Clinical trial NCT04184271
Conditions: Dental Caries
Keywords: adult fluoride silver silver diamine fluoride pharmacokinetics
Sponsor: Advantage Silver Dental Arrest, LLC
Start date: 2017-08-01; Completion date: 2019-03-31
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study aim is to characterize the kinetics of silver and fluoride after topical application of silver diamine fluoride.

Detailed description:
The purpose of this study is to characterize basic PK parameters (Cmax, t1/2, AUC, and total urinary recovery) to contribute to evidence for the safety of Advantage Arrest, consistent with Guidance for Industry--Exposure--Response Relationships (April 2003).

Arms: arm 1: 38% silver diamine fluoride, topical, 1 drop, single application
Interventions: intervention 1: 38% silver diamine fluoride
Intervention descriptions: intervention 1: Topical application of SDF to teeth

Protocol documents:
Prot_002.pdf: 
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PROTOCOL_SDFPK-2016-11-08_(clean).docx 
Protocol: Pharmacokinetics of Advantage Arrest 
 
Protocol version: 2016-11-08 
NCT04184271 
Document Date: 11/08/2016 
 
 
Sponsor:  
  
 
Advantage Silver Dental Arrest, LLC 
 
 
  
442 SW Umatilla Ave, Suite 200 
 
 
 
Redmond, OR 97756 
 
 
  
United States 
 
Investigator:  
 
Peter Milgrom, DDS 
 
 
  
University of Washington 
  
Box 357475 
Seattle, WA 98195 
  
United States 
 
 
  
Email: dfrc@uw.edu 
 
 
  
Phone: 206-685 4183 
 
Sub-investigators:  
Yvonne Lin, PhD 
 
 
 
University of Washington 
 
 
 
Phone: 206-616-8728 
 
 
 
 
Jeremy Horst, DDS, PhD 
 
 
 
University of California, San Francisco 
 
 
 
Phone: 415-370-0061 
 
Research Site: 
 
University of Washington 
 
 
  
Regional Clinical Dental Research Center 
 
 
  
HSB Room D-453 
1959 NE Pacific Street 
Seattle, WA 98195 
  
United States 
 
 
  
Phone: 206-685 8132 
 
Regulatory Monitor:  
William Cooley, PhD 
 
 
 
 
Cooley Consulting, Inc. 
 
 
 
 
531 Chisholm Trail 
Wyoming, OH 45215 
United States 
Phone: 513-522-3797 
 
 


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Purpose of the Study and Background 
 
Objective: The purpose of this study is to characterize basic PK parameters (Cmax, t1/2, 
AUC, and total urinary recovery) to contribute to evidence for the safety of Advantage 
Arrest, consistent with Guidance for Industry--Exposure--Response Relationships (April 
2003). On a preliminary basis, we will also characterize the microbiome before and 24-
hours after the topical treatment.  
 
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. 
 
Assumptions: 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. The total urinary recovery of fluoride, 
adjusted for baseline levels, will be calculated to estimate the minimum amount 
absorbed in each patient following application of the varnish.  As biliary excretion is the 
principle route of elimination of silver (Lansdown et al., 2010), it is unlikely that 
significant amounts of silver will be recovered in the urine. 
 
 
Criteria for Subject Selection 
 
Number of subjects: There will be up to 20 healthy adult subjects enrolled in the study 
with the goal of at least 16 subjects to complete the study.  
Gender of subjects: The subjects will be approximately half male and half female. 
Age of subjects: Subjects must be 18 years of age or older. 
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 have at least 20 teeth. Subjects will be healthy and 
taking no prescription or OTC medications, including topical fluoride gels or rinses. 
Healthy status will be determined by self-reported medical history by the attending 
clinician. 
 


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Exclusion criteria: Subjects will be excluded if they have oral mucositis or any 
ulcerative lesions or hypersensitivity to silver or fluoride.  Subjects who are pregnant, 
breastfeeding, or weigh less than 110 pounds will not be eligible to participate. 
 
 
Methods and Procedures 
 
Design of the Study and Minimization of Bias: Open label exposure--response study. 
 
Randomization: Not applicable 
 
Blinding:  Not applicable 
 
Baseline procedures: When informed consent has 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 24-hour blood draw period. An 
18 gauge sterile venous cannula will be placed in an upper extremity. An initial blood 
sample of 6 mL (one tube for serum collection) will be withdrawn using a fluoride free 
tube (BD Vacutainer with Clot Activator Plus Royal Blue Stopper). Subject will void for a 
baseline urine sample collection. Using a dental microbrush, dental plaque will be 
collected from the buccal surfaces of the upper posterior teeth and the microbrush 
inserted in a sampling tube and agitated.  
 
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 that 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 facial 
cervical surfaces of 5 posterior teeth 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 3 minutes and then rinsed with water and high volume evacuation. 
Subjects will not eat for at least 2 h following application of the test agent. 
 
Blood, urine and plaque sampling following intervention: 
Subjects will have blood samples of 6 mL withdrawn at 30 min, 1h, 2h, 3h, 4h, 6h, 8h, 
12h and 24 hours.  Urine will be collected for a 24-hour cumulative sample following 
application of the study intervention.  Subjects will continue to collect urine in the 
original container until 12h and be provided instructions and a container to continue the 
urine collection to 24 hours. Subjects will remain at the research site through the 12 
hour blood and urine collection and return for the 24-hour timepoint.  A 24-hour plaque 
sample will be obtained in the same manner as the baseline sample. 


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Blood, urine and plaque sample processing: 
Blood samples will be spun in a clinical centrifuge, the serum withdrawn, and then the 
serum will be frozen for later analysis. The total volume of urine at baseline, 12 and 24 
hours will be recorded and a 10 mL aliquot will be taken of each sample and frozen for 
later analysis. Plaque samples will be placed in a receiving tube, the tube agitated, and 
the contents frozen for later analysis. 
 
Sample Analysis: Serum and urine 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. Total amount recovered will be calculated from urine samples.  
Plaque will be analyzed by 16S ribosomal RNA profiling. 
 
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 Clinical Research 
Center at the UWMC and in a locked cabinet and on password protected computers at 
the Regional Clinical Dental Research Center at the University of Washington School of 
Dentistry. Only investigative personnel will have access. The data will be available for 
inspection by regulatory monitors and FDA. 
 
 
Risk-Benefit Assessment 
 
Risk Category: Greater than Minimal Risk 
 
Potential Risk: Hypersensitivity to silver or fluoride, changes to intraoral tissues: 
erythema, gingival inflammation, or soft tissue changes. Advantage Arrest has been 
used extensively since clearance as a medical device in 2014 and the Sponsor knows 
of no adverse effects. The same agent is approved in 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 in the Clinical Research 
Center at the University of Washington Medical Center and the Regional Clinical Dental 
Research Center at University of Washington School of Dentistry by licensed personnel 
under the Institute of Translational Health Sciences.  
 


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Potential Benefits:  There is no direct benefit to the participant. 
 
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 from among University of Washington (UW) employees, 
patients, or visitors.  Flyers will be posted in the UW Health Sciences to notify potential 
subjects of the opportunity to participate. They will call or email staff at the School of 
Dentistry Regional Clinical Dental Research Center (RCDRC) 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 dental staff and enrolled.  
 
Process of Consent: Potential participants 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 to take part in the study.  
They will be reminded that whether or not they decide to participate will not affect their 
care at the UWMC or the School of Dentistry and they can ask questions about 
participation or discontinue participation at any time.   
 
Subject Capacity: Participants must have the capacity to give informed consent, be 
English speaking and able to read and understand English.   
 
Subject / Representative Comprehension: Potential participants 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: Once potential participants have had a chance to read 
the approved consent form and had their questions answered following the consent 
discussion, they will be asked to sign the form.  The study staff will sign the form and 
provide the participant a fully signed and dated copy.  The original signed consent form 
will be stored in a locked cabinet at the Regional Clinical Dental Research Center at the 
University of Washington School of Dentistry. 
 
Costs to the Subject: The participants will not incur any costs associated with the 
study. 
 
Payment for Participation: A $400 volunteer compensation will be provided following 
the 24-hour timepoint to defray the costs of parking, transportation and any 
inconvenience from 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. 
 


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PROTOCOL_SDFPK-2016-11-08_(clean).docx 
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. 
 
 

SAP_001.pdf: 
Analysis Plan: Pharmacokinetics of Advantage Arrest 
NCT04184271 
Document Date: 07/30/2020 
For the pharmacokinetic analysis, baseline serum fluoride and silver concentrations will be 
assessed and when appropriate, subtracted from other timed serum concentrations to adjust for 
baseline levels.   
Pharmacokinetic analysis will be performed using Phoenix WinNonlin (Certara).  
• 
The time to peak concentration (Tmax), observed and baseline-corrected peak 
concentrations (Cmax), and observed 24-h concentration (C24 h) will be reported.  
• 
The elimination rate constant (kelim) will be determined by nonlinear regression with a 
minimum of 3 time points with decreasing concentrations over time observed after the 
peak concentration. 
• 
Half-life (t1/2) will be calculated as ln(2)/kelim. 
• 
Area under the curve (AUC): The 24-hour AUC (AUC0-24 hr) will be calculated using a log-
linear trapezoidal rule of baseline-corrected serum concentrations from time = 0 to 24 h. 
The AUC0-∞ will be calculated using a log-linear trapezoidal rule of baseline-corrected 
serum concentrations and extrapolated to infinite time by C24hour/kelim, where C24hour is the 
24 hour concentration.  
• 
The percent extrapolated AUC will be calculated as (AUC0−∞ − AUC0–24 hr)/AUC0−∞ x 100. 
• 
The total urinary recovery of fluoride and silver will be determined by multiplying the 
concentration measured in the urine collected over 24 hours by the total volume of urine 
collected over 24 hours.  
Statistical analysis will be performed using Excel to calculate the mean ± standard deviation for 
the pharmacokinetic parameters.  No statistical comparisons will be made as it is a single arm 
study.