Effectiveness of Silver Diamine Fluoride in Arresting Early Approximal Carious Lesion Progression: A Pilot Study
Phase: NA
Conditions: Dental Caries
Sponsor: Justine Kolker

• Oﬃcial Title:  EﬀecƟveness of Silver Diamine Fluoride in ArresƟng Early Approximal Carious Lesion 
Progression: A Pilot Study 
• NCT Number:  NCT02591147 
• Document Date: May 1, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ObjecƟve: The objecƟve of this study is to evaluate the eﬀecƟveness of 38% Silver Diammine 
Fluoride (SDF) in arresƟng iniƟal non-cavitated approximal carious lesion in adults aged 21-64 years 
uƟlizing three methods: pairwise comparison of individual radiographs, visual assessment of subtracƟon 
radiographs and histogram analysis of subtracƟon radiographs.  
Design: This study is a randomized, triple-blinded, and placebo-controlled clinical trial 
(ClinicalTrials.gov identiﬁer-NCT02591147). The study populaƟon consisted of adults aged 21-64 years 
old who are seeking care at the University of Iowa, College of DenƟstry and Dental Clinics. Eligibility for 
the study includes having at least one iniƟal non-cavitated approximal posterior carious lesion 
(Radiologic scores RA1, RA2, or RA3 using the InternaƟonal Caries ClassiﬁcaƟon and Management 
System (ICCMS) scoring system) that was in contact with an adjacent non-restored tooth surface.  
Methods: Consented subjects will be randomly assigned to one of the two study arms, either 
treatment (38% SDF soluƟon) or placebo (water) designated as soluƟons “A” and “B”. ParƟcipants will 
complete beverage intake and caries risk quesƟonnaires at baseline and 12 months.  The selected lesion 
will be followed at 6 and 12 months. A bitewing radiograph will be made at baseline uƟlizing a bite 
registraƟon holder to insure close geometrical alignment of subsequent follow up radiographs. Lesion 
progression will be monitored radiographically through three methods: pairwise comparison of 
individual radiographs, visual assessment of subtracƟon radiographs and histogram analysis of 
subtracƟon radiographs.  
StaƟsƟcal Analysis Plan: The primary outcome of interest is whether there is caries progression 
based upon radiographic evaluaƟon, evaluated at 12 months, for the two study arms. The analyƟc 
approach, which will uƟlize binary logisƟc regression modeling for correlated data, will consider the 
dependencies (correlaƟons among data points) that typically arises with longitudinal data. For analyses 
targeƟng a speciﬁc Ɵme point, this is not a concern, because there is only a single measurement per 
individual, and standard binary logisƟc regression methods can be applied. A widely accepted method to 
deal with these types of dependencies is using generalized esƟmaƟng equaƟons (GEE). We will also 
consider mixed modeling approaches as part of these invesƟgaƟons as appropriate. Model selecƟon will 
be guided by the use of Akaike’s criterion and its modiﬁcaƟons; parƟcular consideraƟons will be given to 
selecƟon of the covariance structure addressing data dependencies, for which approaches have been 
developed in both the GEE and mixed modeling contexts. A primary goal in all analyses will be to 
formally compare the two treatment arms and, in doing so, to obtain esƟmates of eﬀect sizes and 
associated variability for the planning of future trials. Throughout, the primary covariate of interest will 
be treatment arm; the eﬀects of covariates including paƟent demographics, dietary intakes and 
behaviors, other aspects of caries risk assessment, and caries score (DMFT/DMFS) as a measure of 
disease burden and risk will also be assessed. All analyses will be carried out in accordance with 
intenƟon-to-treat principles.  The analyses just described will provide esƟmates of treatment eﬀects and 
associated measures of variability to assist in planning a future deﬁniƟve trial. In addiƟon, atriƟon rates 
will be esƟmated, and 95% conﬁdence intervals will be constructed for each Ɵme point and treatment 
arm.  Because there is evidence that silver diamine ﬂuoride is also a prevenƟve agent, assessment of 
diﬀerences in incident caries between the two treatment groups is of parƟcular interest as a secondary 
aim. We will consider measures reﬂecƟng the development of new lesions, considering issues of tooth 
erupƟon and loss between examinaƟons (caries increment). The crude caries increment will be 
supplemented with net caries increment allowing for examiner reversals, and with the adjusted caries 
increment. Poisson models, or Poisson models augmented with an over dispersion parameter or an 

extension to account for zero count inﬂaƟon, have generally been found useful for examining the 
relaƟonships between counts of aﬀected teeth or surfaces, and can be applied to incident disease while 
accounƟng for correlated outcomes, including correlaƟons among surfaces or subgroups of surfaces 
within an individual. AlternaƟves, such as the negaƟve binomial model, are available if the Poisson is not 
appropriate. We note that linear regression approaches have someƟmes been appropriately used to 
model caries increment. Candidate independent variables are as described above.  Inter-and intra-rater 
reliability will be assessed for both radiographic and clinical measures of progression, using intraclass 
correlaƟons for quanƟtaƟve outcomes, and kappa staƟsƟcs for categorical outcomes; weighted kappa 
will be used for ordinal categorical measures. RelaƟonships between radiographic and clinical measures 
of progression will be assessed, using Spearman rank correlaƟon when the two measures being 
compared are ordinal or quanƟtaƟve. Binary outcomes (presence or absence of progression) will be 
assessed using McNemar’s test (or the exact binomial test if appropriate); in this instance, evaluaƟon of 
the level agreement of the two approaches will also be assessed using unweighted kappa. DescripƟve 
staƟsƟcs and graphics will further illustrate any idenƟﬁed relaƟonships.