Conditions: Dental Caries
Keywords: child pharmacokinetics silver diamine fluoride
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: yes

Brief summary:
The purpose of this study is to characterize basic PK parameters (Cmax, t1/2, AUC) in healthy children to contribute to evidence for the safety of Advantage Arrest, consistent with Guidance for Industry--Exposure--Response Relationships (April 2003).

Detailed description:
This is a topical agent where the active ingredients are applied to the teeth and eventually swallowed and may be absorbed through the GI tract or excreted. Minimal amounts are absorbed through the oral mucosa. Serum concentrations of silver and fluoride will be be proportional to the dose of silver and fluoride administered topically to the teeth as part of Advantage Arrest. This is an open label exposure-response study with up to 50 healthy children ages 3-13 years of age. Subjects will be treated with Advantage Arrest and have one blood sample withdrawn at a randomly assigned time point. A minimum of 3 subjects per time point at 2,4,6,24,48,96 and 168 hours. Serum samples will be analyzed for F and Ag.

Arms:
arm 1: 38% silver diamine fluoride, topical, 1 drop, single application

Interventions: intervention 1: Silver Diamine Fluoride
Intervention descriptions: intervention 1: 38% aqueous silver diamine fluoride \[Ag(NH3)\]2F, CAS RN 33040-28-7

Protocol document:
Prot_SAP_000.pdf: 
IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
1 
Protocol: Pharmacokinetics of Advantage Arrest in Children 
Protocol version: 2019-06-23 
 
Sponsor:  
  
 
Advantage Silver Dental Arrest, LLC 
 
 
  
PO Box 12746 
 
 
 
Salem OR 97309-0746 
 
  
 
 
 
 
United States 
 
Investigators:  
 
Hellene Ellenikiotis, DDS 
 
 
 
University of California, San Francisco 
 
 
 
Email: Hellene.Ellenikiotis@ucsf.edu  
 
 
 
Phone: 408.313.0166 
 
                                Pinelopi Xenoudi, DDS, MS 
 
 
 
University of California, San Francisco 
 
 
 
Email: Pinelopi.Xenoudi@ucsf.edu 
 
 
 
Phone: 415.502.2755 
 
Sub-investigators:  
Peter Milgrom, DDS 
 
 
  
University of Washington 
  
Box 357475 
Seattle, WA 98195 
  
United States 
 
 
  
Email: dfrc@uw.edu 
 
 
  
Phone: 206.685.4183 
 
Yvonne Lin, PhD 
 
 
 
University of Washington 
 
 
 
Box 357610 
Email: Yvonlin@uw.edu 
 
 
 
Phone: 206.616.8728 
 
Research Site: 
 
University of California, San Francisco (UCSF) 
 
 
  
Clinical and Translational Science Institute  
 
 
 
 
UCSF Benioff Children’s Hospital 
1825 4th Street 
San Francisco, CA 94158 
  
United States 
 
 
  
Phone: 415.353.3000 
 
Regulatory Monitor:  
William Cooley, PhD 
 
 
 
 
Cooley Consulting, Inc. 
 
 
 
 
531 Chisholm Trail 
Wyoming, OH 45215 
United States 
Phone: 513-522-3797 


IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
2 
Purpose of the Study and Background 
 
Objective: The purpose of this study is to characterize basic PK parameters (Cmax, t1/2, 
AUC) in healthy children to contribute to evidence for the safety of Advantage Arrest, 
consistent with Guidance for Industry--Exposure--Response Relationships (April 2003).  
 
Background: The Sponsor/Investigator conducted a preliminary PK study in six adults 
(Vasquez et al., 2012) in which 38% diammine silver fluoride (silver diamine fluoride) 
was applied topically to three teeth in each subject and maximum serum concentration 
and time to maximum serum concentration were studied over four hours. Mean amount 
of the agent applied was 7.57 mg. Over the four-hour observation period the mean 
maximum serum concentrations were 1.86 umol/L for fluoride and 206 nmol/L for silver. 
These maximums were reached at 3 h and 2.5 h for fluoride and silver, respectively. 
Fluoride exposure was below the EPA oral reference dose. Silver exposure exceeded 
the EPA oral reference dose for cumulative daily exposure over a lifetime, but for 
occasional use was well below concentrations associated with toxicity. Nevertheless, 
the number of subjects was limited and the follow-up period too short to calculate the 
AUC. Although diammine silver fluoride is available in many countries, there are no 
other published PK studies to our knowledge. 
The Sponsor/Investigator conducted an additional PK study to further 
characterize the kinetics of silver and fluoride with sixteen healthy adults (Lin et al., 
2019) in which 38% silver diamine fluoride was applied topically to five teeth in each 
subject (estimated 4-11milligrams per subject), and maximum serum concentration and 
time to maximum serum concentration were studied via serum and urine samples over 
24 hours. Over the 24-hour observation period, the silver serum peak was .67ng/mL. 
This maximum was reached at 3 h, and the elimination half-life of silver was estimated 
to be 46 hours. Baseline fluoride serum levels were between less than 10 through 
50ng/mL. The estimated urinary fluoride was 1.29mg, and no silver was recovered in 
the urine. The study duration was too short to fully capture the pharmacokinetics of 
silver and return of serum silver to baseline levels. A study duration of 4-7days with 48, 
72, 120, and 168-hour sampling time points is needed.    
In both studies, the dose and time to peak serum silver was comparable. Peak 
serum silver concentrations were higher in the Vasquez et al study which could be due 
to lack of rinsing post-application. In both studies, there was a 400-fold safety margin in 
the amount applied compared to the US EPA’s lowest allowable effect level for silver 
exposure at 1g. 
 
There are no published PK studies with children. The investigative team at the 
University of Washington developed a physiologically-based pharmacokinetic (PBPK) 
model to predict silver disposition in children, as there are data establishing the safety of 
fluoride exposure in children in both the anesthesia and dental literature. The predictive 
performance of the model was assessed by comparing the predicted PK profiles and 
parameters with the observed data from published rat and human data following 
intravenous or oral silver administration. The PBPK model was applied to the pediatric 
population by accounting for developmental physiological changes.   From this model, 
the predicted silver concentrations were within 2-fold of observed blood and tissue silver 
concentrations in rats and within the 95% confidence interval of observed plasma silver 
concentrations in healthy human adults.  For a given SDF dose, the simulated peak 
plasma silver concentrations were 5.2-, 4.3-, 2.7-, 1.3-fold higher in children aged 1-2 


IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
3 
years, 2-4 years, 5-10 years and 12-17 years, respectively, compared to adults.  The 
half-life of silver was comparable in all ages and plasma and tissue silver concentrations 
were predicted to return to baseline levels within 10 days after SDF application.  Based 
on the predictions, younger children will have transiently higher silver plasma 
concentrations than adults, though smaller increases are expected if less SDF is 
applied.  
 
Assumptions for Proposed Study: This is a topical agent where the active ingredients 
are applied to the teeth and eventually swallowed and may be absorbed through the GI 
tract or excreted. Minimal amounts are absorbed through the oral mucosa. Serum 
concentrations of silver and fluoride will be be proportional to the dose of silver and 
fluoride administered topically to the teeth as part of Advantage Arrest.  
 
 
Criteria for Subject Selection 
 
Number of subjects: There will be up to 50 healthy children subjects enrolled in the 
study with the goal of at least 21 subjects to complete the study.  
Gender of subjects: The subjects will be approximately half male and half female. 
Age of subjects: Subjects will be 5-12 years of age. 
Racial and Ethnic Origin: In a small study it is not possible to fully represent the 
racial/ethnic distribution of the region or US. The investigator will attempt to recruit a 
racial/ethnic diverse population. 
Inclusion criteria: Subjects will be healthy. Healthy status will be determined by self-
reported medical history evaluated by the attending clinician. Subjects will have at least 
one carious lesion.  
Exclusion criteria: Subjects will be excluded if they have oral mucositis, any ulcerative 
lesions, or hypersensitivity to silver or fluoride. Subjects with a history of SDF treatment 
within 3 months will be excluded.  
 
 
Methods and Procedures 
 
Design of the Study and Minimization of Bias: Open label exposure--response study. 
 
Randomization: Not applicable. 
 
Blinding:  Not applicable. 
 
Baseline procedures: Once informed consent and assent have been obtained, age, 
race, gender, and ethnicity information will be collected at baseline along with a brief 
health history. A brief visual examination will be conducted to note any evidence of 
inflammatory or ulcerative changes to the gums or other oral tissues. Non-fluoride 
toothpaste will be used on the day of the baseline appointment through the blood draw 
period. A blood sample of 6 mL (one tube for serum collection) will be withdrawn at an 
assigned time point using a fluoride free tube.  
 


IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
4 
Study intervention: Advantage Arrest, Aqueous Diamine Silver Fluoride [Ag(NH3)] 2F,  
CAS RN 33040-28-7, 38.3% to 43.2% in purified water 5.0 - 5.9% (w/v) fluoride; 24.4 -
28.8% (w/v) silver, Silver Diamine Fluoride. 
 
Teeth will be brushed with a soft toothbrush to remove debris and dried with cotton prior 
to application. The specific procedure is 5 mg (1 drop) of Advantage Arrest will be 
dispensed into a plastic dappen dish and all of the material will be applied to the carious 
lesion/s with an applicator. To calculate the amount of Advantage Arrest applied: the 
dappen dish with the initial amount of Advantage Arrest dispensed and applicator will be 
weighed before application and after application. The amount applied will be calculated 
as the difference in weights before and after application. The amount applied will be 
recorded. The teeth will remain isolated with cotton rolls for 1 minute and then rinsed 
with water and high volume evacuation. Subjects will not eat for at least 2 h following 
application of Advantage Arrest. 
 
Blood sampling following intervention: Subjects will have one blood sample of 6 mL 
withdrawn at an assigned time point: 3 subjects per timepoint at 2, 4, 6, 24, 48, 96 and 
168 hrs. 
 
Blood processing: Blood samples will be spun in a clinical centrifuge, the serum 
withdrawn, and then the serum will be frozen for later analysis.  
 
Sample Analysis: Serum samples will be analyzed for F- by ion chromatography and 
Ag by ICPMS (Inductively coupled plasma mass spectrometry). Cmax, Tmax, Cmin (last 
measurable time point), t1/2, and the AUC will be calculated from serum samples.  
 
Data Analysis and Monitoring: 
Subject disposition: The frequency and reason for subject withdrawal will be 
summarized.  
 
Data Analysis and reporting: The PI and sub-investigators will be responsible for 
performing all analyses, creating the output for the analyses and disseminating results 
to the study team. The Principal Investigator and the rest of the study team will then 
review the results. The Principal Investigator will be responsible for drafting and 
preparing a final report of the study.  
 
Data Storage and Confidentiality: The data will be stored on password protected 
computers in the UCSF Pediatric Dental Clinic in a password protected room. Only 
investigative personnel will have access. The data will be available for inspection by 
regulatory monitors and FDA. 
 
 
Risk-Benefit Assessment 
 
Risk Category: Minimal Risk. 
 
Potential Risk: Hypersensitivity to silver or fluoride, changes to intraoral tissues: 
erythema, gingival inflammation, or soft tissue changes. Advantage Arrest has been 


IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
5 
used extensively since clearance as a medical device in 2014 and the Sponsor knows 
of no adverse effects. The same agent is approved in Canada and Japan and there 
have no harms reported. There may be bruising at the site of the blood collection. 
 
Protection Against Risks:  The study will be carried out at UCSF Benioff Children’s 
Hospital in the University of California, San Francisco in Pediatric Dental Clinic and the 
Clinical and Translational Science Institute by licensed personnel under the Clinical and 
Translational Science Institute. 
 
Potential Benefits: The Advantage Arrest will help slow or arrest their existing carious 
lesion/s and aid in the prevention of new lesions. 
 
Alternatives to Participation: The alternative is to decline participation. 
 
 
Subject Identification, Recruitment and Consent/Assent 
 
Method of Subject Identification and Recruitment: Subjects will be recruited among 
patients at the University of California, San Francisco Pediatric Dental Clinic. Flyers will 
also be posted in at the University of California, San Francisco Pediatric Dental Clinic to 
notify potential subjects of the opportunity to participate. They will call or email Hellene 
Ellenikiotis, DDS for more information or to schedule an appointment. Subjects who 
meet the study’s criteria for entry will be recruited into the study by the PI and enrolled.  
 
Process of Consent: Potential subjects will have the opportunity to ask questions and 
will be informed that participation is voluntary. They will have the opportunity to take the 
consent home to consider whether or not they want their child to take part in the study. 
They will be reminded that whether or not they decide to participate will not affect their 
care at University of California, San Francisco Pediatric Dental Clinic and they can ask 
questions about participation or discontinue participation at any time.   
 
Process of Assent: Potential subjects will have the opportunity to ask questions and 
will be informed that participation is voluntary. All communication will be had at an age-
appropriate level. They will have the opportunity to take the assent home to consider 
whether or not they want to take part in the study. They will be reminded that whether or 
not they decide to participate will not affect their care at University of California, San 
Francisco Pediatric Dental Clinic and they can ask questions about participation or 
discontinue participation at any time.   
 
Minimize Pressure to Participate: Pressure to participate will be minimized by 
ensuring all subjects are aware that their decision to participate or not will have no 
consequences. They can say yes or no, and nothing will be different. Everyone will be 
just as happy with them. 
 
Parent/Subject Capacity: Parents must have the capacity to give informed consent 
and subjects must have the capacity to give assent. Subjects must be English speaking 
and able to read and understand English.   
 


IND124808 
 
 
Protocol_SDFPK051919CTG.docx 
6 
Parent/Subject Comprehension: Potential parents and subjects will be asked to clarify 
their understanding of the objectives of the study. They will also be asked to clarify their 
understanding of the risks and benefits of participation.   
 
Documentation of Consent and Assent: Once potential parents and subjects have 
had a chance to read the approved consent and assent forms, and had their questions 
answered following the consent/assent discussion, they will be asked to sign the forms. 
The study staff will sign the form and provide the participant a fully signed and dated 
copy. The original signed consent and assent forms will be stored in a locked cabinet at 
the University of California, San Francisco Pediatric Dental Clinic at Benioff Children’s 
Hospital. 
 
Costs to the Subject: The participants will not incur any costs associated with the 
study. 
 
Payment for Participation: A $100 volunteer compensation will be provided. 
 
Reimbursement for Participation: Reimbursement will be provided to defray the costs 
of parking and transportation for study participation. 
 
 
References: 
Lansdown AB. A pharmacological and toxicological profile of silver as an antimicrobial 
agent in medical devices. Adv Pharmacol Sci. 2010;2010:910686. 
 
Vasquez E, Zegarra G, Chirinos E, Castillo JL, Taves DR, Watson GE, Dills R, Mancl 
LL, Milgrom P. Short term serum pharmacokinetics of diammine silver fluoride after oral 
application. BMC Oral Health 2012;12:60. 
 
Lin YS, Rothen ML, Milgrom P. Pharmacokinetics of 38% topical silver diamine fluoride 
in healthy adult volunteers.  J Am Den Ass 2019;150(3):186-192.