A Clinical Study to Compare Caries Detection in Children Between the iTero Element 5D System (NIRI=Near Infra Red Imaging) and Bitewing Radiographs (BWR) as a Diagnostic Aid for the Detection of Primary Carious Lesions Above the Gingiva.
Phase: NA
Conditions: Dental Caries, Patient Compliance
Sponsor: Hadassah Medical Organization

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Study Title: 
A study to compare caries detection in pediatric 
population between the iTero Element 5D system 
and bitewing radiographs as a diagnostic aid for 
the detection of primary carious lesions above the 
gingiva 
Funder: 
Align Technology, Ltd. 
Derech Yitshak Rabin 1,  
Petach Tikva , Israel 
03-6341441 
 
Protocol Version/Date: 
June 1st, 2022 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND BACKGROUND ................................................................................ 5 
1.1 
BACKGROUND ........................................................................................................................... 5 
2. 
DESCRIPTION AND INDICATIONS FOR USE ..................................................................... 5 
2.1 
DEVICE DESCRIPTION ........................................................................................................... 6 
2.2 
ITERO ELEMENT 5D INTENDED USE ............................................................................................ 8 
3. 
STUDY PURPOSE AND OBJECTIVES ................................................................................... 8 
3.1 
STUDY OBJECTIVES ............................................................................................................... 8 
3.2 
SECONDARY OBJECTIVES: ................................................................................................... 8 
3.3 
DEFINITIONS ............................................................................................................................ 8 
4. 
STUDY DESIGN ........................................................................................................................... 9 
4.1 
OVERVIEW OF STUDY DESIGN ............................................................................................ 9 
4.1.1 
MATERIALS ............................................................................................................................ 9 
4.1.2 
METHODS .............................................................................................................................. 9 
4.1.3 
END STUDY ......................................................................................................................... 10 
4.2 
NUMBER OF SUBJECTS/ ASSIGNMENT TO TREATMENT GROUPS ............................ 10 
4.3 
SITE .......................................................................................................................................... 11 
4.4 
SUBJECT WITHDRAWAL ..................................................................................................... 11 
4.5 
CLINICAL DATA MANAGEMENT ...................................................................................... 12 
5. 
STATISTICAL AND ANALYTICAL PLANS ........................................................................ 12 
5.1 
HYPOTHESIS .......................................................................................................................... 12 
5.2 
ASSUMPTIONS ............................................................. ERROR! BOOKMARK NOT DEFINED.12 
5.3 
SAMPLE SIZE.......................................................................................................................... 13 
5.4 
STUDY MEASURES ............................................................................................................... 13 
5.4.1 
Primary effectiveness endpoint measures ............................ Error! Bookmark not defined.13 
5.4.2 
Secondary effectiveness endpoint measures ........................ Error! Bookmark not defined.13 
5.5 
STATISTICAL ANALYSIS PLAN ......................................................................................... 14 
7. 
POTENTIAL SUBJECT RISKS AND BENEFITS ............................................................ 1414 
7.1 
POTENTIAL SUBJECT RISKS ..................................... ERROR! BOOKMARK NOT DEFINED.14 

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STUDY SUMMARY 
Title 
A clinical study to compare caries detection in children between the iTero Element 
5D system (NIRI) and bitewing radiographs (BWR) as a diagnostic aid for the 
detection of primary carious lesions above the gingiva. 
Purpose 
A comparison of caries detection in pediatric population between the iTero Element 
5D system and bitewing radiographs as a diagnostic aid for the detection of primary 
carious lesions above the gingiva. 
Design 
This is a non-significant risk, single site, prospective clinical study. The study will 
be conducted in the department of pediatric dentistry of the faculty of dental 
medicine of the Hebrew university, Israel  
Objectives 
Primary Objective: 
The objective of this study is to compare caries detection in pediatric population 
between the iTero Element 5D system and bitewing radiographs as a diagnostic aid 
for the detection of primary interproximal carious lesions above the gingiva. 
Secondary Objectives: 
• To compare users’ experience using a qualitative questionnaire  
• To compare carious lesions depth as appears in NIRI and BWR images to 
clinical depth observed during caries excavation  
 
Primary 
Endpoint  
Primary effectiveness endpoint measures:  
The iTero 5D will be non-inferior to BWR in detecting the existence of primary 
interproximal caries lesions above the gingiva in pediatric population. 
 
Secondary effectiveness endpoint 
• Qualitative users’ feedback relating to: chair time, the ability to capture tooth 
surfaces (reachability), patient’s experience (gag reflex, discomfort) will be 
collected through questionnaire 
• Lesion depth will be documented in cases where caries debridement was 
conducted. NIRI and BWR images will be compared to the clinical findings 
 
Study Device 
iTero Element 5D 
Eligibility 
Criteria 
Inclusion Criteria: 
A subject will be considered eligible if the following inclusion criteria are fulfilled: 
• Ages 4-9 years 
• Subjects scheduled for bilateral BWR as part of their standard of care 

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• Subjects with a recent bilateral BWR which were obtained up to 14 days 
prior to study visit 
Exclusion Criteria: 
A subject will be considered ineligible if any one of following exclusion criteria are 
fulfilled: 
• Subjects who have been diagnosed with epilepsy 
• Subjects with a known allergy to latex or plastic 
• Subjects with allergies to any dental or oral health products 
• Subjects who have undergone a dental treatment since the acquisition of the 
recent bilateral BWR 
 
Sites 
This study will be conducted in the department of pediatric dentistry of the 
Hadassah Medical Center, Faculty of Dental Medicine, Hebrew University of 
Jerusalem, Israel 
Sample Size 
70 subjects 
Length of 
Study 
Approximately 6 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION AND BACKGROUND 
1.1 BACKGROUND 
In 2007, Cadent Ltd. (now Align Technology, Ltd.) started marketing intraoral scanner systems to the 
dental industry. iTero scans have been used in more than 3.6 million restorative crowns, bridges, and 
custom implant abutment cases and more than 13.5 million iTero orthodontic scans, for a total of 17.1 
million scans. 
The iTero Element 5D system is an intraoral scanner with near-infrared imaging (NIRI) technology.  
Near-infrared Imaging (NIRI) is a nonionizing imaging technology that leverages differences in 
scattering and absorption of near-infrared light depending on the degree of tooth mineralization. In vivo1 
and vitro2 studies investigating the iTero Element 5D system for the detection of caries have yielded 
encouraging results.  
This prospective study is designed to compare caries detection in pediatric population between the iTero 
Element 5D system and bitewing radiographs as a diagnostic aid for the detection of primary 
interproximal carious lesions above the gingiva without using harmful radiation. 
2. DESCRIPTION AND INDICATIONS FOR USE 
2.1 DEVICE DESCRIPTION 
The iTero Element 5D (figure 1) is an intra-oral optical scanner for acquiring digital impressions. The 
system digitally captures the 3D geometry and color of the patient's intraoral dental structures using a 
proprietary optical, non-contact, focus detection technique using a Class 1 laser technology. 

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Figure 1. The iTero Element 5D 
 
The iTero Element 5D incorporates near-infrared illumination capabilities used to provide a near-
infrared image of the teeth enabling the detection of both occlusal and proximal caries, at the various 
stages, ranging from initial enamel caries to established caries reaching the DEJ. 

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Figure 2. The NIR Cam mode. NIR images are displayed on the main screen while a color image is displayed in    
the View Finder window 
 
NIR functionality is implemented by using 850nm wavelength LEDs.  Incorporating both the NIR 
images and the color images captured by the system can aid in the detection of caries (Figures 3 and 4). 
                           
             
Figure 3.  
 
 
  
 
 
 
Figure 4.   
Color Image as captured by the iTero Element                                      NIRI image demonstrating two proximal carious lesions  
 
 
 
  
 
 
 
(Red circles)  

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2.2 iTero Element 5D Intended Use 
The iTero Element 5D system is indicated for intra oral scanning. NIRI technology of the iTero Element 
5D aids in detection and monitoring of interproximal caries lesions above the gingiva without using 
harmful radiation. 
3. STUDY PURPOSE AND OBJECTIVES  
3.1 STUDY OBJECTIVES 
The objective of this study is to scan subjects intraorally with iTero Element 5D system and compare 
caries detection in pediatric population to common practice (bitewing radiographs) as a diagnostic aid 
for the detection of primary interproximal carious lesions above the gingiva.  
3.2 SECONDARY OBJECTIVES:  
• To compare users’ experience using a qualitative questionnaire  
• To compare carious lesions depth as appears in NIRI and BWR images to clinical depth observed 
during caries excavation when indicated.  
 
3.3 DEFINITIONS  
 
Term or Abbreviation 
Definition 
AE 
Adverse Event 
BWR 
Bite Wing Radiographs 
CRF 
Case Report Form 
DEJ 
Dentin-enamel junction 
Device 
iTero Element 5D system 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
Investigator 
The person responsible for the conduction of this 
study at each individual site.  This person will be 

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the treating dentist. The term “Investigator” is 
used synonymously in this Protocol with 
“Principal Investigator”, “Dentist” and “Doctor”. 
IR 
Infrared 
NIR 
Near Infra-red 
NIRI 
foutcome 
PID 
Patient Identification Number 
SAE 
Serious adverse event 
 Funder 
Align Technology, Ltd. 
Study Monitor or Clinical Research Associate 
(CRA) 
Person who monitors the study data for 
completeness, accuracy through on-site visits, 
remote monitoring, etc. 
 
4. STUDY DESIGN 
4.1 OVERVIEW OF STUDY DESIGN 
This is a non-significant risk, single site, prospective study to be conducted in the department of 
pediatric dentistry of the Hadassah Medical Center, Faculty of Dental Medicine, Hebrew University of 
Jerusalem, Israel. Subject participation will require one visit during which consent, screening, 
enrollment, and imaging will be performed.  An additional follow-up call to the Investigator will take 
place a month later to review patient records and capture any clinical information recorded since last 
trial visit if a treatment was planned.  
Each subject will be assigned a unique ID number that will link to their data. De-identified data sets will 
be used for analysis. 
Clinical and diagnostic methods to be used during this study are those that are routinely used in the 
diagnosis of caries in this site, which include bitewing radiographs (BWR). This standard of care is 
provided for all site’s patients, including the patients who don’t participate in this clinical study.  
A standard set of BWR for subjects ages 4-9 years will be taken to include the complete dentition of the 
subjects.  Any recent bilateral BWR which were obtained up to 14 days prior to study visit may be used. 
No additional x-ray should be taken for the sole purpose of this trial. 
In addition to the routine clinical diagnostics, the subjects will be scanned using the 5D system. The 
investigator will capture a full arch scan of the maxillary arch and mandibular arch of each subject with 
the iTero Element 5D system. For each subject, the Investigator will grade carious lesions in the BWR 
and Element intra-oral scan according to ADA staging guidelines3. The results will be documented using 

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Caries Evaluation Forms. The Investigator will assess and document the findings of each diagnostic test 
separately before reviewing the next test. 
In cases where caries debridement indicated, carious lesion depth will be documented during and 
compared to NIRI and BWR images. All treatment decisions will be made according to the standard 
of care in the clinic and no treatment will be conducted for the sole purpose of the study. 
The study will include an interim analysis to assess the iTero Element 5D system useability among the 
first 20 pediatric subjects. Based on the findings’ evaluation, modifications in the study protocol for the 
remaining 50 subjects will be considered.  
Once images from the iTero Element 5D system and the bilateral BWR are obtained, the subject will 
have completed the study visit.  
Data regarding caries treatments that were executed in accordance with the clinic standard of care during 
a follow-up period of 1 month post study visit will be captured in the CRF.   
Duration of the study is estimated to be six months. 
All participating doctors and designated office coordinators will be trained on the clinical study protocol 
and Good Clinical Practices (GCP). 
4.1.1 MATERIALS 
See section 2.  
4.1.2 METHODS 
4.1.2.1 INCLUSION CRITERIA   
A subject will be considered eligible if the following inclusion criteria are fulfilled: 
• Ages 4-9 years 
• Subjects scheduled for bilateral BWR as part of their standard of care 
• Subjects with a recent bilateral BWR which were obtained up to 14 days prior to study visit 
 
4.1.2.2 EXCLUSION CRITERIA 
A subject will be considered ineligible if any one of following exclusion criteria are fulfilled: 
• Subjects who have been diagnosed with epilepsy  
• Subjects with a known allergy to latex or plastic 
• Subjects with allergies to any dental or oral health products 
• Subjects who have undergone any dental treatment since the acquisition of the recent bilateral 
BWR 
 
4.1.2.3 SCHEDULE OF STUDY VISITS 
Subject participation will require one patient visit during which consent, screening, enrollment, imaging 
and study exit will be completed.  

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• Initial Visit 
1. Review inclusion and exclusion criteria (Eligibility criteria) 
2. Inform subject and obtain written assent form  
3. Enrollment Form 
4. Intraoral Scan: Subjects will be scanned intraorally using the iTero Element 5D system.  
5. Acquisition of recent BWR data.  
6. Caries Evaluation Form 
4.1.3 END STUDY 
The End of Study occurs when a subject has completed all study-related procedures and follow-up. 
When all subjects have completed the study, a report will be written concluding the findings from the 
study. Subsequent clinical evaluation and treatment, if indicated will be performed after study 
completion by each patient’s dentist. 
4.2 NUMBER OF SUBJECTS/ ASSIGNMENT TO TREATMENT GROUPS 
70 subjects will be enrolled in one site.   
The study will include an interim analysis to assess the iTero Element 5D system useability among the 
first 20 pediatric patients. Based on the findings’ evaluation, modifications in the study protocol for the 
remaining 50 subjects will be considered. 
4.3 SITE 
This study will be conducted by Prof' Moti Moskovitz in the department of pediatric dentistry of the 
Hadassah Medical Center, Faculty of Dental Medicine, Hebrew University of Jerusalem, Israel. The 
Investigator will be proficient with the use of the iTero Element 5D system.   
4.4 SUBJECT WITHDRAWAL  
Subjects have the right to withdraw from the study at any time for any reason.  The Investigator may 
withdraw the subject at any time for any reason.  If any subject withdraws or is withdrawn from the 
study, any non-study records that were taken while the subject was enrolled in the study will not be 
shared with the study Funder and there will be no requirement to continue treatment according to this 
protocol.  Withdrawal from the study will not result in any penalties and will not preclude or interfere 
with the Investigator’s treatment of the subject outside of the study.  Additional subjects may be enrolled 
to substitute for any withdrawn subjects until the study target enrolment is reached. 
The schedule of all study activities and procedures is provided in Table 1.  No additional invasive or 
other burdensome interventions in comparison to the standard care will be performed. 
Data will be entered into a database, located on a secure server. Each subject will be assigned a unique 
ID number which will link to their data. Data will be examined for completeness and checked for 
accuracy.  De-identified data sets will be used for analysis.  

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4.5 CLINICAL DATA MANAGEMENT  
 CASE REPORT FORMS 
The Case Report Forms (CRF) for this Study are as follows: 
• Subject Enrollment Form 
• Caries Evaluation Forms 
• User experience questionnaire 
• Data regarding caries extend observed during caries excavation 
• Withdrawal Form (if applicable) 
• Adverse Event Form (if applicable) 
• Protocol Deviation Form (if applicable) 
 
5. STATISTICAL AND ANALYTICAL PLANS 
5.1 HYPOTHESIS 
The test results can be summarized in the following 2x2 table:  
  
X-ray is the ground truth  
NIRI   
Negative (no caries) 
Positive (caries) 
Negative (no caries) 
P00 
P01 
Positive (caries) 
P10 
P11 
Where Pij = the percentage of tooth surfaces under certain condition out of all included surfaces.  
As we are taking X-ray as the ground truth, P01 is the percentage of surfaces that can be detected as 
caries by X-ray but not NIRI (NIRI missed detection rate), P10 is the percentage of surfaces that can be 
detected by NIRI, but not X-ray (NIRI over detection rate). By showing that NIRI over detection rate 
(P10) is not less than NIRI missed detection rate (P01) by non-inferiority margin of M, we can conclude 
that NIRI is non-inferior than X-ray in detecting caries. Thus, P10-P01 provides a measure for assessment 
of a non-inferiority between two procedures.  
Null Hypothesis: P10-P01 ≤ -M 
Alternate Hypothesis: P10-P01 > -M 
5.2 ASSUMPTIONS 
5.2.1 Test results 
By assuming [3]: 
1. 50% of the participants will have active caries 
2. On average there are 1 carious surface per patient with active caries 
3. there is minimum of 2 naïve IP surfaces per pediatric patient which may be captured in BWR 
Approximately, out of all patients included in the trial, 1.8% of all tooth surfaces are carious and 98.2% 
of all tooth surfaces are non-carious.  

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Based on previous iTero 5D study1, we can assume that for NIRI, the sensitivity for early enamel lesions 
is 0.51 and specificity is 0.90.  
The assumed test results can be summarized as: 
  
X-ray is the ground truth  
NIRI   
Negative (no caries) 
Positive (caries) 
Negative (no caries) 
88.38% 
0.88% 
Positive (caries) 
9.82% 
0.92% 
5.2.2 Non- inferiority margin 
Based on relevant literature [5] and the results from previous trials, we can assume that the non-
inferiority margin to be 5%.  
 
5.3 SAMPLE SIZE 
Sample size can be calculated from the sample size equation for comparing paired nominal data by using 
McNemar’s test [4]: 
𝑛=
[𝑧𝛼√𝑝01 + 𝑝10 + 𝑧𝛽√𝑝01 + 𝑝10 −(𝑝01 −𝑝10)2]2
(𝑝10 −𝑝01)2
 
Similar formulae can be obtained for the one-sided non-inferiority test by substituting 𝑧𝛼/2, 𝑝10 with 𝑧𝛼 
and 𝑝10 + 𝑀: 
𝑛=
[𝑧𝛼√𝑝01 + 𝑝10 + 𝑀+ 𝑧𝛽√𝑝01 + 𝑝10 + 𝑀−(𝑝01 −𝑝10 −𝑀)2]2
(𝑝10 + 𝑀−𝑝01)2
 
where significance level 𝛼= 0.05, power 1 −𝛽= 0.8, non-inferiority margin M = 5%, assumed 
detection rate 𝑝01 = 0.22%, 𝑝10 = 2.46% 
The minimum sample size required is 89 surfaces. Assuming the drop off rate to be 30%, an additional 
39 surfaces will be recruited, so the total number of surfaces needed for the clinical trial is 128. 
assuming a minimum of 2 naïve IP surfaces per paediatric patient. 
The minimum required patient count and site count 70 patients in one trial site.  
5.4 STUDY MEASURES  
5.4.1 Primary effectiveness endpoint measures 
The iTero 5D will be non-inferior to BWR in detecting the existence of primary interproximal caries 
lesions above the gingiva. 
5.4.2 Secondary effectiveness endpoint measures 
The iTero 5D will be non-inferior to BWR when comparing clinical findings during caries 
debridement 
 

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5.5 STATISTICAL ANALYSIS PLAN 
Statistical tests will be performed to show comparison between iTero NIRI technology of the iTero 
Element 5D and bite-wing x-ray in detecting the existence of primary interproximal caries lesions above 
the gingiva  
• Two-sided McNemar’s Chi-square test to show if there is a statistically significant difference 
between the detection ability of the iTero NIRI technology of the iTero Element 5D and bite-
wing x-ray 
 
• Asymptotic Non-Inferiority test to show if the false positive (FP) rate (P10) is non-inferior than 
false negative (FN) rate (P01) with non-inferiority margin as 0.05, which means iTero NIRI 
technology of the iTero Element 5D is non-inferior than bite-wing x-ray in detecting primary 
interproximal caries 
 
• One-sided binomial test to show if the false positive (FP) count (C10) is significantly higher than 
false negative (FN) count (C01), which indicates if iTero NIRI technology of the iTero Element 
5D can detect more primary interproximal caries than bite-wing x-ray 
 
• Kappa coefficient will be calculated to assess the agreement between two methods. (Moderate 
agreement (Kappa 0.41–0.60) is expected) 
 
6. POTENTIAL SUBJECT RISKS  
Generally, there are no additional risks to patients involved in this study. Patients undergoing dental 
diagnosis will not have any additional risk due to the 3D intraoral scan.  Procedures and treatments 
described in this protocol are in accordance with current dentistry practices. All patient contacting 
material are commercially available, and have met all applicable regulatory standards. 
Very rare, soft electrical shock. One case of soft electric shock originating from the backside of the base 
unit and without physical harm reported during 2018. For persons who have been diagnosed with 
Epilepsy, there is a risk of epileptic shock from the flashing light from the system. These persons are 
excluded from this clinical study. Potential minimal risk could be if a subject has an allergic reaction to 
the materials used during treatment.  
 
 
 
 
 

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7. SCHEDULE OF ASSESSMENT (TREATMENT PERIOD)  
Table 1: Schedule of Assessments  
Procedures/Forms 
Visit 1 
Week 5  
1 month follow-up on patient 
records  
Evaluation of eligibility 
criteria 
X 
 
Informed Consent 
X 
 
Intraoral Scan 
X 
 
Obtain recent BWR 
Radiographs data 
X 
 
CRF - Enrollment Form 
X 
 
CRF - Caries Evaluation 
Form (BWR, 5D Intraoral 
scan) 
X 
 
Review Patient records 
and capture any clinical 
information recorded 
since last trial visit, if 
treatment was performed. 
 
X 
 
 
 
 
 
 
 
 
 
 

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8. REFERENCES: 
 
1. Metzger Z, Colson DG, Bown P, Weihard T, Baresel I, Nolting T. Reflected near-infrared light 
versus bite-wing radiography for the detection of proximal caries: A multicenter prospective 
clinical study conducted in private practices. J Dent. 2021 Oct 24 
 
2. Litzenburger F, Heck K, Kaisarly D, Kunzelmann KH. Diagnostic validity of early proximal caries 
detection using near-infrared imaging technology on 3D range data of posterior teeth. Clin Oral 
Investig. 2021 Oct 12. 
 
3. Young, Douglas A., et al. "The American Dental Association caries classification system for 
clinical practice: a report of the American Dental Association Council on Scientific Affairs." The 
Journal of the American Dental Association 146.2 (2015): 79-86. 
4.  
5. National Institute of Dental and Craniofacial Research https://www.nidcr.nih.gov/research/data-
statistics/dental-caries/adults 
6. Kühnisch J. In vivo validation of near-infrared light transillumination for interproximal dentin 
caries detection. Clin Oral Investig. 2016 May;20(4):821-9. 
7. Ahn, S., Park, S.H. and Lee, K.H., 2013. How to demonstrate similarity by using noninferiority 
and equivalence statistical testing in radiology research. Radiology, 267(2), pp.328-338. 
8. Chow, S.C., Shao, J., Wang, H. and Lokhnygina, Y., 2017. Sample size calculations in clinical 
research. Chapman and Hall/CRC. page 155.