Great Beginnings for Healthy Native Smiles: An Early Childhood Caries Prevention Project
Phase: NA
Conditions: Early Childhood Caries, Dental Caries
Sponsor: Northern Arizona University

Great Beginnings for Healthy Native Smiles 
Version 2.1 
Protocol 19-054-E 
4 November 2021 
 
________________________________________________________________________________________________________ 
 
Great Beginnings for Healthy Native Smiles: An Early 
Childhood Caries Prevention Project 
NIDCR Protocol Number: 19-054-E  
NIDCR Grant Number: 1U01DE028508-01 
Principal Investigator: Julie Ann Baldwin, PhD 
Grantee Institution: Northern Arizona University 
NIDCR Program Official: Margaret M. Grišius, DDS 
NIDCR Medical Monitor: Kevin McBryde, MD 
Draft or Version Number: 2.1 
29 July 2021 
 

Great Beginnings for Healthy Native Smiles 
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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Council for 
Harmonisation guidelines for Good Clinical Practice (GCP) (ICH E6) and the Code of 
Federal Regulations on the Protection of Human Subjects (45 CFR Part 46). National 
Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP 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 study 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. 
Principal Investigator or Clinical Site Investigator: 
Signed:  
 
Date:  
 
Name:  
Title:  

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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ............................................................................................... I 
SIGNATURE PAGE ..................................................................................................................... II 
TABLE OF CONTENTS .............................................................................................................III 
LIST OF ABBREVIATIONS ...................................................................................................... VI 
PROTOCOL SUMMARY......................................................................................................... VIII 
1 
KEY ROLES AND CONTACT INFORMATION ...............................................................1 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE ..........................................................................................................................4 
2.1 
Background Information ..........................................................................................4 
2.2 
Rationale ....................................................................................................................5 
2.3 
Potential Risks and Benefits ...................................................................................6 
2.3.1 Potential Risks ..............................................................................................6 
2.3.2 Potential Benefits .........................................................................................7 
3 
OBJECTIVES AND OUTCOME MEASURES .................................................................8 
3.1 
Primary .......................................................................................................................8 
3.2 
Secondary .................................................................................................................8 
4 
STUDY DESIGN.................................................................................................................10 
5 
STUDY POPULATION ......................................................................................................12 
5.1 
Participant Inclusion Criteria .................................................................................12 
5.2 
Participant Exclusion Criteria ...............................................................................12 
5.3 
Strategies for Recruitment and Retention ..........................................................12 
5.4 
Treatment Assignment Procedures .....................................................................14 
5.4.1 Randomization Procedures ......................................................................14 
5.4.2 Masking Procedures ..................................................................................14 
5.5 
Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention ........................................................................................15 
5.5.1 Reasons for Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention ............................................................................15 
5.5.2 Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention .....................................................15 
5.6 
Premature Termination or Suspension of Study ...............................................16 
6 
STUDY INTERVENTION ..................................................................................................17 
6.1 
Study Product Description ....................................................................................17 
6.1.1 Acquisition ...................................................................................................17 
6.1.2 Formulation, Packaging, and Labeling ...................................................17 
6.1.3 Product Storage and Stability ...................................................................17 
6.2 
Dosage, Preparation and Administration of Study Product .............................17 
6.3 
Modification of Study Product Administration for a Participant .......................18 
6.4 
Accountability Procedures for the Study Product ..............................................18 
6.5 
Assessment of Participant Compliance with Study Product 
Administration .........................................................................................................18 
6.6 
Study Behavioral or Social Intervention(s) Description ....................................18 

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6.6.1 Oral Health Intervention ............................................................................18 
6.7 
Administration of Intervention ...............................................................................20 
6.8 
Procedures for Training Interventionists and Monitoring Intervention 
Fidelity ......................................................................................................................20 
6.9 
Assessment of Participant Compliance with Study Intervention ....................21 
7 
STUDY SCHEDULE ..........................................................................................................22 
7.1 
Screening.................................................................................................................22 
7.2 
Visit 1 Overview/Baseline .....................................................................................22 
7.3 
Study Visit Descriptions.........................................................................................23 
7.3.1 Visit 1 (3-7 months pregnant) ...................................................................23 
7.3.2 Visit 2 (7-9 months pregnant) ...................................................................23 
7.3.3 Visit 3 (Child 6 months of age ± 1 month) ..............................................23 
7.3.4 Visit 4 (Child 12 months of age ± 1 month) ............................................23 
7.3.5 Visit 5 (Child 18 months of age ± 2 months) ..........................................24 
7.3.6 Visit 6 (Child 24 months of age ± 2 months) ..........................................24 
7.4 
Final Study Visit 7 (Child 30-36 months of age [early cohort only]) ...............24 
7.5 
Withdrawal Visit ......................................................................................................25 
7.6 
Unscheduled Visit...................................................................................................25 
8 
STUDY PROCEDURES/EVALUATIONS.......................................................................26 
8.1 
Study Procedures/Evaluations .............................................................................26 
8.1.1 Survey Assessments .................................................................................26 
9 
ASSESSMENT OF SAFETY ............................................................................................27 
9.1 
Specification of Safety Parameters .....................................................................27 
9.1.1 Unanticipated Problems ............................................................................27 
9.1.2 Adverse Events...........................................................................................27 
9.1.3 Serious Adverse Events ............................................................................27 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ..............28 
9.3 
Characteristics of an Adverse Event ...................................................................28 
9.3.1 Relationship to Study Intervention ...........................................................28 
9.3.2 Expectedness .............................................................................................28 
9.3.3 Severity of Event ........................................................................................29 
9.4 
Reporting Procedures ............................................................................................29 
9.4.1 Unanticipated Problem Reporting ............................................................29 
9.4.2 Serious Adverse Event Reporting ...........................................................30 
9.4.3 Reporting of Safety Events to FDA .........................................................30 
9.4.4 Events of Special Interest .........................................................................31 
9.4.5 Reporting of Pregnancy.............................................................................31 
9.5 
Halting Rules ...........................................................................................................31 
10 
STUDY OVERSIGHT ........................................................................................................32 
11 
CLINICAL SITE MONITORING .......................................................................................33 
12 
STATISTICAL CONSIDERATIONS ................................................................................34 
12.1 
Study Hypotheses ..................................................................................................34 
12.2 
Sample Size Considerations ................................................................................35 
12.3 
Planned Interim Analyses (if applicable) ............................................................37 
12.4 
Final Analysis Plan .................................................................................................37 

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13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........39 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................40 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................42 
15.1 
Ethical Standard .....................................................................................................42 
15.2 
Institutional Review Board ....................................................................................42 
15.3 
Informed Consent Process ...................................................................................42 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) ...........43 
15.5 
Subject Confidentiality ...........................................................................................43 
Certificate of Confidentiality ..................................................................................44 
NIH Data Sharing Policies ....................................................................................44 
15.6 
Future Use of Stored Specimens and Other Identifiable Data ........................44 
16 
DATA HANDLING AND RECORD KEEPING ...............................................................45 
16.1 
Data Management Responsibilities .....................................................................45 
16.2 
Data Capture Methods ..........................................................................................45 
16.3 
Types of Data ..........................................................................................................46 
16.4 
Schedule and Content of Reports .......................................................................46 
16.5 
Study Records Retention ......................................................................................46 
16.6 
Protocol Deviations ................................................................................................46 
17 
PUBLICATION/DATA SHARING .....................................................................................48 
18 
LITERATURE REFERENCES .........................................................................................49 
SUPPLEMENTAL MATERIALS ................................................................................................51 
APPENDICES ..............................................................................................................................52 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................53 
APPENDIX B: FLUORIDE VARNISH REGULATORY DATA SHEET ...............................54 
APPENDIX C: FLUORIDE VARNISH MATERIAL SAFETY DATA SHEET ......................56 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CAB 
Community Advisory Board 
CFR 
Code of Federal Regulations 
CHR 
Community Health Representative 
CSI 
Clinical Site Investigator 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DMFS 
Decayed, missing, and filled tooth surfaces 
DMFT 
Decayed, missing, and filled teeth  
DSMB 
Data and Safety Monitoring Board 
ECC 
Early Childhood Caries 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FV 
Fluoride Varnish 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IHS 
Indian Health Service 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NAU 
Northern Arizona University 
NIDCR 
National Institute of Dental and Craniofacial Research, NIH, DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PO 
Program Official, NIDCR, NIH 
PS 
Project Scientist, NIDCR, NIH 

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QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 

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PROTOCOL SUMMARY 
Title: 
Great Beginnings for Healthy Native Smiles: An Early 
Childhood Caries Prevention Project. 
Précis: 
Early Childhood Caries (ECC) is the most common chronic 
disease among children. American Indian (AI) children are 4 
times more likely to have untreated dental decay than white 
children. This is a four year parallel group randomized clinical 
trial evaluating the impact of a bundled best practices oral 
health intervention on early childhood caries in American 
Indian children as indicated by the number of decayed, missing 
and/or filled primary tooth surfaces (dmfs). The intervention is 
delivered during pregnancy and through child age 24-36 
months. The bundled best practices include motivational 
interviewing with mothers and fluoride varnish applied to the 
child’s teeth. The oral health intervention also includes Tribe-
specific individual, social and health needs identified in an 
earlier formative assessment. The oral health intervention 
group (n=175 mother-child dyads) will be compared to a group 
(n=175 mother-child dyads) receiving a standard 
prenatal/postnatal healthy lifestyle intervention. All study 
treatments will be delivered by Community Health 
Representatives in the Hopi (Arizona) and Crow (Montana) 
communities. Children will be followed until 2 - 3 years of age. 

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Objectives: 
Primary Objective: To determine whether children in the OH 
group compared to the Healthy Lifestyle group have on 
average fewer decayed, missing and/or filled primary tooth 
surfaces (dmfs) measured at the last visit. 
Secondary Objective 1: To determine whether children in the 
OH group compared to the Healthy Lifestyle group have on 
average fewer decayed missing or filled teeth (dmft) measured 
at the last visit. 
Secondary Objectives 2-4: To examine if women in the OH 
group compared to the Healthy Lifestyle group have greater 
increases in:  
• Oral health knowledge 
• Oral health behavior 
• Positive attitudes towards oral health care 
These will be compared as changes from baseline (Visit 1) to 
the last (Visit 6) survey assessment. 
Secondary Objective 5: To examine if women in the Healthy 
Lifestyle group compared to the OH group have greater 
increases in knowledge of developmental milestones, 
pregnancy related nutrition, breastfeeding and prenatal health 
at Visit 6 relative to baseline (Visit 1).  
 
Population: 
Healthy pregnant women who are American Indian (AI) or 
giving birth to an AI child on or near the Hopi and Crow Nations 
in Arizona and Montana, respectively, and their infants, once 
born.  
Phase or Stage: 
Not applicable 
Number of Sites: 
Study activities will take place at WIC and Head Start centers 
in two locations, the Hopi Nation in Arizona and the Crow 
Nation in Montana. The study will be overseen by three IRBs- 
Northern Arizona University, Phoenix Area IHS and the Rocky 
Mountain Tribal IRB. 

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Description of 
Intervention: 
The Oral Health intervention for pregnant women/new mothers 
in the oral health intervention group will include motivational 
interviewing and oral health education intended to protect their 
children from ECC. They may receive care-coordination 
assistance in obtaining preventive and therapeutic oral health 
care for mother and newborn/infant. Newborn/infant 
participants will receive oral health interventions, fluoride 
varnish up to four times and oral health care referral where 
indicated. The Healthy Lifestyle intervention will provide 
pregnant women/new mothers with a standard 
prenatal/postnatal education curriculum which includes 
educational material from the National Head Start curriculum. 
The Healthy Lifestyle intervention educates women on nutrition 
and diet, physical activity, breastfeeding/formula feeding, 
substance use, mental/emotional health, personal and family 
goals, prenatal/postpartum health care access, labor and 
delivery, family support, infant/child care, oral health, and 
development milestones. Because of the high ECC risk 
environment, fluoride varnish will also be applied to children in 
the Healthy Lifestyle group at 12 and 24 months of age and 
receive oral health care referral where indicated. Community 
Health Representatives will deliver the treatments to both 
groups.  
Study Duration: 
Four years. 
Subject 
Participation 
Duration: 
Participation duration is 29 (late cohort) to 41 (early cohort) 
months depending on whether enrolled in the first or second 
half of recruitment. 
Estimated Time to 
Complete 
Enrollment: 
Approximately 14 months. 
 

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Schematic of Study Design: 
 
Screen potential participants by inclusion and exclusion criteria; obtain informed consent; 
enroll  
Baseline survey 
Administer Oral Health and Healthy Lifestyle Interventions 
Child oral health assessment for caries assessment 
Administer Oral Health and Healthy Lifestyle Interventions 
Apply FV in OH & HL arms; Oral health knowledge, attitudes and behavior surveys 
Administer Oral Health and Healthy Lifestyle Interventions 
Apply fluoride varnish in Oral Health arm; Social determinants survey 
Final Assessments 
Child oral health assessment (N175); 
Apply FV in OH & HL arms 
Randomize 
Arm 2 
175 participants 
Arm 1 
175 participants 
Additional baseline survey 
Administer Oral Health and Healthy Lifestyle Interventions 
Prior to 
Enrollment 
Visit 1  
3-7 months 
pregnant 
Visit 2  
7-9 months 
pregnant 
Visit 3  
child aged 6 
(±1) months  
Visit 6  
child aged 24 
(±2) months 
(late cohort 
only) 
Visit 4  
child aged 12 
(±1) months  
Administer Oral Health and Healthy Lifestyle Interventions 
Apply fluoride varnish in Oral Health arm 
Dentist trust, social support, financial stability assessments 
Visit 5  
child aged 18 
(±2) months  
Child oral health assessment for caries assessment (N175) 
Apply FV in Oral Health and Healthy Lifestyle arms 
Administer Oral Health and Healthy Lifestyle Interventions; final survey 
Visit 7 
child aged 30-36  
Months (early 
cohort only) 
***Birth of child*** 

1 KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator:  
Julie Baldwin, Ph.D.  
Northern Arizona University 
Director, Center for Health Equity Research 
PO Box 4065 
Flagstaff, AZ 86011-4065 
Phone: 928-523-6566  
Fax: 928-523-4648  
Email: Julie.Baldwin@nau.edu  
 
Medical Monitor: 
Kevin McBryde, MD 
Program Official 
NIDCR/NIH 
6701 Democracy Blvd Rm. 650  
Bethesda, MD 20892-878 
Phone: 301-594-9652 
Email: Kevin.McBryde@nih.gov  
 
NIDCR Program 
Official: 
Margaret M. Grišius, DDS 
Director, Clinical Research & Epidemiology Program 
National Institute of Dental and Craniofacial Research (NIDCR) 
6701 Democracy Blvd, Room 632 
Bethesda, MD 20892-4878 
Phone: (301) 451-5096 
Email: Margaret.Grisius@nih.gov   
 
NIDCR Project 
Scientist: 
Hiroko Iida, DDS, MPH 
Director, HIV/AIDS & Oral Health Research Program 
Acting Director, Oral Health Disparities & Inequities Research 
Program 
National Institute of Dental and Craniofacial Research (NIDCR) 
6701 Democracy Blvd, Room 630 
Bethesda, MD 20892-4878 
Phone: (301) 594-7404 
Email: hiroko.iida@nih.gov 
 
 
Clinical Site 
Investigators: 
N/A 

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Other Key 
Personnel: 
  
Statistician/co-
investigator 
Steven D. Barger, Ph.D.  
Northern Arizona University 
Department of Psychological Sciences 
PO Box 15106 
Flagstaff, AZ 86011 
928-523-9619 phone 
928-523-2442 fax 
Email: Steven.Barger@nau.edu  
NAU Project 
Coordinator, 
Senior 
Carolyn (Carly) Camplain, JD 
Center for Health Equity Research 
PO Box 4065 
Applied Research and Development, Suite 140 
Flagstaff, AZ 86011 
Phone: (928) 523-3060 
Email: carolyn.camplain@nau.edu  
Co-Investigator 
Heather Thomas, RDH, B.S., M.Ed. 
Assistant Clinical Professor 
Dental Hygiene Department 
Northern Arizona University 
Phone: 928-523-0953 
Email: Heather.Thomas@nau.edu  
Data Collection 
Coordinator 
Christine Kirby, M.A. 
Center for Health Equity Research 
PO Box 4065 
Applied Research and Development, Suite 120 
Flagstaff, AZ 86011 
Phone: 928-523-4926 
Email: Christine.Kirby@nau.edu 
Fidelity Monitoring 
Coordinator 
-was Kate; do we have someone do double duty here? 
Site Co-
Investigator 
Frederica Lefthand 
Little Big Horn College 
8645 S. Weaver Dr. 
Crow Agency, MT 59022-0001 
406-638-3131  
Email: lefthandfv@lbhc.edu  

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Site Co-
Investigator 
Royce Jenkins 
Department of Health and Human Services 
The Hopi Tribe 
One Main Street 
PO Box 123 
Kykotsmovi, Arizona 86039 
RJenkins@hopi.nsn.us 
Consultant 
Sara Young, M.Ed. 
Email: saralyoung@hotmail.com 
Site Project 
Coordinator 
Gerlinda Morrison, PhD 
Email: morrisong@lbhc.edu 
Site Project 
Coordinator 
Vacant   
Co-Investigator 
Anne Wilson, DDS, MS 
Professor and Delta Dental of Colorado Endowed Chair 
School of Dental Medicine 
University of Colorado Anschutz Medical Campus 
Aurora, CO 80045 
720-777-8892 
Email: Anne.Wilson@childrenscolorado.org  
Consultant 
Kamilla Venner, PhD 
Assistant Professor 
Department of Psychology 
University of New Mexico 
Albuquerque, NM 87106 
505-925-2377 
Email: kamilla@unm.edu  

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE  
2.1 
Background Information 
Early Childhood Caries (ECC) is the most common chronic disease among children. 
American Indian (AI) children are 4 times more likely to have untreated dental decay 
than white children. If left untreated, ECC can lead to chronic pain, loss of teeth, poor 
nutrition, and impaired growth. This project aims to reduce the burden of ECC in two AI 
communities through a community based participatory approach. Previously we 
partnered with 2 tribes, the Hopi Tribe (Arizona) and the Crow Tribe (Montana) to 
conduct a formative assessment on oral health (OH). From this work the present study 
adapted a “bundled” best practices OH intervention to be locally and contextually 
relevant for each of the tribal communities. This protocol describes a randomized, 
controlled trial to evaluate the impact of the “bundled” best practices OH intervention 
(compared to a prenatal/postnatal healthy lifestyle intervention) on the reduction of ECC 
across these communities.  
Two rigorous randomized trials in American Indian communities did not reduce ECC. A 
trial of Navajo children aged 3-5 years old included personalized oral health interactions 
for children and parents as well as fluoride varnish applications for children. Although 
caregiver knowledge and oral health behavior improved there was no difference in 
caries increment or prevalence at follow up.1 Caries prevalence was almost universal by 
three years of age in this study, illustrating the substantial ECC burden in AI children 
and indicating that earlier intervention is desirable. A second trial2 recruited pregnant AI 
women and compared enhanced community services to enhanced services plus 
motivational interviewing. Despite reasonable adherence and initiating the intervention 
shortly after birth, no caries differences were observed after 3 years of follow up.  
However, an Australian clinical trial indicates that the combination of early intervention 
and fluoride varnish application may be effective in preventing caries among very young 
children in indigenous settings.3 Jamieson et al. enrolled pregnant aboriginal Australian 
women.3 The active treatment arm included motivational interviewing for caregivers and 
fluoride varnish application for children aged 6 to 24 months. This treatment 
combination resulted in fewer decayed teeth in two year old children compared to a 
usual care control group (means of 0.62 teeth [95%CI 0.59, 0.65] versus 0.89 [95%CI 
0.85, 0.92], respectively).  
Together these studies suggest that to prevent caries in indigenous children, 
interventions should a) start at birth before caries develop; b) utilize behavioral 
strategies such as motivational interviewing; and c) complement behavioral strategies 
with fluoride varnish application. The present study will recruit expectant mothers in two 
AI communities (Hopi and Crow) and utilize both motivational interviewing and multiple 
fluoride varnish applications (at 6, 12, 18 and 24+ months of age) to reduce ECC. This 
Oral Health intervention will include prenatal education regarding oral hygiene practices, 

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oral health screening and referral for children and fluoride varnish application every 6 
months. These treatments are provided by community health representatives who 
incorporate locally and contextually relevant strategies for ECC prevention and use AI 
community members to implement the intervention. Contextually relevant strategies 
were identified in a formative assessment of each community prior to clinical trial 
enrollment. 
2.2 
Rationale 
Sixty percent of American Indian children have dental caries by the age of three.4 Small, 
rural tribal communities in particular have numerous obstacles to good oral health 
including long distances to services, low support for caregivers and limited resources. In 
partnership with the Hopi and Crow tribes we will implement an oral health intervention 
in these two communities. Although childhood oral health interventions have occurred 
among other western tribal communities, no such interventions have occurred within 
Hopi and Crow communities.  
To date, best intervention practices include intervening during pregnancy - a time when 
expectant mothers are learning about dietary and other health promoting practices 
which align with and complement oral health promoting practices. Qualitative interviews 
of oral health care providers, expectant mothers and reproductive health services 
providers in each tribal community identified barriers and resources for caregiving, oral 
health care and community-level resources. This formative assessment, in turn, 
provides the foundation for culturally specific intervention materials. Motivational 
interviewing (MI), an individualized approach to guiding health behavior change, will be 
used to improve the capacity of caregivers to build self-efficacy, enact behavior change, 
and positively impact the OH of their children. Using MI to reduce ECC prevalence is 
recommended by the American Academy of Pediatric Dentistry.5 The intervention will 
explicitly incorporate interpersonal level inputs (practices of other mothers in the 
community; family member expectations), community level inputs (e.g., requirements 
and supports provided by social service organizations); and key values within the larger 
society regarding the health and wellbeing of infants and toddlers (societal level). 
Locally recruited community health representatives will enact the intervention and 
provide instrumental support (signing children up for OH services), informational support 
(referring women to needed social services), and appraisal support (providing positive 
reinforcement when the mother/caregiver is able to successfully adhere to their child’s 
OH appointments). 
This approach is consistent with evidence showing that childhood caries prevention 
efforts among indigenous populations are most effective when targeting the expectant 
mother before birth and continuing treatment through the child’s first tooth eruption.3 
This early treatment is optimized by motivational interviewing, individual and community 
support and the application of fluoride varnish to primary teeth. In contrast, interventions 
with indigenous communities that start later in childhood (ages 3-4)1 or that do not 
incorporate fluoride varnish have not been effective in reducing early childhood caries. 

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Thus the present study will combine the most potent interventional approaches at the 
optimal stage of the child’s oral health-before the child is born. 
The comparison group will receive a “healthy lifestyle” maternal and child health 
intervention. This intervention will approximately match the contact duration of the oral 
health care arm and will cover prenatal care, maternal self-care, developmental 
milestones, infant nutrition, identifying food allergies, breastfeeding, and strategies to 
manage work and family demands. Thus, this comparison arm will comprise beneficial 
non-oral health related education and support for the comparison group. Although this 
treatment includes a brief oral health component it does not have oral health as its main 
focus.  
We hypothesize that children in the oral health treatment arm will have fewer caries 
surfaces (dmfs) at 24-36 months old compared to the healthy lifestyle group. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
There are no known risks to any of the recommended oral hygiene practices, which all 
follow established guidelines in pediatric dentistry. There is a risk of disclosure of 
confidential information, including oral health status, extent of oral disease, and oral 
health behavioral information. Study processes intended to maintain data confidentiality 
are described in Section 16.1.  
There is also the possibility of psychological distress associated with the oral 
assessment and the MI intervention. Participants will be asked some personal questions 
pertaining to their children and their daily oral health habits which could cause some 
distress. Mothers will have the opportunity to terminate their involvement in the study at 
any time and/or decline to respond to any questions.  
The oral health treatment arm includes up to four fluoride varnish applications and 
children in the healthy lifestyle group will receive fluoride varnish at 12 and 24 months of 
age. Early cohort enrollees will receive another application at Visit 7. A review of three 
clinical trials where children received an average of four varnish treatments found zero 
(0) fluoride varnish related adverse events.6 Despite the low potential risk of allergic 
reaction to FV we will withdraw children if they have ulcerative gingivitis or stomatitis or 
known sensitivity to colophony or other FV ingredients. Study staff will monitor 
participants for allergic reactions to the fluoride varnish. 
Potential risks of educational interventions are low. Children in the healthy lifestyle 
group will not receive focused oral health information (although the mother will receive a 
short module related to oral health). The latter is not a risk per se but represents the 
absence of a potentially beneficial treatment in that group.  

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2.3.2 
Potential Benefits 
Participants in the oral health intervention arm will receive potentially useful information 
about maintaining good oral health. If the bundled best practices intervention 
demonstrates efficacy, children in that arm may have fewer decayed tooth surfaces than 
they would without the intervention. Participants in the healthy lifestyle arm will receive a 
number of potentially useful exposures including information regarding maternal self-
care, identifying appropriate developmental milestones for their infant/child, as well as 
two FV applications. Information learned in this study could ultimately be beneficial to AI 
communities experiencing a high burden of ECC. 

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3 OBJECTIVES AND OUTCOME MEASURES 
3.1 
Primary 
Objective 
Brief 
Description/Justification 
of Outcome Measure 
Outcome Measured 
By  
Time Frame 
To determine whether 
children in the OH 
group compared to the 
Healthy Lifestyle 
group have on 
average fewer 
decayed, missing 
and/or filled primary 
tooth surfaces (dmfs) 
measured at the last 
visit  
The primary outcome measure 
is the number of decayed, 
missing and/or filled primary 
tooth surfaces (dmfs). It was 
chosen as the primary outcome 
measure because dmfs is a 
direct measure of disease and 
is a clinical standard for 
assessing caries. 
Differences in dmfs scores 
across treatment groups will 
indicate less disease. 
Indian Health Service 
dentists and/or trained 
hygienists (masked to 
treatment group, 
calibrated) will visually 
inspect every tooth in 
children in both treatment 
groups and indicate any 
decayed, missing, or filled 
surfaces (dmfs).  
We will compare 
treatment group 
differences from the 
last follow up oral 
health assessment 
(either 24 months 
[late cohort] or 30-36 
months [early 
cohort]). Differential 
follow up rationale 
and description in 
Section 12.   
3.2 
Secondary 
Objective 
Brief Description/ 
Justification of Outcome 
Measure 
Outcome Measured By  Time Frame 
To determine 
whether children in 
the OH group 
compared to the 
Healthy Lifestyle 
group have on 
average fewer 
decayed, missing 
and/or filled primary 
teeth (dmft) 
measured at the last 
visit 
The number of decayed missing 
or filled teeth (dmft) 
complements the tooth surface 
assessment and provides a 
bridge assessment to compare 
with other oral health literature. 
The dmfs scores will be 
converted to binary values 
for each tooth. Caries 
experience is defined by a 
dmfs score greater than 1 
for each tooth. The 
number of teeth with 
caries is summed for each 
child. 
We will compare 
treatment group 
differences from the 
last follow up oral 
health assessment 
(either 24 months 
[late cohort] or 30-36 
months [early 
cohort]). Differential 
follow up rationale 
and description in 
Section 12. 
To determine 
whether 
mothers/caregivers 
in the OH group 
compared to the 
Healthy Lifestyle 
group show 
increases in oral 
health knowledge 
 
Oral health knowledge is a 
target of the intervention and will 
provide a benchmark for the oral 
health manipulation.  
We will assess oral health 
knowledge with a 20-item 
assessment that includes 
a decoy item and two filler 
items. Source items come 
from the BRFQ survey and 
will be scored as a percent 
correct, excluding the filler 
items.  
This outcome is 
measured at 
baseline (Visit 1; 
while expecting), 
after the child is 12 
months of age (Visit 
4) and each visit until 
the child is 24 
months (Visits 5 & 6). 

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Objective 
Brief Description/ 
Justification of Outcome 
Measure 
Outcome Measured By  Time Frame 
To determine 
whether 
mothers/caregivers 
in the OH group 
compared to the 
Healthy Lifestyle 
group perform more 
of the optimal care 
practices for their 
child’s teeth (oral 
health behavior) 
Optimal oral health care is 
reflected in the oral health 
behavior survey items (e.g., 
regular checking of teeth/gums; 
use of fluoride toothpaste; 
avoiding sugary food and drink; 
caregiver brushing frequency). 
These care behaviors are 
inversely correlated with 
childhood dmfs scores7 and may 
reflect a treatment pathway.  
We will assess oral health 
behavior with a 16-item 
assessment adapted from 
the BRFQ and prior 
studies of AI 
infants/children. 
Responses will be scored 
as the percent of 
responses with “adherent” 
or optimal oral health 
behavior.  
This outcome is 
measured after the 
child is 12 months of 
age (Visit 4), 18 
months of age (Visit 
5) and again at child 
age 24 months (Visit 
6). 
To determine 
whether 
mothers/caregivers 
in the OH group 
compared to the 
Healthy Lifestyle 
group show more 
favorable attitudes 
towards oral health 
care 
Attitudes towards desirable oral 
health behavior should change 
following the intervention and 
may track with intervention 
efficacy.  
Attitudes are measured 
using 14 items that parallel 
the behavior questions 
(e.g., How important is it to 
you to check teeth/gums 
every month?). A sum of 
Likert-style ratings will 
comprise the attitudes 
These items are labeled 
“motivation” in the BRFQ 
instrument. 
This outcome is 
measured at 
baseline (Visit 1; 
while expecting), 
after the child is 12 
months of age (Visit 
4) and again at child 
age 24 months (Visit 
6). 
To determine 
whether 
mothers/caregivers 
in the Healthy 
Lifestyle group 
compared to the OH 
group show 
increases in  
maternal/child health 
knowledge (non-oral 
health) 
Maternal/child health knowledge 
is a target of the comparison 
group treatment and will be 
assessed to compare this 
knowledge across the two study 
groups. 
We will assess 
maternal/child health 
knowledge with a 20-item 
assessment. Source items 
come from the Healthy 
Lifestyle modules and will 
be scored as a percent 
correct, excluding the filler 
items. 
This outcome is 
measured at 
baseline (Visit 1; 
while expecting), 
after the child is 12 
months of age (Visit 
4) and each visit until 
the child is 24 
months (Visits 5 & 6). 
 

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4 STUDY DESIGN 
The study is a two group parallel randomized trial. There are two study sites but the 
study is overseen at Northern Arizona University in Flagstaff, AZ. Only the primary 
outcomes assessors are masked. For this trial both participants and the community 
health representatives providing the interventions will be aware of treatments received.  
The study population is expectant mothers on the Hopi (AZ) and Crow (MT) Nations, 
and their infants, once born. These women will receive either 1) a bundled best 
practices oral health intervention including motivational interviewing and fluoride varnish 
application to their children’s teeth beginning at 6 months of age (N=175 dyads) or 2) a 
“healthy lifestyle” intervention that focuses on maternal/child health, the peripartum 
period, nutrition, breastfeeding, etc. (N=175 dyads). This population was selected 
because of the extremely high burden of caries among American Indian children. 
Mothers will be recruited at 3-7 months gestation and followed through their child’s 
second birthday (late cohort) or up to the child’s third birthday (early cohort). Later follow 
up of approximately half of the enrolled children and mothers/caregivers (early cohort) is 
to increase statistical sensitivity for the intervention (see Section 12 Statistical 
Considerations). Mothers will be in the study from 29-41 months. After the first enrollee 
we anticipate 12-14 months of enrollment thereafter to achieve our target sample size.  
The oral health arm will receive motivational interviewing treatment to improve 
knowledge, attitudes and behavior towards maternal and child oral health. Motivational 
interviewing tailors treatment to participant preferences and motivations. Motivational 
interviewing will be implemented by community health representatives (CHR) using a 
culturally informed treatment approach. Six motivational interviewing sessions are 
scheduled for the oral health treatment arm; two prior to giving birth and four more when 
the child is 6, 12, 18 and 24-27 months of age. The dose schedule has no planned 
variation. Motivational interviewing permits participant choice of topics within a set and 
thus it is likely that some oral health treatment arm participants will complete different 
subsets of MI topic areas. This variation is not considered a threat to study efficacy. 
Children in the oral health arm will receive fluoride varnish applications at ages 6, 12, 
18, and 24 months. 
The healthy lifestyle intervention will provide education and support for mothers 
regarding pregnancy, postpartum challenges, food preparation for children 12 months 
and older, infant nutrition, and parenting. This also includes a short module on oral 
health. The intervention will be administered by trained CHRs. Six sessions are 
scheduled for the healthy lifestyle group, with timing parallel to the timing of sessions in 
the oral health arm. Children in this arm will receive a fluoride varnish application by 
study staff at 12 months and 24 months. Children in the HL arm in the early cohort will 
receive a third FV application after their final study visit at child age 30-36 months. 
Children in both groups will be scheduled for a full oral health assessment at 12 (Visit 4) 
and 24-27 months (Visit 6). Earlier recruits (through month 8 recruitment) will be 
followed up longer for a final oral assessment (Visit 7 at 30-36 months of age). 

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Assessments will be conducted by calibrated dentists and/or hygienists, masked to the 
study condition. Mothers will be reminded of their appointments through follow-up phone 
calls and/or in person visits from the Community Health Representatives. Dentists will 
provide oral assessment data to study staff who will securely upload the data into 
REDCap and securely store the records. 
Secondary outcomes of oral health knowledge, behaviors, and attitudes and knowledge 
of maternal and child health issues not related to oral health will be assessed using 
questionnaires. Oral health knowledge and maternal child health knowledge will be 
assessed at Visits 1, 4, 5 and 6. Oral health attitudes will be assessed at Visits 1, 4 and 
6 and oral health behavior will be assessed at Visits 4, 5 and 6. Survey data will be 
securely collected via laptop or tablet using REDCap software.  
 

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5 STUDY POPULATION 
5.1 
Participant Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provide signed and dated informed consent form 
2. Be willing and able to follow study procedures and instructions and be available 
for the duration of the study 
3. Be at least 18 years of age  
4. Be American Indian or giving birth to an AI child, and living on or near 
(approximately 100 miles) the Hopi or Crow Nations. American Indian status is 
self-identified-no tribal enrollment verification will be required.  
5. Be currently pregnant—preferably in month 4 of pregnancy at enrollment but 
mothers are eligible when 3-7 months pregnant (9-31 weeks pregnant). 
6. Be willing to participate until the child is age 3 
7. Mothers of twins will be included, but only one child will be enrolled as the study 
child. 
5.2 
Participant Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation 
in this study:  
• Anything that would place the individual at increased risk or preclude the 
individual’s full compliance with, or completion of, the study. 
• Enrolled in other community health interventions that incorporate oral health 
intervention, e.g., Family Spirit program at Hopi. 
• A member of the Northern Cheyenne Tribe 
• Living on the Navajo Nation and a member of the Navajo Tribe 
5.3 
Strategies for Recruitment and Retention 
Methods for recruitment include flyers, face to face, and referral phone calls. 
Project staff will collaborate with IHS facilities, WIC clinic and Head Start (at Hopi) staff 
to identify pregnant women who meet inclusion criteria. At Crow we will recruit using 
community partners and suggestions from the CAB. A total of 350 mother-child pairs will 
be enrolled over approximately 14 months and randomized into 1) OH intervention or 2) 

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HL comparison. Intervention and comparison groups will receive the same number (6) 
of intervention sessions (Table 3). Because of the monthly enrollment plan, we will have 
a range of final assessment time points for participating children (between 24-36 
months of age). Extending follow up for early enrollees will increase our statistical power 
by permitting follow up from a minimum of 2 years (late cohort) to a maximum of 3 years 
of age (early cohort), averaging ~ 2.5 years (see Section 12). Recruitment challenges 
will be addressed by establishing an achievable recruitment target that reflects current 
birth rates in our study populations. For example, at Hopi, we will aim to recruit 7 out of 
9 women who give birth each month; in the Crow community, we will aim to recruit 18 
out of 23 women who give birth each month. Our field staff are tribal members and have 
deep and trusting relationships with community members which should maximize 
recruitment and retention. Following the approach of Batliner et al.8 we will partner with 
local maternal and child health services to enhance study recruitment. Little Bighorn 
College and the Crow CAB will be our primary partners at Crow. At Hopi, staff from 
Early Intervention and Head Start will participate in Community Advisory Board (CAB) 
meetings. Eligible pregnant women will be invited to participate and after providing 
informed consent will be randomly assigned to the OH intervention or HL comparison 
condition. 
Study staff will collect a minimum of three additional contacts for each consenting 
participant (three points of contact with a phone number and address). Study staff will 
call participants to remind them of scheduled sessions at two weeks prior, one week 
prior, and one day prior intervals. During the span of these reminder calls, if a 
scheduling conflict arises, there is more time to remedy the possible missed session. 
Study staff will reschedule the session at the earliest possible convenience for both the 
CHR and the participant. If the participant does not confirm the session appointment at 
the two week or one-week interval, study staff will begin to call the additional contacts 
requested at enrollment. Study staff will have a script they can follow for voicemail/text 
reminders. To keep a good rapport, study staff will send birthday cards for children 
during the duration of the study. During the consent process, participants will provide 
study staff their preferred method of contact and all methods of contact that they will 
allow study staff to conduct. Contact methods will include but are not limited to phone 
calls, text messages, email, voicemail, and social media. 
Community Health Representatives/Health Educators 
The CHRs for the duration of the study will be members of the communities where 
recruitment will occur. Because of the small communities and closeness of members of 
the communities, recruitment and retention will be easier. CHRs will attempt follow-up 
not only through the aforementioned phone calls, texts, email, social media, and 
voicemail but CHRs will also attempt to contact participants through home visits. Study 
staff will utilize private direct messaging when using social media channels. 
Compensation schedule: 
$ 25.00 gift card at Visit 1 
$ 25.00 gift card at Visit 2 
$ 25.00 gift card at Visit 3 

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$ 25.00 gift card at Visit 4 
$ 25.00 gift card at Visit 5 
$ 25.00 gift card at Visit 6 ($50 for late cohort) 
$ 50.00 gift card at Visit 7 (early cohort only) 
 
A very detailed call log will be created for each participant in a locked excel file only 
accessible by study staff. This call log will detail each call made to participants, what 
number was called, what day/time, and what was said or if the study staff left a 
message (and which message). If study staff call the additional points of contact, that 
will be noted in the call log. The conversation between study staff and the additional 
contact will be summarized in case follow-up needs to occur. Study staff will attempt to 
contact participants who were unreachable throughout the duration of the study. 
Participants will be considered lost to follow up if they cannot be scheduled for their final 
dental assessment, i.e., within two months of their last scheduled study visit (Visit 6 or 7 
depending upon initial enrollment). We will not replace any lost or withdrawn 
participants.  
5.4 
Treatment Assignment Procedures 
The study statistician will create computer generated randomized treatment group 
allocations for each site. These randomized permuted blocks will be uploaded into 
REDCap to provide treatment group assignment. Following eligibility screening and 
informed consent documentation study staff will authorize participants for enrollment. 
Following this authorization (in REDCap) participants will be officially enrolled in the 
study and the REDCap system will then assign the next computer generated treatment 
group allocation (within site) to one of the two treatment conditions. Participants will be 
assigned in a 1:1 ratio to Oral Health and Healthy Lifestyle treatment groups.  
5.4.1 
Randomization Procedures 
Randomization codes will be generated by the study statistician. The randomization list 
containing treatment assignment codes will be retained by the study statistician and will 
not be accessible to study staff. This is an electronic document that will be uploaded 
into REDCap on NAU’s secure server. Permuted blocks will prevent field staff from 
knowing what treatment the next participant will receive during the recruitment process 
and ensure approximately equal numbers of participants in each study arm at any given 
time during study enrollment.  
No break of randomization codes is anticipated but if necessary could be done in 
collaboration with the study statistician. Separate permuted blocks will be generated for 
each of the two sites. 
5.4.2 
Masking Procedures  
Due to the nature of the interventions, the CHRs cannot be masked in this study. 
However, the dentists/hygienists who perform the annual oral assessments for dmfs will 

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be masked to participants’ intervention arm. Dental assessments will take place before 
the scheduled Visit. 
5.5 
Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention 
5.5.1 
Reasons for Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention 
Participants are free to withdraw from participation in the study at any time upon 
request. If a family has a child with an identifiable high needs condition at birth they may 
choose to withdraw as they may need to focus time on those needs.  
Participants may choose to discontinue the intervention or study procedure but continue 
to be followed.  
Mother-child dyads may be withdrawn from the study if the child is born with congenital 
oral anomalies expected to adversely affect the development of primary teeth, 
ectodermal dysplasia, or diseases other than ECC that affect the dentition or oral 
mucosa upon examination. This includes children with ulcerative gingivitis, stomatitis or 
other conditions resulting in chronically disrupted or irritated oral mucosa as reported by 
parent/caregiver or documented by a dental professional.  
Mother-child dyads may be withdrawn from the study if the study child is allergic to any 
of the components of the FV as reported by parent/caregiver 
Participants will also be withdrawn if informed consent is withdrawn by the 
parent/guardian or if they move permanently from the area. 
An investigator may discontinue an individual’s participation in an intervention or 
withdraw an individual from the study if: 
• Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant. 
• The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
5.5.2 
Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention 
If the mother/caregiver wants to drop out of the study early, we will ask if they wish to 
stop the intervention or drop out of the study entirely. If they want to stop the 
intervention, we will ask if they are willing to continue to be followed without the 
intervention and permit additional caries assessment(s). The purpose of this is to collect 
sufficient data to be able to conduct a more robust intent-to-treat analysis.  

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If a mother/caregiver drops out of the study early and refuses additional follow-up, an 
early termination visit will be requested. If this request is accepted, a dmfs measure for 
the child will be obtained along with a questionnaire to the mother/caregiver about 
dental knowledge, attitudes, and behavior; psychological influences; other health and 
risk factors; other dental interventions received; and the reasons for early termination.  
If the mother/caregiver wants to withdraw from the study entirely we will include their 
data to that point in the analyses. If the mother/caregiver wants to completely withdraw 
consent then that record will be excluded from all analyses, including the intention-to-
treat analysis. All withdrawals and discontinuations will be recorded using the Case 
Report Form. 
If a person other than the mother becomes the child’s primary caregiver we will invite 
that person to participate so that the child may continue in the study. We would 
complete informed consent to enroll the new caregiver. Although we expect this to be 
rare, the advantage of maintaining the child’s participation would outweigh the 
disadvantage of a caregiver that does not receive the full set of intervention sessions. 
Caregivers meeting inclusion criteria 1, 2, 3 and 6 in Section 5.1 would be eligible to 
enroll. Caregiver changes will be tracked and any study visits occurring prior to the 
change will be noted as missed interventions. 
5.6 
Premature Termination or Suspension of Study 
We do not anticipate any circumstance that would necessitate premature termination or 
suspension of the study. The study will not yield any early outcomes that would indicate 
that it should be stopped prior to completion. Similar randomized trials were categorized 
as minimal risk, had good adherence to protocol requirements using similar methods 
and there were no adverse events.6  
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, 
will be provided by the suspending or terminating party to Julie Baldwin (PI) and the 
NIDCR and the Hopi and Crow Tribes. The principal investigator will also promptly 
inform the IRB and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants. 
• Insufficient adherence to protocol requirements.  
• Data that are not sufficiently complete and/or evaluable.  

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6 STUDY INTERVENTION 
6.1 
Study Product Description 
As part of the Oral Health intervention enrolled infants/children will receive fluoride 
varnish on all erupted teeth up to four times during the study. Children in the Healthy 
Lifestyle comparison group will receive fluoride varnish applications at 12 and 24 
months of age and again at Visit 7 for the HL children in the early cohort. 
3MTM VanishTM is a 5% sodium fluoride white varnish with tri-calcium phosphate. After 
application the varnish combines with saliva to release calcium and fluoride which 
combine to enhance the mineral content of saliva need to form tooth mineral. Tooth 
surfaces do not require cleaning before varnish application. Fluoride varnish is 
associated with a 37% reduction in decay of primary tooth surfaces.9  
6.1.1 
Acquisition 
The fluoride varnish will be ordered from 3M and shipped to Northern Arizona 
University. NAU based staff will verify the quantities ordered, invoiced, and shipped and 
will forward the fluoride varnish from Flagstaff to the Crow and Hopi staff. 
6.1.2 
Formulation, Packaging, and Labeling 
The clearly labeled box contains various quantities of 0.5ml unit dose packets with 
applicator brushes and patient instructions. Product information is included as 
Appendix B. 
6.1.3 
Product Storage and Stability 
The fluoride varnish will be labeled and stored at the Hopi and Crow field offices in a 
locked cabinet. The manufacturer suggests storage in a “cool, dry place” (see 
Appendix C) so room temperature storage (between 10°C and 24°C; 50°F-75°F) 
should be satisfactory.  
6.2 
Dosage, Preparation and Administration of Study Product 
The entire contents of the unit-dose package is dispensed onto a mixing surface, such 
as the gloved hand of the CHR. The dose is mixed using the applicator brush. Mixing is 
required because varnish components may separate during storage. A thin layer is 
applied with sweeping horizontal brush strokes onto the infant/child’s teeth. As per the 
manufacturer’s instructions applying fluoride varnish does not require drying teeth. It is 
not necessary to use all of the provided varnish-only enough to form a thin coating is 
required. As per manufacturer’s recommendations mothers/caregivers will be asked to 
refrain from cleaning their child’s teeth/mouth for 24 hours. The number and location of 
treated teeth will be recorded at each session.  
CHRs will ask the mother/caregiver about fluoride supplements and if so, will be told to 
discontinue their use for 3 days following the FV application. 

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6.3 
Modification of Study Product Administration for a Participant 
Fluoride varnish will be dispensed in proportion to the number of erupted teeth. No other 
dosage modifications are anticipated.  
6.4 
Accountability Procedures for the Study Product 
Inventory of fluoride varnish will be controlled using an inventory control form. Product 
lot numbers and expiration dates also will be tracked. Study staff involved in the 
administration of the fluoride varnish will sign out limited inventory prior to use and will 
return any un-used unit dose packages after fluoride varnish administration sessions 
are completed. The field office will maintain and periodically submit to the Project 
Coordinator records of fluoride varnish units in inventory and signed out to the study 
intervention personnel. These records will be audited biannually. 
6.5 
Assessment of Participant Compliance with Study Product Administration 
The CHRs will be trained in the application of fluoride varnish according to the 
manufacturer’s instructions. The CHRs will practice this skill during their initial training 
and will be evaluated for competency at the conclusion of their training. Data collection 
forms and visit windows will be used to standardize the delivery of FV throughout the 
intervention period. During the training period a dental hygienist member of the study 
team will show the CHR how to apply FV and observe each CHR applying FV to at least 
two people.  
 _______________________________________________________________  
6.6 
Study Behavioral or Social Intervention(s) Description 
6.6.1 
Oral Health Intervention 
The behavioral intervention for pregnant women/new mothers in the oral health 
intervention group will include: 
• Motivational interviewing and support provided by CHRs. They will learn via oral 
health education to be better able to protect their children from ECC. They may 
receive care-coordination assistance in obtaining preventive and therapeutic oral 
health care for mother and newborn/infant. 
• Newborn/infant participants will receive oral health interventions, fluoride varnish 
up to four times and oral health care referral where indicated.  
• CHRs will receive training in oral health assessment for adults and infants. They 
will also be trained in Motivational Interviewing (MI) techniques which are 
recommended for pediatric dental care.5 
The MI content will begin with existing materials developed for other AI/AN projects 
(e.g., American Indian and Alaska Native Motivational Interviewing Guide developed by 
Dr. Kamilla Venner and modified for the prevention of ECC10). The ECC behavioral risk 
factors listed below will be emphasized, along with the 5 main principles that govern MI 

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sessions: 1) the expression of empathy; 2) the development of discrepancy between 
what is and what is desired; 3) the avoidance of argumentation; 4) rolling with 
resistance; and 5) support for self-efficacy. MI was identified as a culturally resonant 
technique to employ in this study because previous literature suggests that MI 
communication strategies are congruent with AI values and practices.11 
Each MI session will follow this general outline: 1) introduction of the specific subject of 
the session, relating this to community educational and promotional materials; 2) 
exploration of the pros and cons of change in the specific area; 3) assessment of the 
importance of change to the participant and confidence of the participant in their ability 
to make the change; 4) enhancement of the participant's self-efficacy through 
identification of what they think they will be able to accomplish; 5) elicitation of 
commitment language to follow through on the decision reached in the session; and 6) 
development of a follow-up plan, with specific action steps. The MI manual has been 
developed in an iterative process using the CAB’s at each site. 
CHRs will be AI lay persons, with a high school education or higher, selected from 
within the AI communities. Two CHRs will be hired at each site, one to implement the 
OH intervention and the other to implement the HL comparison intervention. CHRs 
implementing the OH intervention will complete didactic and clinical education including 
basics of OH care.  
 
The OH educational intervention consists of six 1-hour sessions covering the following 
topics/modules: maternal oral health, take your child to the dentist, clean infant’s 
mouth/brush child’s teeth two times a day, limit sweets/offer non-sugar foods and 
drinks, offer only plain water in bottles or sippy cups in bed, and germs cause 
cavities/reduce germ sharing. The first session (baseline) will cover maternal oral health 
and the remaining five sessions will be selected by the mothers per topic on the agenda 
setting worksheet within the MI framework. All sessions will utilize MI dialogue, visuals, 
some hands-on activities or skill-building practice, and hand-outs summarizing the 
topics covered. Sessions will occur at approximately 4 and 7 months prenatal, and 6, 
12, 18, and 24-27 months postnatal. At Visit 2, mothers will receive OH homecare 
supplies (toothbrush and toothpaste) for themselves. At Visits 3, 4 and 6 mothers will 
receive toothbrush and toothpaste for their baby.  
CHRs will guide mothers through agenda and goal setting for each topic by asking 
questions about what their goals are for baby’s teeth, what is important to them, what 
concerns/worries they have about baby’s oral health, what makes them want to change 
ways of caring for their child’s teeth, why it is important, and what makes them feel a 
need for change. Mothers will rate the importance of their goals and their level of 
confidence in achieving them. Consistent with MI processes, the CHRs will encourage 
commitment language, assist mothers in developing a change plan, and distribute take 
home sheets. 

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Maternal Oral Health Module  
This is presented at the first session in the 4-month prenatal period and focuses on 
maternal oral healthcare needs/going to the dentist, oral-systemic connection, 
preventing germ-sharing, daily brushing and flossing/oral care, modeling good 
behaviors, and fresh food is best/best foods for oral health. Details of the oral health 
intervention are in the Manual of Operations. 
Healthy Lifestyle Intervention 
The behavioral intervention for participants in the healthy lifestyle comparison group will 
include a standard prenatal/postnatal education curriculum which includes educational 
material from the National Head Start curriculum. The goal is to educate women on 
topics such as nutrition and diet, physical activity, breastfeeding/formula feeding, 
substance use, mental/emotional health, infant/child care and development milestones. 
Details of the healthy lifestyle intervention are in the Manual of Operations. Parallel to 
the OH arm, at Visit 2 mothers will receive adult toothbrush and toothpaste for 
themselves and at Visits 3, 4 and 6 mothers will receive toothbrush and toothpaste for 
their baby. 
6.7 
Administration of Intervention 
The interventions will be delivered by the trained CHRs. There are 6 one-hour sessions 
for each treatment arm, two prepartum and four postpartum. The CHRs will be 
scheduled to meet with study participants in their homes and, whenever possible, the 
same CHR will meet with the same study participants for each of the study sessions. 
6.8 
Procedures for Training Interventionists and Monitoring Intervention 
Fidelity 
All research team members from both Montana and Arizona (including CHRs) will 
attend a 2-day training in Flagstaff, Arizona. All will be trained on the research protocol, 
consent process, and data collection methods. Oral health and motivational interviewing 
specialists will train the OH CHRs in motivational interviewing techniques, including 
practicing MI skills. The OH CHRs training will encompass ECC detection, fluoride 
varnish application, and oral health education skills. Another set of team members will 
train the HL CHRs in delivering the HL comparison intervention based on the standard 
Head Start curriculum.  
After the two days of initial training, each of the CHRs will be scheduled to have follow-
up calls with the trainers to clarify any further questions they might have. Initial 
calibration of CHRs with study participants will be done by continued monitoring of MI 
sessions through audio recording, transcription, and review. CHRs will receive 
immediate feedback. To ensure consistent intervention delivery at each site, CHR 
adherence and competence will be monitored throughout the study period. During 
bimonthly site visits team staff will meet with the site PIs and coordinators to review any 
difficulties and brainstorm responses to site-specific challenges. NAU and Tribal 
research team members will conduct follow-up trainings on a monthly basis for the first 

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6 months of the intervention and telephone coaching thereafter. CHRs delivering the 
Healthy Lifestyle intervention will also provide feedback regarding difficulties and site-
specific challenges. MI trainings and fidelity monitoring will be recorded in a MI Training 
and Fidelity log. 
A manual of instructions for conducting the MI intervention will be developed. The MI 
CHRs will be thoroughly trained on conducting the MI intervention, and this training will 
be reinforced annually. The study investigators will be present at all training sessions. 
The MI CHRs will also be able to refer to the manual of instructions on a daily basis for 
reinforcement.  
The on-site project coordinators for the study will observe each MI CHR on a monthly 
basis to make sure that the MI intervention is being competently performed at the field 
level. The study investigators at NAU will review the data collected at the home MI visits 
as described above.  
During the study, all MI sessions will be audio recorded using the hand-held recorders 
which are then uploaded onto encrypted laptop computers to be saved on the secure 
data server. NAU staff will review a random sample of 20% of the intervention 
recordings, scoring them against the MITI criteria (Motivational Interviewing Treatment 
Integrity Scale, available through the University of New Mexico Center for Center on 
Alcoholism, Substance Abuse, and Addiction12). Details of the scoring criteria are in the 
MOP. Adequate MI proficiency will be based on meeting or exceeding each of the 
following criteria: covering an average of 3.5 out of 5 global score dimensions 
(Evocation, Collaboration, Autonomy/Support, Direction, and Empathy); maintaining a 
1:1 question to reflection ratio; asking 50% of questions in an open vs. closed manner; 
90% or higher MI adherent statements. CHRs will be given immediate feedback for 
each of the audited intervention sessions as to their adherence and competence in the 
use of MI. CHRs will be asked to participate in self-reflection on their adherence and 
competence as part of the supervision and feedback sessions. 
We will make every effort to retain CHRs for the entire duration of the data collection 
phase of the study. However, if a CHR leaves, our lead MI trainer will be asked to train 
a new CHR and after training, calibration will be done in a manner identical to the first 
CHRs. 
6.9 
Assessment of Participant Compliance with Study Intervention 
CHRs for both the Oral Health intervention and the Healthy Lifestyle intervention will 
keep detailed records on their encounter forms for each visit with each family, including 
the date of the visit, term of pregnancy or age of the child, what content was selected for 
discussion (oral health group only), their satisfaction with the visit, dental aids left with 
the family (oral health group only) and other members of the family participating. CHRs 
will also keep track of all missed visits, including the number of attempts to schedule 
each visit through use of a password protected call log. Missed attendance within the 
pre-specified visit window (see Study Schedule Section 7) will be considered a protocol 
violation. Missed appointments within the visit window will be recorded but are not 
protocol violations.  

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7 STUDY SCHEDULE 
7.1 
Screening 
Project staff will collaborate with LBHC and the CAB at Crow and the WIC clinic and 
Head Start staff at Hopi to identify pregnant women who meet inclusion criteria. Written 
information explaining the study purpose will be disseminated to all potential 
participants. Participants will be given an orientation to the project, including the 
intervention schedule and study risks and benefits. No medical record screening is 
required for participation. 
Screening Visit (Day -28 to -1)  
Confirm that potential participants are: 
• 18 years or older 
• Pregnant (3-7 months) 
• American Indian or giving birth to an AI child (as reported by the mother) 
• Able and willing to participate until the child is age 3 
• Living within approximately 100 miles of the Crow or Hopi Nations 
• Not enrolled in other community health interventions that incorporate oral health 
intervention, e.g., Family Spirit Program at Hopi 
• Not a member of the Northern Cheyenne Tribe 
• Not living on the Navajo Nation and a not a member of the Navajo Tribe 
Following confirmation of eligibility participants may be consented into the study. At 
this point the formal coverage of the consent form will occur and study staff will 
obtain and document consent from potential participants. Following completion of 
informed consent (documented in REDCap) the participant will be randomized by 
NAU staff to either the Healthy Lifestyle or Oral Health arm. At this point participants 
are officially enrolled in the study and will be referred to a CHR to schedule the first 
study visit. A small subset of demographic questions (~20 items) will be assessed at 
the consent visit. 
7.2 
Visit 1 Overview/Baseline 
Baseline data will be collected on the mothers/caregivers, including oral health 
knowledge and attitudes; social support, insurance and health care utilization. 
Mothers/caregivers in the OH group will receive the first MI intervention module. 
Mothers in the HL group will receive the first Healthy Lifestyle intervention module. 

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7.3 
Study Visit Descriptions 
7.3.1 
Visit 1 (3-7 months pregnant; 9-31 weeks pregnant) 
The range of months is broad because of the potential difficulty of enrolling 
expectant mothers at a precise gestational epoch. We will make every effort to 
recruit women shortly after the first trimester but to facilitate enrollment women 
through 7 months of pregnancy are eligible which will still permit a second 
intervention session at least 30 days after the first session and prior to giving 
birth. 
• Obtain sociodemographic assessments; oral health knowledge and attitudes; oral 
health self-efficacy; maternal and child health knowledge.  
• Administer the OH or HL intervention.  
7.3.2 
Visit 2 (7-9 months pregnant; 28-40 weeks) 
• Visit 2 must occur at least 30 days after visit 1.  
• Administer the OH or HL intervention. 
• Assess social determinants such as transportation, health literacy, dentist trust, 
social relationship resources. 
• Record participant’s compliance with OH or HL intervention.  
• Record adverse events as reported by participant or observed by investigator. 
7.3.3 
Visit 3 (Child 6 months of age ± 1 month) 
• Assess child demographics, insurance and transportation; social determinants; 
communication, trust and satisfaction with CHR. 
• Administer the OH or HL intervention.  
• Administer fluoride varnish to any erupted teeth among OH arm children. 
• Record participant’s compliance with OH or HL intervention. 
• Record adverse events as reported by participant or observed by investigator. 
7.3.4 
Visit 4 (Child 12 months of age ± 1 month) 
• Visit 4 may take place over two days. The child’s oral health assessment and FV 
application will always go first (i.e., on Day 1) and the OH/HL intervention will 
follow (on Day 2). These may be completed on the same day as long as the oral 
assessment and FV application happen first. 
• Child oral health assessment for both OH and HL arms. 
• Administer fluoride varnish to erupted teeth among OH and HL arm children. 

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• Assess oral health knowledge, behavior and attitudes; maternal/child health 
knowledge; social determinants; dental self-efficacy, trust and satisfaction with 
CHR; social support.  
• Administer the OH or HL intervention.  
• Record participant’s compliance with OH or HL intervention. 
• Record adverse events as reported by participant or observed by investigator. 
7.3.5 
Visit 5 (Child 18 months of age ± 2 months) 
• Assess oral health locus of control, health literacy, social integration, financial 
stability, transportation health care utilization, trust and satisfaction with CHR. 
• Administer the OH or HL intervention.  
• Record number of erupted teeth in children in OH and HL groups. 
• Administer fluoride varnish to erupted teeth among OH arm children. 
• Record participant’s compliance with OH or HL intervention. 
• Record adverse events as reported by participant or observed by investigator. 
7.3.6 
Visit 6 (Child 24 months of age ± 2 months) 
• Visit 6 may take place over two days. The child’s oral health assessment and FV 
application will always go first (i.e., on Day 1) and the OH/HL intervention will 
follow (on Day 2). These may be completed on the same day as long as the oral 
assessment and FV application happen first. 
• Child oral health assessment for both OH and HL arms. 
• Administer fluoride varnish to erupted teeth among OH and HL children. This will 
be the final visit for late cohort participants. 
• Obtain psychosocial assessments; oral health knowledge and behavior; oral 
health self-efficacy; maternal and child health knowledge, attitudes towards oral 
health; child oral health quality of life; insurance and health care utilization; trust 
and satisfaction with CHR. Record number of erupted teeth in each treatment 
group. 
• Administer the OH or HL intervention. 
• Record participant’s compliance with OH or HL intervention. 
• Record adverse events as reported by participant or observed by investigator. 
7.4 
Final Study Visit 7 (Child 30-36 months of age [early cohort only]) 
• Child oral health assessment for both OH and HL arms. 
• Administer fluoride varnish to erupted teeth among OH and HL arm children 
(early enrollees only; this will be their final visit). 

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• Record number of erupted teeth in children in each arm. 
• Record participant’s compliance with OH or HL intervention. 
7.5 
Withdrawal Visit 
If a mother/caregiver/child drops out of the study early and refuses additional follow-up, 
an early termination visit will be requested. If this request is accepted, a dmfs measure 
for the child will be obtained along with a questionnaire to the mother/caregiver about 
sociodemographic factors; dental knowledge, attitudes, and behavior; psychological 
influences; other health and risk factors; other dental interventions received; and the 
reasons for early termination. If the early termination visit is refused, we will ask if they 
are willing to continue to be followed without the intervention. If the participant wishes to 
fully withdraw we will withdraw them and their child from the study. 
7.6 
Unscheduled Visit 
If an unscheduled visit is done, the home visit data will be collected, including reason for 
visit, date of visit, age of child, content of visit, mother/caregivers decisions regarding 
next steps, mother/caregiver's satisfaction with visit, and other family members 
participating. 

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8 STUDY PROCEDURES/EVALUATIONS 
8.1 
Study Procedures/Evaluations 
All children in the study will have an oral assessment at ages 12 and 24 months with 
approximately half of children followed until 30-36 months with a third oral assessment. 
Oral assessments will include dmfs evaluation. Procedures for the oral assessments will 
be defined by the Caries Outcome Work Group of the ECC consortium. The criteria for 
the determination of dmfs measures will be according to Drury, et al.13 These criteria 
include the counting of cavitated caries lesions. Dmft scores for the secondary outcome 
will be derived from dmfs scores. The number of teeth with decayed surfaces will be 
divided by the number of erupted teeth to create the dmft score. If no teeth have been 
filled or are missing due to disease this will be dt rather than dmft. 
8.1.1 
Survey Assessments 
We will use surveys to assess the remaining secondary outcomes as well as other 
social and community resources and barriers related to health. The secondary 
outcomes include oral health knowledge, oral health behavior, attitudes towards oral 
health care and maternal/child health knowledge. These are described in Section 3.2. 
Other domains include social determinants of health (e.g., insurance, transportation; 
physical living conditions; social support),  and trust and satisfaction with the CHR. 
Specific survey items and scoring are in the MOP. 

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9 ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety parameters will include all serious adverse events (SAEs) experienced by 
participants in this study. Unanticipated problems (UPs) occurring in the research will 
also be reported as per IRB requirements. 
9.1.1 
Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; 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. 
9.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research. 
9.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event 
as it occurred) 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect  

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• An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE 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. 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up 
The PI will record all events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation for those completing the full study period and who agree to be recontacted. 
At each study visit, the CHR will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
9.3 
Characteristics of an Adverse Event 
Each event will be recorded on an appropriate case report form that includes 
assessment of the characteristics defined below. These characteristics, along with the 
frequency of an event’s occurrence, will be considered in determining if the event is a 
UP. 
9.3.1 
Relationship to Study Intervention 
To assess relationship of an event to study intervention the following guidelines are 
used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention, and/or 
b. There is a temporal relationship between the intervention and event onset 
and/or 
c. The event abates when the intervention is discontinued, and/or 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset, and/or 
b. An alternate etiology has been established. 
9.3.2 
Expectedness  
The PIs will be responsible for determining whether an AE is expected or unexpected. 
An adverse event will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the 
intervention.  

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9.3.3 
Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact 
on ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks 
medical attention, needs major assistance with ADL 
9.4 
Reporting Procedures 
9.4.1 
Unanticipated Problem Reporting  
Incidents or events that meet the OHRP criteria for unanticipated problems require the 
creation and completion of an unanticipated problem report form. OHRP recommends 
that investigators include the following information when reporting an adverse event, or 
any other incident, experience, or outcome as an unanticipated problem to the IRB: 
• appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number; 
• a detailed description of the adverse event, incident, experience, or outcome;  
• an explanation of the basis for determining that the adverse event, incident, 
experience, or outcome represents an unanticipated problem;  
• a description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported 
using the following timeline:  
• Unanticipated problems that are serious adverse events will be reported to the 
IRB within 10 business days (as per NAU guidelines; https://nau.edu/wp-
content/uploads/sites/74/2018/05/Reporting-Local-Information_v2019.8.pdf) of 
the investigator becoming aware of the event. Any other unanticipated problem 
will be reported to the IRB within 10 business days of the investigator becoming 
aware of the problem 
• All unanticipated problems should be reported to appropriate institutional officials 
(as required by an institution’s written reporting procedures), the supporting 
agency head (or designee), and OHRP within one month of the IRB’s receipt of 
the report of the problem from the investigator. 
All unanticipated problems will be reported to NIDCR Medical Monitor concurrently with 
reporting to the IRB. These reports will be made to NIDCR’s centralized reporting 
system via Rho Product Safety: 

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• Product Safety Fax Line (US): 1-888-746-3293 
• Product Safety Fax Line (International): 919-287-3998 
• Product Safety Email: rho_productsafety@rhoworld.com  
General questions about UP reporting can be directed to the Rho Product Safety Help 
Line (available 8:00AM – 5:00PM Eastern Time):  
• US: 1-888-746-7231 
• International: 919-595-6486 
9.4.2 
Serious Adverse Event Reporting  
Any AE meeting the specified Serious Adverse Event criteria will be submitted on an 
SAE form to NIDCR’s centralized safety system via Rho Product Safety. This report 
may be sent by fax or email. Once submitted, Rho Product Safety will send a 
confirmation email to the investigator within 1 business day. The investigator should 
contact Rho Product Safety if this confirmation is not received. This process applies to 
both initial and follow-up SAE reports. 
SAE Reporting Contact Information: 
• Product Safety Fax Line (US): 1-888-746-3293 
• Product Safety Fax Line (International): 919-287-3998 
• Product Safety Email: rho_productsafety@rhoworld.com  
General questions about SAE reporting can be directed to the Rho Product Safety Help 
Line (available 8:00AM – 5:00PM Eastern Time):  
• US: 1-888-746-7231 
• International: 919-595-6486 
The study’s clinically responsible individual will complete a Serious Adverse Event Form 
and submit via fax or email within the following timelines:  
• All deaths and immediately life-threatening events, whether related or unrelated, 
will be recorded on the Serious Adverse Event Form and submitted to Product 
Safety within 1 day (as per NAU IRB requirements) of site awareness.  
• Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported by fax within 10 days of site 
awareness.  
All SAEs will be followed until resolution or stabilization.  
9.4.3 
Reporting of Safety Events to FDA 
Not applicable 

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9.4.4 
Events of Special Interest  
Not applicable. 
9.4.5 
Reporting of Pregnancy 
Not applicable. 
9.5 
Halting Rules 
The frequency of UPs or SAEs in this study is expected to be very small. If the number 
of SAEs is unexpectedly large, or of a particular type, NIDCR and the DSMB may 
consider temporarily suspending enrollment to the study and the study intervention until 
a safety review is convened. The objective of the safety review would be to make a 
decision on whether the study should continue per protocol, proceed with caution, be 
further investigated, be discontinued, or be modified and then continued. 

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10 STUDY OVERSIGHT 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of a Data and Safety Monitoring Board (DSMB) appointed by the NIDCR. The 
DSMB will operate under the rules of an NIDCR-approved charter that will be approved 
at the organizational meeting of the DSMB. The conduct of the DSMB and rules 
regarding how often the Board will meet will be defined by the DSMB charter for the 
study. At this time, most data elements that the DSMB needs to assess will be clearly 
defined. It is anticipated that the DSMB will meet at least once per year via 
teleconference to assess safety and efficacy data, study progress, and data integrity for 
the study. If safety concerns arise, more frequent meetings may be held. The DSMB will 
operate under the rules of an NIDCR-approved charter that will be approved at the 
organizational meeting of the DSMB. At this time, most data elements that the DSMB 
needs to assess will be clearly defined. The DSMB will provide recommendations to the 
NIDCR. 

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11 CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are 
protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained. Monitoring for this study will be performed by the NIDCR’s 
Clinical Research Operations and Management Support (CROMS) contractor. The 
monitor will evaluate study processes and documentation based on the International 
Council for Harmonisation (ICH), E6: Good Clinical Practice guidelines (GCP). 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan 
(CMP). The CMP will specify the frequency of monitoring, monitoring procedures, the 
level of clinical site monitoring activities (e.g., the percentage of participant data to be 
reviewed), and the distribution of monitoring reports. Some monitoring activities may be 
performed remotely, while others will take place at the study site(s). Staff from CROMS 
will conduct monitoring activities and provide reports of the findings and associated 
action items in accordance with the details described in the CMP.  Documentation of 
monitoring activities and findings will be provided to the site study team, the study PIs, 
NIDCR-OCTOM, and NIDCR Program staff. The NIDCR reserves the right to conduct 
independent clinical site monitoring as necessary. 

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12 STATISTICAL CONSIDERATIONS 
12.1 
Study Hypotheses 
This study examines the effect of a bundled “best practices” intervention that includes 
locally tailored dietary and oral health education provided during pregnancy and the 
postnatal period; 2) oral health care of children including the application of fluoride 
varnish; 3) motivational interviewing with children’s mothers; and 4) patient navigation of 
existing oral health and other social services in each study community, facilitated by 
CHRs. This treatment will be compared to a healthy lifestyle intervention which includes 
maternal and child health, child developmental milestones, nutrition and other healthy 
behavior.  
Primary outcome  
 
Number of decayed, missing or filled primary tooth surfaces – dmfs – at the last oral 
assessment 
The hypothesis for the primary outcome dmfs is that a bundled “best practices” oral 
health and fluoride varnish intervention will reduce early childhood caries relative to a 
healthy lifestyle intervention comparison group.  
Ho: mean oral health group dmfs = mean healthy lifestyle group dmfs 
Ha: mean oral health group dmfs  mean healthy lifestyle group dmfs 
 
If this hypothesis is confirmed we will then calculate the prevented fraction which “…is 
the difference in mean caries increments between the treatment and control groups 
expressed as a percentage of the mean increment in the control group” (Marinho et al. 
2013, p. 1). This will be a descriptive supplement to the primary endpoint analysis rather 
than a separate statistical hypothesis test. We do not plan to analyze twelve month 
dmfs data but will incorporate 12 month assessments in models to multiply impute 
missing dmfs scores for the last assessment.  
 
Secondary endpoints 
 
Average number of decayed, missing or filled teeth at the last oral assessment (dmft; 
excluding non-cavitated lesions) 
Hypothesis: average dmft will be lower in the oral health group 
Ho: oral health group average dmft = healthy lifestyle group average dmft 
Ha: oral health group average dmft  healthy lifestyle group average dmft 
 
Mother/caregiver oral health knowledge at Visit 6 
Hypothesis: caregiver oral health knowledge will be higher in the oral health group 
Ho: mean oral health group oral health knowledge = mean healthy lifestyle group oral 
health knowledge 
Ha: mean oral health group oral health knowledge  mean healthy lifestyle group oral 
health knowledge 
 

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Mother/caregiver oral health behavior at Visit 6 
Hypothesis: caregiver oral health behavior will be higher in the oral health group 
Ho: mean oral health group oral health behavior = mean healthy lifestyle group oral 
health behavior 
Ha: mean oral health group oral health behavior  mean healthy lifestyle group oral 
health behavior 
 
Caregiver attitudes towards oral health care at Visit 6 
Hypothesis: caregiver oral health attitudes will be higher in the oral health group 
Ho: mean oral health group attitudes = mean healthy group lifestyle attitudes  
Ha: mean oral health group attitudes  mean healthy lifestyle group attitudes  
 
Maternal/child health knowledge at Visit 6 
Hypothesis: caregiver maternal/child health knowledge will be higher in healthy lifestyle 
group 
Ho: mean oral health group maternal/child knowledge = mean healthy lifestyle group 
maternal/child knowledge 
Ha: mean oral health group maternal/child knowledge  mean healthy lifestyle group 
maternal/child knowledge 
12.2 
Sample Size Considerations 
A Cochrane meta-analytic review9 estimated that fluoride varnish reduces the 
prevalence of decayed, missing and filled first teeth surfaces (dmfs) by 37%. An Indian 
Health Services survey reported a mean dmfs in 2-year olds of 10.05 (standard 
deviation [SD]=16.27).14 A 37% reduction from this low base rate would require 
prohibitively large samples from these communities. To increase sensitivity and 
efficiency we will follow our sample from a minimum of 2 years and some children to a 
maximum of 3 years of age. Recent data from 3-year olds on the Navajo Nation showed 
a mean dmfs of 18.2 (SD=19.4). Therefore, for sample size calculations, we estimate 
values halfway between ages 2 and 3, i.e., mean dmfs=14 (SD=17.25). Using Stata 
15.1 (StataCorp, College Station, TX) with power = 0.80, alpha = 0.05 (two tailed) for an 
independent t-test a sample of 352 is necessary to detect a 37% reduction in caries 
experience (dmfs of 14 vs 8.8; SD=17.25). To cover the estimated 19% attrition rate 
reported in the Cochrane review would require 434 participants. This is the theoretical 
maximum sample size necessary in this context. However, sample size estimates are 
highly sensitive to the estimated variability of dmfs measurements. A 35% reduction in 
the standard deviation (SD=11.2) for the same effect size would require only 150 
participants for power = 0.80 (N=185 to cover attrition). Prior studies in AI groups have 
not evaluated fluoride varnish application in combination with prenatal maternal 
intervention using MI techniques and care coordination. This novel and intensive 
treatment combination should produce a larger effect than varnish alone and also 
reduce extreme caries experience, i.e., reduce dmfs variability. Our statistical sensitivity 
is also enhanced by following early enrollees up to an average expected age of ~ 2.5 
years. Our recruitment timeline targets enrollment of 350 pregnant women across both 
sites. With 19% attrition we would retain an effective sample size of 283.5. To be 

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conservative we round down to an even number of 282 (141 per group) which provides 
power of 0.71 for a 2-tailed test with alpha .05 and a 37% treatment group difference in 
dmfs. This sample size achieves power = 0.97 under the smaller standard deviation 
assumption. Current standards of care recommend FV application for all children at high 
risk for caries. Study staff will therefore apply FV to children in the Healthy Lifestyle 
group at 12 and 24 months of age. This will potentially dilute between groups caries 
differences but is a necessary accommodation given the high caries burden in AI 
communities.  
We feel this is a statistically defensible target enrollment given the high fluoride varnish 
application frequency in our study and the ~ 2.5 years of follow-up time from birth. 
Moreover, genuine treatment effects occurring below our statistical detection threshold 
or within highly variable decay experiences are unlikely to be clinically and ecologically 
relevant. Both calculations are based upon the average effects of fluoride varnish alone9 
and thus should be conservative. In this regard an Australian trial that enrolled 
expectant Aboriginal women suggests the combination of MI and fluoride varnish results 
in a larger treatment effect than varnish alone3 and that this difference persisted over 5 
years of follow up.15 Power analysis based upon their data is presented in the section 
below.  
On average 9 and 23 women per month give birth at Hopi and Crow, respectively. We 
target recruiting 7 per month at Hopi and 18 per month at Crow. This will achieve our 
target enrollment by 14 months and will accrue a larger number of participants at Crow 
(N=252) than Hopi (N=98). Our study is not designed to compare intervention 
effectiveness across tribes but rather across treatment groups. Therefore, the 
enrollment imbalance across sites does not affect our primary research question as 
both groups will be combined when evaluating all outcomes. 
Secondary outcome power analysis 
Secondary outcomes include a complementary caries measure and a set of caregiver-
assessed health knowledge and behavior domains.  
Average number of teeth with decay. The secondary oral health outcome measure is 
the average number of decayed, missing or filled teeth (dmft) as defined by cavitated 
lesions (or worse). We count only cavitated lesions because this threshold is used in 
other AI studies1,2 and because of low examiner reliability for identifying noncavitated 
lesions.16 Treatment with three fluoride varnish applications and motivational 
interviewing produced an average difference of –0.19 teeth with cavitated lesions (95% 
CI –0.23, –0.16) among 2-year old children.3 Because the variability of this measure is 
substantially lower (SD=0.22), statistical power to detect this treatment difference with 
100 per group using an independent t-test exceeds 0.99 with alpha = 0.05 two-tailed. 
Doubling this variability estimate (SD=0.44) provides power of 0.86 with 100 per group. 
Another approach is to calculate power using the lower 95% confidence limit for the 
treatment group difference in Jameison et al. That difference estimate (–0.16) provides 
power > 0.99 with 100 per group. If no missing or filled teeth are observed (as was the 
case in Jamieson) we will analyze the outcome as dt. 

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Oral health knowledge. With a sample size of 282 this study has power of 0.81 to detect 
a 15% difference in post-test knowledge scores across the treatment groups (e.g., 65% 
vs. 80% correct). 
12.3 
Planned Interim Analyses (if applicable) 
There are no planned interim analyses for the primary or secondary outcomes. We will 
provide summary statistics of social health determinants (insurance, transportation, 
social relationship resources) and health behavior (tobacco and alcohol use) to each 
Tribal community based upon the baseline assessment only. This will be returned after 
we complete our last enrollee (expected in month 14 of recruitment).   
12.4 
Final Analysis Plan 
Descriptive analyses will include calculating means and proportions and their 
associated measures of variability. We will also compare key sociodemographic 
differences across those who do and do not complete the study (attrition analysis). As 
per CONSORT guidelines17 we will not statistically compare participant baseline 
characteristics across treatment arms.  
Missing data. We will multiply impute missing values for the primary outcome for all 
participants enrolled and randomly assigned to a treatment (intention to treat). We will 
impute within each treatment group18 based upon key sociodemographic factors 
(maternal age and education; tribe; child sex) assuming the data are missing at random. 
Multiply imputed estimates of regression coefficients and standard errors will be 
combined using Rubin’s rules. The primary outcome is a continuous variable. 
The focal intention to treat analysis of the intervention will be evaluated by regressing 
dmfs at follow up on a binary treatment group variable using robust variance estimates. 
We will include child sex, child age in months at follow up and site (Hopi/Crow) as 
covariates. Although randomization should balance the treatment groups, age and sex 
are strongly associated with dmfs scores7 and covarying those variables should 
increase efficiency. Covarying child age also statistically controls for follow up length. In 
contrast, covarying the (log) number of tooth surfaces in analysis of childhood caries did 
not predict dmfs in a similar RCT.2 We are not powered to compare treatment 
differences across site but using site as a covariate will increase sensitivity in the 
context of possible site differences in caries. 
Robust variance estimation in OLS regression will provide more accurate variance 
estimates in the presence of assumptive violation, i.e., heteroscedasticity. If the model 
is homoscedastic robust regression will provide estimates close to non-robust OLS 
estimates.19 This approach obviates the need to prespecify the correct form of 
assumptive violation. 
Analysis of the oral health secondary outcome (dmft) will parallel dmfs analyses. Other 
secondary outcomes involving questionnaires will regress post-test scores (Visit 6) on a 
binary treatment indicator variable using baseline values as a covariate. 

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Should we observe treatment effects on caries we will conduct exploratory analysis of 
possible mediators including oral health knowledge, behavior, efficacy, and structural 
barriers such as transportation. 

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13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of participants. Study staff will permit authorized 
representatives of NIDCR and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress, and data validity.  
Source documents will include both paper and electronic data forms. Paper data forms 
include informed consent forms, encounter forms, and SAE and UP report forms. 
Electronic data forms include sociodemographic and oral health survey data, dental 
assessment data, and IHS dental and health records. Consent forms will be kept in 
locked file cabinets, separate from all other participant records. Identifying information 
such as name, address, and phone number will be maintained on each mother or 
caregiver/child in the study for the purposes of recontact and follow-up. This information 
will be kept in locked file cabinets in the study field offices. 
The web-based Clinical Trials Management Software (CTMS) system REDCap will be 
the original source for scheduled and actual study visits; questionnaire data; adverse 
event reports, and protocol deviations. Data from other sources (dental assessment 
data) will be uploaded into REDCap. These data will be kept on a secure password-
protected server (ADAMS) accessible only to project staff. 
Whenever possible, data will be entered directly into an iPad. Based on available data, 
the rate of possible system failure is estimated at <1%. In the eventuality of a system 
outage or internet service failure, back-up paper forms for data capture and subsequent 
system entry are available. 

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14 QUALITY CONTROL AND QUALITY ASSURANCE 
The PI has the ultimate responsibility for implementing and maintaining quality 
assurance and quality control systems with written operating procedures to ensure that 
the trial is conducted and data are generated, documented and reported in compliance 
with the protocol. The Fidelity Monitoring Coordinator and Data Collection Coordinator 
will provide regular reports on the fidelity and administration of the intervention to the PI. 
The study team leadership will meet monthly to ensure the intervention trial is meeting 
objectives and to consider all aspects of the project for oversight, feedback and 
suggestions enhancing future progress along with monitoring of expenditures and cost 
allocations as the project progresses. Their oversight includes verification that the PI 
has secured appropriate agreements from all involved parties, has adequately secured 
the data/documents and reports and all protocols and standard operating procedures 
have been followed and quality assurance and quality control of the data, its reliability 
and assessment have been appropriately recorded, maintained and evaluated during 
the intervention trial.   
The PI and key personnel will have oversight responsibility to ensure compliance of the 
intervention trial with the protocols, the accuracy and completeness of the documents, 
reports, notes, etc. and quality management of the overall intervention program. 
The Data Collection Coordinator will serve as the Quality Management Coordinator and 
will utilize clinical trials monitoring systems available through REDCap, NIDCR and 
study documents to monitor quality control of all study activities. This will include the 
documentation and maintenance of records, and generation of regular reports for both 
internal (within study team) and quarterly and/or annual reports, as scheduled, to the 
NIDCR. These will provide the status of study preparation (including CHR trainings, 
dental examiner trainings and calibration sessions and results) and study activities 
(including participant recruitment, activities completion including intervention deliveries 
by sites, incentives dispersal, and data (withdrawals) and safety (AE, SAE) monitoring). 
All of these major activities will utilize checklists to ensure and document completion of 
procedures. (More details can be found in the Data Management Plan and the Quality 
Management Plan). 
A. Recruitment and tracking. NAU staff and CHRs at Hopi and Crow will be trained on 
procedures and scripts, will use eligibility checklists, and will document study eligibility. 
Participant personal identifying information will be maintained in a secure location 
(REDCap) to allow tracking across study activities. 
B. Consent procedures. Informed consent will be obtained by Site Coordinators at Hopi 
and Crow. Participants will complete paper consents, and consents will be collected and 
stored in locked files. Documentation of informed consent will be maintained in 
REDCap. 
C. Assessment completion. All study staff will be trained to complete data collection 
processes. All staff trainings will be documented as to activity and date completed. 
Assessment completion will be overseen and recorded by date in REDCap. 1) CHRs 
will be trained to administer questionnaires using mobile devices via REDCap 2) The 

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dental assesor will conduct the oral assessment and the CHR will enter dental 
assessment data into REDCap.  
D. Intervention training, delivery, and fidelity monitoring. Study interventions will be 
delivered by CHR facilitators who are trained by study investigators/personnel and 
evaluated for fidelity to the intervention plan. Training binders and toolboxes will be 
utilized to increase standardization and fidelity. All trainings will be documented. New 
CHRs will receive the same training. All intervention sessions will be documented and 
audiotaped for fidelity monitoring purposes. Facilitators will receive feedback to address 
any issues identified in the fidelity evaluation.  
E. Examiner training and calibration. Persons performing the oral assessments will 
attend trainings and calibration sessions conducted by our oral health training team. We 
will model calibration procedures found in Warren et al.16 These are described in the 
MOP. 

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15 ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 
Ethical Standard 
The 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.  
15.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the NAU, Phoenix Area IHS and the Rocky Mountain 
Tribal IRBs for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRBs before the changes are 
implemented in the study.  
15.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and benefits of participation in the study will be provided to 
the mothers/caregivers and their families. Consent forms describing in detail the healthy 
lifestyle and the MI intervention, study duration and procedures, and risks and benefits 
will be given to the mothers, and written documentation of informed consent will be 
required prior to starting the study.  
All adult participants will be required to sign a written consent form before participating 
in the study. Verbal consent will not be accepted. A form with contact information for the 
study PI and Project Coordinators will be provided to each participant. Participants will 
be given an orientation to the project, including intervention schedule, study risks and 
benefits, and compensation information. All participants will have adequate time to ask 
questions or request more information  
Extensive discussion of risks and possible benefits of study participation will be 
provided to participants and their families, if applicable. A consent form describing in 
detail the study procedures and risks will be given to the participant. Consent forms will 
be IRB-approved, and the participant is required to read and review the document or 
have the document read to him or her. The participant will sign the informed consent 
document prior to any study-related assessments or procedures. Participants will be 
given the opportunity to discuss the study with others or think about it prior to agreeing 
to participate. They may withdraw consent at any time throughout the course of the 
study. A copy of the signed informed consent document will be given to participants for 
their records. The rights and welfare of the participants will be protected by emphasizing 

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to them that the quality of their clinical care will not be adversely affected if they decline 
to participate in this study. 
Consent forms will be required for the calibration participants and expectant mother 
participants, who also consent for their babies in their original baseline consent forms. 
Re-consent is necessary only in the event of a protocol change. 
The consent process will be documented in REDCap.  
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
The proposed clinical trial participants will include pregnant women and eventually their 
newborn infants. Participants must be a tribal member (as defined by the mother) or be 
giving birth to an AI child. Males are not excluded, but a male would only be enrolled 
should the study child have a change in caregiver. In that case we would seek informed 
consent of the new primary caregiver and enroll that caregiver in the study. 
15.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
study sponsor(s) and their agents. This confidentiality is extended to cover all clinical 
information, sociodemographic data, and data on psychosocial measures and dental 
knowledge, attitudes, and behaviors.  
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No identifiable information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the study 
sponsor and the Tribal authorities.  
The study monitor or other authorized representatives of the study sponsor may inspect 
all study documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) for the study participants. 
The clinical study site will permit access to such records. 
Research records will be handled as confidentially as possible. All study data used for 
research purposes will contain only a study ID and have names, addresses, and other 
information removed for data analysis so they cannot be identified by name. Paper 
study records will be kept in locked files available only to those persons requiring 
access for research purposes. No individual identities will be used in any reports or 
publications resulting from the Healthy Smiles trial. 
Subject PHI, including contact information, and study visit windows and actual dates will 
be stored in a tracking database residing on NAU’s secure servers accessible only to 
study staff.  

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Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human 
Services (HHS), has issued a Certificate of Confidentiality (CoC) to all researchers 
engaged in biomedical, behavioral, clinical, or other human subjects research funded 
wholly or in part by the federal government. Recipients of NIH funding for human 
subjects research are required to protect identifiable research information from forced 
disclosure per the terms of the NIH Policy (https://humansubjects.nih.gov/coc/index). As 
set forth in 45 CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-
supported research covered by this Policy are required to establish and maintain 
effective internal controls (e.g., policies and procedures) that provide reasonable 
assurance that the award is managed in compliance with Federal statutes, regulations, 
and the terms and conditions of award. It is the NIH policy that investigators and others 
who have access to research records will not disclose identifying information except 
when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants 
of the protections and the limits to protections provided by a Certificate issued by this 
Policy. 
NIH Data Sharing Policies  
As described in section 17, it is NIH policy that the results and accomplishments of the 
activities that it funds should be made available to the public (see 
https://grants.nih.gov/policy/sharing.htm). PIs and funding recipient institutions will 
ensure that all mechanisms used to share data include proper plans and safeguards to 
protect the rights and privacy of individuals who participate in NIH-sponsored research.  
15.6 
Future Use of Stored Specimens and Other Identifiable Data 
N/A 

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16 DATA HANDLING AND RECORD KEEPING 
The investigators are responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. The investigators will 
maintain adequate case histories of study participants, including accurate case report 
forms (CRFs), and source documentation. 
16.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the Principal Investigator. All source documents must be 
reviewed by the study team and data entry staff, who will ensure that they are accurate 
and complete. Unanticipated problems and adverse events must be reviewed by the 
investigator or designee.  
Staff will utilize a secure web-based data-entry system (REDCap, Forte Research 
Systems) to input questionnaire and clinical data and to monitor study participant status. 
Each staff person will have a unique login ID with strong passwords and access and 
permissions restricted to data consistent with their given roles within the study. Each 
participant will be assigned a unique study ID number to be used on each electronic 
case report form for identification and tracking purposes. 
Systems and procedures will comply with HIPAA. In addition to unique IDs for each staff 
member, passwords will be required to have a specific length and combination of 
alphanumeric and special characters to mitigate social hacking of passwords. Users are 
required to register for access to the ADAMS server at NAU and accept strict conditions 
for handling and analyzing the data. ADAMS is a remote desktop server that is available 
for researchers to store and analyze what “high risk data.” High risk data may be 
considered any data set that contains personally identifiable information, personal 
health information, or anything controlled by an IRB. The ability to use the server is 
governed and restricted by the registration process. ADAMS storage is internally 
backed up on the server. 
16.2 
Data Capture Methods 
Questionnaires will be self-administered in English directly into REDCap using cellular-
enabled tablets which will upload responses directly to the secure NAU server. In the 
absence of cellular service responses may be acquired and stored offline within the 
REDCap environment on the tablet and uploaded later. CHRs will also carry hard copy 
surveys as backup in case of catastrophic tablet failure. Dental assessment results will 
be directly entered into a REDCap database via a custom graphical interface. Access to 
REDCap is password protected and study staff will be authorized to access data 
acquisition areas limited to their site and study responsibilities.  

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16.3 
Types of Data 
Data stored in paper format include the consent forms and the HIPAA documents and 
other intervention forms. Electronic data will include sociodemographic data; dental 
knowledge, attitudes, and behaviors; other psychosocial data; MI visit data; dental 
utilization data; and data from the children’s oral health assessment. Study 
administrative data, such as contact information, data collection windows, and 
intervention appointments will also be maintained electronically. A separate REDCap 
shell will house safety data. 
16.4 
Schedule and Content of Reports 
Periodic reports documenting study progress will be generated by REDCap and 
reviewed by the PI and co-investigators at monthly meetings. These reports include: (i) 
a tabular enrollment report that summarizes enrollment progress, number of participants 
who completed the study protocol, number of participants who discontinued early; (ii) a 
listing of each subject deviation and protocol deviation with dates, descriptions, and 
actions taken; (iii) a listing of participant study activities (e.g., questionnaire, dental 
assessment) that were completed and missed; (iv) a report with graphical and tabular 
summaries of cumulative (versus planned) accrual and follow-up visit attendance; 
dental assessment visit completion. 
Aggregated annual reports will be submitted to the DSMB. 
16.5 
Study Records Retention 
Study records will be maintained for at least three years from the date that the last grant 
federal financial report (FFR) is submitted to the NIH 
(https://grants.nih.gov/grants/policy/nihgps/html5/section_8/8.4.2_record_retention_and
_access.htm). 
All study records and computer files will be retained for at least 3 years after the final 
study manuscript is published. All paper study records will be destroyed 3 years after 
IRB acknowledgement of study closure in accordance with HIPAA regulations. 
Electronic study records will be destroyed after the 3 year window according to Tribal 
agreements. 
16.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or Good 
Clinical Practice requirements. The noncompliance may be on the part of the 
participant, the investigator, or study staff.  
Protocol deviations, unplanned deviations from expected protocol that are unintended, 
will include study events that are missed (interventions not delivered, delivered at a 
different time point than scheduled, or not received), and assessments and dental 
assessments conducted outside of the expected protocol windows. Deviations will be 
recorded and monitored in REDCap and reported to the NIDCR, NAU and IHS IRBs, 

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and the DSMB, according to their requirements. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. 
These practices are consistent with investigator and sponsor obligations in ICH E6. 

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17 PUBLICATION/DATA SHARING  
This study will comply with all applicable NIH Data Sharing Policies. These policies may 
be modified by Tribal agreements.  
This study will comply with the NIH Public Access Policy which requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to PubMed 
Central immediately upon acceptance for publication. This ensures that the public has 
access to the published results of NIH funded research.  
Following completion of the study, the investigators will prepare manuscripts of the 
results to be submitted to peer-reviewed scientific journals for publication. 
As with all NIDCR-supported research, all materials submitted for publication, 
publications and reports resulting from activities supported by this award will 
acknowledge support from the National Institute of Dental and Craniofacial Research, 
NIH, specifically referencing the grant number. An acknowledgment shall be made to 
the effect that: 
“The project was supported by Award Number 1U01DE028508-01 from the National 
Institute of Dental & Craniofacial Research. The content is solely the responsibility of 
the authors and does not necessarily represent the official views of the National Institute 
of Dental & Craniofacial Research or the National Institutes of Health.”  
As requested by the REDCap team, we will also acknowledge NIH grant support 
provided to the REDCap development team for that data acquisition system (UL1 
TR000445 from NCATS/NIH). 
“REDCap is supported in part by NIH/NCATS UL1 TR000445” 
Authorship 
Investigators will decide on authorship of scientific documents prior to writing them. The 
principles set forth in the ICMJE Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals (the “Vancouver Rules”) will be followed and/or the authorship 
rules of the specific journals. 
The study is a clinical trial and will comply with the NIH policy that establishes the 
expectation that all investigators conducting clinical trials funded in whole or in part by 
the NIH will ensure that these trials are registered at ClinicalTrials.gov, and that 
summary results of these trials are submitted to ClinicalTrials.gov. A “responsible party” 
(i.e., the principal investigator or designee) will register the trial before recruitment 
begins and report summary results of the clinical trial at the end of the study. 

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18 LITERATURE REFERENCES 
1. 
Braun PA, Quissell DO, Henderson WG, et al. A cluster-randomized, community-
based, tribally delivered oral health promotion trial in Navajo Head Start children. 
J Dent Res. 2016;95(11):1237-1244. 
2. 
Batliner TS, Tiwari T, Henderson WG, et al. Randomized trial of motivational 
interviewing to prevent early childhood caries in American Indian children. JDR 
Clin Trans Res. 2018;3(4):366-375. 
3. 
Jamieson L, Smithers L, Hedges J, et al. Dental disease outcomes following a 2-
year oral health promotion program for Australian aboriginal children and their 
families: a 2-arm parallel, single-blind, randomised controlled trial. 
EClinicalMedicine. 2018;1:43-50. 
4. 
Phipps KR, Ricks TL. The oral health of American Indian and Alaska Native 
children aged 1-5 years: results of the 2014 IHS oral health survey. Indian Health 
Service Data Brief. 2015. https://www.ihs.gov/doh/documents/IHS_Data_Brief_1-
5_Year-Old.pdf. Accessed 14 July 2019. 
5. 
Review Council American Academy of Pediatric Dentistry. Behavior guidance for 
the pediatric dental patient. Pediatr Dent. 2017;40(6):254-267. 
6. 
Garcia RI, Gregorich SE, Ramos-Gomez F, et al. Absence of fluoride varnish-
related adverse events in caries prevention trials in young children, United 
States. Prev Chronic Dis. 2017;14:E17. 
7. 
Tiwari T, Quissell DO, Henderson WG, et al. Factors associated with oral health 
status in American Indian children. J Racial Ethn Health Disparities. 
2014;1(3):148-156. 
8. 
Batliner T, Fehringer KA, Tiwari T, et al. Motivational interviewing with American 
Indian mothers to prevent early childhood caries: study design and methodology 
of a randomized control trial. Trials. 2014;15:125. 
9. 
Marinho VC, Worthington HV, Walsh T, Clarkson JE. Fluoride varnishes for 
preventing dental caries in children and adolescents. Cochrane Database Syst 
Rev. 2013(7):CD002279. 
10. 
Venner K, Feldstein SW, Tafoya N. Native American Motivational Interviewing: 
weaving Native American and western practices; A manual for counselors in 
Native American communities. 2006. 
https://www.samhsa.gov/sites/default/files/programs_campaigns/samhsa_hrsa/n
ative-american-motivational-interviewing.pdf. Accessed 14 July 2019. 
11. 
Albino JEN, Orlando VA. Promising directions for caries prevention with 
American Indian and Alaska Native children. Int Dent J. 2010;60(3S2):216-222. 
12. 
Moyers TB, Martin T, Manuel JK, Miller WR, Ernst D. Revised Global Scales: 
Motivational Interviewing Treatment Integrity 3.1.1 (MITI 3.1.1). In. Center on 
Alcoholism, Substance Abuse and Addictions (CASAA): University of New 
Mexico; 2010. 
13. 
Drury TF, Horowitz AM, Ismail AI, Maertens MP, Rozier RG, Selwitz RH. 
Diagnosing and reporting early childhood caries for research purposes: A report 
of a workshop sponsored by the National Institute of Dental and Craniofacial 

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Research, the Health Resources and Services Administration, and the Health 
Care Financing Administration. J Public Health Dent. 1999;59(3):192-197. 
14. 
Indian Health Service. An oral health survey of American Indian and Alaska 
Native dental patients: findings, regional differences and national comparisons. 
ND. 
http://dhss.alaska.gov/dph/wcfh/Documents/oralhealth/docs/Oral_Health_1999_I
HS_Survey.pdf. Accessed 15 July 2019. 
15. 
Jamieson L, Smithers L, Hedges J, et al. Follow-up of intervention to prevent 
dental caries among indigenous children in Australia: A secondary analysis of a 
randomized clinical trial. JAMA Network Open. 2019;2(11):e1915611-e1915611. 
16. 
Warren JJ, Weber-Gasparoni K, Tinanoff N, et al. Examination criteria and 
calibration procedures for prevention trials of the Early Childhood Caries 
Collaborating Centers. J Public Health Dent. 2015;75(4):317-326. 
17. 
Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and 
Elaboration: Updated guidelines for reporting parallel group randomised trials. J 
Clin Epidemiol. 2010;63(8):e1-37. 
18. 
Bell ML, Fairclough DL. Practical and statistical issues in missing data for 
longitudinal patient-reported outcomes. Stat Methods Med Res. 2014;23(5):440-
459. 
19. 
Stata Corporation. Hetregress — heteroskedastic linear regression. In: Stata 
base reference manual, release 15. College Station, TX: Stata Press; 2017:1075. 
 
 
 
 
 
 

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SUPPLEMENTAL MATERIALS 
Dental assessment calibration protocol 
Data and Safety Monitoring Board charter 
Manual of Procedures 
 
 
 
 
 

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APPENDICES 

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APPENDIX A: SCHEDULE OF EVENTS 
 
Gestation in 
months 
 
Child age in months 
 
 
 
 
 
 
 
Procedures 
 
Screening/enrollment (3-7 
months) 
Visit 1 (3-7 months) 
Visit 2 (7-9 months) 
 
Visit 3* (6 months ± 1) 
Visit 4 (12 months ± 1) 
Visit 5 (18 months ± 2) 
Visit 6 (24 months ± 2; ½ 
cohort) 
Visit 7 (30-36 months ± 2; 
½ cohort) 
Premature 
Discontinuation 
Assessment of eligibility criteria  
X 
 
 
Birth of child 
 
 
 
 
 
 
Signed consent form 
X 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
X 
 
 
 
 
 
Oral Health Intervention 
 
X 
X 
X 
X 
X 
X 
 
 
Fluoride varnish - Oral Health 
arm 
 
 
 
X 
X 
X 
X 
X (early  
cohort) 
[X] 
Healthy Lifestyle Intervention 
 
X 
X 
X 
X 
X 
X 
 
 
Fluoride Varnish – Healthy 
Lifestyle arm 
 
 
 
 
X 
 
X (late  
cohort) 
X (early  
cohort) 
[X] 
Oral assessment (dmfs) 
 
 
 
 
X 
 
X (late 
cohort) 
X (early  
cohort) 
[X] 
Assessment of adverse events 
 
 
X 
X 
X 
X 
X 
X  
[X] 
Oral health behavior 
 
 
 
 
X 
 
X 
 
 
Oral health attitudes 
 
X 
 
 
X 
 
X 
 
 
Oral health knowledge 
 
X 
 
 
X 
 
X 
 
 
Maternal/child health knowledge 
 
X 
 
 
X 
 
X 
 
 
Social determinants (e.g., 
insurance, transportation) 
 
X 
 
X 
 
X 
 
 
 
Social determinants (social 
relationship resources)  
 
 
X 
 
X 
X 
X 
 
 
Social determinants (dental care 
provider trust, satisfaction) 
 
 
X 
 
X 
X 
X 
 
 
Community health representative 
communication, trust, 
satisfaction 
 
 
 
X 
X 
X 
X 
 
[X] 
Pediatric health related quality of 
life 
 
 
 
 
 
 
X 
 
 
*Postnatal study treatments are based upon child age not gestation period. Therefore times for 
Visits 3-7 are based upon child age. Cells with [X] denotes observation or treatment provided 
conditional on premature discontinuation.  
 
 

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APPENDIX B: Fluoride Varnish Regulatory Data Sheet 
 
Regulatory Data Sheet
Copyright,2018,3M Company.
All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is 
allowed provided that: (1) the information is copied in full with no changes unless prior written agreement is obtained from 
3M, and (2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon.
This Regulatory Data Sheet is provided as a courtesy in response to a customer request.
Document Group:
26-9856-1
Version Number:
5.00
Issue Date:
06/25/18
Supercedes Date:
08/07/17
12149/ 12150/ 12151/ 12154/ 12159/ 12160 3M™ ESPE™ 
VANISH™ 5% NaF WHITE VARNISH WITH TCP  
3M
Oral Care Solutions Division
3M Center, St. Paul, MN  55144-1000, USA
1-888-3M HELPS (1-888-364-3577)
RDSs are available at www.3M.com
Regulations and Industry Standards
SDS (US OSHA)
See Safety Data Sheet (SDS) for hazard and other regulatory data. 
US FALCPA
This product complies with the United States Food Allergy Labeling and Consumer Protection Act of 2004, as there is no 
intentionally added milk, egg, fish, crustacean shellfish, tree nuts, wheat, peanuts, soybeans, and/or proteins thereof. 
EU CMR Directive
This product contains an ingredient at >= 0.1% that is classified as a Category 1 or 2 carcinogen, mutagen, or reproductive 
toxicant according to Annex VI (Table 3.2) of European Regulation 1272/2008 on Classification, Labelling, and Packaging of 
Dangerous Substances and Mixtures or that is classified by 3M or its vendors as an EU Category 1 or 2 carcinogen, mutagen, 
or reproductive toxicant according to the criteria of European Council Directive 67/548/EEC (the Dangerous Substances 
Directive). 
EU Food Allergens
This product complies with Regulation (EU) 1169/2011 on the provision of food information to consumers, as there is no 
intentionally added component identified in Annex II of this regulation. Specifically, none of the following are intentionally 
added:  cereals containing gluten, crustaceans, eggs, fish, peanuts, soybeans, milk, nuts, celery, mustard, sesame seeds, 
sulphur dioxide and sulphites at concentrations of more than 10 mg/kg or 10 mg/L expressed as sulphur dioxide, lupin, 
mollusks, and/or derivatives thereof. 
Halal
This product has not been certified Halal. 
Kosher
This product has not been certified Kosher. 
California Proposition 65

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This product contains a chemical/chemicals that have been recognized by the State of California to cause cancer or 
reproductive harm.
Chemicals and/or Compounds of Interest
Arsenic and (As) Compounds : This chemical or chemical compound is not intentionally added. 
Beryllium and (Be) Compounds : This chemical or chemical compound is not intentionally added. 
Bismuth and (Bi) Compounds : This chemical or chemical compound is not intentionally added. 
Bisphenol A (BPA) : This chemical or chemical compound is not intentionally added. 
Butyl Benzyl Phthalate (BBP) : This chemical or chemical compound is not intentionally added. 
Cadmium and (Cd) Compounds : This chemical or chemical compound is not intentionally added. 
Chromium and (Cr) Compounds : This chemical or chemical compound is not intentionally added. 
Colophony (Rosin) : This product is known to contain this chemical or chemical compound. An inactive ingredient of this 
product is "Pentaerythritol Glycerol Ester of Colophony Resin" which is a modification of the naturally occurring rosin 
(colophony) derived from pine tree sap.  For more information on this, please contact the 3M Customer Care Center at 1-
800-634-2249.
Dibutyl Phthalate (DBP) : This chemical or chemical compound is not intentionally added. 
Dibutyl Tin Compounds : This chemical or chemical compound is not intentionally added. 
Di(2-Ethylhexyl) Phthalate (DEHP) : This chemical or chemical compound is not intentionally added. 
Diisodecyl Phthalate (DIDP) : This chemical or chemical compound is not intentionally added. 
Diisononyl Phthalate (DINP) : This chemical or chemical compound is not intentionally added. 
Di-n-Octyl Phthalate (DNOP) : This chemical or chemical compound is not intentionally added. 
Dyes : This chemical or chemical compound is not intentionally added. 
Flavorings : This product is known to contain this chemical or chemical compound. 
Formaldehyde : This chemical or chemical compound is not intentionally added. 
Gluten : This chemical or chemical compound is not intentionally added. 
Hexavalent Chromium and (Cr+6) Compounds : This chemical or chemical compound is not intentionally added. 
Lead and (Pb) Compounds : This chemical or chemical compound is not intentionally added. 
Melamine : This chemical or chemical compound is not intentionally added. 
Mercury and (Hg) Compounds : This chemical or chemical compound is not intentionally added. 
Natural Rubber Latex : This product is not made with natural rubber latex. 
Nickel and (Ni) Compounds : This chemical or chemical compound is not intentionally added. 
Nuts : This chemical or chemical compound is not intentionally added. 
Organotin Compounds : This chemical or chemical compound is not intentionally added. 
Phthalates : This chemical or chemical compound is not intentionally added. 
Selenium and (Se) Compounds : This chemical or chemical compound is not intentionally added. 
Tributyl Tin Compounds : This chemical or chemical compound is not intentionally added. 
Triphenyl Tin Compounds : This chemical or chemical compound is not intentionally added. 
Zinc and (Zn) Compounds : This chemical or chemical compound is not intentionally added. 
Disclaimers:The information provided in this document related to material content represents 3M's knowledge and belief, which may be based in whole or in 
part on information provided by suppliers to 3M. This is intended to answer commonly asked questions about 3M products and is not intended to be a 
comprehensive listing of all substances that may be of interest or that may be regulated in this or other 3M products, nor is it intended to be a comprehensive 
summary of any and all regulations that may apply to this product. Where substances are listed, their listing does not infer or constitute a judgment as to their 
safety, environmental or health impacts. Information is supplied upon the condition that the persons receiving the same will make their own determination as 
to its suitability for their purposes prior to use. Customers are encouraged to consult with legal and regulatory experts to determine applicable regulations in 
light of intended use of the product.
Limitation of Remedies and Liability:In the event any Product is proven not to conform with the information in this document, then to the extent permitted 
by law, 3M's entire liability and Buyer's exclusive remedy, will be at 3M's option either:  (i) replacement of Product with a conforming product, or (ii) 
refund of the purchase price paid by Buyer for each non-conforming Product, within a reasonable time after written notification of said non-conformance and 
return of said Product to 3M. 3M shall not under any circumstances be liable for direct, incidental, special, or consequential damages (including but not 
limited to loss of profits, revenue, or business) related to or arising out of this certification, including, the use, misuse or inability to use the Product. Unless 
stated otherwise in writing, the foregoing language cannot be waived, modified, or supplemented in any manner whatsoever.

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APPENDIX C: Fluoride Varnish Material Safety Data Sheet 
 

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