The Effectiveness of Silver Diamine Fluoride as a Treatment for Caries in Comparison to Traditional Restorative Techniques: A 12 Month Randomized Controlled Trial
Phase: PHASE3
Conditions: Caries
Sponsor: University of Michigan

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The Effectiveness of Silver Diamine Fluoride as a 
Treatment for Caries in Comparison to Traditional 
Restorative Techniques: A 12 Month Randomized 
Controlled Trial 
 
 
 
NCT 02601833 
 
 
 
 
Version Number: 4.0 
27 Apr 2016 
 
 
PI Margherita Fontana, DDS, PhD 
University of Michigan School of Dentistry 
 
 

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1. Introduction 
Dental caries is the most common chronic disease in children, and is even four times as common 
as asthma in adolescents.1  According to the National Health and Nutrition Examination Survey 
(NAHNES) from 1999 – 2004, 27.9 percent of children ages 2 – 5 have caries in the primary 
dentition, and that number increases to 51.17 for ages 6 – 11.  When the income level for these 
children’s families is 200 percent that of the Federal Poverty Level, 42 percent of children have 
caries, but when compared to those at 100 percent of the poverty level the caries rate reaches that 
of 54.3 percent of children, with 32.3 percent of children at this level of poverty having untreated 
decay.2  For these children, living with this untreated dental disease may lead to problems with 
food intake, daily sleep, difficulty in school, restriction of daily activities, and negative impact to 
their self-esteem.3  Primary prevention of caries in children is always preferable, but is not always 
possible.  When primary prevention fails, effective secondary prevention using treatments that are 
safe, simple, low-cost, and acceptable to patients can be efficacious in preventing morbidity to 
these children, which is our ultimate goal. 4  
 
2. Objectives 
The objectives of this clinical study are to evaluate:  
• The effectiveness of treatment of cavitated caries in children by application of silver 
diamine fluoride (SDF) in comparison to conventional restorative treatments  
• The perceptions of parents and patients to both treatment modalities and their levels of 
acceptability 
• The opinions of dental providers in terms of ease of use and clinical time spent 
• The relative cost-effectiveness of the two treatment approaches regarding both practitioner 
chair time and material-based cost  
 
 
 
 
 

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3. Review of Literature 
3.1. Silver in Dentistry 
Silver has been used in medicine for hundreds, even thousands, of years.5  Some of the earliest 
reports of the use of silver compounds in dentistry to reduce the incidence of caries in the primary 
dentition date back to the 1840s.6   In the late 60’s and early 70’s research by many groups 
worldwide began regarding the use of silver diamine fluoride to prevent caries.7,8,9,10  In more 
recent years, clinicians have come to the realization that finding treatments especially for those 
children in disadvantaged communities, is of utmost importance on a worldwide level.  Because 
of the great need and often the inaccessibility of standard dental care, discussions have arisen 
regarding Arresting Caries Treatment (ACT) as opposed to traditional restorative dental 
treatments, which typically would  involve complete caries removal and replacement of missing 
tooth structure with a restoration.11  Silver diamine fluoride offers many proposed advantages as 
an ACT – 1. It offers control of pain and infection. 2. Its ease of use is great. 3. It is highly 
affordable. 4. There is minimal time involvement for its application. 5. It is a non-invasive option.12  
      
3.2. Silver Diamine Fluoride Mechanism of Action 
The favored caries prevention agent today worldwide is fluoride, and professional topical fluoride 
applications, such as fluoride varnish are now-a-days the most commonly used strategy in the U.S. 
for primary and secondary prevention of carious lesions, even though this caries prevention use 
for varnishes is off-label in the U.S. This use has been endorsed by organized dentistry in the U.S., 
including the American Dental Association, the American Academy of Pediatric Dentistry, State 
preventive programs funded by the Centers for Disease Control and Prevention, etc. SDF is a type 
of professional topical fluoride which has been approved in the U.S. with an application similar to 
that of fluoride varnishes.13  In fact, Oregon now allows hygienists and expanded function dental 
assistants to apply SDF under general supervision just as with any other fluoride or antimicrobial 
agent.14   SDF incorporates both of the advantages of fluoride to reduce dental caries and promote 
remineralization, and also offers a quite potent germicidal effect. 12   It has been reported that it not 
only strengthens the sound tooth structure, but also offers the ability to kill bacteria and arrest 
caries progression once a cavity has developed.12  Research has shown that SDF has the ability to 

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inhibit colonization of Streptococcus mutans, Actinomyces naeslundii, and Enterococcus faeclis.4  
Being of utmost importance to the caries progression process, the direct effects on S. mutans have 
been noted for years, with literature dating back to 1976.15   It is important to note that not only 
does SDF have the ability to prevent biofilm formation, but it also has the ability to kill the bacteria 
present at time of placement.16 
 
In addition to directly inhibiting bacterial growth, SDF also can reduce against acid solubility and 
facilitate enamel remineralization via other mechanisms.4  Early researchers believed the silver-
salt formation stimulated sclerotic or calcified dentin formation.12  For decades now, it continues 
to be shown that the fluoride and silver present in SDF interact together to form fluorapatite 
strengthening the tooth.8  It has also been shown that not only is the depth of penetration of SDF 
far greater than that of other fluoride containing materials, but the tooth retains two to three times 
more SDF than with other fluoride combinations.17  Furthermore, the amount of reparative dentin 
formation has shown great increase when used prior to dental materials that have silver added.18  
The combination of all this information demonstrates  why SDF has been shown to be such an 
effective desensitizer as well.19  In comparison to active carious lesions with no treatment, those 
which were arrested at 24 months via biannual SDF application showed more well aligned and 
highly organized crystallites.20  The underlying collagen fibers were protected from exposure, and 
there was also a rich zone of calcium and phosphate, suggesting that clinically there is a highly 
positive effect on dentin remineralization due to the SDF application.20 
 
3.3. Previous Research Involving Silver Diamine Fluoride 
Research over the past few decades regarding the effectiveness of SDF has been relatively 
consistent.  In comparison to 5 percent sodium fluoride (NaF; used commonly in professionally 
applied fluoride varnishes), 38 percent SDF was found to be more effective in arresting active 
caries in the primary anterior teeth of preschool children at 30 month follow-up.21  Continued 
research showed that not only could SDF arrest active caries, but additionally it could reduce the 
incidence of caries in the primary teeth as well as the first permanent molars in school children.22  
Most recently it has been shown that annual SDF application has a similar rate of effectiveness in 

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arresting caries comparable to that of sealant placement or biannual application of 5 percent NaF 
after 24 months.23   
 
3.4. Negative Aspects of Silver Diamine Fluoride 
In addition to the numerous apparent positive effects of SDF there are a minimal number of 
drawbacks, the most notable being the black stain it leaves on the carious dentin.12  While 
esthetically unpleasing to some, this black stain is not of any physical harm to the patient. 19, 21   In 
fact when compared to applications of sodium fluoride and no treatment, all treatments had teeth 
presenting at recall with blackened dentin.21  Recent studies have shown this black discoloration 
appears to be a non-issue, as the coloration of the teeth following treatment did not decrease patient 
satisfaction.21  However, additional research has still been aimed at reducing the black 
discoloration of the tooth by placing potassium iodide (KI) following SDF application or by 
completely placing an alternative agent, such as ammonium hexofluorosilicate ((NH4)2SiF6).4  
Placing potassium iodide may eliminate the staining, but whether this reduces the effectiveness of 
the SDF is still in need of further evaluation, especially in vivo.24  Research on ammonium 
hexofluorosilicate, on the other hand, shows that it is not effective in reducing caries progression 
and is therefore not a viable replacement option to SDF.4 
 
The most common concern with any product used intraorally is its compatibility with intraoral 
soft-tissues.  Recent research has confirmed that tissue ulcerations and argyria were not present 
following treatment with SDF.19 Only transient mild erythema of the gingiva near the SDF-treated 
tooth and a metallic taste in the patients’ mouths were noted in some patients, supporting that the 
use of silver diamine fluoride is quite safe. 19, 21  
 
3.5. Silver Diamine Fluoride Variations in Application 
While much of the previously presented research suggests that there are potential positive effects 
of SDF, there are still many potential variations in regimens for application.  Many would assume 
that for effective arrest of caries, it would be important for carious debris to be removed reducing 
the bacterial load.25,26 However, it has been shown that caries removal did not offer any significant 
beneficial effect in terms of arresting carious lesions and only showed a reduction in the number 

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of arrested lesions that turned black in the NaF group, as 100 percent of the lesions in the SDF 
group presented with a black coloration regardless of caries removal.21   For this reason, it has been 
suggested that caries removal would be unnecessary, which would make the procedure more 
simple and could increase the potential for patient acceptability which is important because it is 
one of the advantages of this product.21      
 
Many studies have shown a variation in number of applications and concentrations, leading to the 
research question of determining an exact regimen.4  In terms of concentration, when observed at 
6 months, it was noted that a single application of 38 percent SDF could arrest caries in comparison 
to 12 percent SDF, which could not.27  Regarding the optimal number of applications, it was shown 
that an annual topical application of 38 percent SDF would arrest 37 percent of caries at 12 months 
and up to 79.2 percent of caries at 24 months, while biannual applications resulted in 53 percent 
arrested caries at 12 months and 90.7 percent arrested caries at 24 months.28   
 
Due to the potentially highly positive caries arrest effects of SDF, research has been conducted in 
an attempt to prevent washing away of the product when placed on the tooth surface.29  It has been 
postulated that if the treated surface was to turn instantaneously black, this would indicate that the 
process had been accelerated and was in turn more effective.29  Studies have shown that 
applications of 10% stannous fluoride or tannic acid were not shown to have an additional benefit 
in arresting caries although they may have appeared to accelerate the process of SDF uptake by 
the tooth surface.29,27  
 
3.6. Current Research 
According to Rosenblatt at el., the advantages of SDF are numerous.  While it can control the 
infection, it is also easy to use, highly affordable, involves minimal chair time, and is quite non-
invasive.12  They also concluded there is no [published] research that addresses all of these topics. 
SDF was approved in the United States in July 2014 and currently there have been no clinical trials 
in the United States testing the application of SDF to arrest caries in children. 13  Also, there seem 
to be no studies that address the failure rates of SDF in comparison to conventional one and two-
surface restorations for the treatment of dentin caries.  The researchers’ aims in this study will be 

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to address affordability, ease of use, and both patient/parent and provider acceptance, in addition 
to clinical success rates when compared to conventional restorations. 
 
4. Materials and Methods 
4.1. Purpose 
To determine the effectiveness of the application of silver diamine fluoride (SDF) in comparison 
to conventional restorative treatments in International Caries Detection and Assessment System 
criteria (ICDAS) 5 and 6, one and two surface carious lesions in primary molars which will be 
assessed based on major and minor failure criteria when followed for one year. Additionally, 
parents’/children’s and providers’ perceptions will be assessed as well as the cost of both regimens, 
to include both chair time spent and materials’ costs. 
 
4.2. General Outline 
Children, 2-10 years of age will be invited to participate. The original study site is Mott Children’s 
Health Center (MCHC) in Genesee County, Michigan. Following a slow recruitment period, the 
University of Michigan School of Dentistry (UMSOD) Children’s Clinic was added as a second 
study site.  Given the current data in the literature, the combined failure rate for conventional 
restorative techniques (e.g. compomers) is approximately 29% at one year follow-up,30 while 
application of silver diamine fluoride has a failure rate of 63% at one year follow-up, with 
increased success over time.28  Although the failure rate of SDF at one-year follow-up seems 
alarming, as indicated by Zhi, et al. it may be possible to increase the success rate with additional 
applications providing success rates up to 90.1% at 24 months. 28  Using these data, α-value of 0.05 
and a Power set at 80%, the resulting sample size would be 68 (34 per group) as calculated using 
the software, nQuery (Appendix 1). To account for 30% attrition, the final number needed for the 
initial study will be 98 (92 for 25% attrition, 86 for 20% attrition). Subjects will be contacted by 
phone regularly and invited to two intermediate clinic visits (plus a final study visit) to reduce 
attrition (Table 1). Given a review of the current literature of the few Randomized Controlled 
Clinical Trials involving SDF worldwide, the majority of this research has been completed with 
pre-school aged children. Almost all research discusses arresting or prevention of caries in the 

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primary dentition, as well as prevention of caries on first permanent molars. Due to the strength of 
the current research, this study will be focused on the primary dentition of children in the U.S. 
These children and their parents will be approached when presenting for examination/recall/or 
treatment at Mott Children’s Health Center, Flint, MI, or the University of Michigan School of 
Dentistry Children’s Clinic, Ann Arbor, MI.  Interested families with children that qualify 
following screening examination will be provided with an Informed Consent/Assent (Appendix 3) 
and an Enrollment Information Form (Appendix 4). 
 
4.3. Inclusion and Exclusion Criteria 
Eligible children will be identified during a screening at initial presentation.  They must fulfill the 
inclusion criteria which include (Appendix 10, CRF 10): 
• Patients must be ages 2-10. 
• Presence of at least one active (soft) cavitated carious lesions in the primary dentition, 
extending into dentin (ICDAS 5 or 6) – Only one tooth will be selected for the study. All 
others will be restored and monitored according to the American Academy of Pediatric 
Dentistry (AAPD) guidelines. 
• The selected tooth must have a one or two surface lesion (more than 1/3 of the crown of 
the tooth must be remaining) and must allow for direct application of SDF. 
• Study teeth will not have any spontaneous or elicited pain due to caries, tooth mobility, or 
signs of pulpal infection.  
• Selected primary teeth must have an anticipated exfoliation date greater than 12 months 
away. 
 
Exclusion criteria include children with: 
• Hereditary developmental defects such as Amelogenesis Imperfecta and Dentinogenesis 
Imperfecta 
• Severe medical conditions that do not allow the child to be managed in the 
MCHC/UMSOD clinics 
• Known allergy /sensitivity to dental materials being used, including SDF 

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• Inability of the child to cooperate for treatment, recall examinations, or periapical 
radiographs.  
• Wards of the State, for consenting reasons 
 
After approaching the parent with a brief discussion of the study, determining interest and asking 
brief pre-screening eligibility questions as approved by the Institutional Review Board (IRB), the 
informed consent process will occur. Parents will provide both written and verbal consent, and 
written and verbal assent will also be asked of the children older than age 8 (Appendices 2 &3).  
Following the informed consent process, full study eligibility criteria will be reviewed with the 
pediatric dental resident performing the procedure.  At time of consent, the parent will also be 
provided the Enrollment Information Form (Appendix 4) as a reminder of important information 
and frequently asked questions.  This form will include information regarding study purpose, 
duration (12 months, including application/restorative appointment, 3 follow-up visits, and 
additional follow-up phone calls/contacts), possible resulting appearance, and overall study 
protocol. 
 
Children who are enrolled to participate in the study will receive a full mouth caries examination 
using the ICDAS criteria (Examiners will be trained and calibrated in the ICDAS criteria prior to 
study initiation.), and will be randomly divided into two groups: 
 
1. Conventional management of caries group: This group will receive traditional 
restorative care for one tooth with a one or two surface lesion – including composite, 
amalgam, or glass-ionomer restorations according to the current AAPD treatment 
guidelines.  
 
2. SDF management of caries group: This group will receive applications of SDF applied 
to their carious lesion, in lieu of restoration placement, with the goal of “arresting caries”.   
 
4.4. Participant Allocation and Blinding  

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Subjects enrolled in the study will be randomly assigned to one of the two caries management 
groups in a 1:1 ratio. Although treatment will be randomly assigned, it will not be possible to blind 
parents, children, or dentists to the assigned treatment group as the post-operative appearance is 
likely to differ markedly between groups. In the event treatment for the patient is failing, regardless 
of the treatment arm assigned, the provider will recommend additional treatment and can withdraw 
the patient at any time and appropriate reasoning will be recorded. Patients/parents have the right 
to withdraw from the study at any time and for any reason as well.  Additionally their reasoning 
for withdrawal will be recorded (Appendix 10, CRF 04, 11, 14-17).   
 
5. Interventions  
Patients will be randomly assigned to the following groups, and managed under that philosophy 
for a 12 month period.  Each appointment for either intervention group will follow the designated 
Workflow for that appointment (Appendix 5-8) and appropriate subsequent documents will be 
completed at each visit (Appendix 9). 
 
5.1. Conventional management of caries 
These children will receive restorative dental care in alignment with the AAPD guidelines, 
within the confines of the MCHC or UMSOD clinics.  This treatment typically includes 
administration of local anesthesia, placement of rubber dam, caries removal with rotary and 
hand instruments, and placement of a final restoration. Following completion of the 
conventional caries management, the provider will complete the CRF 02 Intervention Visit: 
Conventional Restoration CRF (Appendix 10, CRF 02).  For both study interventions, fluoride 
varnish application should not be applied within one week before or after study intervention 
so that the effects noted will not be confused with known positive effects of topical fluoride 
varnish applications. 
 
 
 
5.2. SDF management of caries  

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• The selected tooth with notable decay into dentin will be isolated with cotton rolls. 
• No caries removal will be performed, except for food or other obvious debris.21 
• Tooth will be dried with gauze and SDF solution will be placed on the carious dentin 
until it is saturated. 
• Excess SDF will be blotted dry with a cotton pellet.  
• A second application of SDF solution will then be placed to ensure that the entire 
carious surface is wetted, and excess will again be blotted with a cotton pellet. 
• Following the second application of SDF, the area will be isolated for 3 minutes to 
allow for ample drying before allowing contact with saliva and soft tissues 
• Should the SDF come in contact with any soft tissues, soft tissue should immediately 
be wiped with a saline wipe 
• Following completion of the SDF intervention visit, the provider will complete the CRF 
03 Intervention Visit: Silver Diamine Fluoride CRF (Appendix 10, CRF 03). 
• A second application of SDF will be applied at 6 month recall, following the same 
protocol as noted above (Due to the potential for increased caries arrest rate with a 6 
month application28). 
• Any new carious lesions that develop after the initial treatment will be recorded, and 
treated using conventional treatment methods and will not be included in the study. 
• 
Following the completion of this study, teeth in the SDF group will be treated according 
to AAPD guidelines or observed for exfoliation. The parent of an SDF treated child 
can elect a restoration following AAPD guidelines at the 12 month visit. 
 
Both groups will receive the following, according the standard procedures at the MCHC/UMSOD: 
• Oral Health Instruction (OHI) and diet instruction 
• Tooth brushing/dentifrice use at home 
• Fissure sealants for permanent teeth will be placed if deemed necessary. 
• Traditional preventative care at recalls based on AAPD guidelines (Regular recall exams, 
prophylaxis, scaling, flossing, and fluoride varnish at 6 month recalls will be provided 
for both treatment arms.  Special care will be taken to not apply fluoride varnish directly 
to the carious lesion which is being treated with SDF.) 
 

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6. Study Visits and Intermediate Contacts 
Recalls for both groups will occur via phone questionnaire as well as follow-up visits.  Participants 
will be contacted at 1 month, 2 months, 4.5 months and 9 months (± 2 weeks) following restoration 
placement or application of SDF.  Subjects will need to present to the clinic for follow-up visits at 
3 months (± 6 weeks), 6 months (± 6 weeks), and for study completion at 12 months (± 6 weeks) 
(Table 1). Subjects will also be called to schedule and confirm these follow-up visits; these short 
calls will require no payment to the study subjects. In the case of an emergency, an emergency 
visit will be scheduled at Mott Children’s Health Center or the University of Michigan School of 
Dentistry. An emergency will be evaluated and treated according to the AAPD guidelines, 
followed by completion of appropriate case report forms (CRFs) and reporting to IRBs and study 
sponsors (Appendix 10, CRF 14-17). In the event of minor or major failure in either study group, 
the subject will we withdrawn from the study and teeth will be given the appropriate treatment as 
stated in the AAPD Guidelines free of charge, these teeth will be categorized as a failure, and a 
CRF 04 Treatment Deviation CRF (Appendix 10, CRF 04) will be completed.   
 
Table 1. Patient Contact Interval 
Patient Contact 
Recall Interaction 
Time Scale 
Clinic Visit #1 
Consent/Assent, baseline 
questionnaires, initial caries 
assessment, radiographs*, 
intervention 
T = 0 
Intermediate Contact 
Attrition prevention, update 
contact information, follow-up on 
pain 
T = 1 month, 2 months 
(Additional reminder for Clinical 
Visit #2) 
Clinic Visit #2 
Assessment for major and minor 
failure & assessment of pain and 
parent satisfaction 
T = 3 months 
Intermediate Contact 
Attrition prevention, update 
contact information, follow-up on 
pain 
T = 4.5 months (Additional call 
reminder for Clinical Visit #3) 
Clinic Visit #3 
Reapplication of SDF in that 
group; Assessment for major & 
minor failure, radiographs*, and 
assessment of pain and parent 
satisfaction 
T = 6 months 

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Intermediate Contact 
Attrition prevention, update 
contact information, follow-up on 
pain 
T = 9 months (Additional call for 
scheduling/reminder for Clinical 
Visit #4) 
Clinic Visit #4 
Assessment for major & minor 
failure, radiographs*, and final 
questionnaires 
T = 12 months 
* Radiographs will be obtained only if an existing radiograph within 30 days of the visit is 
not available. 
 
7. Study Outcomes 
7.1. Questionnaires + Acceptability Measures31,32 
At the baseline clinical visit: 
• Pediatric Medical History Form 
o Mott Children’s Health Center/University of Michigan School of Dentistry 
Children’s Clinic standard form  
• CRF 05 Baseline Parent Questionnaire (Appendix 10, CRF 05) 
• CRF 06 Child Questionnaire (Appendix 10, CRF 06) 
 
When scheduled intermediate contact occurs via phone (or in person if presenting to 
MCHC/UMSOD for other reasons) at 1, 2, 4.5, and 9 months, the following form will be completed 
by the personnel making the contact, documenting the answers provided by the parent: 
• CRF 07 Intermediate Contact (Appendix 10, CRF 07) 
 
At recall visits (3 & 6 months, 12 month final recall, plus emergency visits) the parent and patient 
will complete: 
• CRF 08 Follow-up Parent Questionnaire (Appendix 10, CRF 08)  
OR 
• CRF 09 6 & 12 Month Parent Questionnaire (Appendix 10, CRF 09) 
• CRF 06 Child Questionnaire (Appendix 10, CRF 06) 
 
7.2. Clinical Variables 

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At the baseline visit the study teeth carious lesions will be assessed based on size (mm), dentin 
color (yellow, brown, black), dentin hardness (soft - any explorer penetration of dentin when very 
light force is applied or hard – no dentin penetration when using an explorer with very light 
force21), and periapical radiographs (outer/middle/inner third of dentin, major/minor failure 
criteria).  All information will be noted on the respective CRF Intervention Visit by the provider 
prior to treatment.  These clinical characteristics will also be recorded for the SDF groups at 
follow-up visits (as the lesion is exposed clinically). Recall clinical visits will involve assessment 
of the lesion based on minor and major failure criteria (Table 2). All assessments will be noted on 
the respective CRF 3 & 6 Month (Appendix 10, CRF 10 & 11) or on the CRF 12 Month at the 
patient’s 12 month recall (Appendix 10, CRF 12 & 13). Both groups will have periapical 
radiographs taken at the baseline and 6 and 12 month recalls (and at any other time if deemed 
clinically necessary). If a radiograph from within 30 days of the visit is available, a radiograph will 
not be taken at the study visit unless deemed clinically necessary. De-identified clinical photos 
will also be taken as deemed necessary for research and publication purposes, with parental 
consent. Length of time and cost for each intervention will be calculated and analyzed for 
comparison. 
 
Table 2. Major and Minor Failure Criteria30 
 
 
SDF Application 
Conventional Restoration 
Success 
• Caries arrested – dentin feels 
hard to explorer 
• No clinical signs or symptoms of 
pulpal pathology 
• Tooth exfoliated without major or 
minor failure 
• Restoration appears satisfactory 
• No clinical signs or symptoms of 
pulpal pathology 
• Tooth exfoliated without major or 
minor failure 
Minor Failure 
• Caries progression – soft dentin, 
increase in lesion size clinically or 
radiographically 
• Reversible pulpitis to be treated 
without pulpotomy or extraction 
• Secondary caries 
• Restoration fracture or wear 
requiring repair 
• Loss of restoration 
• Reversible pulpitis to be treated 
without pulpotomy or extraction 

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Major Failure 
• Pulpitis requiring pulpotomy or 
extraction 
• Abscess formation 
• Caries progress to the extent that 
tooth is unrestorable 
• Pulpitis requiring pulpotomy or 
extraction 
• Abscess formation 
• Restoration loss leaving tooth 
unrestorable 
 
 
7.3. Providers: 
Dentists’/pediatric residents’ preferences for the 2 treatment options and time needed to complete 
a baseline visit will be recorded for each of the 2 interventions and logged on the respective CRF 
Intervention Visit (Appendix 10, CRF 02 & 03).  
 
Provider preference of treatment modality cannot be collected through the clinical measurements 
on the study Case Report Forms. Therefore, collecting this data from the provider in addition to 
the clinical measurements will show feasibility and likelihood of future use. It would also be of 
great interest to the dental community.  
 
7.4. Economic Measures 
The economic evaluation of the two treatment strategies will be based on the time and material-
based cost which will be calculated with the assistance of a Masters of Public Health student. 
 
Additionally, this study offers the potential opportunity for continued research in long-term recalls 
and histological analysis of the study teeth upon exfoliation. 
 
8. Retention Strategy for Participants 
Mott Children’s Health Center serves children and families 200% of the poverty level and below.  
While the children are receiving care at Mott Children's Health Center and the University of 
Michigan School of Dentistry, their parents, however, are not. The intention of this study is to 
assess the effect of SDF, yet we are very interested to promote oral health (which in the case of 
young children is very dependent on family health), so we will seek a study participant fee to 

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account for transportation costs to study visits and funds that can be used for assistance with the 
oral health care needs of any family members of the study participants, if necessary.  Parents will 
receive $50 for their child’s participation in the intervention appointment. Following successful 
recall contacts, the parents will be provided with a $10 reimbursement (this has been used very 
successfully by members of the study team in an NIH study to increase retention over time33). 
Parents will receive payment for each of three clinical recall visits: $60 at 3 months, $70 at 6 
months and $80 at 12 months.  Following initial intervention ($50), four recall contacts ($10 each) 
and three recall visits ($210 total) this will result in a total possible participation fee of $300.  All 
payments will be provided in the form of a gift card, and given to the parent of a participant.  The 
parent will acknowledge receipt.  Payments are funded by Delta Dental, study sponsor, and are in 
no way funded by Mott Children’s Health Center or the University of Michigan School of 
Dentistry. 
 
9. Withdrawal Procedures 
Subjects will have the right to withdraw at any time.  Alternative conventional treatment can also 
be provided to the SDF group at any time, if it is believed by the provider to be in the patient’s 
best interest. Reasoning will be recorded, as a preference for or against one treatment arm may 
provide further information as to public acceptance of a treatment, and these subjects will be 
withdrawn, CRF 04 Treatment Deviation (Appendix 10, CRF 04) and appropriate additional forms 
will be completed and the parent will receive a Study Completion or Disenrollment Letter 
(Appendix 11). Although no adverse events are expected CRF 15 Unanticipated Problem & CRF 
16 Adverse Event Logs will be available if necessary (Appendix 10, CRF 15 & 16 ).  In the event 
that the protocol is ever deviated from (ie. Missed recall or appropriate study procedure not 
completed) a CRF 14 Protocol Deviation (Appendix 10, CRF 14) will be completed.   
 
 
 
10. Statistical Analysis 
Power of the study will be fixed at 80% (β=0.20) just as was used in calculation for necessary 
sample size, with α = 0.05 as the significance level.  Data will be entered into SSPS Statistics or 

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another secured data collection system and data will be analyzed.  Information will be stored on a 
password protected computer using an encrypted file and will be maintained as confidential 
protected health information (PHI). Examiners will be trained at the start of the study and 
calibrated on the use of the ICDAS criteria, and on the clinical outcome variables using extracted 
teeth to determine intra and inter-examiner reliability (dentin color, dentin hardness, and lesion 
size in mm), which will be measured with kappa statistics. A Chi-square test will be applied to 
determine if there is a difference in distribution of variables such as age, gender, brushing habits, 
fluoride exposure, etc. Chi-square tests will also be used to determine differences in dropout rates, 
failure rates, patient satisfaction/acceptance, and overall cost. The primary outcome, the proportion 
of children reporting major failures during the 12 month follow up period, will be analyzed using 
a mixed model with a binomial error structure. We will also analyze minor failures in a similar 
manner. The dependent variables will be a binary indicator of major failure, with differences 
between study treatments fitted as fixed effects. Estimates of the relative risk of major failure in 
the two groups will be presented in the form of odds ratios and associated 95% confidence 
intervals. Within this framework we will be able to estimate: 
1. The mean difference between groups at the end of the follow up period; 
2. The mean difference between groups across the whole of the follow up period; and 
3. The difference in the rate of change of the outcome across the follow up period 
 
11. Potential Limitations 
An initial potential problem in the study may be to obtain the 98 patients needed per the power 
analysis calculation.  Hopefully this will not remain too much of an obstacle, as children are 
frequently seen at Mott Children’s Health Center and University of Michigan School of Dentistry 
Children’s Clinic with carious lesions of this nature. When enrolling in this study, parents are 
either simply enrolling their children in a study where they would be provided the care that they 
would otherwise be provided outside of the study or, if receiving the alternative SDF treatment, 
they always have the ability to opt out and receive their definitive, conventional treatment. At the 
completion of the study, children who received care in the SDF group will have their study teeth 
restored according to AAPD guidelines or monitored for exfoliation, whichever is deemed most 
appropriate by their final provider or elected by the parent. 

Version 4.0 27Apr2016 
18 
 
In order to prevent confusion and withdrawal from the study following intervention due to 
misinformation, all residents at Mott Children’s Health Center and the University of Michigan 
School of Dentistry Children’s Clinic who are providers for this study will be standardized in terms 
of the presentation of the study to the parents and patients and in the informed consent and assent 
process for the parents and children involved.  It is important that these patients and their parents 
understand especially how the tooth may look following treatment. Teeth treated with SDF may 
become darker, and it is important to standardize this presentation by all residents so that patients 
are not withdrawing from the study simply because they were unaware of these anticipated 
consequences of the treatment. 
    
In order to achieve a sample population of this size in such a short amount of time, five or six 
residents at each clinical site will be completing the screening, treatment, and recall of these 
patients.  While having many providers is a limitation of the study, all providers will be trained 
and calibrated in their assessment of the tooth color and hardness as well is in their SDF application 
technique.  
  
As with any treatment provided in children, especially those as young as two, it is possible that the 
children may be uncooperative for their appointments and that recall procedures cannot be 
performed. If a complete recall procedure cannot be fully completed, it is possible to simply 
complete the portions of the recall that are able to be completed safely. Children who cannot 
complete an intermediate clinical recall visit but still wish to remain in the study will be continued 
to be monitored until the final study visit, and the reason for failure to complete the recall will be 
noted.  
 
Finally, given the socioeconomic status of these patients, it may be difficult for parents to miss 
work as well as arrange transportation to and from appointments. For this reason, it was determined 
that study participants will receive a study participant fee to help offset transportation costs and to 
hopefully additionally assist with any other oral health care needs of the patient's immediate family 
if necessary.  
 
 

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