Double Blind Randomized Controlled Clinical Trial of Lesion Progression After Treatment With Icon vs. Placebo in Caries Lesions in Young Adults Over 36 Months
Phase: NA
Conditions: Caries, Salivary Function, Tooth Sensitivity
Sponsor: DMG Dental Material Gesellschaft mbH

 
 
 
 
 
 
NCT Title:  
Lesion Progression After Icon Treatment 
in Young Adults 
 
NCT Number:   
 
NCT01988337 
 
IRB Approval Date:   
10/03/2014 
 
 
 
 
 
Content: 
 
1. Study Protocol 
 
2. Statistical Analysis Plan 
 
 
 
 
 
 
 

Study Protocol 
Title: 
Double Blind Randomized controlled clinical trial of 
lesion progression after treatment with Icon vs. Placebo 
in caries lesions in young adults over 36 months 
Short Title: 
 
 
Lesion progression after Icon treatment in young adults 
Running Title:  
 
TOPIC_36_Study  
Protocol-ID: 
 
 
NCT01988337  
+ 1 Amendment  valid as of 30.11.2015 (Appendix 9) 
+ 1 Amendment valid as of 21.12.2016 (Appendix 10) 
Sponsor: 
 
 
DMG Dental Material Gesellschaft mbH 
 
 
 
 
Elbgaustraße 248 
 
 
 
 
22547 Hamburg 
 
Study Site: 
 
 
University of Alabama at Birmingham 
 
 
 
 
School of Dentistry 
 
 
 
 
1919 7th Avenue South 
 
 
 
 
Birmingham, AL 35294 
 
 
 
 
United States 
Version:  
 
 
StudyProtocol_NCT01988337_5.0
 
Replaces Version:  
 
StudyProtocol_NCT01988337_4.0
 
Date:  
 
 
21-Dec-2016 
 
  
 
 
 

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1 Synopsis of the Clinical Investigation 
Introduction 
Dental caries is the most widespread of all diseases. It causes destruction of tooth structure by 
dissolving the enamel on the outside of the tooth first and then progressing into the inside of the 
tooth. While it is possible to use traditional dental fillings to replace diseased tooth structure, it is far 
better to slow down or reverse the disease process so that no fillings are needed. One of the most 
difficult places to use preventive or non-surgical treatment is the contact area between teeth. 
Recently there is evolving interest in using composites to infiltrate enamel and dentin areas that have 
just begun to be destroyed by caries. The infiltration technique arrests the lesion progression by 
sealing the porous surface and restores the damage avoiding ongoing acidic damage of tooth 
structure. 
 
Objective 
Assess the clinical efficacy s of using Icon to infiltrate initial lesions below the tooth surfaces that 
exist on the contact surfaces between posterior teeth as a means of stabilizing diseased tooth 
structure and arresting further lesion development.  
 
Materials and Methods 
One hundred fifty volunteers (14+ years) with two early lesions in posterior teeth will be enrolled 
into a clinical trial to evaluate the clinical efficacy of infiltrating the lesions as compared to current 
watch-and-wait approaches that are combined with good oral hygiene and fluoride application. Each 
subject will have a treated lesion and a control lesion. Only small early lesions without clinical signs of 
surface cavitation will be selected. The control lesions will be stabilized through a normal preventive 
regimen, while the treatment lesions will be infiltrated with a resin. Lesion status will be monitored 
every six months by clinical examination and as well using annual radiographs. 
 
Clinical Significance 
Infiltrating a caries lesion is a potential effective strategy to strengthen damaged tooth structure and 
to reduce caries progression without any surgical intervention. 
 
 

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1.1 Description of the CIP 
The objectives of the CIP are to provide a full description of the planned clinical trial. The preceding 
short narrative (Synopsis) introduced the goal of the project and its approach to investigate the 
clinical efficacy of management of early caries lesions by resin infiltration. 
1.2 Sponsor 
DMG 
Dental Material Gesellschaft mbH 
Elbgaustraße 248 
22547 Hamburg 
GERMANY 
www.dmg-dental.com 
+49 40 840 060 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.3 The Study Organization 
The trial organization is located at the School of Dentistry at the University of Alabama, Birmingham, 
AL, USA. 
 has broad experiences in clinical research being engaged in patient-
oriented research for years. He will be the Principal investigator and the main contact for study 
communications (clinical site) 
 
1.3.1 
Principal Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2 Head of the Clinical study (Sponsor) 
 
 
1.3.3 Regulatory Affairs/ Clinical Monitoring 
 
  
 

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1.4 Abstract 
This is a three year single site clinical evaluation of a FDA approved (510(k):K100062) lesion 
penetrating resin used to infiltrate and hamper progression of proximal carious lesions. The purpose 
of this study is to compare lesion progression infiltrated with (Icon, Hamburg, Germany) to a similar 
sized lesion in the same patient treated with a placebo. The study is designed as a randomized, 
controlled, prospective clinical trial with a three year follow-up evaluation period. 
The clinical site will enroll 150 subjects (in the age range of 14 years or older) with 2 study lesions. 
The patients will be evaluated at six time points over a period of 3 years. Lesion status and caries risk 
will be monitored at 6-month intervals, while radiographic evaluation will be conducted at 12-month 
intervals at 1-, 2- and 3-year recall visits. 
This controlled trial will assess the positive effects of caries lesion infiltration by Icon and may open a 
new therapeutic strategy in dentistry to establish a micro-invasive therapy. 
 
 

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2.3 Instructions for use 

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3 Objectives of the Clinical Investigation Plan (CIP) 
The objectives of the CIP are to provide a full description of the planned clinical trial. The preceding 
short narrative (Synopsis) introduced the goal of the project and its approach to investigate the 
clinical effectiveness of management of early caries lesions by resin infiltration. The Background and 
Rationale section addresses the relevance of the project to oral health and the rationale for the 
proposed project. The existing knowledge is briefly stated, including literature citations and 
highlights of relevant data, indicating the gap that the project is intended to fill. The research plan 
includes the Study Design and Methods addressing the hypotheses to be tested, followed by Specific 
Aims. The data collection and analysis (including assessment of statistical significance) will be 
described and used to prove or disprove the hypotheses. Previous experience with the materials 
involved is described including attention to risk analysis. Expected results, potential difficulties and 
limitations are discussed and solutions or alternative approaches indicated. 
 
Project Overview and Professional Support 
Based on internationally accepted protocols we have designed a prospective, randomized controlled 
clinical trial (RCT) to investigate the effect of a novel infiltration method as an alternative treatment 
option for early caries lesions. The Clinical Investigation Protocol for this study includes all 
components and documentation as required to conform to international standards for clinical 
research (CONSORT], ISO/DIN 14155:2011 and Good Clinical Practice Guidelines.20-22  
 
 
 

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4 Preliminary Investigations and Justification of the CIP 
4.1 Background and Rationale  
Fissure sealing has been shown to inhibit not only the formation of occlusal caries but also to impede 
the progression of existing caries lesions.27-29 Pit-and-fissure sealants are an effective way at 
preventing caries in children and adults—even in early noncavitated (incipient) lesions, according to a 
new set of ADA evidence-based clinical recommendations.30 Lately, the concept of sealing caries to 
arrest lesion progression has been transferred to approximal surfaces. 31,32 In a clinical study sealed 
approximal lesions showed significantly reduced progression after 18 month compared with those 
that were treated only with preventive measures.32 In addition, it has been shown in contemporary 
European populations that lesions, radiographically progressed into dentin, were not cavitated in 
60% of the cases.33 This indicates that non-invasive management of such lesions is preferred above 
invasive operative-restorative treatment options. The pores of enamel caries lesions provide 
diffusion pathways for acids and dissolved minerals. The aim of lesion infiltration is to occlude these 
pores by infiltration with light curing resins in order to block the diffusion of acids into the lesion 
body.33-34 In contrast to sealing of caries, caries lesion infiltration aims to occlude the pores within the 
lesion rather than placing a diffusion barrier on the lesion surface. Several in-vitro studies showed 
significantly reduced progression of infiltrated enamel lesions in demineralizing environments.35-36  
Caries results from a dynamic series of demineralization and remineralization cycles when 
demineralization dominates. Demineralization initially produces a small non-cavitated area on 
enamel (white spot lesion) which can progress to a cavitated lesion unless remineralization 
dominates.  In the initial lesion development white spot lesions have an intact hyperminerialized 
surface with subsurface demineralization.  As demineralization continues, surface enamel cavitates 
and this defect must be restored to create proper form and function to the tooth. Caries is a 
multifactoral disease caused by cariogenic bacteria established in the oral biofilm. These bacteria23 
metabolize sucrose or other cariogenic carbohydrates (fructose or glucose) and secrete organic acids 
(lactic, propionic, and formic) that cause mineral ion loss (calcium and phosphates) and 
demineralization of the tooth. Mineral lost by this method can be replaced during periods of neutral 
pH (remineralization) from calcium and phosphates in the saliva. Remineralization is facilitated by 
fluoride and can arrest carious demineralization in enamel by the formation of a hard outer surface. 
Periods of demineralization and remineralization make up a continuous cycle by which minerals in 
tooth structure are removed and replaced. If the balance is tipped toward demineralization, carious 
lesions develop. 

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The caries process in dentin is similar to enamel, except that dentin demineralization begins at a 
higher pH (6.4, compared to 5.5 for enamel) and proceeds about twice as rapidly; this is because 
dentin has only half the mineral content of enamel. Low fluoride levels24 are insufficient to initiate 
dentin remineralization but are adequate to facilitate enamel remineralization. Fluoride-ion 
concentration in saliva is low, averaging about 0.03 ppm (1.6 pmol/L) in the normal subject. In 
enamel, at fluoride levels around 3 ppm25-26, if adequate calcium is present the balance of mineral 
uptake and loss is shifted from net demineralization to net remineralization. 
Dental decay is a slowly progressing disease taking several years to advance through the enamel into 
the dentin of permanent teeth. Progression of caries through enamel and dentin are variable and 
depend upon the amount of saliva, oral hygiene practices, fluoride use as well as the frequency of 
sucrose intake, however if proximal caries has reached the inner part of the enamel radiographically, 
it is difficult to halt further progression and many lesions having reached this stage are restored.  
This is based partly on the assumption that carious lesions once reaching dentin will continue to 
progress and that a restoration is necessary at this stage.  A Swedish longitudinal study following 
teenagers that participated in a rigorous oral hygiene program were clinically and radiographically 
followed during a 15-year period. 27 Even with this high level of preventive care, many had 
progressing proximal lesions. For a long time sealants have been used to prevent caries on occlusal 
surfaces with great success. Sealants have also been successfully used therapeutically when initial or 
even moderately deep occlusal caries developed.28,29 Sealing lesions on smooth surfaces has also 
been tried in vitro and the suggestion was that such an approach might delay lesion progression 
rather than arrest the lesion. 30-32 The latter authors suggested adopting the sealing approach of 
initial carious lesions on proximal surfaces. There are many possibilities for stopping or reversing the 
advancement of the lesion. For non-cavitated lesions, remineralization is the natural repair process 
that relies on the local environment: sufficient saliva flow, availability of calcium and phosphate ions, 
fluoride, microflora and optimal environmental pH to rebuild a new surface after demineralization. 
However, if the environment favors demineralization the lesion will continue and cavitate spreading 
to dentin. Due to the structural difference of dentin, lesions in dentin progress more rapidly than 
enamel lesions requiring earlier intervention. Improvements in dental materials are promising but 
there is yet to be a material that carries all mechanical and physical characteristics of the natural 
tooth. Therefore, it is important to maintain the structure and arrest lesions before they advance.  
Lesion treatments of enamel caries focus on remineralization using topical applications of fluoride or 
amorphous calcium phosphate and emphasizing oral hygiene procedures. However, the success of 
these treatments is dependent on the patient’s compliance which is especially difficult in the 

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proximal areas, where plaque removal is more difficult. Typically, most clinicians will observe small 
proximal lesions which are located entirely in enamel and typically recommend preventive measures 
rather than restoration.  If the subject is lost to recall and the lesion continues, a larger lesion 
develops which requires restoration.  Treating carious tooth pulp exposures is consequential, often 
requiring either extraction or root canal therapy. Both the loss of the tooth and its replacement, or 
endodontic treatment and tooth restoration, involve multiple appointments and considerable 
expense. A procedure which does not depend upon patient’s compliance would be a micro-invasive 
treatment such as resin infiltration of the subsurface lesion which would eliminate dependence on 
the patient’s compliance.  A newly developed surface infiltrating resin has been developed by DMG 
(Hamburg, Germany).  The infiltration technique has significant advantages since it is a non-invasive 
system requiring no irreversible removal of tooth structure and eliminates drilling and most pain 
associated with tooth restoration. Evidence is building that this system stops or slows the proximal 
carious lesion progression.  Paris and Meyer-Lückel evaluated the effectiveness of resin infiltrated 
carious proximal lesions in an 18 month study using standardized radiographs and digital 
subtraction.12  They concluded that a resin infiltration into the inner half of enamel or the outer third 
of dentin is an effective way to reduce carious lesion progression.33 Martignon et al, using a 
radiographic comparison technique, reported that a caries infiltrating resin was more effective 
method for treating proximal enamel lesions than sealing or flossing over a two year period. 8,34 
Ekstrand et al compared resin infiltration and fluoride varnish to fluoride varnish only in primary 
molars after one year.  Resin infiltration and fluoride varnish was 35% more effective than fluoride 
varnish alone. 8,35 Alkilzy and Splieth reported that caries infiltration provided a simple, minimally 
invasive method for treating proximal initial caries.36 The objective of this three year study is to 
evaluate the efficacy of sealing initial proximal lesions. 
 
Clinical Significance 
Infiltrating a caries lesion is a potentially effective strategy to strengthen damaged tooth structure 
and to reduce caries progression without any surgical intervention. Management of early lesions by 
infiltration instead of or postponing restorative treatment would have a great impact towards 
improving oral health care by means of its non-invasive nature. It will drastically lengthen the life-
cycle of a tooth. Infiltration would provide a simple and cost-effective management option with the 
least possible iatrogenic effect and diminished need for future re-treatment due to deteriorating of 
restoration margins. There are only few clinical data reported comparing the recent development to 

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infiltrate lesions with a standard preventive regimen. Therefore, a randomized controlled clinical trial 
is warranted to study lesion progression with and without resin infiltration, while the patients receive 
standard-oral care hygiene treatment, diet counselling and fluoride regimen. 
4.2 Hypotheses  
The objectives of the investigation are to study the short-term clinical performance of resin 
infiltrated teeth in a caries-active environment. We hypothesize that in a high caries risk population 
and with a regular preventive regimen as control management the infiltration of early approximal 
caries lesions leads to arrest of the lesion and reduction of lesion progression. 
4.2.1 Hypothesis I 
Infiltrated early caries lesions in a high caries risk population have a lower incidence of lesion 
progression when compared to lesions managed by regular preventive regimen. The number of 
lesions requiring an invasive intervention (filling) is significantly lower than for lesions treated with 
standard regimens. 
4.2.2 Hypothesis II 
Infiltrated early caries lesions in a high caries risk population have a lower rate of lesion progression 
when compared to lesions managed by regular preventive regimens.  
 
4.3 Previous Experience with the Study Material 
4.3.1 Description of the clinical procedure 
The proposed components of the infiltration kit are substantially equivalent to a variety of currently 
marketed dental materials in terms of physical and mechanical properties. The indication for use of 
the DMG “Infiltration kit for caries lesions” is micro-invasive treatment of early approximal caries. 
The FDA approved (510(k): K100062) materials will be used according to the label. 
 

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4.3.2 Preclinical Testing 
The materials to be used for infiltration (etchant and infiltrant) have received EEC market 
authorization for medical devices 
 Therefore, complete documentation of preclinical 
testing and biological evaluation of the device and its results has passed the appropriate regulatory 
bodies. Documentation and approvals are on file with the sponsor (510(k): K100062). 
 
4.3.3 Previous Clinical Experience 
The devices used in this study have seen clinical application for several years for infiltration indication 
with excellent results. The materials in the infiltration kit will be used according to label and for 
approved indication (micro-invasive treatment of early proximal caries).  
 
4.3.4 Clinical Studies  
Infiltrating a caries lesion is a strategy to strengthen damaged tooth structure and to reduce caries 
progression without any surgical intervention.1-3 Management of early lesions by infiltrating instead 
of or postponing restorative treatment would have a great impact towards improving oral health 
care by means of its non-invasive nature. It will drastically lengthen the life-cycle of a tooth.3 
Infiltration would provide a simple and cost-effective management option with the least possible 
iatrogenic effect and diminished need for future re-treatment due to deteriorating of restoration 
margins.4 
The promising in vitro results of caries infiltration on extracted teeth were underlined by different 
clinical trials. Several groups reported slower caries progression in infiltrated sites compared to 
controls: Radiographically obtained quantification reveals lesion progression in 16% of infiltrated 
sites compared to 53% for controls after one year and for 24% (infiltration group) and 62% (control) 
after two years. Recently, the three year follow-up data were published, reporting 32% progression 
for infiltrated lesion and 70% for controls in this split-mouth study.5 Meyer-Lueckel et al. measured 
progression rates of 7% (infiltrated sites) and 37% (controls) after 18 month in young adults.6 The 
currently available 3-year data of this study report 4% progression in infiltrated lesion and 42% for 
controls.7 Ekstrand et al. aimed to assess the efficacy of resin-infiltrated lesions covered by fluoride 
varnish (FV) versus FV treatment only of proximal lesions on deciduous molar teeth in a one year 

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split-mouth study. Radiographically, 23% of the test lesions and 62% of the control lesions had 
progressed, comparable to the aforementioned results in young adults. 8 
 
 
 

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5 Device Risk Analysis and Assessment 
5.1 Risk Analysis of the Medical Device 
There is a minimal risk associated with the device itself and the procedures involved in its use, as 
identified by risk assessment and post-market experience of substantially equivalent materials, 
beyond the common risks related to standard dental treatment. 
Definition:  
Minimal risk is the probability and magnitude of harm or discomfort 
anticipated in the research and not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of routine 
physical or psychological examinations or tests [45 CFR 46.102(i)] 
The entire treatment in each aspect, including lesion size and location, all materials, equipment and 
techniques used, is part of regular daily life. Dentist visits, like in this study, resulting in caries 
detection, diagnosis and management by regular preventive regimen or sealant are not at all out of 
the ordinary. It is –alas- rather ubiquitous and a common part of daily oral health care provisions that 
our professions provides to the public. Therefore, the risk is NOT greater than routine dental 
practice. The care provided meets this definition of minimal risk. 
 
5.2 Risk Management of the Clinical Device 
Although the exclusion criteria mention allergy to methylmethacrylate (a commonly used monomer 
as a component in many commercial medical, dental, and non-medical applications), this allergy has 
a low prevalence and materials containing methylmethacrylate or its analogues are managed 
routinely in dental practices around the world every day. In the case of the rare occurrence of an 
allergy, patients are isolated immediately from contact, treated using well-known emergency 
procedures, and recover quickly. In almost every case, a patient knows in advance that they have 
these types of allergies because they must avoid contacts with a huge number of acrylic materials 
present normally in world as parts of garments, containers, and common household items. No other 
adverse effects are known, and none are anticipated. 
 
 

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6 Objectives of the Clinical Investigation 
6.1 Objectives 
The main purpose of the present study is to evaluate the efficacy of the Icon Caries Infiltration 
system, DMG, Hamburg, Germany) in controlling the progression of non-cavitated proximal lesions in 
posterior teeth. 
 
6.2 Specific Aimes (Primary Endpoints) 
 
6.2.1 Specific Aim I 
Significant lower rate of invasive interventions (filling) compared to standard treatment 
 
6.2.2 Specific Aim II 
Change in lesion size (Radiographic analyses) 
 
 
6.3 Secondary Endpoints 
No sensitivity to percussion  
No color change 
No sensitivity to periapical palpation 
No prolonged response to hot or cold 
 
 
 

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6.4 Study Overview 
To confirm or reject the hypotheses a prospective, double-blind, randomized controlled trial (RCT) is 
designed to investigate the clinical performance of resin-infiltration as early caries management in a 
caries-prone population. 
This CIP describes a three-year longitudinal, prospective, randomized controlled trial in split mouth 
design. The study includes a clinical team involving one on-site Principal Investigator (Site-
PI)/operator and one back-up Clinical Investigator (CI)/operator. 
The clinical site will enroll 150 subjects (in the age range of 14 years or older) with 2 study lesions. If 
the lesion management provided in the study appears to be insufficient within the investigated 
period, the study will provide a maximum of 2 traditional restorations for free to participants. The 
patients will be evaluated at six time points over a period of 3 years. Lesion status and caries risk will 
be monitored at 6-month intervals, while radiographic evaluation will be conducted at 12-month 
intervals at 1-, 2- and 3-year recall visits. 
 
 

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7 Design of the Clinical Investigation 
The study will be designed as a controlled, double blind, randomized, prospective trial with a three 
year follow-up period regarding to CONSORT22 recommendations as a single-center study to 
investigate the effect of caries infiltration as an alternative treatment option.   
7.1 Clinical Investigation Protocol 
Study enrolment phase includes patient interviews, dental screening and bite-wing radiographs 
taking.  
 
7.2 Participant Selection 
Subjects recruited for this investigation will be selected from patients attending the clinical research 
area and recruited from advertisements (Attached). 150 patients aged 14 years and older will be 
recruited into the study to provide 150 resin infiltrated and control (no Treatment) lesions. 
7.2.1 Inclusion Criteria 
To be considered appropriate for inclusion in the study a patient must: 
 Be age 14 years and older 
 Have at least two vital carious teeth with caries ranging from enamel to just into 
dentin.  
o If the lesion is not on a 3rd molar 
o If the lesion is not developmental. 
o If the lesion is not cavitated 
 Be a regular dental attendee able to return for assessments 
 Be in good medical health and able to tolerate the dental procedure  
 Have no chronic periodontitis which could compromise tooth retention. 
 Have normal salivary function.   
 Have normal bone levels  
 No lingering cold sensitivity 
 No periapical sensitivity 
 
No sensitivity to percussion 
 

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7.2.2 Exclusion Criteria 
Patients will be excluded from participating in the study if: 
 
Do not meet the inclusion criteria 
 
Are not able to tolerate the time required for the study 
 
There is a history of an adverse reaction to any materials used in the study 
 
They are irregular dental attendees 
 
They maintain an unacceptable standard of oral hygiene. 
 
They have chronic periodontitis  
 
There is severe salivary gland dysfunction or reduced salivary flow is observed 
 
They are unable to return for recall appointments 
 
 
 

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8 Clinical Evaluations 
At the screening visit and at each yearly recall a clinical evaluation will be conducted. The patient will 
be interviewed and receive a clinical examination. Additionally, at the screening and at annual visits a 
bitewing radiograph will be taken. The data of each visit is documented in the respective clinical 
report forms (Appendix 1). The criteria and codes used on the forms are documented in the protocol.  
8.1 Baseline Records (Radiographs) 
This section was revised and specified in Amendment 1 valid as of 30.11.2015! 
Additional radiographs will not be taken for purpose of the trial only. The policy described below 
reflects the widely accepted, current best practice regarding detection, diagnosis and monitoring of 
approximal lesions. Standardized diagnostic bitewing radiographs will be taken using a standardized 
position device (DMG, Hamburg, Germany). The device facilitates optimal direction of the x-ray beam 
and thus leads to optimal diagnostic representation of the caries lesion.  
Radiographic evaluation of the lesions and the quality of the adjacent enamel contact surface by 
standardized bitewing radiographs at baseline will be used to detect and diagnose the caries and 
monitor lesion change. An extensive review of the scientific evidence supports the importance of 
initial bitewings and radiographic recall examinations for description of caries progression.9-13 Both, 
the guidelines by Pitts and Kidd 4 widely used in Europe, and the ADA/FDA-coordinated guidelines 14 
advise that in high risk children (age 10-16) the interval should be 6-12 month. The proposed timing 
of bitewings in our study (screening and at yearly intervals) falls well within these guidelines. They 
rather represent a minimum of the advised frequency for a caries-prone study population of young 
adults in the age range of 14+ years. 
Quantification of caries lesions is greatly facilitated by digital processing of the radiographs.15 The 
advantage of using digital images is that electronic contrast enhancement may aid in visualization of 
the complex image.16 Recently, subtraction radiography was reported to be more accurate and 
reproducible for detecting mineral loss than subjective comparison of paired digital images.17 A 
digital subtraction program will be used to detect the differences in extent and density of the lesion. 
These programs have been successfully used to detect simulated and clinical caries progression.17-19 
 
 

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8.3 Evaluation Categories 
Following is a description of the different evaluation categories that will be used to determine caries 
risk status, to monitor the lesions and to determine the primary and secondary endpoints of this 
investigation. 
 
8.3.1 History Taking (Interview) 
- 
Oral Health care behavior 
8.3.2 Diet 
- 
Snacking: frequency and content 
- 
Softdrinks: frequency and sipping 
 
8.3.3 Local Ecology 
- 
salivary function 
- 
bone levels  
- 
cold sensitivity 
- 
periapical sensitivity 
- 
sensitivity to percussion 
 
8.3.4 Caries Experience 
- 
DMFT/ WHO Standard 
 
8.3.5 Individually standardized record (Radiographs) 
- 
DMG criteria for Icon treatment 

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Figure 3: DMG criteria for treatment planning for Icon infiltration therapy. Adopted from DMG, Hamburg, 
Germany. 
 
8.4.3 Local ecology 
Sensitivity (Cold response/Biting response) 
Sensitivity will be measured using a visual analogue scale. 
Preoperatively –Cold response on the selected carious tooth will be measured by applying a cotton 
pellet soaked in Endo Ice to the tooth for 3 seconds and asking the subject to place an X on a 10 cm 
line labeled 1 on the left and 10 on the right.  They will be told that 10 represents the worst pain they 
can imagine (childbirth, major surgery or kidney stones) and 1 represents no sensation at all.  Stimuli 
– biting pressure (biting on a cotton tip applicator) and cold tests will be measured using the same 
scale.     
Saliva function 
Saliva function will use stimulated saliva flow measurement.  Patient will chew paraffin for 2 minutes, 
hold saliva in their mouth, and then expectorate into a graduated cylinder. Amount of saliva flow will 
be expressed as ml. 
 
DMFT Score 
Teeth will be scored as D = decayed, M = missing, F = filled and T = teeth and the final DMFT value 
will be calculated as recently described.37 
 
 

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9 Clinical Measurements and Procedures 
9.1 Screening Visit 
The screening phase allows confirmation of subject eligibility for the trial based on inclusion and 
exclusion criteria. Screening includes patient information, eligible lesion are evaluated by a study 
investigator and randomly selection of caries lesions for treatment. 
 
9.2 Selection of Lesions (Screening visit only) 
After allowing each subject an opportunity to read and consider the consent form and answering any 
questions concerning the study, each subject will be asked to complete and sign the consent form. 
Appropriate vitality and radiographic assessments will be completed and any pathology noted and 
recorded. A radiograph will be made of each carious tooth lesion to be included in the study. The 
depth of the carious lesions will be measured and recorded (E1-2 or D1). Periapical lesions will be 
recorded. Digital images of the tooth will be made and filed. Cold and hot response will be recorded 
and the time after the stimulus is applied for any pain to stop will be recorded.  Patient age and tooth 
number will be recorded.   
 
9.3 Randomization 
A random assignment of the treatment to teeth is based on equal distribution of the two treatments; 
each subject will receive both a placebo controlled or an Icon resin treatment for the two proximal 
carious teeth, assigned by beginning with the tooth with the lowest number, the specific procedure 
applied to each tooth will be determined by selecting from a box containing two choices (A or B) 
by the clinician doing the procedure. One tooth (the one with the lowest tooth number in 
the universal numbering system) will receive the treatment drawn from a box containing 
the names placebo or Icon.  The universal numbering system begins with #1 - the maxillary 
right third molar and proceeds to #16 the maxillary left molar.  In this system the 
mandibular left third molar is # 17 and the mandibular right third molar is tooth number 
#32. The treatment (the first one drawn) will be placed on the tooth with the lowest 
number.  The remaining tooth will receive the second treatment.  Clinicians and patients 

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receiving the two treatments will be blinded as to the treatment applied to the specific 
tooth. 
9.4 Intervention Visit 
9.4.1 Intervention Site “TREATMENT” 
During the screening examination and after informed consent has been obtained from the subject, 
bite wing radiographs will be made using a customized holder for the digital sensor using VPS 
impression material. The subject position will be controlled in 3 dimensions by placing holders in the 
subject’s ears and placing their chin in a holder. The positions used for the initial set of radiographs 
will be recorded and used for all subsequent x rays to standardize their position at each recall.  At a 
separate appointment, each selected subject will be instructed in oral hygiene procedures to include 
brushing, flossing and the use of a fluoride containing toothpaste.  To be included in this study the 
subject must have two teeth with similar sized lesions.  After the lesions are selected, one of two 
treatments will be selected from a box by the clinician doing the procedure.  One of the “treatment 
tooth” will randomly receive the infiltrating resin (Icon). Teeth will be isolated with a rubber dam, the 
tooth surface cleaned with non-fluoride prophylactic paste and pumice. The Icon material will be 
applied following the manufacturer’s instructions and light cured with S 10 curing light (3M ESPE, St 
Paul, MN). Output from the curing light will be measured and recorded weekly. The Icon infiltrating 
resin will be polished using interproximal finishing/polishing strips (Sof Lex, 3M ESPE, St Paul, MN). 
Subjects will be given a letter to take to their local dentist asking them not to treat the selected 
lesions without informing the investigator first. Subjects will be recalled at 6, 12, 24 and 36 month 
intervals and at radiographs will be made of the control and test lesions after 12, 24 and 36 month .  
During all visits, oral hygiene will be reinforced.  
 
9.4.2 Intervention Site “CONTROL” 
During the screening examination and after informed consent has been obtained from the subject, 
bite wing radiographs will be made using a customized holder for the digital sensor using VPS 
impression material. The subject position will be controlled in 3 dimensions by placing holders in the 
subject’s ears and placing their chin in a holder. The positions on the initial set of radiographs will be 
recorded and used for all subsequent x rays to standardize their position at each recall.  At a separate 
appointment, each selected subject will be instructed in oral hygiene procedures to include brushing, 

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flossing and the use of a fluoride containing toothpaste. To be included in this study the subject must 
have two teeth with similar sized lesions. After the lesions are selected, one of two treatments will 
be selected from a box by the clinician doing the procedure. One tooth will randomly receive the 
infiltrating resin (Icon) while the other will receive a placebo.  Teeth will be isolated with a rubber 
dam, the tooth surface cleaned with non-fluoride prophylactic paste and pumice. Syringes identical 
to the Icon materials will be supplied by DMG for the placebo procedure. The syringes will be filled 
with the solutions having the same consistency and color as the Icon material.  The placebo material 
will be applied following the manufacturer’s instructions and light cured with an S 10 curing light (3M 
ESPE, St Paul, MN). Output from the curing light will be measured and recorded weekly. The placebo 
material and the Icon infiltrating resin will be polished using interproximal finishing/polishing strips 
(Sof Lex, 3M ESPE, St Paul, MN). Subjects will be given a letter to take to their local dentist asking 
them not to treat the selected lesions without informing the investigator first. Subjects will be 
recalled at 6, 12, 24 and 36 month intervals and at each recall radiographs will be made of the 
control and test lesions. During these visits, oral hygiene will be reinforced.  
 
9.5 Follow-up Evaluations 
At each recall (baseline, 6-month, one, two and three years) all lesions will be assessed according to 
the asked criteria.  In addition to the clinical and radiographic assessment (see below), each 
evaluation will include an evaluation of surface roughness, color match, post-operative 
sensitivity/discomfort, and presence or absence of secondary caries. Every attempt will be made to 
schedule the six month, one and two year recalls within 2 weeks of the recall interval.  When 
assessors differ, a consensus will be reached before the patient is dismissed.  In the event an Icon 
resin is unsatisfactory, details of the mode of failure will be documented and the necessary 
replacement / repair made.   
 
9.6 Concomitant Treatment 
The clinical study is concerned with two lesions per patient. Within the study no additional 
concomitant treatment will be offered to the subjects outside the normal local clinical routines. At 
the recall appointments, normal recall procedures will be applied. 
 

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10 Data Management 
10.1 Data Management Plan 
10.1.1 Data collection  
Data collection is done using the CRF that exists in the form of a paper version. The method is to 
employ paper CRFs to collect the data responses, which are subsequently translated to the 
monitoring database. These paper CRFs are compiled by the investigator according to the protocol. 
10.1.2 CRF tracking  
The entries made in the CRF will be monitored by the designated DMG clinical monitor to confirm all 
requested info and completed CRFs are entered into the database. CRFs are tracked for missing 
pages and illegible data manually to assure that the data are not lost. In case of missing or illegible 
data, a clarification is obtained from the investigator and the issue is resolved. 
10.1.3 Data validation  
Data validation is the process of testing the validity of data in accordance with the protocol 
specifications. Discrepancy is defined as a data point that fails to pass a validation check. Discrepancy 
may be due to inconsistent data, missing data, range checks, and deviations from the protocol. 
Ongoing quality control of data processing is undertaken by the monitor at regular intervals during 
the course of clinical trial. 
10.1.4 Discrepancy management/query resolution 
Discrepancy management includes reviewing discrepancies, investigating the reason, and resolving 
them with documentary proof or declaring them as irresolvable. Discrepancy management helps in 
cleaning the data and gathers enough evidence for the deviations observed in data.  For 
discrepancies that require clarifications from the investigator, the monitor will discuss the query with 
the investigator or will be sent to the site. The Investigators will correct the resolution or explain the 
circumstances that led to the discrepancy in data. 
10.2 Data Privacy Protection  
Electronic study files will be password protected and reside on a computer that is also password 
protected. Paper records will be maintained in a locked cabinet in a space that has locked entryways. 

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10.3 Study Database 
Electronic study files as well as paper records, such as CRFs, will be collected and checked for 
completeness by the clinical monitor during the on-site visits.  
A copy of the paper records will be stored at sponsor site. Moreover study data will be transferred 
into a monitoring specific database. 
 

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11 Biostatistical Design 
11.1 Prospective Design 
Controlled, randomized, double blind study, single center design. 
 
11.2 Determination of Sample Size 
Subjects recruited for this investigation will be selected from patients attending the clinical research 
area and recruited from advertisements (Attached). 150 patients aged 14 years and older will be 
recruited into the study to provide 150 resin infiltrated and control (no Treatment) lesions. Based on 
previous studies approximately 20% loss of these subjects will occur over the three year period 
producing a subject population of 120 who will be available for the 3 year recall.   
 
11.3 Evaluation Strategy 
Four trained operators will complete the direct and indirect evaluations of the carious teeth and seal 
the carious lesions.  Two trained and calibrated examiners will complete the evaluation process at 
each recall.  The PI will select all lesions for this study.  
 
 
11.4 Statistical Analysis 
11.4.1 Descriptive Statistics 
For the digital subtraction procedure, the ANOVA for Repeated Measures, will be used to determine 
significance between the two groups (p=.05).  The remaining endpoints will be listed as percentages 
rather than subjected to statistical analyses.  
 

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11.4.2 Blinding    
Both the placebo and the Icon materials are same in their delivery system, material color, and 
viscosity.  Therefore, the investigators are blinded as to the material used, as are the patient and the 
evaluators. 
 
11.4.3 Evaluation of Records 
This section was revised and specified in Amendment 1 valid as of 30.11.2015! 
The outcome variable will be the caries progression status (regression, no changes or progression) for 
the selected lesions after 3 years. The radiographs will be read by 2 methods (1) visual independent 
reading and (2) subtraction radiography of digitized images. 
For visual readings the depth of each selected lesion will be visually assessed and recorded by the PI 
independently on the conventional baseline and follow-up radiographs, respectively. The depth of 
the selected lesion will be classified into the following scales 1- lesion regressed, 2- lesion expanded, 
3 no change in lesion size. A score of 4 (missing surface, generally fractured) and 5 (presence of a 
restoration) may be assigned when needed. For all visual readings, the examiner will be blinded as to 
whether the examined radiograph was a radiograph of the lesion was Icon sealed or a control. The 
examiner will be asked to determine the status (1 to 5) of the right positioned image against the left 
positioned image of the radiograph.  
 
To assess the progression status on subtraction images the conventional radiographs will be first 
digitized (Epson Expression 1680 Pro scanner, Photoshop software) in a standard way (TPU format, 8-
bit, 3,200 resolution), and contrast and gamma levels will be pre-adjusted pair-wise in the baseline 
and follow-up images. The images will be stored uncompressed (TIFF 3,650 x 2,425 grayscale) at an 
individual size of 9–14 Mb. Next, the images will be converted to a readable format for the 
subtraction software in Adobe Photoshop 6.0 and stored as TIFF 600 x 400 files, with a code 
corresponding to case number, test/control lesion, baseline or follow-up and involved surface.  
The digital subtraction of the digitized images will be undertaken by one of the examiners by means 
of the Compare software (Dental Health Unit, University of Manchester, UK), which runs as a plug-in 
to the Image Tool software, version 1.23 [University of Texas Health Science Center at San Antonio, 

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Texas, 2002]. The subtraction images will be obtained by subtracting the follow-up from the baseline 
images of each lesion. First, the two images will be automatically aligned to obtain a relationship with 
the least difference between them. The difference in density between the two images will then be 
normalized. Subtraction of images will be conducted, and the contrast stretched. The subtraction 
images will be coded and randomly organized, as described above, then saved in a Microsoft 
Powerpoint presentation. For their reading, the subtraction images will be viewed by an external 
trained examiner 10 days after the visual assessment of conventional radiographs. The presentation 
will be viewed on a 43.2-cm Hewlett Packard monitor in one session.  Additionally, the examiner will 
be able to access the conventional baseline radiograph to confirm  the vertical location of the lesion 
within the proximal surface.  The subtraction progression will be observed as the presence of black 
points corresponding to an extension of the proximal lesion. Conversely, regression will correspond 
to the presence of white points and stabilization as an evenly grayish appearance on the image.  
Intraexaminer reproducibility will be obtained by rereading 25% of the independent and paired 
radiographs and of the subtraction images 2 days after the first reading. 
 
11.4.4 Missing Data 
Missing data due to dropouts have been accounted for in adjusted sample size. The missing data will 
be at random. 
 
11.4.5 Statistical Software 
 
The statistical software that will be used for this study is Statview. 
 

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12 Method of Reporting 
12.1 Periodic Reports to the Sponsor/Monitoring 
Periodic reports will be given to the sponsor in line with the frequently held monitoring visits.  
The activities/reporting by the monitor that take place during the on-site visit include, but are not 
limited to the following: 
• 
Only subjects who meet the study eligibility criteria are enrolled 
• 
Informed consent process was conducted appropriately and that informed consent will be 
obtained prior to proceeding with any study procedures 
• 
Data was collected and analysed as specified in the protocol 
• 
Adverse events were reviewed promptly and reported as required  
• 
Privacy and confidentiality of subjects was maintained 
• 
Documentation of dropouts 
• 
Evaluation of primary and secondary endpoints 
• 
During an annual visit, the Monitor focuses on the areas where the majority of the 
deficiencies were identified or addresses other problems or issues noted since the last visit. 
• 
The Monitor identifies and reports any suspected fraud and scientific misconduct if 
discovered during the review.  
The clinical monitoring process of the sponsor can be classified into the following periodical visits:  
Study initiation visit 
The monitor conducts the study initiation visit after the sponsor submits the protocol to its IRB and in 
advance of study activation.  
The study initiation visit is held at the study site. The monitor prepares a clinical study initiation visit 
report to document the study initiation visit. The PIs, Sub-Investigators, and Site Coordinators must 
be prepared to discuss the procedural as well as the scientific aspects of the protocol during the 
initiation visit.   
Annual Monitoring Visit 
The monitor schedules and conducts on-site monitoring visits. The first annual monitoring visit to the 
study site occurs 12 months after a study opens; then annually thereafter until study closure. 

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The monitor may conduct interim visits as requested. An interim visit can be conducted as a follow-
up to an annual visit where a number of deficiencies were identified, or it can be requested for 
reasons such as the complexity of the study, staff changes, or number of subjects enrolled. 
The annual visit is generally scheduled for two days. The monitor prepares a follow-up-monitoring 
report to document the visit. 
Close-Out Visit 
The monitor schedules the close-out visit. The close-out visit usually takes one full day. If accrual is 
exceptionally large, an additional day can be required.  
The activities/assessments by the monitor during the close-out visit include, but are not limited to, 
the following: 
• 
Complete any outstanding site monitoring tasks (e.g., regulatory review and/or review of 
participant records) through the date of study termination or completion; 
• 
Confirm that the IRB has been informed of the study closure 
• 
Ensure the PI understands follow-up requirements for reporting AEs for subjects who have 
completed the study 
• 
Conduct a summary meeting with Study Principals to discuss findings and plans for resolution 
of outstanding issues 
A final report will be prepared after finishing all monitoring activities. 
 

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13 Changes of the Clinical Investigation Plan 
13.1 Amendments to the CIP 
All amendments to the CIP shall be agreed to by the principal clinical investigator and be recorded 
with a justification for the amendments. Deviations will be reviewed to determine the need to 
amend the CIP or to terminate the investigation. 
 

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14 Deviations from the Clinical Investigation Plan (CIP) 
14.1 Deviations from the CIP 
Any deviation from the CIP will be documented together with an explanation for the deviation. 
Deviations will be reported to principal investigator who is responsible for analyzing the deviations 
and assessing their significance. 
Other Reportable Information and Occurrences (ORIOs: such as protocol deviations, 
accidents/incidents, and compliants) will be reported to IRB in the form of an ORIO report: 
- 
Within 7 days when urgent subjects safety or regulatory concerns exist and/or oversights 
letter is received 
- 
Within 15 days when situations or event potentially alters risk-benefit assessment and/or 
may jeopardize integrity of study results and/or potential benefits to subjects 
- 
With scheduled continuation review or concurrently with report to oversight body, 
whichever comes first, when ORIO falls outside of other IRB timeframe parameters 
 
 
 
 
 
 
 
 
 
 
 

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14.3 Length of follow-up – Potential Study Extension 
Based on the actual study design there is no extension planned. If obtained data indicate a necessity 
for follow-up investigations this issue will be discussed with the sponsor and documented in the 
study files. 
 
 

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15 Confirmation of Study Material Application 
Application of study material will be documented in the Study Material Application form (Appendix 
A2) including patient ID, investigator, date of application, material batch number and signature. 
 
 
 

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16 Ethical Considerations 
This protocol was approved by the IRB from the Federal University of Alabama (Appendix 3). Parents 
or guardians will sign an informed consent (Appendix 4). Operative dental treatment will be provided 
to the participants when necessary.  
 
 

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17 Relevant Standards and Guidelines 
The Clinical Investigation Protocol for this study includes all components and documentation as 
required to conform to international standards for clinical research (CONSORT, ISO/DIN and Good 
Clinical Practice Guidelines).20-22 
 
 

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18 Adverse Events 
18.1 Adverse Events 
An adverse event (AE) is defined as any unintended adverse experience associated with the study 
materials or study procedures that results in an unplanned medical assessment or treatment, or 
changes the risk to subjects. Any adverse reaction to the treatment provided as part of the study will 
be fully investigated and reported to the IRB.  AEs will be reported according to the IRB defined 
timelines using appropriate forms.   
All materials and devices used in this study have been approved by local regulatory bodies and are 
currently on the market in various parts of the world. Their clinical use is according to label. 
Therefore, no foreseeable adverse events are expected. 
 
18.2 Serious Adverse Events 
Emergency contact details for reporting of serious adverse events are included in the CIP (Appendix 
A5). 
Serious Adverse Events are adverse events that: 
a) led to a death, 
b) led to a serious deterioration in health that either: 
1) resulted in a life-threatening illness or injury, or 
2) resulted in a permanent impairment of a body structure or a body function, or 
3) required in-patient hospitalization or prolongation of existing hospitalization, or 
4) resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 

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In case of a serious adverse event and subsequent need for un-blinding the name-code list can be 
assessed immediately and breaking the code will not cause any further problem. The data recorded 
until the report of adverse event will remain included in the dataset. 
 
18.3 Report by the investigator to the sponsor 
DMG has implemented and maintains a system to ensure that the reporting of the reportable events 
will be provided by the investigator to the sponsor in acceptable timely conditions using the Adverse 
Event/ Adverse Device Effect (AE/ADE) Report Form (Appendix A6). 
 
18.4 Report by the sponsor to the National Competent Authorities 
Reportable events will be reported at the same time to all National Competent Authorities where the 
clinical investigation has commenced. 
 
a SAE which indicates an imminent risk of death, serious injury, or serious illness and that 
requires prompt remedial action for other patients/subjects, users or other persons or a 
new finding to it: immediately, but not later than 2 calendar days after awareness by 
sponsor of a new reportable event or of new information in relation with an already 
reported event. 
 
any other reportable events or a new finding/update to it: immediately, but not later 
than 7 calendar days following the date of awareness by the sponsor of the new 
reportable event or of new information in relation with an already reported event. 
 
 

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19 Early Termination or Suspension of the Investigation 
All materials and devices used in this study have been approved by local regulatory bodies and are 
currently on the market in various parts of the world. Their clinical use in this investigation is 
according to label. Therefore, early termination or suspension of the investigation due to problems 
with the restorative materials is not anticipated. 
If the investigation is terminated prematurely or suspended, the principal clinical investigator will 
promptly inform the clinical investigators of the termination or suspension and the reason(s) for this. 
The IRB will also be informed promptly and provided with the reason(s) for the termination or 
suspension by the principal clinical investigator. 
 
 

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20 Publication Policy 
Publication of (parts of) the trial by the Research Team will take place only with the written consent 
of the Sponsor, or following a period of one year from the date the Sponsor receives the related 
report.  
 

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21 Administrative Arrangements 
21.1 The Research Team and its Responsibilities 
Site 
 
 
 
University of Alabama at Birmingham (UAB) 
 
 
 
 
School of Dentistry 
 
 
 
 
1919 7th Avenue South 
 
 
 
 
Birmingham, Alabama 35294 
 
 
 
 
United States 
 
Principal Investigator:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Biometrics/Statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21.2 Head of the Clinical study (Sponsor) 
 
 
 
 
 
 
 

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21.3 Regulatory Affairs/ Clinical Monitoring 
 
 
 
 
 
 
 
21.4 Clinical Study Contact (Sponsor)  
 
 
 
 
 
 
 
 
 
21.5 Projected Time Frame 
The clinical study will start as soon as the required ethical approvals have been received and Training 
has been provided to the clinical team. 
 
 
The time frame is summarized in table 22.5 
Table 22.5 Overview of the study´s time frame 

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21.8 Insurance of the Subjects 
The study materials in this investigation are cleared by the governing bodies of the participating 
countries (US, Germany). Therefore, the subjects taking part in the trial are insured by the Sponsor 
against any injury caused by the study materials under investigation. If applicable, additional 
regulatory requirements in participating countries will be observed and are part of a separate 
contract. 
 
21.9 Confidentiality 
All unpublished information concerning this trial and the materials supplied to the principal clinical 
investigator and the investigators by the Sponsor will be treated confidentially by all parties involved 
until the sponsor gives written consents that the information may be published or handed over to 
third parties. 
 
The Sponsor has the rights on all data and information acquired during the investigation. 
 
 

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22 Appendices 
A1 Case Report Form 

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A2 Study Material Application Form 

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A4 Informed consent form 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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You
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 

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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 

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A5 Emergency contact information 
In any case of emergency please contact: 
 
 
 
 
 
 
 
and/or 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 6  ADVERSE EVENT / ADVERSE DEVICE EFFECT (AE/ADE) FORM  

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Appendix 10 
Study protocol Amendment 2 valid as of 21.12.2016 

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26. Seppd L, Korhonen A, Nuutinen A. Inhibitory effect on S. mutans by fluoride-treated 
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28. Mertz-Fairhurst EJ, Schuster GS, Fairhurst CW. Arresting caries by sealants: results of a clinical 
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33. Paris S, Meyer-Lueckel H. Infiltrants inhibit progression of natural caries lesions in vitro. J Dent 
Res. 2010 
34. Martignon S, Tellez M, Santamaría RM, Gomez J, Ekstrand KR. Sealing distal proximal caries 
lesions in first primary molars: efficacy after 2.5 years. Caries Res. 2010;44:562-70.    
35. Ekstrand KR, Teller M, Elkstrand KR, Lara JS, Gomez J, Cortes A.  Progression of active initial-
proximal lesions after infiltration, sealing or flossing-instructions. J Dent Res 89: 2519:2010. 
36. Alkilzy M, Splieth CH. Clinical applicability and safety of resin infiltration of proximal caries.  
Caries Res 2010:44:171 (abst49). 
37. Oral Health Methods and Indices." WHO Oral Health Country/Area Profile Programme, 1997. 
<http://www.whocollab.od.mah.se/expl/methods.html> 
 

Statistical Analysis Plan 
 
NCT Number:  
Lesion Progression After Icon Treatment in Young Adults 
 
NCT Number:   
 
NCT01988337 
 
 
Sample Size Determination 
A previous infiltration study by Martignon et al. [5] reported a 3-year difference of 
proportions of 37.8% (95%CI: 20.5-55.2%) with (resin infiltration (68%) vs. control (30%)). 
Based on this and with alfa = 0.05 and a power of 80% the calculated sample size (t-test; 
matched pairs) would be 23 lesion pairs (thus 23 participants) to find significant differences. 
However, this study aimed to enroll 150 participants to not only allow for a potentially high 
attrition rate (20%) over a period of 3 years, but also aiming to better quantify the efficiency 
of the treatment effect.  
 
Statistical Analysis 
All evaluations are performed by two trained and calibrated examiners. The primary 
outcome is proportion of lesions that required restorative treatment (filling) after 3 years as 
measured via dental examination. Differences between groups will be tested using Fisher’s 
exact test and ANOVA for Repeated Measures for subgroup analysis based on caries risk. 
Secondary outcomes are change in categorical lesion depth (progression to next depth 
category lesion; E1->E2->D1->D2->filling) after 6 months and 1, 2 and 3 years as measured 
by pairwise comparison of radiographs as well as the influence of Icon treatment on clinical 
parameters. Differences will be analyzed with McNemar’s test with 95% confidence interval 
(95% CI) and P = .05.