Clinical Efficacy of Caries Infiltration (Icon) - A Randomized, Blinded and Controlled Pilot Study of Early Caries Progression Detection
Phase: NA
Conditions: Caries,Dental
Sponsor: DMG Dental Material Gesellschaft mbH

 
 
 
 
 
 
NCT Title:  
Clinical Trial Proximal Caries Infiltration 
and Detection 
 
NCT Number:   
 
NCT01796106 
 
IRB Approval Date:   
02/06/2015 
 
 
 
 
 
Content: 
 
1. Study Protocol 
 
2. Statistical Analysis Plan 
 
 
 
 
 
 
 

 Study Protocol 
Title: 
Clinical 
Efficacy 
of 
Caries 
Infiltration 
(Icon) 
– 
A 
Randomized, Blinded and Controlled Pilot Study of Early 
Caries Progression Detection 
 
Short Title: 
Clinical Trial proximal Caries Infiltration and Detection 
Running Title:  
 
DETECT13 
 
Protocol-ID: 
 
 
NCT01796106 
 
Sponsor: 
 
 
DMG Dental Material Gesellschaft mbH 
 
 
 
 
Elbgaustraße 248 
 
 
 
 
22547 Hamburg 
 
Study Site: 
 
 
The Center for Pediatric Dentistry 
6222 NE 74th St 
Seattle, Washington 98115 
United States 
 
Version:  
 
 
StudyProtocol_NCT01796106_V6
 
Replaces Version:  
 
StudyProtocol_NCT01796106_V5
 
 
Date:  
 
 
13 February, 2015 
  
 
 
 
 

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Content 
1 
Synopsis of the Clinical Investigation .............................................................................................. 7 
1.1 
Description of the CIP .............................................................................................................. 7 
1.2 
Sponsor .................................................................................................................................... 7 
1.3 
The Study Organization ........................................................................................................... 8 
1.4 
Abstract ................................................................................................................................... 9 
2 
Description and Properties of the Medical Device to be investigated .......................................... 10 
2.1 
Icon Kit for caries infiltration ................................................................................................. 10 
2.2 
Chemical Composition ........................................................................................................... 11 
2.2.1 
Chemical Composition Infiltrant (Resin)........................................................................ 11 
2.2.2 
Chemical Composition Ethanol Solution (Dry-it) ........................................................... 11 
2.2.3 
Chemical Composition HCl Etching Gel (Hydrochloric Acid Gel) ................................... 11 
2.3 
Instructions for use ................................................................................................................ 12 
3 
Objectives of the Clinical Investigation Plan (CIP) ......................................................................... 17 
4 
Preliminary Investigations and Justification of the CIP ................................................................. 18 
4.1 
Background and Rationale .................................................................................................... 18 
4.2 
Hypotheses ............................................................................................................................ 22 
4.2.1 
Hypothesis I ................................................................................................................... 22 
4.2.2 
Hypothesis II .................................................................................................................. 22 
4.3 
Previous Experience with the Study Material ....................................................................... 22 
4.3.1 
Description of the clinical procedure ............................................................................ 22 
4.3.2 
Preclinical Testing .......................................................................................................... 22 
4.3.3 
Previous Clinical Experience .......................................................................................... 22 
4.3.4 
Clinical Studies ............................................................................................................... 23 
5 
Device Risk Analysis and Assessment ............................................................................................ 24 
5.1 
Risk Analysis of the Medical Device ...................................................................................... 24 
5.2 
Risk Management of the Clinical Device ............................................................................... 24 
6 
Objectives of the Clinical Investigation ......................................................................................... 25 

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6.1 
Objectives .............................................................................................................................. 25 
6.2 
Specific Aimes (Primary Endpoints) ....................................................................................... 25 
6.2.1 
Specific Aim I ................................................................................................................. 25 
6.2.2 
Specific Aim II ................................................................................................................ 25 
6.3 
Secondary Endpoints ............................................................................................................. 25 
6.4 
Study Overview ..................................................................................................................... 25 
7 
Design of  the Clinical Investigation .............................................................................................. 26 
7.1 
Clinical Investigation Protocol ............................................................................................... 26 
7.2 
Participant Selection ............................................................................................................. 26 
7.2.1 
Inclusion Criteria ............................................................................................................ 26 
7.2.2 
Exclusion Criteria ........................................................................................................... 27 
8 
Clinical Evaluations ........................................................................................................................ 28 
8.1 
Baseline Records (Radiography) ............................................................................................ 28 
8.2 
Clinic visits ............................................................................................................................. 28 
8.3 
Evaluation Categories ............................................................................................................ 30 
8.3.1 
History Taking (Interview) ............................................................................................. 30 
8.3.2 
Diet ................................................................................................................................ 30 
8.3.3 
Local Ecology ................................................................................................................. 30 
8.3.4 
Caries Experience .......................................................................................................... 30 
8.3.5 
Individually standardized record (Radiographs) ........................................................... 30 
8.4 
Evaluation Criteria ................................................................................................................. 30 
8.4.1 
Preamble ....................................................................................................................... 30 
8.4.2 
Eligibiltiy Criteria............................................................................................................ 30 
8.4.3 
Local ecology ................................................................................................................. 31 
9 
Clinical Measurements and Procedures ........................................................................................ 32 
9.1 
Screening Visit ....................................................................................................................... 32 
9.2 
Selection of Lesions (Screening visit only) ............................................................................. 32 

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9.3 
Randomization ...................................................................................................................... 32 
9.4 
Intervention Visit ................................................................................................................... 33 
9.4.1 
Intervention Site “TREATMENT” ................................................................................... 33 
9.4.2 
Intervention Site “CONTROL” ........................................................................................ 33 
9.5 
Follow-up Evaluations ........................................................................................................... 33 
9.6 
Concomitant Treatment ........................................................................................................ 34 
10 
Data Management ..................................................................................................................... 35 
10.1 
Data Management Plan ......................................................................................................... 35 
10.1.1 
Data collection ............................................................................................................... 35 
10.1.2 
CRF tracking ................................................................................................................... 35 
10.1.3 
Data validation .............................................................................................................. 35 
10.1.4 
Discrepancy management/query resolution ................................................................. 35 
10.2 
Data Quality Assurance ......................................................................................................... 35 
10.3 
Data Privacy Protection ......................................................................................................... 36 
10.4 
Study Database ...................................................................................................................... 36 
11 
Biostatistical Design................................................................................................................... 37 
11.1 
Prospective Design ................................................................................................................ 37 
11.2 
Determination of Sample Size ............................................................................................... 37 
11.3 
Evaluation Strategy ............................................................................................................... 37 
11.4 
Statistical Analysis ................................................................................................................. 37 
11.4.1 
Descriptive Statistics...................................................................................................... 37 
11.4.2 
Blinding .......................................................................................................................... 38 
11.4.3 
Evaluation of Records .................................................................................................... 38 
11.4.4 
Missing Data .................................................................................................................. 38 
11.4.5 
Statistical Software ........................................................................................................ 38 
12 
Method of Reporting ................................................................................................................. 39 
12.1 
Periodic Reports to the Sponsor/Monitoring ........................................................................ 39 

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12.1.1 
Study initiation visit ....................................................................................................... 39 
12.1.2 
Annual Monitoring Visit ................................................................................................ 40 
12.1.3 
Close-Out Visit ............................................................................................................... 40 
13 
Changes of the Clinical Investigation Plan ................................................................................. 41 
13.1 
Amendments to the CIP ........................................................................................................ 41 
14 
Deviations from the Clinical Investigation Plan (CIP) ................................................................ 42 
14.1 
Deviations from the Clinical Investigation Plan ..................................................................... 42 
14.2 
Withdrawal / Dropout of Subjects ........................................................................................ 42 
14.3 
Length of follow-up – Potential Study Extension .................................................................. 43 
15 
Confirmation of Study Material Application ............................................................................. 44 
16 
Ethical Considerations ............................................................................................................... 45 
17 
Relevant Standards and Guidelines ........................................................................................... 46 
18 
Adverse Events .......................................................................................................................... 47 
18.1 
Adverse Events ...................................................................................................................... 47 
18.2 
Serious Adverse Events ......................................................................................................... 47 
18.3 
Report by the investigator to the sponsor ............................................................................ 48 
18.4 
Report by the sponsor to the National Competent Authorities............................................ 48 
19 
Early Termination or Suspension of the Investigation .............................................................. 49 
20 
Publication Policy ...................................................................................................................... 50 
21 
Administrative Arrangements ................................................................................................... 51 
21.1 
The Research Team and its Responsibilities .......................................................................... 51 
21.2 
Head of the Clinical study (Sponsor) ..................................................................................... 52 
21.3 
Regulatory Affairs/ Clinical Monitoring (Sponsor) ................................................................ 52 
21.4 
Clinical Study Contact (Sponsor) ........................................................................................... 52 
21.5 
Projected Time Frame ........................................................................................................... 53 
21.6 
Financing ............................................................................................................................... 53 
21.7 
Reimbursement to Subjects .................................................................................................. 53 

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21.8 
Insurance of the Subjects ...................................................................................................... 54 
21.9 
Confidentiality ....................................................................................................................... 54 
22 
Appendices ................................................................................................................................ 55 
23 
References ................................................................................................................................. 71 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 Synopsis of the Clinical Investigation 
1.1 Description of the CIP 
The objectives of the Clinical Investigative Plan (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, which may be imaged through a SFE laser optical device comparable to radiographic 
results. 
 
 
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 Center for Pediatric Dentistry, Seattle, Washington, US. The 
designated research team will conduct clinical studies to investigate results of alternative treatment 
options for dental caries.  
This team includes 
 
 
 
 
 
 
 
 
 
 
 
 
Contact details and responsibilities are listed in 21.1. 
 is a world-renowned Pediatric Dentist and expert on early caries.  
 will 
provide oversight and leadership on this study as the Principal Investigator.  
 has 
broad experiences in clinical research being engaged in patient-oriented research for years. She will 
be the Co-investigator and the main contact for study communications (clinical site). 
The study is encouraged by DMG Dental Material Gesellschaft mbH, thereafter named “sponsor”. 
The sponsor will provide comprehensive support during study design, implementation and post 
processing by notified study contacts. 
The study contacts  
 
 
 
 
 
 
 
 
  
take responsibility for monitoring the clinical trial and ensure proper supervision of all study 
belongings. Contact details and responsibilities are listed in 21.2, 21.3 and 21.4. 
 
 
 
 

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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 caries lesions by resin infiltration. 
The Background and Rationale section addresses the relevance of the project to oral health and 
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 material involved is described including attention to risk analysis. 
Expected results, potential difficulties and limitations are discussed and solutions or alternative 
approaches are indicated. 
 
 

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4 Preliminary Investigations and Justification of the CIP 
4.1 Background and Rationale 
Icon, by DMG, is a caries infiltration system developed to arrest early caries rather than drill, fill or 
“wait and see.” Icon is used as a restorative therapy for caries lesions thought of as too early for 
conventional restorative treatment.  Icon prevents lesion progression and increases life expectancy 
for the tooth by establishing a diffusion barrier which prevents cariogenic acids from breaking down 
tooth structure and causing further demineralization. This barrier also serves to help maintain the 
mineral content of the dentition by blocking mineral content from leaching from the tooth. Icon is 
also an aesthetic treatment for white spot lesions by allowing the white spot to take on the 
appearance of the surrounding healthy enamel. 
White spot lesions occur when the sub-surface porosity of the lesion fills with an air/fluid mixture 
thus changing the way light is refracted.4 This change in refractive index causes the tooth to appear 
milky, yellow or brown in color and can also diffuse in streaks across the teeth.  These discolorations 
can also be caused by excessive exposure to fluoride during development, also known as fluorosis.  
White spots, or areas of demineralization, often indicate early caries lesions and there are currently a 
few treatments to prevent further acid damage. 
Current alternative forms of treatment for early caries include the following: 1) microabrasion, 2) 
fluoride treatments, and 3) sealants/commercial adhesives.  Microabrasion tends to be used more 
for cosmetic purposes, and unlike Icon, is not used to arrest caries.  A study on eight orthodontic 
patients with white spot lesions found that using microabrasion improved the cosmetic appearance 
of these lesions.23  However, the authors suggest that this treatment is far from standard-of-care and 
there should be further research into the effects of microabrasion on loss of enamel and tooth 
structure.   
Studies involving the topical application of fluoride to early caries lesions have demonstrated high 
rates of caries prevention, arrest, and/or reversal effectiveness, in both children and adults.14  
Although full mineral recovery might be achieved through such measures, in the case of 
shallow enamel lesions, the same treatment in deeper white spot lesions have demonstrated 
negligible remineralization effects.36 Furthermore, the esthetic effect on white spots is often not 
corrected with the application of fluoride treatments; and thus, defeating one of the main purposes 
of treating white spots or areas of demineralization. 

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The use of sealants or commercial adhesives to halt the progression of early caries has also been 
researched.  However, these studies have shown that these materials are unable to fully penetrate 
the lesion, leaving potential for further demineralization.22 To prevent progression, it was necessary 
to treat the area deeper than just the immediate surface area, which these products are unable to 
do.  
Icon is unique in that it can penetrate deeper into the tooth to arrest caries progression.  Also, unlike 
the other treatment options discussed previously, it works on both halting caries progression as well 
as diminishing white spots/demineralization area appearance for better esthetics results.  
In vitro and in vivo studies have been done on the treatment of caries lesions with resins such as 
Icon.  A number of studies were found in which Icon by DMG was used to evaluate the effect on 
these lesions.   Each of the studies reviewed verified that Icon can be used as a restorative treatment 
for early caries and white spots.25 Another study evaluated Icon’s application time on penetration of 
enamel caries.  This study found that three minutes was a sufficient time for the Icon to penetrate 
caries lesions.20  
From an aesthetic standpoint, Icon was found to be an effective treatment in masking white spot 
lesions.31 This in vitro study monitored the effect of Icon on white spots over an eight week period.  
Icon had a significant effect on returning the subjected teeth to their natural color, whereas the 
fluoride toothpaste and gel applications did not. 
Current standard-of-care for early caries detection relies on visual examinations with tactile 
sensation, aided by radiographs.  Typically an explorer is used to determine enamel surface hardness, 
and visual clues such as color and translucency are relied upon to evaluate the caries status of a 
patient.  The methodology is unsophisticated and fails to differentiate between varies stages of 
caries progression.  In a study of 12 year old children with caries, it was found that the visual/tactile 
method, with or without diagnostic adjuncts, can diagnose cavitated lesions efficiently, but not non-
cavitated carious lesions.3 Furthermore, visual-tactile techniques are known to be unreliable due to 
subjectivity.  Lesions can go undetected because teeth are typically examined by the naked eye, and 
there is need for supplemental analysis when faced with clinical signs that will leave a dentist 
uncertain, including dark occlusal or approximal shadows.15 Caries detection through radiograph 
examination is problematic because it is a flawed imaging system; and caries is detected after it has 
progressed through enamel and/or dentin. 9, 17 

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The last 2 decades have seen various technological advances developed toward visualization and 
evaluation of caries.  These include quantitative laser or light fluorescence (QLF), electrical 
conductance measurements (ECM), infrared (IR) laser fluorescence, direct digital radiography and 
Digital Imaging Fiber-Optics Trans-Illumination (DIFOTI).  The research and data supporting 
effectiveness of this technology are at different stages of development, but there is no gold standard 
for dental imaging devices thus far. 23 
The scanning fiber endoscope was developed at the University of Washington’s Human Photonic 
Laboratory (HPL) over the past decade.  A completely new imaging technology was developed to 
provide high-resolution imaging from a very small and flexible scope.  By placing a sub-millimeter 
fiber-optic scanner and lens assembly at the scope tip, the number of pixels (picture elements) is no 
longer related to the number of camera sensor elements.  The result is near HDTV resolution from a 
scope the size and feel of a single strand of cooked spaghetti, with production of real time color 
video-rate images with 600 X 600 line resolution using scanned low-power red, green, and blue laser 
light.   
The ultrathin endoscope developed at the UW Mechanical Engineering Department has been applied 
to numerous biomedical areas such as esophageal cancer screening, bile duct imaging, and bladder 
surveillance.  This threadlike imaging device is less than 1.5 mm in diameter and is highly flexible 
behind its short rigid tip, making it ideal for intraoral use in pediatric populations.  (See Figure 1.) 
 
 
 
Figure 1: The ultrathin Scanning Fiber Endoscope (SFE) optical device is pointed toward the occlusal surface of 
an extracted human molar. The threadlike imaging device is less than 1.5 mm in diameter. 

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Following the trend for higher performance in low-cost lasers used in DVD players, a violet laser light 
source has been integrated into the system for detecting early stages of tooth decay. Enhanced 
surface detail of teeth is more apparent using violet 405-nm wavelength compared to red 635-nm 
wavelength illumination, as shown in monochrome images of the same tooth (See Figure 2).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Monochrome images of the same tooth taken with red (635nm) and violet (405nm) laser light using 
the device in Figure 1. 
 
The majority of visible light from conventional incandescent and natural light sources consists of 
wavelengths closer to the red 635-nm that penetrates more deeply into the tooth.  Compared to 
images obtained at 635-nm, images captured using a violet light are not contaminated and blurred by 
superposition of light reflected from dental tissue at greater depths.  Thus, 405-nm laser illumination 
of enamel surfaces of teeth produces enhanced image details.  The ultrathin endoscope with short-
wavelength illumination may be used to visualize surface manifestations of phenomena such as 
demineralization associated with early caries, thus better aiding the clinician for detection of tooth 
decay before caries progresses into cavitation. 
Currently no single method for caries detection can be used on all tooth surfaces under all conditions. 
These diagnostic devices and methods lack sensitivity and specificity; with caries detection at a point 
when surgical or restorative intervention is required.  Additionally, these optical imaging devices are 
cumbersome, and often lead to inaccuracy due to user failure. Ultimately, these approaches result in 
caries lesions diagnoses overlooked at the earliest stages when less invasive measures, including 
remineralization techniques such as Icon, may be effective. Clinical caries detection sensitive to early 
lesions would bring about innovations in treatment modalities through medicinal therapeutic and 
preventive approaches, including chemotherapeutic approaches such as Icon.  An imaging system 
such as the SFE optical device, specifically designed for dentistry, would be the ideal approach.   

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4.2 Hypotheses  
4.2.1 
Hypothesis I 
The hypothesis to be tested is that Icon performs similarly to an established prevention strategy for 
early caries (Oral hygiene instruction and topical fluoridation) for caries arrest.  
4.2.2 
Hypothesis II 
Caries progression may be imaged through a SFE laser optical device. 
 
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 materials will be used according to the label. 
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. 
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 approximal caries). The materials have a low 
incidence of adverse events and no serious adverse events have become known.  
The concept of caries infiltration applying the penetration of a low-viscosity resin into the porous 
lesion of enamel caries was proven on extracted teeth.25, 39 Furthermore, the positive effect on white 
spot depletion was shown on artificial lesions.25  This in vitro study monitored the effect of Icon on 

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white spots over an eight week period.  Icon had a significant effect on returning the subjected teeth 
to their natural color, whereas the fluoride toothpaste and gel applications did not. 
4.3.4 
Clinical Studies 
Infiltrating a caries lesion is a currently introduced strategy to strengthen damaged tooth structure 
and to reduce caries progression without any surgical intervention.39-40 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.25 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.41 
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.42 Meyer-Lueckel et al. measured 
progression rates of 7% (infiltrated sites) and 37% (controls) after 18 month in young adults.43 The 
currently available 3-year data of this study report 4% progression in infiltrated lesion and 42% for 
controls.44 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 
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. 45 
 
 

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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. 
The SFE technology has been used in multiple human applications safely and efficaciously.  
Therefore, there is low risk in use of the technology in the dental setting.  The device was deemed to 
be a non-significant risk device by the FDA.  If a child expresses dismay or stress during the SFE 
imaging process, the participant will be withdrawn from further study participation.   
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 a low viscosity resin (Infiltrant; 
DMG, Hamburg, Germany) in controlling the regression of White Spot lesions. As a secondary 
purpose, this study intends to evaluate the usage of SFE for investigation of penetration success and 
for visualization of early caries. 
6.2 Specific Aimes (Primary Endpoints) 
6.2.1 
Specific Aim I 
 
Caries arrest evaluated by bitewing radiographs 
6.2.2 
Specific Aim II 
 
 Confirm optical measurements from SFE laser device correlate with clinical measures 
6.3 Secondary Endpoints 
 
White spot reversal 
 
Secondary caries 
 
Post-operative sensitivity 
 
Color match / surface staining 
 
Surface quality / texture 
 
SFE for visualization of early caries and lesion depth assessment  
6.4 Study Overview 
We propose a randomized, blinded, clinical study of Icon vs. Control (Oral Hygiene Instruction [OHI] 
and topical fluoridation) as early caries interventions for caries arrest in pediatric populations. 50 
non-cavitated early caries lesions, or areas of demineralization, in proximal surfaces of primary 
molars will be enrolled in this study. Up to 2 early caries lesions may be enrolled per patient, 
providing the second lesion is in a separate quadrant. Early caries lesions with demineralization seen 
on occlusal surfaces will be excluded from participation, along with white spot lesions from 
hypoplasia or fluorosis.   

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7 Design of  the Clinical Investigation 
The study will be designed as a controlled, randomized, blinded trial following CONSORT42 
recommendations as a single center study to investigate the effect of caries infiltration as an 
alternative treatment option for approximal caries lesions.   
 
7.1 Clinical Investigation Protocol 
Study enrollment phase includes patient interviews, dental screening and bite-wing radiographs 
taking.  
 
7.2 Participant Selection 
Individuals will be selected among the children who come to the Center for Pediatric Dentistry 
Seattle, Washington, USA for dental treatment. Healthy children between 6 and 13 years old, 
presenting at least one pair of early carious lesions in primary molars. 
 
7.2.1 
Inclusion Criteria 
Children ranging in age from 6-13 years will be eligible to participate.  The patients must have a one 
early caries lesions present in primary molars. Up to 2 early caries lesions may be enrolled per 
patient, providing the second lesion is in a separate quadrant .  All patients must be in good general 
health and free of any systemic disease or disability, preventing any unnecessary procedures.  
Patients must be available, as well as can be anticipated, for one-year, and two-year recalls. 
Criteria used to assess teeth for acceptance into this study include: (1) teeth fully erupted, in 
functional occlusion and (2) radiographic evidence of early caries in interproximal areas (1 or 2, 
Ekstrand’s criteria9).  The patients will be appointed for a pre-study appointment after the legal 
guardian has undergone the informed consent process for the patients to take part in the study. 
Selected teeth will be dried for at least 5 seconds with compressed air and study lesions examined 
under a standard operating light in the CPD clinic. Visual exam: Ekstrand's criteria9 will be used to 
evaluate and record (Table 8.4.2.1). Study lesions scored in categories 1 or 2 from Ekstrand’s criteria 
will be enrolled in the study. 

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For radiograph examinations the DMG’s criteria7 will be used to evaluate and record carious lesions. 
Study lesions scored in categories E1 and E2 from DMG’s criteria7 will be enrolled in the study (Table 
8.4.2.2 and Figure 3). 
 
7.2.2 
Exclusion Criteria 
Patients will be excluded from the study if they are currently enrolled in a study that includes 
evaluation of other restorative materials or systems involving posterior teeth.  Patients will be 
excluded if they have a documented history of any adverse reaction to clinical materials of the type 
to be used in the study; is an irregular dental attendee; exhibits sensitivity in test teeth during 
screening visit; and the study teeth are thought to have poor access.  Early caries lesions with 
demineralization seen on occlusal surfaces will be excluded from participation, along with white spot 
lesions from hypoplasia or fluorosis.  Patients refusing radiograph exam will also be excluded from 
the study as well as pregnant female participants. 
 
 

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8 Clinical Evaluations 
8.1 Baseline Records (Radiography) 
Additional radiographs will not be taken for purpose of the trial only, they will be performed as part 
of standard of care. 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 an aiming device. 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.49-53 Both, 
the guidelines by Pitts and Kidd 4 widely used in Europe, and the ADA/FDA-coordinated guidelines 54 
advise that in high risk children (age 10-16) the interval should be 6-12 month. The proposed timing 
of bitewings in our study (baseline 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 
adolescents and young adults in the age range of 6-13 years. 
 
8.2 Clinic visits 
A trained study clinician will perform all standard clinical assessments of study lesions in groups 1 
and 2, including visual exam and radiograph exam.  The study clinician will provide Icon treatment to 
all study participants randomized to study arm 1 after the radiograph and visual exam.  The study 
clinician will provide oral hygiene instruction and topical fluoridation therapy (Duraphat fluoride 
varnish) to all study participants randomized to study arm 2 after the radiograph and visual exam. 
A trained study clinician will capture the SFE laser optical device image of the study lesions from all 
study participants.  The study examiner will be trained and calibrated by the HPL research team prior 
to start of study.  SFE laser optical device image diagnoses from baseline will be compared to 
diagnoses from radiograph and visual exams from chart review from the same visit.  
 
 

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8.3 Evaluation Categories 
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 
- 
No other scores will be documented 
8.3.4 
Caries Experience 
- 
Ekstrand´s criteria 
- 
Additionally, the caries experience and caries risk shall be recorded for each patient in the 
caries activity form supplied by DMG.  
8.3.5 
Individually standardized record (Radiographs) 
- 
DMG criteria for Icon treatment 
 
 
8.4 Evaluation Criteria 
8.4.1 
Preamble 
None 
8.4.2 
Eligibiltiy Criteria 
To be eligible for the study, each participant must meet preliminary eligibility criteria and the 
participant and the guardian must be willing to sign a statement of informed consent. This will 
document the agreement of the participant to participate in the studies activities. 
Additionally, participants will be asked by study personnel not to participate in any other therapeutic 
research studies during the participant´s follow-up period from baseline to the 24 month visit. 

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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 in inclusion and 
exclusion criteria. Screening includes patient information, eligible lesions are evaluated by a study 
investigator and randomly selected for treatment. 
Upon successful completion of the informed consent process by a parent/legal guardian, the 
participant will be enrolled in the study and randomized to an intervention group.  Both groups 1 and 
2 will return to clinic 2 weeks prior to intervention baseline visit for a pre-study visit.  During this visit 
orthodontic spacers will be placed interproximally in the study lesion area between the primary 
molars.  The spacer will be maintained in the interproximal area until the patient returns for the 
intervention baseline visit.  The spacer is non-invasive and placed to separate the teeth for better 
access during the intervention baseline visit for improved visualization and access for Icon/fluoride 
application.  Once the spacer is removed the space will close naturally within 3-4 weeks. 
 
9.2 Selection of Lesions (Screening visit only) 
Study participants will be recruited from the Resident Clinic at the Center for Pediatric Dentistry at 
new patient or non-invasive recall visits.  Resident clinicians and the research team will assist 
recruitment by identifying potential candidates with appropriate interproximal early caries lesions.  
All participants will be in general good health, aged 6-13 years, and enrolled into the study upon 
successful completion of the informed consent process.   
 
9.3 Randomization 
25 non-cavitated early caries lesions will be randomly assigned, using a random numbers table, to 
study arm 1) the Icon treatment group; and 25 non-cavitated early caries lesions will be randomly 
assigned, using a random numbers table, to study arm 2) the Control group (OHI and topical 
fluoridation). 
 
 
 

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9.4 Intervention Visit 
9.4.1 
Intervention Site “TREATMENT” 
All groups will undergo visualization of lesions with radiograph exam, visual exam, and SFE laser 
optical device exam.  2 weeks prior to the SFE laser optical device exam orthodontic rubber spacers 
will be inserted next to the study lesions to separate the proximal space for better visualization.   The 
initial SFE exam will occur prior to tooth separation at this visit. 
Prior to Icon placement, SFE laser optical device will be performed. The study clinician will provide 
Icon treatment to all early lesions randomized to study arm 1 after the radiograph and visual exam 
and a post SFE laser optical device will be performed. The test lesions will be treated using Icon 
(DMG, Hamburg, Germany) following the instruction for use.  
9.4.2 
Intervention Site “CONTROL” 
The study clinician will provide oral hygiene instruction and topical fluoridation therapy (Duraphat 
fluoride varnish; Colgate Oral Pharmaceuticals, New York, NY, United States) to all study participants 
randomized to study arm 2 after the radiograph, visual exam and SFE Laser Exam. The initial SFE 
exam will occur at this visit. 
 Topical fluoridation treatment will be provided is varnish (Duraphat) per manufacturer’s instructions.   
9.5 Follow-up Evaluations 
Follow-up assessments will occur at months 12 and 24 from baseline +/- 3 months.  Study patients 
will be reminded of their follow up visit. The following will occur at all follow-up visits: 
 
Two weeks prior to the appointment (-21 to -7 days) Orthodontic rubber spacers will be 
inserted next to the iconized lesions to separate the proximal space for better visualization. 
 
Radiograph exam of study lesion 
 
Visual exam of study lesion 
 
SFE laser optical device imaging of study lesion  
Results are documented in CRF (Appendix A1). 
If study lesions are noted to be progressing at any point the study clinician will refer the participant 
for standard-of-care treatment to the CPD Resident Clinic.  Progression is defined as lesion changes 

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from E2 to D category according to DMG’s criteria.  The study participant will no longer participate in 
the study at this point.  
 
 
9.6 Concomitant Treatment 
The clinical study is concerned with no more than 2 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 filled up 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 for 
completeness and filled up 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 write the resolution or explain the 
circumstances that led to the discrepancy in data. 
 
10.2 Data Quality Assurance 
Data Quality Assurance is a critical phase in clinical research, which leads to generation of high-
quality, reliable, and statistically sound data from the clinical trial. The clinical monitor is actively 

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involved in all stages of clinical trial right from inception to completion. For Data Quality DMG has 
implemented an adequate process knowledge that helps to maintain the quality standards of data 
management processes. Various procedures in Clinical Data Management including Case Report 
Form (CRF) designing, CRF annotation, monitoring database designing, data-entry, data validation, 
discrepancy management are assessed by the monitor for quality at regular intervals during a trial. 
10.3 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. 
10.4 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 continuous on-site visits.  
A carbon 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, blinded study, single center design. 
 
11.2 Determination of Sample Size 
50, non-cavitated early caries lesions, or areas of demineralization, in proximal surfaces of primary 
molars will be enrolled in this study.  Early caries lesions with demineralization seen on occlusal 
surfaces will be excluded from participation, along with white spot lesions from hypoplasia or 
fluorosis.   
 
11.3 Evaluation Strategy 
The bitewing radiographs will be examined and assessed by evaluators for positive, none or negative 
change in size and density. 
 
11.4 Statistical Analysis 
11.4.1 Descriptive Statistics 
Descriptive statistics (means, standard deviations, counts, and percentages) will be calculated for all 
variables.  A Chi-square test of association will be performed to evaluate if there is a significant 
difference in caries arrest by treatment group at a significance level of 0.05.  Additional Chi-square 
tests of association will be performed to determine if there is a significant association with the 
secondary outcomes by treatment group. 
 

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11.4.2 Blinding 
Each subject enrolled into this study will be assigned a unique identifying code number. Every effort 
will be made to maintain the confidentiality of each study subject's identity. No presentation or 
publication of the study data will identify any study subject.   
 
11.4.3 Evaluation of Records 
SFE laser optical device image diagnoses from each time point will be compared to diagnoses from 
radiograph and visual exams from chart review from the same visit.   
- 
For radiograph and visual exams: Assessments of caries lesions per standard of care will be 
abstracted from the electronic dental record system (Axium) and recorded on CRF.   
- 
For SFE laser optical device image: Recordings from the device will be used to assess caries 
lesions and recorded on CRF. 
 
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. Data of dropouts will be assigned as “last observation carried forward”. 
 
11.4.5 Statistical Software 
STATA Data Analysis and Statistical Software will be utilized to perform data analysis. 
 

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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:  
 
12.1.1 Study initiation visit 
The monitor conducts the study initiation visit after the site 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.   

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12.1.2 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. 
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. 
12.1.3 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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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 ethical committee from the Center for Pediatric Dentistry, Seattle, 
Washington (Appendix A3). Parents or guardians will sign an informed consent. (Appendix A4). 
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 46, ISO/DIN47 and Good 
Clinical Practice Guidelines48). 
 
 

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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 ethics committees will also be informed promptly and provided with the reason(s) for the 
termination or suspension by the principal clinical investigator. 
If the results of Icon or Control failed or is found to be clinically unsatisfactory, the Principal 
Investigator will provide an alternative treatment (of a different tooth colored restorative such as a 
composite resin restorative and bonding system, or other direct restorative system, at the discretion 
of the clinician,) to the subject.  The subject will then be discontinued from the study.   
 
 
 

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20 Publication Policy 
The study investigator may present or publish the results of scientific investigation involving this 
study. Details are described in the study contract section 6 in detail. 
 

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21 Administrative Arrangements 
21.1 The Research Team and its Responsibilities 
Principal Investigator:  
 
 
 
 
 
 
 
Co-Investigator:  
 
 
 
 
 
 
 
 
 
 
 
Co-Investigator:  
 
 
 
 
 
 
 
Co-Investigator:  
 
 
 
 
 
 
 
 
 

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21.2 Head of the Clinical study (Sponsor) 
 
 
 
 
 
 
 
 
21.3 Regulatory Affairs/ Clinical Monitoring (Sponsor) 
 
 
 
 
 
 
 
21.4 Clinical Study Contact (Sponsor)  
 
 
 
 
 
 
 
 

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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 trail 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 

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A2 Study Material Application Form 

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A3 Ethical approval 

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

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A6 Adverse Event/ Adverse Device Effect (AE/ADE) Report Form 

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23 References 
(1) 
Almeida AG, Roseman MM, Sheff M, Huntington N, Hughes CV. Future caries susceptibility in 
children with early childhood caries following treatment under general anesthesia. Pediatr 
Dent. 2000;22:302-306. 
(2) 
Anusavice K. Management of dental caries as a chronic infectious disease. J Dent Educ. 1998 
Oct 1998;62(10):791-802.  
(3) 
Assaf, V., Meneghim, C., Zanin, L., Pardi, V., Pereira, C., and Ambrosano, M. Influence of 
diagnostic adjuncts to the measurement of caries prevalence at different caries thresholds. 
International Dental Journal. December 2003. Volume 53, Issue 6, p. 485-490. 
(4) 
Belli, R., Christos Rahiotis, Edward W. Schubert, Luiz N. Baratieri, Anselm Petschelt, Ulrich 
Lohbauer, Wear and morphology of infiltrated white spot lesions, Journal of Dentistry, Volume 
39, Issue 5, May 2011, Pages 376-385. 
(5) 
Blank, M, Friedrich, M., Hamilton, J., Lee, P., Berg, J., and Seibel, EJ (2011) Laser scanning 
dental probe for endodontic root canal treatment, Lasers in Dentistry XVIII, Proc SPIE vol 7884, 
788403-1-7. 
(6) 
Delgado-Angulo EK, Bernabe E. Influence of host related indicators on dental caries in the 
permanent dentition. Acta Odontal Latinoam 2006; 19:85-92. 
(7) 
DMG 
Icon 
Brochure. 
http://www.dmg-
america.com/files/product/literature/[nid]/New Icon 8pg Brochure.pdf 
Accessed 
02/15/2012. 
(8) 
Du M, Luo Y, Zeng X, Alkhatib N, Bedi R. Caries in preschool children and it’s risk factor in 2 
provinces in China. Quintessence Int 2—7; 38:143-151. 
(9) 
Ekstrand KR, Ricketts DN, Kidd EA, Qvist V, Schou S. Detection, Diagnosing, Monitoring and 
Logical Treatment of occlusal caries in Relation to Lesion activity and severity. An in vivo 
examination with histological validation. Caries Res 1998;32:247-54. 
(10) Featherstone JBD, Duncan JF, Cutress TW. A mechanism for dental caries based on chemical 
process and diffusion phenomena during in-vitro caries simulation on human tooth enamel. 
Archs Oral Biol 1979; 24: 101-112. 
(11) Featherstone JBD. Remineralization, the natural caries repair process-the need for new 
approaches.  International Conference on Novel Anti-caries and Remineralizing Agents, held in 
Vina del Mar, Chile 2008. 
(12) Goel A, Chawla HS, Gauba K, Goyal A. Comparison of validity of DIAGNOdent with conventional 
methods for detection of occlusal caries in primary molars using the histological gold standard: 
An in vivo study.J Indian Soc Pedod Prev Dent 2009;27:227-234. 
(13) Gomes PR, Costa SC, Cypriano S, Rosaro de Sousa ML. Dental caries in Paulina, Sao Paulo, Brazil 
an World Health Organization goals for 2000 and 2010. Cad Saude Publica 2005; 20:866-870. 
(14) Griffin, S.O., E. Regnier, P.M. Griffin and V. Huntley, Effectiveness of fluoride in preventing 
caries in adults. Journal of Dental Research,  86  (2007), pp. 410–415. 
(15) Ismail AI. Visual and Visuo-tactile Detection of Dental Caries. J Dent Res 2004;83Suppl1:C56-
C66.  
(16) Ismail AI. Determinants of Health in Children and the Problem of Early Childhood Caries. 
Pediatr Dent. 2003;25:328-333. 
(17) Ismail, A. Caries Process and Prevention Strategies: Diagnosis. http://www.dentalcare.com/en-
US/dental-education/continuing-
education/ce373/ce373.aspx?ModuleName=coursecontent&PartID=3&SectionID=-1. accessed 
Oct 04, 2011. 
(18) Kagihara LE, Stark M. Assessment, management, and prevention of early childhood caries. J 
Am Acad Nurse Pract 2009; 21:1-10. 

CIP <NCT01796106> 
Author:  
 
 
 
 
Study Protocol <NCT01796106> Version 6 valid as of 13 February 2015  
 72 
 
(19) Lee CM, Engelbrech CJ, Soper TD, Helmchen F, Seibel, EJ. Scanning fiber endoscopy with highly 
flexible, 1 mm catheterscopes for wide-field, full-color imaging. J Biophotonics. Jun 2010:3(5-
6):385-407. 
(20) Meyer-Lueckel, H., Chatzidakis, A., Naumann, M., Dörfer, C.E., and Paris, S., Influence of 
application time on penetration of an infiltrant into natural enamel caries, Journal of Dentistry, 
Volume 39, Issue 7, July 2011, Pages 465-469. 
(21) Meyer-Lueckel, H., Paris, S., and Kielbassa, A.M. Surface layer erosion of natural caries lesions 
with phosphoric and hydrochloric acid gels in preparation for resin infiltration. Caries Res. 
2007; 41(3):223-30. 
(22) Mueller, J., H. Meyer-Lueckel, S. Paris, W. Hopfenmuller and A.M. Kielbassa, Inhibition of lesion 
progression by the penetration of resins in vitro: influence of the application 
procedure. Operative Dentistry,  31  (2006), pp. 338–345. 
(23) Murphy, T.C., Willmot, D.R., and Rodd, H.D., Management of postorthodontic demineralized 
white lesions with microabrasion: A quantitative assessment, American Journal of 
Orthodontics and Dentofacial Orthopedics, Volume 131, Issue 1, January 2007, Pages 27-33. 
(24) Paris, S., Meyer-Lueckel, H., Colfen, H.,and Kielbassa, A.M. Penetration coefficients of 
commercially available and experimental composites intended to infiltrate enamel carious 
lesions. Dent Mater. 2007 Jun;23(6):742-8. 
(25) Paris, S., Meyer-Lueckel, H., and Kielbassa, A.M Resin infiltration of natural caries lesions. J 
Dent Res. 2007 Jul; 86(7):662-6. 
(26) Paris, S. and Meyer-Lueckel, H. Caries inhibition by infiltrants in situ. Caries Res 43 (3): p. 228 
(Abstr. No.136), 2009 
(27) Reich E, Lussi A, Newbrun E. Caries-risk assessment. Int Dent J. 1999 Feb 1999;49(1):15-26.  
(28) Rocha RO, Ardenghi TM, Oliveira LB, Rodrigues CR, Ciamponi AL. In vivo effectiveness of laser 
fluorescence compared to visual inspection and radiography for the detection of occlusal 
caries in primary teeth. Caries Res 2003;37:437-41. 
(29) Sgan-Cohen HD, Mann J. Health, oral health and poverty. J Dent Res Assoc 2007; 138:1437-
1442. 
(30) Tinanoff N, Douglass J. Clinical decision making for caries management in children. Pediatr 
Dent. 9154;24(5):386-392.  
(31) Torres, C., Borges, A.B., Sarmento Torres, L.M., Gomes, I.S., and Simões de Oliveira, R., Effect 
of caries infiltration technique and fluoride therapy on the colour masking of white spot 
lesions, Journal of Dentistry, Volume 39, Issue 3, March 2011, Pages 202-207. 
(32) Tsai AI, Chen CY, Li LA, Hsiang CL, Hsu KH. Risk indicators for childhood caries in Taiwan. 
Community Dent Oral Epidemiol 2006; 34:437-445. 
(33) Valera, B., Pessan, P., Valera, C., Mondelli, J., and Percinoto, C. Comparison of visual 
inspection, radiographic examination, laser fluorescence and their combinations on treatment 
decisions for occlusal surfaces. American Journal of Dentistry. February 2008, Volume 21, Issue 
1, p. 25-29. 
(34) Winn DM, Brunelle JA, Selwitz RH, et al. Coronal and root caries in the dentition of adults in 
the United States, 1988-1991. Journal of Dental Research. Feb 1996;75:642-651.  
(35) Zandona AF and Zero DT.  Diagnostic tools for early caries detection.  JADA. 2006; 137:1675-
84. 
(36) Zantner, C., P. Martus and A.M. Kielbassa, Clinical monitoring of the effect of fluorides on long-
existing white spot lesions. Acta Odontologica Scandinavica,  64  (2006), pp. 115–122. 
(37) Zhang, L., Nelson, L.Y., and Seibel, E.J. (2011) Red shifted dental fluorescence in enamel and 
dentin, Journal of Biomedical Optics 16(7): 071411-1-5. 
 

CIP <NCT01796106> 
Author:  
 
 
 
 
Study Protocol <NCT01796106> Version 6 valid as of 13 February 2015  
 73 
 
(38) Zhang, L., Nelson, L.Y., Berg, J.H., and Seibel, E.J. (accepted)  Spectrally enhanced image 
resolution of tooth enamel surfaces.  Lasers in Dentistry XVIII, Proc. SPIE vol. 8208. 
(39) Meyer-Lueckel H, Paris S. Progression of artificial enamel lesions after infiltratin with 
experimental light curing resins. Caries Res 2008; 42:117-124. 
(40) Gomez SS, Basili CP, Emilson CG. A 2-year clinical evaluation of sealed noncavitated approximal 
posterior carious lesions in adolescents. Clin Oral Invest 2005;9:239-243. 
(41) Martignon S, Ekstrand KR, Ellwood R. Efficacy of sealing proximal early active lesions: an 18-
month clinical study evaluated by conventional and subtraction radiography. Caries Res 
2006;40:382-388. 
(42) Martignon S, Ekstrand KR, Gomez J, Lara JS, Cortes A. Infiltrating/Sealing Proximal Caries 
Lesions: A 3-year Randomized Clinical Trial. J Dent Res 2012;91(3):288-292 
(43) Paris S, Hopfenmueller W, Meyer-Lueckel H. Resin infiltration of caries lesions: an efficacy 
randomized trial. J Dent Res 2010;89:823-826 
(44) Meyer-Lueckel H, Bitter K, Paris S. Ranodmized Controlled Clinical Trial on Proximal Caries 
Infiltration: Three-Year Follow-Up. Caries Res 2012;46:544-548 
(45) Ekstrand KR, Bakhshandeh A, Martignon S. Treatment of proximal superficial caries lesions on 
primary molar teeth with resin infiltration and fluoride varnish versus fluoride varnish only: 
efficacy after 1 year. Caries Res 2010;44:41-46 
(46) Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for 
improving the quality of parallel-group randomized trials. Lancet 2001;357:1191-1194. 
(47) ISO (International Organization for Standardization), Clinical Investigation of medical devices 
for human subjects - #14155:2011, ISO Central Secretariat: Geneva, Switzerland 
(48) EMEA (European Medicines Agency), Guideline for Good Clinical Practice, 2002, London, Great 
Britain 
(49) Kidd E, Mejàre I, Nyvad B. Clinical and radiographic diagnosis. In: Fejerskov O, Kidd E. Dental 
caries – The disease and its clinical management. Copenhagen: Blackwell Munksgaard; 2003. 
p.111-128. 
(50) Murray JJ, Majid ZA. The prevalence and progression of approximal caries in the deciduous 
dentition in British children. Brit Dent J 1978;145:161-164.  
(51) Araújo FB, Araújo DR, Sanots CK, Souza MAL. Diagnosis of approximal caries in primary teeth: 
radiographic versus clinical examination using tooth separation. Am J Dent 1996;9:54-56 
(52) Kidd E, Pitts NB. A reappraisal of the value of the bitewing radiograph in the diagnosis of 
posterior approximal caries. Brit Dent J 1990;169:195-200. 
(53) Rimmer PA, Pitts NB. Temporary elective tooth separation as a diagnostic aid in general dental 
practice. Br Dent J 1990;169:87-92. 
(54) American Academy of Pediatric Dentistry, Endorsement: Prescribing dental radiographs for 
infants, children, adolescent and person with special health care needs, in 2005-06 Oral Health 
Policies and Clinical Guidelines (AAPD) 2005 
 
 
 
 

Statistical Analysis Plan 
 
NCT Number:  
Clinical Trial Proximal Caries Infiltration and Detection 
NCT Number:   
 
NCT01796106 
 
Sample Size Determination 
The primary endpoint in this study is the proportion of study lesions that have progressed, whereby a 
difference in caries progression of 40% after 2 years between resin infiltrated teeth and control will 
be assumed. This difference is based on a previous infiltration study by Ekstrand et al. [45] who 
reported a 1-year difference in caries progression in primary teeth of 39% (resin infiltration (23%) vs. 
control (62%)), which was furthermore comparable to results obtained in young adults. Martignon et 
al [42] for example reported a difference in caries progression in permanent teeth of 37% and 38% 
after 1 and 2 years respectively; and Meyer-Lueckel et al. of 30% after 18 months.  
Based on an assumed difference in caries progression of 40%  between resin infiltrated teeth and 
control, with alfa = 0.05 and a power of 80% the calculated sample size (t-test; matched pairs) would 
be 42 lesions to find significant differences. To allow for a potentially attrition rate of at least 20% 
over a period of 2 years a total of 50 lesions will be included.  
 
Statistical Analysis 
All evaluations are performed by one trained examiner. The primary outcome is proportion of study 
lesions that progressed after 2 years as measured via dental examination and pairwise comparison of 
radiographs. Differences between groups will be tested using Fisher’s exact test.  
Secondary outcomes are the proportion of study lesions that progressed after 1 year as well as 
change in categorical lesion depth (progression to next depth category lesion; E1->E2->D1->D2-
>filling) after 1 and 2 years as measured by pairwise comparison of radiographs. In addition, the 
change in categorical lesion depth will be determined via SFE laser optical device imaging after 1 and 
2 years and compared to the change in categorical lesion depth as measured by pairwise comparison 
of radiographs. Differences in categorical lesion depth will be analyzed with Chi-square tests with 
95% confidence interval (95% CI) and P = .05.