoride’s (NaF) ability to foster remineralization of 
tooth enamel (Gao et al., 2016).  Dental NaF varnish preparations are the recommended vehicle 
for delivering topical NaF for dental caries prevention and arrest in young children under 6 years 
of age according to guidelines from the American Dental Association (ADA), the American 
Academy of Pediatrics, the American Academy of Pediatric Dentistry and the US Preventive 
Services Task Force (Weyant et al., 2013; Clark et al., 2014; American Academy of Pediatric 
Dentistry, 2013; Moyer VA 2014).  In children, less than 6 years of age, at high risk for dental 
caries, the recommendation is application of NaF varnish every three months (Weyant et al., 
2013).  Fluoride varnishes have been shown safe in very young children (Milgrom et al., 2014). 
 
However, topical fluorides alone are not enough to prevent tooth decay in high-risk 
populations.  Caries researchers for some time have suggested strategies that combine topical 
antiseptic application to reduce or eliminate tooth surface colonization by cariogenic bacteria in 
addition to topical fluoride applications that primarily remineralize enamel (Milgrom et al 2009). 
Povidone iodine is an FDA-approved and widely used bactericidal antiseptic. For the oral flora, 
iodine has preferential activities against streptococcal species, pathogens implicated in the 
causation of dental caries (Tam et al., 2006; Furiga et al., 2008). Moreover, iodine's 
effectiveness may last as long as 6 months (Caufield et al., 1979).   
 
Studies have examined the chemotherapeutic suppression of oral Streptococcus mutans 
(Sm) by povidone iodine (10%) in children with Severe Early Childhood Caries (S-ECC).  In one 
study, the teeth of children two to six years of age were treated topically with povidone iodine 
(10%) or saline following dental treatment under general anesthesia for S-ECC (Zhan et al, 
2006).  Levels of Sm were significantly reduced up to three months in the povidone iodine 
group.  A second study demonstrated suppression of Sm up to 90 days in children with S-ECC 
who received a single application of povidone iodine (10%) followed by a topical application of 
1.23% acidulated phosphate fluoride foam after surgical elimination of active caries lesions 
(Berkowitz et al 2009).  
 
Other studies have assessed the effect of povidone iodine (10%) on dental caries. A clinical 
study involving babies in Puerto Rico who were at high risk for S-ECC as they were all 
colonized by Sm and had decay-promoting feeding behaviors, demonstrated that povidone 
iodine (10%) applied bimonthly was successful in preventing the development of early tooth 
decay lesions in the maxillary primary incisors (Lopez et al., 2002). In a randomized clinical trial, 
povidone iodine (10%) applied bi-monthly significantly reduced the rate of recurrent dental 
decay at six months following treatment of children under general anesthesia for S-ECC (Amin 
et al., 2004).  
 
Two cohort studies have tested the effect of combining these two anti-caries agents by 
sequentially applying povidone iodine (10%) followed 5% NaF varnish. The first study assessed 
the effect of protecting erupting 1st permanent molars from developing dental caries in children 

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five to six years old (Tut & Milgrom, 2010). The second studied the effect in the primary dentition 
of children 12 to 30 months (Milgrom, Tut & Mancl, 2011).  They demonstrated that treatment 
with povidone iodine reduced the rate of new decay significantly over the standard of care 
alone. Yet, to date, such combination products have not been brought to the market. Advantage 
Anti-Caries Varnish was developed to combine the antiseptic povidone iodine and sodium 
fluoride varnish into a single product for ease of application, particularly in high caries risk, pre-
school age children.    
 
A phase 1 study of the safety of the new varnish was conducted in 12 healthy children with 
an average age of 47.6 months (WIRB PRO NUM: 20160539). No child evidenced any intra oral 
erythema or secondary changes as a consequence of the varnish application either immediately 
or within 24-48 hours post application. Neither were there any adverse effects. The FDA has 
reviewed the previous safety work and this protocol and issued IND 128835 for this work.  
 
A phase 1 study (Lin, Rothen & Milgrom, 2018) was carried out to characterize the kinetics 
of iodine and fluoride following topical application of the PVP-I and NaF anti-caries varnish in 
healthy adults (WIRB PRO NUM: 20161181). Sixteen subjects (23 to 57 years) participated in a 
pharmacokinetics study following the application 0.4 mL of a varnish containing 10% (w/v) PVP-
I and 5% (w/v) NaF.  Serum and urine samples were collected at various time points over 24 
hours following application of varnish. Iodine and fluoride concentrations were analyzed, and for 
each time point baseline concentrations were subtracted from observed values.  Following 
varnish application, 2 of 16 participants had nearly undetectable baseline-corrected iodine and 
fluoride levels, suggesting minimal absorption, lack of release iodine and fluoride from the 
varnish, or inconsistent dosing.  The average peak concentrations were 57 ± 33 ng/mL iodine 
and 60 ± 34 ng/mL (0.060 ± 0.034 ppm) fluoride and occurred within 3 hr of application.  The 
average elimination half-life was 5.5 ± 1.4 hr and 3.1 ± 1.6 hr for iodine and fluoride, 
respectively.   Renal clearance of iodine and fluoride were similar to literature values.  No 
adverse events related to the study varnish were observed by the investigative team or reported 
by the participants.  In this study, serum fluoride and iodine transiently increased, but were 
within normal range 24 hr after application of the varnish. This study has shown that the 
combination of PVP-I and NaF in a proposed anti-caries varnish was well tolerated.   
 
Phase 2 Study in FSM. A single center randomized, double-blind, active-controlled, 
parallel-group trial to assess efficacy of the Advantage Anti-Caries Varnish (10% PVP-I, 5.0% 
NaF) was conducted in Pohnpei FSM to determine if it is superior to a varnish containing only 
5% NaF in the prevention of new caries lesions (COM-FSM IRB Protocol #2017-18-05; WIRB 
PRO NUM: 20170090). The study population was healthy children 48 to 84-months-old enrolled 
in 10 Early Childhood Education centers. There were 299 consents in a school population of 
377 children. A study assistant collected healthy history information. Fifteen children were 
excluded and 284 were randomized (1:1 allocation). Two hundred seventy-three children were 
analyzed in year 1 and 262 children were analyzed in year 2.  The dental varnish contained 
10% PVP-I and 5.0% NaF. The comparator contained only NaF. Varnishes were applied once 
every 3 months during two years. The primary outcome was the surface-level primary molar 
caries increment (d2-4mfs) at two-years. Baseline to Year 1 and Year 2, caries increments were 
compared between conditions using log-linear regression adjusting for age, sex and baseline 
caries and whether the tooth was sound (free of caries lesions) at baseline. At year 1, the caries 
increment for primary molars sound at baseline was 0.9 surfaces (SD 1.5) for the test varnish 

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versus 1.8 (SD 2.2) for the varnish with fluoride alone (adjusted RR=0.50; 95% CI: 0.31 to 0.81; 
P = .005).  At year 2, the caries increment for primary molars sound at baseline was 2.3 
surfaces (SD 2.8) for the test varnish versus 3.2 (SD 2.6) for the varnish with fluoride alone 
(adjusted RR=0.74; 95% CI: 0.52 to 1.03; P = .073).  Teeth that were already cavitated at 
baseline did not show a secondary preventive effect.  There were no harms. Results confirm the 
results of an earlier cohort study suggesting a dental varnish containing PVP-I and NaF is 
effective in the primary prevention of cavities in the primary dentition.  
 
The basic dental varnish formula was previously cleared by the FDA as a medical device 
and is currently on the market. To our knowledge there have been no adverse event reports on 
this varnish and it has never been withdrawn from the market. Povidone iodine is widely used in 
children in medicine.  It has been used for intraoral application for many years without problems. 
Dental NaF varnish and povidone iodine have been applied sequentially at the same patient 
visit by clinicians for some time and two cohort studies have been published with no reports of 
harms. Similarly, the recently completed Phase 2 trial reported no harms. 
 
 
2.2 Potential Risks and Benefits 
 
2.2.1  Potential Risks 
 
None of the proposed methods pose any serious risks to the study subjects.  
 
The FDA approves the topical use of 10% PVPI to the skin of children. 
 
Risks from povidone iodine include rash and swelling at the site of application. 
Iodine can cause thyroid gland problems, but this is rare and is very unlikely at the 
amount used in this study.  
 
The recent phase 2 trial demonstrated no harms. 
 
2.2.2  Known Potential Benefits 
 
There are direct benefits to the human subjects participating in this proposal. 
These include the early detection of caries, its timely management and the 
possibility of its prevention.  
 
 
 
 
 
 
 
 

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3.  Objectives 
 
3.1 Study Objectives 
 
Primary Objective: 
 
To determine if Advantage Anti-Caries Varnish (test varnish) is superior to an active control 
varnish (5% NaF) in the prevention of caries lesions in the primary dentition (Severe-Early 
Childhood Caries). Specifically, prevention of caries lesions in primary teeth that either are 
sound, have only d1 (white spots) lesions or unerupted at baseline. 
 
Secondary objectives: 
 
To document the safety of the test varnish. 
 
3.2 Study Outcome Measures 
 
3.2.1  Primary Outcome Measures 
 
• 
New surface-level dental caries lesions at 24 months post baseline 
• 
Presence/Absence of any new dental caries lesions (d2-4mfs) at 12 months 
post baseline 
 
3.2.2  Secondary Outcome Measures 
 
• 
Adverse event occurrence 
 
 
4.  Study Design 
 
This is a single center randomized, double-blind, placebo-controlled, parallel-group trial. 
 
4.1 Rationale for Study Design 
 
The completed phase 2 study demonstrated a preventive effect on primary teeth that were 
sound (not cavitated) at baseline but the study was not specifically designed to test the 
primary prevention efficacy. The hypothesis in this second phase 2 study is that the test 
varnish will be superior to the active control varnish for primary prevention of S-ECC.  There 
will be no difference in the frequency of adverse events. 
 
 
 
 

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4.2  Rationale for Dosage  
 
The treatment group will be exposed at baseline and once every three to four months after 
baseline for a maximum period of 24 months. The control group will be exposed to the control 
varnish in the same manner. The decision for dosing every three to four months with the test 
varnish was based on earlier work (Berkowitz, Koo et al. 2009) and the AAPD Standard of 
Care for children at high risk for dental caries.   
 
 
5.  Study Enrollment and Withdrawal 
 
5.1 Subject Numbers 
 
254 subjects will be enrolled. Half will be randomized to each arm.  
 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
5.2 Subject Inclusion Criteria 
 
1. The subject’s parent or legal guardian must provide signed and dated informed consent 
(parent permission form). 
2. The subject’s parent or legal guardian of the subject must be willing and able to comply 
with study requirements. 
3. The subject is a 6 to 24 months at the time of enrollment. 
4. The subject must be in good general health as evidenced by parent report. 
5. The subject will have at least 1 erupted tooth that is either sound or has only a d1 (white 
spots) lesion. 
 
 
 
 
5.3 Subject Exclusion Criteria 
 
A subject who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Previous treatment with fluoride varnish 
2. Known allergy to iodine 
3. Diagnosis of thyroid disease 
4.   Chronic, prophylactic use of antibiotics   
5.   Treatment with another investigational drug or intervention within 30 days preceding the 
Baseline Visit.  
6.  Visible cavities (d2-4) 

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7. Presence of intraoral pathology that would make assessment of post treatment soft tissue 
ulcerations or inflammation impossible (child could be enrolled if problem is treated and 
lesions cleared) 
8.  Parent anticipates the child will move from Pohnpei during the next 2 years. 
 
In the event of unique circumstances permitting waiver of any of the above eligibility 
criteria, documentation of such a waiver must be generated by the Principal Investigator prior 
to randomization into the study. Enrollment of an otherwise ineligible subject into the study 
without prior approval of a waiver will be considered a protocol violation. 
 
5.4   Discussion of Subject Characteristics 
 
The study population is high risk for Severe-Early Childhood Caries (any dental caries in the 
primary dentition before the age of 5) because of their poverty status and lack of access to 
fluoridated water. The subject population will consist of children who are 10 to 20 months of 
age at the time of enrollment. The study site is Pohnpei State, Federated States of 
Micronesia (FSM). Under US law and the Compact of Free Association between the US and 
FSM, this site is considered to be part of the US.  There are no intrinsic (genetic or 
physiologic) or extrinsic (cultural or environmental) characteristics of the population that 
would influence the safety, efficacy, dosage or dose regiment of the drug. Children consume 
a diet largely of processed foods from the US mainland and the main pathogenic organism in 
the etiology of tooth decay has been shown to be Streptococcus mutans, as it is among 
children in the US proper. These children also use toothpastes produced in the US and 
regulated by FDA. In addition, this trial will be supervised by a regulatory monitor based in 
the US and familiar with US regulations. The consent documents will be in English and 
Pohnpeian.  
 
5.5   Strategies for Recruitment and Retention  
Children attending Maternal and Child Health (MCH) Immunization and Well Child programs 
in Pohnpei State will be enrolled. In 2019 there were 6 MCH centers and a Community 
Health Center enrolling 597 children. In this age range there will be at least 500 children 
available to recruit. Assuming a consent rate of 80% (allowing for a few children with cavities 
and some moving off island), we should be able to recruit 254 children in less than 3 months. 
Based on the recently completed phase 2 trial and our previous work in Micronesian schools 
in the US affiliated states we expect nearly every parent to consent and thus for us to enroll 
the entire sample within two months (Milgrom et al., 2009; Tut et al., 2010; Milgrom et al., 
2011). 
 
The parent (or legal guardian) of the potential subject will be approached by a bilingual study 
assistant who will confirm eligibility of the subject. The proposed study will be explained. 
Written informed consent will be obtained. The child will be screened for presence of dental 
cavities. If the child is cavity free and meets all the inclusion criteria, he/she will be enrolled in 
the study and randomized according to the randomization list created by the study 
biostatistician. 
 

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The Micronesian islands are quite isolated and children do not move from the islands readily. 
In the recently completed phase 2 trial, less than 10% of children were lost to follow-up after 
two years. We have conducted two prospective cohort studies with a similar population in the 
islands. The one-year attrition rate was 1/172 (less than 1%) in one study and no child was 
lost to follow-up in the other study (Tut & Milgrom, 2010; Milgrom, Tut & Mancl, 2011).  
Families whose children complete the first treatment visit will receive a $20 gift card as an 
incentive and then receive an additional $20 gift card at each 3-month treatment visit. 
Families whose children complete a year in the study will receive a $30 gift card at the Year 1 
dental examination; families whose children complete two years in the study will receive 
another $30 gift card at the Year 2 dental examination. In addition, the children will receive a 
study t-shirt at enrolment. All child participants will receive a small tube of fluoridated 
toothpaste and an appropriately sized toothbrush at treatment visits. The incentive levels 
were determined in consultation with the Pohnpei State Department of Health and Social 
Services.  
 
5.6 Treatment Assignment Procedures 
 
5.6.1   Subject Identification Numbers  
Participants will be randomly assigned to one of the two inventions with a 1:1 
allocation as per a computer-generated randomization schedule with stratification 
by MCH center (Nett, Kolonia, Kitti and Sokehs if needed) and with randomly 
permuted blocks of sizes 2 and 4.  Multiple children within the same family unit will 
be randomized independently. Stratification and blocking will ensure the two 
interventions are equally balanced within MCH center and randomly permuted 
blocks sizes will ensure concealment. 
    
5.6.2  Randomization Procedures 
 
The study biostatistician will create the randomization lists using the “sample” 
function of the R statistical software (Version 3.3.0; The R Foundation for Statistical 
Computing, 2016). 
 
The biostatistician will generate treatment assignment lists for each MCH center. 
Treatments will be blinded and coded drug A or B. In each treatment application a 
second staff member will verify on site that the child received the correct coded 
treatment. 
 
5.7  Masking Procedures 
 
All study personnel except for designated personnel in the data center will be blinded to 
the participant treatment assignment. In order to maintain blinding and eliminate 
examiner bias, the staff member applying these varnishes will not perform the caries 
scoring exams.  

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5.8  Reasons for Withdrawal 
 
Subjects’ parents or legal guardians will be advised in the written consent that they have 
the right to withdraw from the study at any time without prejudice, and may be withdrawn 
at the Principal Investigator’s discretion at any time.  
 
 A subject may be withdrawn from the study for the following reasons: 
 
Examples of non-adverse-event related reasons for withdrawal 
 
1. Withdrawal of consent by parent/guardian 
2. Principal Investigator-initiated withdrawal 
3. Request of primary care physician  
4. Failure to meet entry criteria (either newly developed or not previously recognized) 
5. Lost to follow-up/failure to return  
6. Early termination of study  
 
Examples of adverse event-related reasons for withdrawal 
 
1.  New illness that in the opinion of the Principal Investigator warrants withdrawal 
2.  Death 
3.  Other adverse event 
 
5.8.1  Handling of Withdrawals 
 
In the event of voluntary withdrawal from the study, a Premature Withdrawal (PW) 
Visit will be conducted if possible to obtain a final caries exam and ensure that 
appropriate care under medical supervision is provided until the symptoms of any 
AE resolve or the subject’s condition becomes stable or deemed chronic. 
 
Reasonable effort should be made to contact any subject lost to follow up during 
the course of the study in order to complete study-related assessments and collect 
safety data.  
 
Subjects who are withdrawn from the study will not be replaced. 
 
5.9  Termination of Study  
 
The study may be discontinued at the discretion of the Sponsor or the Principal Investigator if 
there is sufficient reasonable cause.  
 
Circumstances that may warrant termination include, but are not limited to: 

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• 
Determination of unexpected, significant, or unacceptable risk to subjects.  
• 
Insufficient rate of subject accrual. 
• 
Insufficient adherence to protocol requirements.  
• 
Data which are not sufficiently complete and/or evaluable.  
Written notification, documenting the reason for study termination, will be provided to the 
Principal Investigator and regulatory authorities. In the event of early termination of the 
study, all subjects will be seen for a final visit for safety purposes. The study site will notify 
the Western IRB and the Pohnpei State Department of Health and Social Services of the 
study termination and provide the reason(s). 
 
6.  Investigational Product 
 
6.1 Investigational Product Description 
 
6.1.1  Acquisition 
Test and control varnishes will be obtained from Cascade Custom Chemistry, 
Eugene, OR 
 
6.1.2  Formulation, Packaging, and Labeling 
 
Advantage Anti-Caries Varnish. The active ingredients are 10% (w/v) Povidone 
Iodine CAS RN 25655-41-8 and 5% (w/v) Sodium Fluoride CAS RN 7681-49-4 in 
Ethanol 200 Proof. The formulation of the dosage form includes 10% Nt-2 Premium 
Shellac, 1% sodium phosphate, dibasic anhydrous, 0.5% ammonium phosphate, 
monobasic, and 1% caramel cream flavor (Bell 29.26303) as inactive ingredients. 
One and two-year shelf life of the varnish has been established according to 
Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and 
Products (Revision 2, November 2003).  
 
The active control varnish will be the same varnish without iodine with an 
appropriate FDA approved food dye added to match the color of the test agent. 
There will be no other differences in the treatment and control varnishes.  
 
The varnishes will be packaged in 12 mL multi use bottles with the following 
labeling. 
 
Advantage Anti Cavity Varnish or Control Varnish 
 
• 
Apply as per protocol 
• 
For Investigational Use Only 
• 
Drug Code A or B 

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• 
Contact: Dr. Peter Milgrom, +1206-251-6831 (24 hours) 
 
 
6.1.3  Product Storage and Stability 
 
All investigational products will be kept in a secure, safe area under recommended 
storage conditions with access limited in the study office. Expiration or use-by 
dates, as applicable, for all products will be documented by staff.  
 
6.2 Dosage, Preparation and Administration of Study Investigational Products 
 
Advantage Anti-Cavity Varnish and Control Varnish 
 
A maximum of 0.2 mL will be applied to the teeth with a dental brush. Test or 
control varnish will be applied topically 4 times per year following enrollment and 
at each 3 to 4-month intervals.   
 
The specific procedure is as follows. The varnish multi-use vial is shaken for 1 
minute before dispensing. The varnish will be dispensed into the well of the 
disposable plastic dappen dish. One drop will be dispensed for every five teeth to 
be treated, up to a maximum of 4 drops if all 20 primary teeth are present. Teeth 
will be dried with cotton gauze prior to application. Varnishes will be applied to 
the teeth with a dental microbrush. 
 
6.3 Accountability Procedures for the Investigational Product(s) 
 
The Principal Investigator (Tut) and Site Director (Gallen) must maintain accurate records 
(including dates) of all supplies received from Advantage. All remaining drug will be returned 
to the sponsor for disposal and documented on the Drug Disposal Log by the Sponsor or 
Principal Investigator.  
 
6.4 Assessment of Subject Compliance with Investigational Product  
 
As the test and control drugs will be administered by the study personnel, it is not anticipated 
that subject compliance with treatment will be an issue. In the event a dose is missed; the 
missed dose will be captured as a protocol deviation and documented in the source 
documents.  
 
6.5 Coding/Emergency Treatment Disclosure  
 
The Principal Investigator will be given a sealed envelope containing the randomized 
treatment assignment code for each subject to be opened only in the event of a medical 
emergency.  
 

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Neither premature withdrawal from the study nor most clinical emergencies necessitate 
disclosure of treatment assignment. Most emergency situations can be handled by 
withdrawing study treatment without disclosure of treatment assignment. However, in rare 
circumstances under which knowledge of the drug assignment is necessary for the treatment 
of a serious adverse event, the Principal Investigator (Tut) must discuss the situation with the 
Site Director (Gallen) and Dr. Milgrom, if circumstances permit, before deciding whether or 
not to disclose treatment assignment. If disclosure of individual treatment assignment is 
undertaken, it must be made by the Principal Investigator responsible for the care of the 
involved subject in consultation with the Medical Monitor. The subject will be withdrawn from 
further exposure to study drug.  
 
Emergency treatment is a reportable event, requiring notification to the Principal Investigator 
and Sponsor within 24 hours when the staff is aware of the event. The assigned treatment 
must not be revealed to other study staff or to individuals who are not involved directly in the 
clinical care of the subject, unless disclosure to the individual is critical to the care of the 
subject. 
 
6.6 Concomitant Medications/Treatments 
 
Subjects may not be receiving treatment with another investigational drug within 30 days 
preceding the baseline visit and throughout participation in this study. 
 
Chronic prophylactic use of antibiotics at enrollment is an exclusion criterion; however, if 
during the course of the study, the subject’s PCP prescribes antibiotics (e.g., for treatment of 
otitis media) the subject can remain in the study. At each varnish application, the study staff 
will question the parent about antibiotic use as part of capturing AEs and this will be recorded 
on the AE form. 
 
Concomitant medication use, including all prescription and over-the-counter medications, will 
be recorded commencing with the screening visit and at each visit through completion of the 
study. 
 
Fluoridated toothpaste will be provided under this protocol to all subjects. Parents will be 
given a handout explaining how much toothpaste to use. At each follow-up, the parent will be 
asked about whether the child is using the fluoride toothpaste. The parent will be asked to 
estimate about how many times per week, in a typical week, that their child is using the 
fluoride toothpaste (e.g., every day, more than half the days, less than half the days, never).  
 
 
7.  Study Schedule/Procedures and Evaluations  
 
7.1   Subject recruitment procedures:  
 
• 
The study assistant will contact the parent/caregiver through the MCH Immunization 
or Well Baby program or at home. This individual will explain the study and obtain 

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informed consent.  The focus will be on Nett, Kolonia, and Kitti districts. Sokehs will 
be included if necessary. 
• 
The informed consent packet will carry a pre-assigned subject number. If a parent 
does not consent, the reason will be recorded and the study number will not be used.  
• 
The study assistant will verify that the subject meets the inclusion and exclusion 
criteria, including age. The study assistant will calculate from the birth date that the 
subject is at least 10 6 months of age exactly and no more than 20 24 months and 0 
days.  
• 
The study assistant will record the subject’s age and sex and medical history based 
on parent/guardian report.  
• 
The study assistant will record concomitant prescription medication and over-the-
counter medication use over the past 90 days.  
• 
A trained and calibrated study dental assistant will conduct the baseline dental 
screening for cavities, chart the number of fully and partially erupted teeth, and any 
abnormal intraoral soft tissue findings. 
• 
If the child meets the Subject Inclusion Criteria, the child will be enrolled for the study 
and entered into the randomization list created by the Study Biostatistician for 
treatment. 
 
 
7.2   Baseline Visit  
 
• 
The visit will be at a center or at the study office. 
• 
At the baseline visit, the Project Site Manager will check the randomization list and 
the drugs, which will be color-coded, and a trained study dental assistant will apply 
the first treatment to the subject according to the treatment code assigned by the 
statistician.  
• 
A toothbrush and a small tube of fluoride toothpaste will be dispensed to the 
parent/caregiver along with a handout explaining how much toothpaste to use.  
• 
24-48 hours later, a trained study dental assistant will see the child again and 
conduct a soft tissue exam, and complete the safety questionnaire. 
 
 
7.3   Visits 2-8 Treatment Visit  
 
• 
The visit will either be at a MCH/CHC Center or the study office. 
• 
A trained study dental assistant will review and record adverse events (AEs) and 
concomitant prescription and over-the-counter medications. 
• 
Fluoride toothpaste use will be collected from the parent/caregiver and recorded by a 
trained study dental assistant.  
• 
A trained and calibrated examiner will conduct the dental caries exam at Visit 5 (Year 
1). 
• 
A trained study dental assistant under the direction of the Project Site Manager, who 
will consult the participant list and randomization, will apply the assigned treatment. 

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• 
A toothbrush and a small tube of fluoride toothpaste will be dispensed to the 
parent/caregiver along with a handout explaining how much toothpaste to use.  
• 
24-48 hours later, a trained study dental assistant will telephone the parent and 
assess any adverse or serious adverse event and complete the safety questionnaire. 
If the parent cannot be contacted the assistant will make a home visit or arrange for 
the child to be brought to study office. If there is an apparent adverse or serious 
adverse event, the child will be seen in person by study staff. see the child again, 
conduct a soft tissue exam, and complete the safety questionnaire.  
 
 
7.4 Visit 9 Year 2 Exam Visit  
 
• 
The visit will either be at a MCH/CHC Center or the study office. 
• 
A trained study dental assistant will review and record adverse events (AEs) and 
concomitant prescription and over-the-counter medications. 
• 
Fluoride toothpaste use will be collected from the parent/caregiver and recorded by a 
trained study dental assistant.  
• 
A trained and calibrated examiner will conduct the dental caries and oral exam (Year 
2). 
 
7.5 Premature Withdrawal  
 
In the event of premature withdrawal from the study, the Premature Withdrawal (PW) visit 
procedures and evaluations should be completed whether or not the decision to withdraw is 
determined at a routine or unscheduled visit.  If it is determined via telephone contact that a 
premature withdrawal will occur, the parent/guardian should be asked to bring the child in for 
a PW visit.  
 
Activities to be completed include: 
 
• 
The Examiner will conduct the Oral Soft Tissue exam 
• 
The Examiner will conduct the caries exam  
• 
The assistant will record concomitant medication use. 
• 
The assistant will review and record AEs and record on the AE Follow-Up Log the status 
of adverse events that are unresolved at the time of the premature withdrawal visit.  
 
Premature withdrawal (including reports of subjects who are lost to follow up) should be 
reported to the Site Director within 24 hours of the site’s knowledge of the event. 
 
7.6 Unscheduled Visit  
 
An unscheduled visit may be performed at any time during the study at the subject’s request 
or as deemed necessary by the Principal Investigator. The date and reason for the 
unscheduled visit will be recorded in the subject’s source documentation.  
 

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Activities to be completed include: 
• 
The Examiner will conduct the Oral Soft Tissue exam 
• 
The Examiner will conduct the caries exam  
• 
The assistant will record concomitant medication use. 
• 
The assistant will review and record AEs and record on the AE Follow-Up Log the status 
of adverse events that are unresolved at the time of the unscheduled visit.  
 
 
8.  Assessments 
 
 
 
 
 
8.1  Primary and Secondary Outcome Variables 
 
 
 
 
 
Primary Outcome Variable 
 
• 
Surface-level dental caries lesions (d2-4mfs) at 24 months post baseline 
• 
Presence/Absence of dental caries lesions (d2-4mfs >0) at 12 months post 
baseline 
 
Secondary Outcome Variable:  Adverse Events 
 
 
8.2  Efficacy Assessments 
 
 
 
 
8.2.1 Caries Examination 
Two examiners will be trained and calibrated according to National Institute of 
Dental and Craniofacial Research Early Childhood Caries Collaborative criteria, 
which are based on the World Health Organization caries classification system. 
The children will be visually examined using a mouth mirror and artificial light. No 
explorers will be used. Training and calibration will be done prior to dental exams 
at year 1 and year 2. At each timepoint, six subjects will be used for training and 14 
subjects will be used to evaluate examiner agreement.  
 
 
 
8.3  Safety Assessments 
 
Adverse events, including frequency and severity, and perceived relationship to the 
investigational product, will be compared between the treatment groups.   
 
8.3.1. General Health (Medical History and Physical Examination) 
 
 
The subject’s general health status at enrollment will be assessed by medical history 
using the parent or legal guardian as the informant.  
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All concomitant medications taken by the subject will be recorded at the time of 
consent and updated at each follow-up study visit (all prescription and over-the-
counter medications taken within the past three months).  
 
 
 
 
 
 
9.  Assessment of Safety 
 
9.1 Specification of Safety Parameters 
 
• 
Adverse events 
 
 
9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Adverse events will be recorded at each 24-48 hour in person or telephone check. At each 
treatment visit, the parent will be questioned about any changes in the child’s health and AEs 
noted. 
 
Adverse events will be reviewed on a quarterly basis by the Medical Monitor (Hedson); 
serious adverse events and other protocol-specified reportable events will be assessed in 
real time by the Principal Investigator (Tut) and Site Director (Gallen). 
 
9.3 Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.  An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with any use of a drug, 
whether or not related to the drug. An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose. This excludes minor fluctuations in signs or symptoms of the disease 
under study, but does include significant worsening of the disease. It also includes any 
apparently unrelated illness and any accident that occurs during participation in the study.  
 
Some examples of adverse events are: 
 
• 
Development of an illness during the study. 
• 
Development of symptoms which may or may not be related to the use of a concomitant 
medication or investigational product. 
 
All adverse events, whether observed by the Principal Investigator, elicited from or 
volunteered by the subject or parent/guardian, should be recorded on a study Adverse Event 
Form and in the Adverse Event Log. This reporting will include a brief description of the 

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event, the date of onset, the date of resolution, the duration and type of event, the severity, 
contributing factors, and any action taken with respect to the investigational product. 
 
AEs occurring after informed consent is obtained but prior to randomization will be recorded 
as medical history, unless possibly related to a study procedure, in which case they will be 
recorded as adverse events in the case report form. New adverse events will be captured 
and reported on the AE log until 30 days following the last treatment or premature withdrawal, 
whichever comes first. 
 
9.4 Expected Adverse Reactions 
 
Risks from povidone iodine include rash and swelling at the site of application. Iodine can 
cause thyroid gland problems.  
 
9.5 Serious Adverse Events 
 
A serious adverse drug event is defined as any adverse event that results in any of the 
following outcomes:  
 
• 
death 
• 
a life-threatening adverse event 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant incapacity; or substantial disruption of the ability to conduct 
normal life functions 
• 
[a congenital anomaly/birth defect – noted as not applicable in this population] 
 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include (but are not limited to) allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, or blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
 
This category also includes any event the Principal Investigator judges to be serious or 
that would suggest a significant hazard, contraindication, side effect or precaution. Any 
adverse event or suspected adverse reaction is considered “life threatening” if, in the 
view of either the Principal Investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
 
Reports of serious adverse events require immediate notification (within 24 hours of the 
site’s awareness) to the Principal Investigator and Sponsor whether or not the Study Site 
Coordinator believes that the event is related to investigational product or is expected.  
 
9.5.1 Unanticipated Problems 

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The Principal Investigator must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which she is responsible, but at 
a minimum those events that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
 
9.5.2 Procedures to be Followed in the Event of Abnormal Clinical Findings 
 
At each child 24-48-hour follow-up, study staff will assess adverse events by 
assessment of parent report and clinical features if the child is seen in person and 
parent questionnaire.  
 
An unscheduled visit may be performed at any time during the study as deemed 
necessary by the Principal Investigator. The Site Director will inform the subject’s 
parent/guardian when medical care is needed for adverse events of which the 
Principal Investigator becomes aware (e.g., illness) and may refer the subject back 
to the PCP for further work-up. The Principal Investigator may determine that the 
subject should be withdrawn from the study treatment.  
 
9.6 Reporting Procedures 
 
9.6.1  Reportable Events 
 
The following incidents will be considered reportable events and will be reported to 
the Principal Investigator within 24 hours of the site’s awareness of the event. 
 
• 
Serious Adverse Event 
• 
Emergency Treatment Disclosure 
• 
Post-Treatment Adverse Events, including 
o Nausea  
o Not eating 
o Vomiting  
o Difficulty swallowing or breathing 
o Swelling around the lips or skin on the face 
o Itchiness around the lips or skin of the face 
o Hives or rash 
 
 
9.6.2 Serious Adverse Events 
 
Within 24 hours of the site’s awareness of the serious adverse event (SAE), the 
site will report the SAE to the Principal Investigator and provide subject 
identification and a brief description of the event, including the Medical Monitor’s 

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assessment of causality (unrelated, possible, probable, definite) related to the 
study drug.   
 
Within 24 hours of the telephone report, the site will complete the AE form and 
update the AE log to ensure that the concomitant prescription medication 
information is current, and enter the SAE report. This report will include: 
documentation that serious adverse event criteria have been met; a detailed 
description of the event and other relevant information; the current status of the 
experience; if the subject has died, the date of death and autopsy report, if 
available; and the Medical Monitor’s current opinion of the relationship between the 
event and the investigational treatment.  
 
 
 
 
9.6.3 Adverse Event Causality Definitions 
 
For each adverse event, the relationship to the study drug (Medical Monitor’s 
attribution of causality) must be recorded as one of the following on the Adverse 
Event Log: 
 
 
 
 
 
 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated No possible relationship  The temporal relationship between drug 
exposure and the adverse event onset/course 
is unreasonable or incompatible, or a causal 
relationship to study drug is implausible. 
    
Not reasonably related, 
although a causal 
relationship cannot be 
ruled out 
While the temporal relationship between drug 
exposure and the adverse event onset/course 
does not preclude causality, there is a clear 
alternate cause that is more likely to have 
caused the adverse event than the study 
drug. 
Possible 
Causal relationship is 
uncertain 
The temporal relationship between drug 
exposure and the adverse event onset/course 
is reasonable or unknown, dechallenge or 
rechallenge information is either unknown or 
equivocal, and while other potential causes 
may not exist, a causal relationship to the 
study drug does not appear probable. 
Probable 
High degree of certainty 
for causal relationship 
The temporal relationship between drug 
exposure and the adverse event onset/course 
is reasonable. There is a clinically compatible 
response to dechallenge (rechallenge is not 
required), and other causes have been 
eliminated or are unlikely. 
Definite 
Causal relationship is 
certain 
The temporal relationship between drug 
exposure and the adverse event onset/course 

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TERM 
DEFINITION 
CLARIFICATION 
is reasonable, there is a clinically compatible 
response to dechallenge, other causes have 
been eliminated, and the event must be 
definitive pharmacologically or 
phenomenologically, using a satisfactory 
rechallenge procedure if necessary. 
 
 
 
9.6.4 Adverse Event Severity Definitions 
 
 
 
 
 
The severity of each adverse event must be recorded as one of the following on the 
Adverse Event Log: 
 
MILD 
 
No limitation of usual activities 
MODERATE 
 
Some limitation of usual activities 
SEVERE 
 
Inability to carry out usual activities 
 
 
 
9.7  Responsibilities of Investigator/Sponsor for Reporting SAEs 
 
Serious adverse events occurring after informed consent is obtained but prior to 
randomization will be recorded as medical history, unless possibly related to a study 
procedure, in which case they will be reported as SAEs to the Medical Monitor within 24 
hours of the site’s awareness.   
 
9.7.1 Regulatory Reporting for Studies Conducted Under an IND 
 
The Principal Investigator will comply with the Micronesian and Western IRB 
regulations regarding the reporting of adverse events.  
 
The Sponsor will report events that are serious, unexpected and that are 
associated with the study drug (SUSAR) to the Food and Drug Administration 
(FDA) within the required timelines as specified in 21 CFR Part 312.32; fatal and 
life-threatening events within 7 calendar days (by phone or fax) and all other SAEs 
in writing within 15 calendar days. All serious events designated as “not 
associated” with study product(s) will be reported to the FDA at least annually in a 
summary format. 
 
9.7.2 Other Unanticipated Problems 
 
Unanticipated problems are those involving risks to subjects or others and include 
any incident, experience, or outcome that meets all of the following criteria: 
 

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• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
WCG IRB-approved research protocol; and (b) the characteristics of the 
subject population being studied;  
•    Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and  
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
An incident, experience, or outcome that meets any of the three criteria above 
generally will warrant consideration of substantive changes or corrective actions in 
order to protect the safety, welfare, or rights of subjects or others.  
 
Unanticipated problems noted by the site will be recorded and reported to the 
Principal Investigator within 24 hours of the site’s awareness and to the 
Micronesian and WCG IRB per local reporting requirements. 
 
9.8 Type and Duration of Follow-up of Subjects after Adverse Events 
 
All adverse events will be followed until resolution or an appropriate endpoint is reached 
(e.g., the Medical Monitor attributes the adverse event to a cause other than the study drug 
or assesses it to be chronic or stable). 
 
9.9 Halting Rules 
 
Adverse events, particularly serious adverse events such as deaths and hospitalizations, will 
be carefully considered by the Sponsor. If necessary, the Sponsor will halt the study. 
 
 
10.  Site Monitoring 
 
10.1 Clinical Site Monitoring 
 
To ensure compliance with Good Clinical Practice (GCP) and other applicable regulatory 
requirements, the Regulatory Monitor (Bierer) is responsible for monitoring to ensure the site 
is conducting the study according to the protocol, Standard Operating Procedures (SOPs), 
and other written instructions and regulatory guidelines. Monitoring visits by a Regulatory 
Monitor will be arranged in advance, at a mutually-acceptable time, with site personnel.  
 
The site personnel must allow sufficient time for the Regulatory Monitor to review CRFs and 
relevant source documents, including access to electronic medical records, and address data 
queries. 

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The Investigators should be available to answer questions or resolve data clarifications. The 
monitoring plan will include written procedures for periodic and closeout monitoring visit 
activities, documentation and communication of visit findings, and maintenance of the record 
of on-site visits. The monitoring plan will serve as a guide to ensure standardization of study-
specific procedures for the Regulatory Monitor who is responsible for ongoing quality review.  
 
 
10.2 Regulatory Inspections 
 
During the course of the study and after it has been completed, it is possible that one or more 
study site visits will be undertaken by authorized representatives of the Sponsor, WCG IRB, 
or regulatory agencies, such as the Food and Drug Administration (FDA). These audits may 
take place at any time during or after the study and are based on the local regulations, as 
well as ICH guidelines.  
 
The purpose of the audit is to determine whether or not the study is being, or has been, 
conducted and monitored in compliance with the protocol as well as recognized GCP 
guidelines and regulations. These audits will also increase the likelihood that the study data 
and all other study documentation can withstand a subsequent regulatory authority 
inspection.  
 
If such audits are to occur, they will be arranged for a reasonable and agreed-upon time.  
 
 
11.  Statistical Considerations 
 
11.1 Study Hypotheses 
 
The hypothesis is that the Advantage Anti-Caries Varnish (test varnish) is superior to an 
active control varnish (5% NaF, no PVP-I) in the prevention of caries lesions in the primary 
dentition (Severe-Early Childhood Caries), and there will be no difference in the frequency of 
adverse events.  Specifically, prevention of caries lesion in primary teeth that either are 
sound, have only d1 (white spots) lesions or unerupted at baseline. 
 
11.2 Sample Size Considerations 
 
The study aims to show differences in the net caries increment (d2-4mfs) at 2 years post 
baseline application (Broadbent & Thomas, 2015) and any new caries at 1 year post 
baseline. Assuming a coefficient of variation of 85% in the caries increment and a 35% 
reduction in caries increment at 2 years (equivalent to an effect size of 0.49), 106 children 
per group will be required for 90% power using a 0.025 significance level. With 106 children 
per group the power is 80% to show a 38% reduction in any new caries at 1 year using a 
0.025 significance level assuming 55% caries in the control group. The effect sizes were 
based on the findings from our prior study on the test varnish involving 4-6 year-old children 

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and our study on topical iodine and fluoride varnish effectiveness involving 12-30 month-old 
children (Milgrom et al 2011). The sample size was inflated 20% to 127 per group to account 
for loss to follow-up, particularly for moving off island.  The follow-up rate in our prior study in 
this population was >90% after two years. 
 
 
 
 
11.3 Statistical Analysis Plan 
11.3.1 Primary Statistical Analysis.   
The primary analysis will be conducted in accordance with the intention-to-treat principle; 
and if needed, multiple imputation procedures will be used to account for missing caries 
information (Schafer, 1997). For the primary outcome at year 2, incremental dental caries 
based on d2-4mfs, the unit of analysis will be the child and the net dental caries increment 
will be compared between the two interventions at 2 years post baseline using a two-sample 
t test assuming unequal variances. The primary comparison will be based on all primary 
teeth and surfaces, and additional comparisons will be based on sound surfaces, surfaces 
with d1 (white spots) or unerupted surfaces of primary teeth at baseline. This approach 
assumes the distribution of dental caries increment is approximately symmetrical, which is 
often true in high-risk caries populations.  In the case of non-symmetry, log-linear regression 
using robust standard errors, which can accommodate count outcomes with a skewed 
distribution, will be used to compare the caries rates between the two interventions (Hardin 
& Hilbe, 2013). Log-regression analysis will use the tooth as the unit of analysis and be 
based on all teeth, but include an indicator for whether a tooth is sound, only has d1 (white 
spots) lesions or unerupted at baseline, an interaction between this tooth indictor and 
intervention arm to allow for separate estimates and tests of the intervention effect based on 
the status of the tooth at baseline. Covariate-adjusted linear or log-linear regression models 
using robust standard errors will be used to compare dental caries increment, adjusting for 
baseline dental caries, stratification variables (MCH center), gender and age of the 
participant (Hardin & Hilbe, 2013). The log of the number of surfaces at risk will be included 
as an offset in the log-linear regression models. 
 
Similar comparisons between the two intervention arms will be performed for the present or 
absence of any new dental caries d2-4mfs >0) one-year post baseline. Unadjusted 
comparisons between the two intervention arms will done using the chi-square test and the 
child as the unit of analysis, and log-binomial regression with the tooth as the unit analysis 
will be used to compute adjusted relative risks and perform comparisons between the two 
intervention arms adjusting for baseline dental caries, stratification variables (MCH center), 
gender and age of the participant (Hardin & Hilbe, 2013). 
 
If needed, pre-protocol analyses will be performed based on the number of varnish 
applications the child received.  In our prior Phase 2 trial, children received all varnish 
applications per the protocol, or at least until the child was lost to follow-up. The proposed 
log-linear and log-binomial regression methods will be used to assess whether adjusting for 
toothpaste use affects the comparison between the two interventions and to test for effect 

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modification of an intervention effect by toothpaste use.  Toothpaste use will be summarized 
for two time periods, between baseline and year 1 between year 1 and year 2, using the 
mode frequency of toothpaste use as reported by the parent. These analyses are 
considered secondary given toothpaste use is measured post-randomization and could 
potentially be influenced by the varnish the child received. 
  
Additional regression analyses using the tooth surface as the unit of the analysis may be 
performed to evaluate the effect of tooth surface factors on the interventions.  GEE methods 
will be used to account for the clustering of teeth and tooth surfaces within individual (Hardin 
& Hilbe, 2013).  Analyses will be performed using R (The R Foundation for Statistical 
Computing, 2016; Version 3.3.0) and SAS (SAS Institute, Cary, NC, Version 9.4). 
 
11.3.2 Analysis of Safety Data.   
Adverse events (AEs) will be tabulated by treatment group, severity, and perceived 
relationship to investigational product.  For each AE, treatment group comparisons regarding 
the occurrence of at least one event will be made using Fisher’s exact tests. The 
comparisons will be repeated excluding all mild symptoms.  Similar analyses will be 
performed after grouping AEs by body system using standard Medical Dictionary for 
Regulatory Activities (MedDRA) coding.  Individual AEs will be listed, with particular attention 
paid to serious AEs. 
 
11.3.3 Participant Disposition.  
The frequency and reasons for withdrawal will be summarized by treatment group, as will the 
number of missed visits and missed treatment applications (compliance). 
 
 
12.  Source Documents and Access to Source Data/Documents 
 
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  
 
12.1 Primary Source Documents  
 
 
 
 
 
The Principal Investigator must maintain primary source documents supporting significant 
data for each subject in the subject’s notes. During monitoring visits, the clinical site monitor 
will validate data in the CRF against these source data. 
 
 
12.2 CRF Worksheets 
 
The site will be supplied with a set of forms-based schedule of activities and corresponding 
source document worksheets (SDW) that correspond to the case report form (CRF) for this 
study. The worksheets will serve as source documents for study observations. Additional 
source documentation for information not specifically included on the source document may 
be recorded on a separate document. 

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Access to the source documents should be limited to those working on the study. Access to 
the database will be restricted. 
 
 
 
 
 
 
13.  Ethics/Protection of Human Subjects 
 
13.1 Ethical Standard 
 
This study will be conducted in accordance with the Good Clinical Practice (GCP) 
guidelines promulgated by the International Conference on Harmonization (ICH) and the 
Food and Drug Administration (FDA), and any applicable national and local regulations 
including FDA regulations under 21 CFR Parts 11, 50, 54, 56, 312 and 314. 
 
The Principal Investigator will ensure that this study is conducted in full conformity with 
the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 
(1997). 
 
13.2 Institutional Review Board 
The WCG IRB will review and approve the submission activities for the conduct of this 
protocol. The trial will not begin until the study has been approved by the WCG IRB, all 
required regulatory documentation is on file at both the site and the Principal Investigator 
and staff are trained on the protocol and data capture procedures.  
 
13.3 Amendments 
 
The Principal Investigator will discuss any proposed protocol changes with the Sponsor and 
no modifications will be made without prior written approval and WCG IRB approval of the 
amended protocol, except where clinical judgment requires an immediate change for 
reasons of subject welfare. The WCG IRB will be informed of any amendments to the 
protocol or consent form, and approval (where and when appropriate) will be obtained 
before implementation. 
 
 
 
 
 
13.4 Informed Consent Process  
This study will be conducted in accordance with the provisions of 21 Code of Federal 
Regulations (CFR) Part 50.  

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In accordance with relevant regulations, a parent informed consent agreement explaining 
the procedures and requirements of the study, together with any potential hazards/risks 
must be read and/or explained to each parent/guardian. Each subject’s parent or legal 
guardian will sign such an informed consent form. The subject’s parent/guardian must be 
assured of the freedom to withdraw from participation in the study at any time. 
 
It is the Principal Investigator’s responsibility to make sure that the subject’s parent/guardian 
understands what he or she is agreeing to and that written informed consent is obtained 
before the subject is involved in any protocol-defined procedures, including screening 
procedures. It is also the Principal Investigator’s responsibility to retain the original signed 
consent forms and provide each subject’s parent/guardian with a copy of the signed consent 
form. 
 
As children will be enrolled in this study, the informed consent process will be documented 
in the form of permission from the parent or legal guardian in the parent permission form; 
child assent (affirmative agreement by a child to participate in research) will not be 
employed in this study. 
 
13.5 Exclusion of Women, Minorities, and Children (Special Populations) 
 
This study will enroll children aged 10 to 20 6 to 24 months. There will be no exclusion due to 
gender, race or ethnicity. 
 
 
13.6 Subject Confidentiality 
The Principal Investigator must assure that the privacy of subjects, including their personal 
identity and personal medical information, will be maintained at all times. Personal medical 
information will always be treated as confidential. The parent/guardian’s Authorization allows 
the Sponsor-Investigator to receive and review the subjects’ protected health information 
that may be re-disclosed to any authorized representative of the Sponsor for review of 
subject medical records in the context of the study. 
 
13.7 Study Discontinuation 
 
At the completion of the study, study closeout procedures will be implemented.  
 
 
 
14.  Data Handling and Record Keeping 
 
The Principal Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  
 
14.1 Data Management Responsibilities 

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The Biostatistician will be responsible for all data collection procedures. The Data 
Management Plan includes, but is not limited to: 
• 
Overview of data management processes utilized for study 
• 
Universal data handling conventions 
• 
Study-specific data handling conventions 
• 
Coding dictionaries and practices 
• 
Specifications for logic and edit checks 
• 
External data handling practices 
• 
Final study closeout activities 
• 
Audit plans 
• 
Sample CRF annotation 
• 
Biostatistician contact information 
• 
Section for tracking revisions to the plan 
• 
Administrative report specifications 
 
The Data Management Plan serves to document the practices and procedures deployed to 
promote consistent, efficient, and effective data management practices leading to the 
creation of a high-quality database ready for analysis. The plan serves as the authoritative 
source, documenting data management practices, and decisions that are agreed to with the 
Principal Investigator at the start of the study and as necessary updates are made during 
the conduct of the study. 
 
Data will be transferred periodically from the study site to the University of Washington to 
prepare reports. At the close of the study, the locked database will be transferred to the 
Biostatistician for analysis.  
 
The Biostatistician will be responsible for design of the randomization scheme, creation of 
analytical databases, and the statistical analysis plan. 
 
14.2 Data Capture Methods 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) will be entered into the study database by the Data Manager. This system is protected 
by 128-bit server certificates and utilizes authenticated, password-protected accounts for 
each site. The system is compliant with relevant FDA regulatory requirements per 21 CFR 
Part 11.   
 
14.3 Types of Data 
 
Data for this study will include clinical assessments, safety, and outcome measures (e.g., 
expected adverse reactions). Safety data are contained in the clinical data set.  
 
14.4 Timing/Reports 
 

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Enrollments and study activity (protocol-specified reportable events, as described in 
Section 9.6.1) reports will be generated as they occur to a pre-determined distribution list 
that includes the Principal Investigator and team. 
 
Clinical monitoring reports will be generated periodically with electronic distribution to the 
PI and team. Per the Clinical Monitoring Plan, the clinical monitor reports include routine 
reports of aggregate, blinded adverse event data for ongoing review for potential trends, and 
adverse event and concomitant medication reports for the PI to review for standardization of 
coding. 
 
Safety monitoring reports will be provided by the Biostatistician per the safety monitoring 
plan.  
 
Missing data, missing electronic signatures of the Principal Investigator, and requests for 
data clarification reports will be generated to the site on a regular basis. 
 
Monitoring Visit Reports will be generated after each clinical site monitoring visit, per the 
monitoring plan. 
 
At the completion of the study, data will be securely transferred to the Biostatistician.  Once 
the Biostatistician and the PI agree that all queries have been adequately resolved and the 
database has been deemed “clean”, the database will be officially signed off and deemed 
locked.  All permissions to make changes (append, delete, modify or update) the database 
are removed at this time.   
 
All site personnel, Sponsor and staff will remain blinded as to treatment assignments until 
the conclusion of the entire study. A designated unblinded biostatistician will have access to 
the treatment assignments, and this individual will not communicate about study-related 
matters to any other staff involved in the study.  The study code will be broken by the study-
responsible statistician after all outstanding substantive data queries have been resolved. 
 
14.5 Study Records  
14.5.1 Study File and Site Documents 
  
The Principal Investigator should have the following study documents accessible to 
the Clinical Site Monitor during the study. These records are kept in the study office 
in Pohnpei. 
 
1. 
Signed Form FDA 1572 
         This study will be conducted under the supervision and direction of the 
Principal Investigator listed in Section 1 of the Form FDA 1572.  Sub-
Investigators are listed in Section 6 of the Form FDA 1572.  The study will be 
conducted at the address(es) listed in Section 3 of the Form FDA 1572. 
2. 
Curriculum vitae for the Principal Investigator and all personnel listed on 
Form FDA 1572 

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         The Principal Investigator is responsible for providing copies of the protocol 
and all other information relating to the preclinical and prior clinical 
experience, which were furnished to him/her, to all other study personnel who 
participate in this study.  The Principal Investigator will discuss this 
information with them to assure that they are adequately informed regarding 
the investigational product and conduct of the study.  The Principal 
Investigator must assure that all study staff members are qualified by 
education, experience and training to perform their specific responsibilities. 
3. 
The signed IRB form/letter stating IRB approval of protocol, consent forms, 
and any other study materials (e.g., patient instruction materials, 
advertisement notices), documentation of the IRB composition, and all IRB 
correspondence including notification/approval of protocol amendments, 
notification of serious, unexpected, suspect adverse drug reactions to the 
IRB, and IRB notification of study termination 
4. 
Training records 
         Records of protocol-specific training will be maintained. 
5. 
IRB-approved consent form 
6. 
Signed protocol (and amendments, where applicable) 
7. 
Signed parent/guardian permission forms 
8. 
Copies of the completed source document worksheets 
9. 
Delegation Log with names, signatures, initials, and functional role of all 
persons completing protocol assessments and providing back-up to the 
Principal Investigator. 
10. Accountability of investigational product 
11. Record of all monitoring visits by Clinical Site Monitor(s) 
12. Copies of correspondence 
13. Certificate for Human Subject Protection Program (HSPP) for each individual 
named on the Delegation Log who has direct subject contact 
14. Copy of professional licensure/registration, as applicable, for each individual 
named on the Delegation Log, who has direct subject contact, ensuring 
licensure is in the locality in which the study will be conducted 
15. The Principal Investigator must also retain adequate documentation, together 
with the subject’s hospital/medical records, as the subject’s source data for 
the study. 
14.5.2 Maintenance and Retention of Records 
It is the responsibility of the Principal Investigator to maintain a comprehensive and 
centralized filing system of all relevant documentation. The Principal Investigator 
will be instructed to retain all study records required by federal regulations in a 
secure and safe facility with limited access for one of the following time periods 
based on notification from the Monitor. 
The Principal Investigator will be instructed to consult with and provide advance 
written notice to the Monitor before disposal of any study records and to notify the 
Monitor of any change in the location, disposition, or custody of the study files. No 

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study document or image should be destroyed without prior written agreement 
between the Sponsor and the Principal Investigator.  
Regulations require retention for: 
• 
A period of at least two years after notification from the Sponsor that a U.S. 
NDA (New Drug Application) has been approved for the indication that was 
investigated or 15 years according to International Conference on 
Harmonization (ICH) guidelines. 
• 
Or, if no NDA is filed or approved for such indication, a period of at least two 
years after the investigation is completed or discontinued, and the FDA (Food 
and Drug Administration) has been notified by the Sponsor. 
 
14.6 Protocol Deviations 
A protocol deviation is accidental or unintentional changes to, or non-compliance with the 
research protocol that do not increase risk or decrease benefit or; do not have a significant 
effect on the subject's rights, safety or welfare; and/or on the integrity of the data. Deviations 
may result from the action of the subject, researcher, or research staff.  
A deviation may be due to the research subject’s non-adherence, or an unintentional 
change to or non-compliance with the research protocol on the part of a researcher. 
Examples of a deviation include:  A rescheduled study visit; Failure to collect an ancillary 
self-report questionnaire; or Subject’s refusal to complete scheduled research activities.  
Protocol deviations will be recorded in the subject’s file and log. 
14.7 Protocol Violations 
 
A protocol violation is any accidental or unintentional noncompliance with the WCG IRB 
approved protocol without prior approval requirements that may increase risk or decrease 
benefit, affects subjects’ rights, safety, or welfare, or the integrity of the study data. The 
noncompliance may be either on the part of the subject, the Principal Investigator, or the 
study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly. These practices are consistent with ICH E6. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of 
the scheduled protocol-required activity. All deviations must be promptly reported to the 
Principal Investigator. The Study will maintain a database of violations that are not already 
documented in the clinical database. Corrective and preventive action plans will be 
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Protocol violations must be sent to the WCG IRB per WCG IRB guidelines. The Principal 
Investigator and staff are responsible for knowing and adhering to the WCG IRB 
requirements.  
 
 
15.  Publication Policy 
Following completion of the study, the Principal Investigator may submit for publication the 
results of this research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a condition for 
publication. This policy requires that all clinical trials be registered in a public trials registry such 
as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Thus, the Sponsor 
will register this trial in the public trials registry, ClinicalTrials.gov. 
 
16.  Literature References 
 
American Academy of Pediatric Dentistry.  Guideline on periodicity of examination, 
preventive dental services, anticipatory guidance/counseling, and oral treatment for infants, 
children, and adolescents. Pediatr Dent. 2013 Sep-Oct;35(5):E148-56. 
 
American Academy of Pediatric Dentistry. Guideline on fluoride therapy. Pediatr Dent. 2013 
Sep-Oct;35(5):E165-8. 
 
Amin AS, Harrison RL, Benton TS, Roberts M, Weinstein P.  Effect of povidone-iodine in 
children with extensive dental caries. Pediatr Dent 2004; 26: 5-10.   
 
Berkowitz RJ, Koo H, McDermott M, Whelehan MT, Karp J, Billings RJ. Adjunctive 
chemotherapeutic suppression of mutans streptococci in the setting of severe early childhood 
caries. J Pub Health Dent 2009; 69(3):163-167.   
 
Broadbent JM, Thomson WM, For debate: problems with the DMF index pertinent to dental 
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17.  Addendum