Clinical trial NCT04183231
Conditions: Dental Caries
Keywords: adults povidone iodine sodium fluoride
Sponsor: Advantage Silver Dental Arrest, LLC
Start date: 2016-11-01; Completion date: 2018-04-25
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study aim is to characterize the kinetics of iodine and fluoride following topical application of a combined PVP-I and NaF anti-dental caries varnish in healthy adults.

Detailed description:
The study was to characterize serum iodine and fluoride levels over 24 hours after application of a topical dental varnish in healthy adults 23 to 57 years old.

Arms: arm 1: topical dental varnish, 10% PVP-I, 2.5% NaF, topical application to teeth, 0.4 ml, single application
Interventions: intervention 1: Anti-caries varnish
Intervention descriptions: intervention 1: topical tooth varnish

Protocol documents:
Prot_SAP_000.pdf: 
Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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Protocol: Pharmacokinetics of Advantage Anti-Caries Varnish 
Protocol version: 2016-04-05 
Amended: 2020-07-29 
NCT04183231 
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: 
Clinical Research Center (7 South) 
University of Washington Medical Center (UWMC) 
1959 NE Pacific Street 
Seattle, WA 98195 
United States 
phone: 206-598-4730 


Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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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,
Cmin, AUC, and total urinary recovery) to contribute to evidence for the safety of 
Advantage Anti-Caries Varnish, consistent with Guidance for Industry--Exposure--
Response Relationships (April 2003). On a preliminary basis, we will also characterize 
the microbiome before and immediately after the topical treatment. 
Background: Topical fluorides have been the mainstay in the prevention of dental 
caries for decades. There is abundant data on sodium fluoride’s (NaF) ability to foster 
remineralization of tooth enamel (Gao et al., 2016).  Dental NaF varnish preparations 
are recommended vehicles for delivering topical NaF for dental caries prevention and 
arrest according to guidelines from the American Dental Association (ADA) and the US 
Preventive Services Task Force (Weyant et al., 2013; Moyer VA 2014). 
However, topical fluoride alone is not enough to thwart tooth decay in high-risk 
populations.  Caries researchers for some time have suggested strategies that combine 
an antiseptic with topical fluoride to reduce or eliminate the oral cariogenic bacteria 
reservoir in addition to topical fluoride, which primarily remineralizes enamel (Milgrom et 
al 2009). Povidone iodine is an FDA-approved and widely used bactericidal antiseptic. 
For the oral flora, iodine has preferential activities against streptococcal species, 
pathogens implicated in the causation of dental caries (Tam et al., 2006; Furiga et al., 
2008). Moreover, iodine's effectiveness may last as long as 6 months (Caufield et al., 
1979).   
Two cohort studies have tested the effect of combining these two anti-caries agents by 
sequentially applying povidone iodine (10%) followed 5% NaF varnish. The first study 
assessed the effect of protecting erupting 1st permanent molars from developing dental 
caries in children five to six years old (Tut & Milgrom, 2010). The second studied the 
effect in the primary dentition of children 12 to 30 months (Milgrom, Tut & Mancl, 2011).  
They demonstrated that treatment with povidone iodine reduced the rate of new decay 
significantly over the standard of care alone. Yet, to date, such combination products 
have not been brought to the market. Advantage Anti-Caries Varnish was developed to 
combine the antiseptic povidone iodine and sodium fluoride varnish into a single product 
for ease of application.    
The FDA has reviewed this protocol and issued IND 128835 for this work after 
extensively reviewing the human experience and safety data provided by the Sponsor. 
The basic dental varnish formula is already cleared by the FDA as a medical device and 
Elevate Oral Care, LLC currently in marketing the varnish. To our knowledge there have 
been no adverse event reports on this varnish and it has never been withdrawn from the 
market. Povidone iodine is widely used in medicine.  It has been used for intraoral 
application for many years without problems. Dental NaF varnish and povidone iodine 
have been applied sequentially at the same patient visit by clinicians for some time and 
two cohort studies have been published with no reports of harms. 
Assumptions: This is a topical agent where the active ingredients are applied to the 
teeth and eventually swallowed and absorbed through the GI tract. Minimal amounts are 


Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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absorbed through the oral mucosa. Concentrations of iodine and fluoride in the serum 
will be be directly in proportion to the dose of povidone iodine administered topically to 
the teeth as part of the varnish.  The total urinary recovery of iodine and fluoride, 
adjusted for baseline levels, will be calculated to estimate the minimum amount 
absorbed in each patient following application of the varnish. 
Criteria for Subject Selection 
Number of subjects: There will be 4 up to 20 healthy adult subjects.  
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. Healthy status will be determined by history 
by the attending clinician. 
Exclusion criteria: Subjects will be excluded if they have oral mucositis or any 
ulcerative lesions or hypersensitivity to iodine. Individuals with known hypothyroidism, 
hyperthyroidism, iodine sensitivity, dermatitis herpetiformis, hypocomplementemic 
vasculitis, nodular thyroid with heart disease, multinodular goiter, Graves’ disease, and 
autoimmune thyroiditis will be excluded from participation in the study.  Subjects who 
are pregnant 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. It will be confirmed that no seafood 
or shellfish has been consumed the day prior to or day of the baseline appointment 
through the 24-hour blood draw period and non-fluoride toothpaste is 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 with a Heparin lock so that the 
cannula will remain patent. An initial blood sample of 10 mL (one tube) will be withdrawn 
using a fluoride free tube. Subject will void for a baseline urine sample collection. 
Subsequent urine will be collected for a 24-hour cumulative sample following application 
of the study intervention.  Using a dental microbrush, dental plaque will be collected 


Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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from the buccal surfaces of the upper posterior teeth and the microbrush inserted in a 
sampling tube and agitated. Subjects will not eat for at least 2 h following application of 
the varnish. 
Study intervention: Advantage Anti-Caries Varnish. The active ingredients are 10% 
(w/v) Povidone Iodine CAS RN 25655-41-8 and 5% (w/v) Sodium Fluoride CAS RN 
7681-49-4 in Ethanol 200 Proof [Cascade Custom Chemistry, Eugene, OR]. The 
formulation of the dosage form includes 10% Nt-2 Premium Shellac, 1% sodium 
phosphate, dibasic anhydrous, 0.5% ammonium phosphate, monobasic, and 1% 
caramel cream flavor (Bell 29.26303) as inactive ingredients.   
The specific procedure is a single topical application of 0.4 mL of Advantage Anti-Caries 
Varnish to the teeth. Teeth will be brushed with a soft toothbrush to remove debris and 
dried with cotton prior to application. The varnish will be dispensed into a disposable 
plastic dappen dish premarked to indicate the proper volume and applied with a dental 
applicator brush. The entire contents of the dappen dish will be applied following the 
baseline procedures. 
Blood, urine and plaque sampling following intervention: 
Subjects will have blood samples of 10 mL withdrawn at 30 min, 1h, 2h, 3h, 4h, 6h, 8h, 
12h and 24 hours.  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 for 12 hours and return for the 24-hour 
timepoint.  A 24-hour plaque sample will be obtained in the same manner as the 
baseline sample. 
Blood, urine and plaque sample processing: 
Blood samples will be spun in a clinical centrifuge, the plasma withdrawn, and then the 
plasma will be frozen for later analysis. The total volume of urine at baseline and 24 
hours will be recorded and a 10 mL aliquot taken 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: Blood and urine samples will be analyzed by ion chromatography 
using EPA standard methods. Cmax, Cmin (last measurable time point), t1/2, and the 
AUC will be calculated. 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 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.  


Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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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 the varnish components, changes to intraoral 
tissues: erythema, gingival inflammation, or soft tissue changes. Both the sodium 
fluoride varnish and povidone iodine are already cleared by the FDA and have been 
used for many years intraorally. Fluoride varnishes are recommended by the US 
Preventive Services Task Force and professional organizations.  There also 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 UWMC by licensed personnel under the Institute of Translational Health 
Sciences.  
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.   


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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 blood draw to defray the costs of parking, transportation and any 
inconvenience from study participation. 
References: 
ATSDR (Agency for Toxicological Substances and Disease Registry), U.S. Department 
of Health and Human Services, Public Health Service. Toxicological Profile For Iodine 
(2004). Available at: http://www.atsdr.cdc.gov/ToxProfiles/tp158.pdf; Last accessed 
October 22, 2015. 
Caufield PW, Gibbons RJ. Suppression of Streptococcus mutans in the mouths of 
humans by a dental prophylaxis and topically-applied iodine. J Dent Res. 1979 
Apr;58(4):1317-26.  
Furiga A1, Dols-Lafargue M, Heyraud A, Chambat G, Lonvaud-Funel A, Badet C. Effect 
of antiplaque compounds and mouthrinses on the activity of glucosyltransferases from 
Streptococcus sobrinus and insoluble glucan production. Oral Microbiol Immunol. 2008 
Oct;23(5):391-400. doi: 10.1111/j.1399-302X.2008.00441.x. 
Gao SS, Zhang S, Mei ML, Lo EC, Chu CH. Caries remineralization and arresting effect 
in children by professionally applied fluoride treatment – systematic review. BMC Oral 
Health. 2016 Feb 1;16(1):12. doi: 10.1186/s12903-016-0171-6. 
Gosselin RE, Smith RP, Hodge HL, Braddock JE. Clinical toxicology of commercial 
products. 5th ed. Baltimore: Williams and Wilkins,1984:III,213–4. 
Milgrom P, Tut OK, Mancl LA.  Topical iodine and fluoride varnish effectiveness in the 
primary dentition: A quasi-experimental study. J Dent Child (Chic). 2011 Sep-
Dec;78(3):143-7. 
Milgrom P, Zero DT, Tanzer JM. An examination of the advances in science and 
technology of prevention of tooth decay in young children since the Surgeon General's 


Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29) 
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Report on Oral Health. Acad Pediatr. 2009 Nov-Dec;9(6):404-9. doi: 
10.1016/j.acap.2009.09.001.  
Moyer VA, US Preventive Services Task Force. Prevention of dental caries in children 
from birth through age 5 years: US Preventive Services Task Force recommendation 
statement. Pediatrics. 2014 Jun;133(6):1102-11. doi: 10.1542/peds.2014-0483. Epub 
2014 May 5.  
Phillips DIW, Lusty TD, Osmond C, Church D. Iodine supplementation: comparison of 
oral or intramuscular iodized oil with oral potassium iodide. A controlled trial in Zaire. Int 
J Epidemiol 1988;17:142–7. 
Tam A1, Shemesh M, Wormser U, Sintov A, Steinberg D. Effect of different iodine 
formulations on the expression and activity of Streptococcus mutans 
glucosyltransferase and fructosyltransferase in biofilm and planktonic environments. J 
Antimicrob Chemother. 2006 May;57(5):865-71. Epub 2006 Mar 20. 
Tut OK, Milgrom P. Topical iodine and fluoride varnish combined is more effective than 
fluoride varnish alone for protecting erupting first permanent 
molars: a retrospective cohort study. J Public Health Dent 2010; (1): 1-4.   
Weyant RJ, Tracy SL, Anselmo TT, Beltrán-Aguilar ED, Donly KJ, Frese WA, Hujoel 
PP, Iafolla T, Kohn W, Kumar J, Levy SM, Tinanoff N, Wright JT, Zero D, Aravamudhan 
K, Frantsve-Hawley J, Meyer DM; American Dental Association Council on Scientific 
Affairs Expert Panel on Topical Fluoride Caries Preventive Agents. Topical fluoride for 
caries prevention: executive summary of the updated clinical recommendations and 
supporting systematic review. J Am Dent Assoc. 2013 Nov;144(11):1279-91.  


Analysis Plan 
For the pharmacokinetic analysis, baseline serum iodine and fluoride concentrations will be 
subtracted from other timed serum concentrations to adjust for baseline endogenous levels of 
iodine and fluoride. Baseline-corrected concentrations that have a negative value (i.e., 
measured concentration was lower than baseline concentration) or result in concentrations at 
the limit of detection for multiple time points (i.e., 10 ng/mL for fluoride) will be excluded.  
Pharmacokinetic analysis will be performed using Phoenix WinNonlin (Certara). 
•
The elimination rate constant (kelim) will be determined by nonlinear regression of the
terminal slope.
•
Area under the curve (AUC): The AUC0-∞ will be calculated using a log-linear trapezoidal
rule of baseline-corrected serum concentrations and extrapolated to infinite time by
Clast/kelim, where Clast is the last concentration used in the estimation of kelim. The 24-hour
AUC (AUC0-24 h) will be calculated using a log-linear trapezoidal rule of total iodine or
fluoride serum concentrations from time = 0 to 24 h.
•
The total urinary recovery of iodine and fluoride 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.
•
The renal clearance of iodine and fluoride will be calculated as the total urinary
recovery/AUC0-24 h.
•
The time to peak concentration (Tmax), observed and baseline-corrected peak
concentrations (Cmax), and observed 24-h concentration (C24 h) will be reported.
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. 
Protocol and Analysis Plan-VarnishPK-ND128835 (amended 2020-07-29)