Evaluation of Effectiveness of a Novel Remineralizing Agent: A Randomized Controlled Clinical Trial
Phase: NA
Conditions: White Spot Lesion
Sponsor: Ivoclar Vivadent AG

Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
ivoclar 
Clinical Study Protocol - 
Evaluation of Effectiveness of a Novel Remineralizing Agent: A 
Randomized Controlled Clinical Trial 
Study Title 
Evaluation of Effectiveness of a Novel Remineralizing Agent: A 
Randomized Controlled Clinical Trial 
Registration 
https://clinicaltrials.gov 
Study-lD 
IVAG-Study-IO: LL4406332 
lnstitution-Studv-lD: N/A 
Product 
Experimental Fluoride Application
Project Number 
62 13 06 
Document-lD 
LL4470462 
Document Version 
1.0 
Document Date 
21.03.2022 
Document Control 
Name 
Date 
Signature 
Study Coordinator 
Cto5 . .?c>12. 
 
Mutlu Özcan 
Prof. Dr. Dr. h.c., Ph.D, 
University of Zurich 
Division of Dental Biomaterials 
Center of Dental Medicine 
Clinic of Reconstructive Dentistry 
Plattenstrasse 11, CH-8032, Zurich, 
Switzerland 
Mobile: 
 
E-mail: 
Revision History 
Version 
Date 
Author 
Remark on Amendments to the CIP 
1.0 
21.03.2022 
Burcu Gözetici <;il 
Initial creation 
Mutlu Özcan 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
ivoclar 
The Coordinating lnvestigator has approved the CIP version [1.0 (dated 21.03.22), and confirm 
hereby to conduct the investigation according to the CIP, the current version of the World 
Medical Association Declaration of Helsinki, 1SO14155 norm, ICH-GCP as far as applicable, 
and the local legally binding requirements. This includes in particular that the clinical 
investigation shall not begin until the required approval(s) have been obtained and that any 
additional requirements imposed by the EC or NCA shall be followed, if appropriate. 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
ivoclar 
Doc-ID: LL4470462 
21.03.22, Version 1.0 
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SPONSOR SIGNATURE PAGE 
We, the undersigned, have read this protocol and agree that it contains all necessary 
information required to conduct the study. 
lvoclar Vivadent AG 
Bendererstrasse 2, 9494 Schaan 
Liechtenstein 
Patrik Oehri 
Senior Director CQM & Regulatory Affairs, PRRC 
Dr. Thomas Völkel 
Head of Department Scientific Services/ Deputy PRRC 
Study Management 

Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
INVESTIGATOR STATEMENT 
ivoclar 
1 have read protocol and agree that it contains all necessary details for carrying out the study 
described and in conformance with Good Clinical Practices (GCPs), the current version of the 
World Medical Association Declaration of Helsinki, IS014155 norm and applicable regulatory 
requirements. 1 agree to maintain the confidentiality of all information received or developed in 
connection with the protocol. 
Burcu Gözetici il 
Printed Name of lnvestigator 
f lnvestigator 
Date 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
1.
Synopsis
Sponsor/ 
Manufacturer 
Ivoclar Vivadent AG 
Bendererstrasse 2 
9494 Schaan 
Fürstentum Liechtenstein 
Study Title 
Evaluation of Effectiveness of a Novel Remineralizing Agent: A 
Randomized Controlled Clinical Trial 
Short Title 
n.a.
Version/ Date 
1.0/ 21.03.22 
Registration: 
 https://clinicaltrials.gov 
Clinical 
investigation 
category and 
Rationale 
Medical Device Clinical Trial 
Background and 
Rationale: 
Active non-cavitated caries lesions on buccal surfaces teeth scored 
with ICDAS code 1 or 2 are characterized by white chalky 
appearance as a result of loss of minerals from the tooth structure. 
The progression of these lesions can be reversed or arrested by 
application 
of 
some 
therapeutic 
agents, 
enhancing 
remineralization. Fluoride varnishes are considered to be the first 
choice of treatment for this purpose. Fluoride varnishes with high 
concentration of fluoride provides calcium fluoride formation which 
acts as a reservoir for both calcium and fluoride. The release of 
these ions during acidic challenges inhibits further dissolution of 
hydroxyapatite crystals of the dental hard tissues. 
In the present pilot clinical study, the test material containing -
calcium fluoride nanosol in addition to high level of ammonium 
fluoride content will be evaluated. Ammonium fluoride solution and 
calcium fluoride solutions are designed to be applied separately to 
form a protective layer. Application of calcium fluoride in 
combination with high concentration of fluoride is anticipated to 
have beneficial effects on the repair of incipient caries lesions with 
ICDAS code 1 and 2. 
Objective(s): 
Comparison between investigational medical device (Exp. 
Fluoride Appl. Ivoclar-Vivadent AG, Schaan, LI) and control 
product (Fluor Protector S, Ivoclar-Vivadent AG, Schaan, LIE)
Outcome(s): 
Primary outcome: 

 
 
 
 
 
 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
•
Evaluation of the change in lesion size and mineral content
based on Qraycam measurements at baseline, after 1, 6
and 12 months.
Secondary outcome: 
•
Clinical evaluation of the lesion progression according to
ICDAS and Nyvad criteria at baseline, 1, 6 and 12 months.
•
Digital pictures for secondary evaluation by the observers
to calculate inter-examiner reliability.
Clinical 
investigation 
design: 
Randomized controlled blinded evaluation in split-mouth design 
Inclusion / 
Exclusion criteria: 
At least two early caries lesions (arrested or progressive) on buccal 
sides of two teeth in two different quadrants. 
Inclusion criteria: 
•
Subjects are required to have at least two active non-
cavitated white spot lesions (WSLs) on buccal surfaces of
anterior teeth or premolars (ICDAS code 1 and 2; Nyvad
score 1)
•
Age between 13 and 50 years
•
No untreated caries lesions or periodontal disease
•
No 
systematic 
disease 
or 
medication 
(such 
as
antidepressants, antibiotics etc.) that affects salivary flow
rate
•
Subjects claimed regular brushing at least twice a day
•
Subjects had to agree to keep the scheduled recall
appointments for 1 year.
Exclusion criteria: 
•
Inactive non-cavitated lesions (Nyvad Score 4)
•
Lesions 
with 
microcavity, 
cavitation, 
chipping 
or
discoloration
•
Lesions at buccal side of the molars
•
Lesions adjacent to restoration
•
Developmental white spot lesions such as enamel
hypoplasia

 
 
 
 
 
 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
•
Pregnant and breastfeeding women
Intervention: 
Measurements and 
procedures 
The 
investigational 
medical 
device 
Experimental 
Fluoride 
Application, consists of an aqueous fluoride solution and an 
ethanol-based solution of calcium fluoride nanosol, which is 
supplied in two separate bottles which will be applied directly on 
enamel.  
Control Intervention 
(if applicable): 
Fluor Protector S (Ivoclar Vivadent AG, Schaan, Liechtenstein) is a 
protective varnish containing ammonium fluoride. It will be applied 
on enamel of teeth in the control group. The application is according 
the instruction for use within the indication. 
Number of 
Participants with 
Rationale: 
23, rationale see statistical considerations 
Duration of the 
investigation: 
6 months estimated duration for the main investigational plan (e.g. 
from start of screening of first participant to last participant 
processed and finishing the clinical investigation) 
1 year 6 months of First-Participant-In until Last-Participant-Out 
Investigation 
Schedule: 
Intervention, 4 weeks, 6 months, 12 months recall 
Study Coordinator: 
Mutlu Özcan 
Prof. Dr. Dr. h.c., Ph.D, 
University of Zurich 
Division of Dental Biomaterials 
Center of Dental Medicine 
Clinic of Reconstructive Dentistry 
Plattenstrasse 11, CH-8032, Zurich, Switzerland 
Mobile: 
 
E-mail: 
Principal 
Investigator: 
Dr. Burcu Gözetici 
Istanbul Medipol University 
School of Dentistry 
Department of Restorative Dentistry 
Birlik Mah., Bahçeler Cd. No:5,  
34230 Esenler 
Istanbul, TURKEY 
E-mail: 
Investigation 
Site(s): 
Single-centre 
Statistical 
Considerations: 
t-test allows a sample size of 23 patient with power of 80% at a
significance level of 5%.

 
 
 
 
 
 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
Compliance 
Statement: 
This clinical investigation will be conducted in compliance with the 
CIP (protocol), the current version of the Declaration of Helsinki, 
ISO EN 14155, ICH-GCP (as far as applicable) as well as all 
national legal and regulatory requirements. 
2.
Definitions, Terms, Abbreviations
ADE 
Adverse Device Effect. Adverse events (see below) that are 
related to the MD under investigation or the comparator and to 
the procedures involved.  
For users or other persons this is restricted to events related to 
the MD.  
AE 
 Adverse event (Art. 2 Abs 57 MDR): 
 Any untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs (including an abnormal laboratory 
finding) in subjects, users or other persons whether or not related 
to the MD. 
Castor EDC 
Electronic data capturing (EDC) platform from the company 
Castor 
CE 
Conformité Européenne (Label on products complaint to 
European Medical Device Legislation) 
CER 
Clinical Evaluation Report 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
Clinical studies 
Systematic investigation in one or more human subjects, 
undertaken to assess the clinical performance, effectiveness or 
safety of a medical device. 
Note: For the purpose of this document, “clinical investigation” or “clinical trial” 
are synonymous with “clinical study” 
DD 
Device Deficiency (Art. 2 Abs 59 MDR): 
Inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, of an investigational 
device, including malfunction, user errors and inadequate 
information supplied by the manufacturer. 
The definition includes deficiencies related to the investigational 
MD or the comparator MD. 
(e)CRF
(electronic) Case Report Form 
ICH-GCP
International Conference on Harmonisation – Good Clinical 
Practice 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ISO 
International Organization for Standardization 
MD 
Medical Device 
Directive) 
PI 
Principal Investigator 
SAE 
Serious adverse event: (Art. 2 Abs 58 MDR) 
Any adverse event (see definition above) that led to any of the 
following: 

 
 
 
 
 
 
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Evaluation 
of 
Effectiveness 
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a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
(a) death,
(b) serious deterioration in the health of the subject that resulted
in any of the following:
(i) life-threatening illness or injury,
(ii) permanent impairment of a body structure or a body function,
(iii) hospitalization or prolongation of patient hospitalization*,
(iv) medical or surgical intervention to prevent life-threatening
illness or injury or permanent impairment to a body structure or a
body function,
(v) chronic disease,
(c) foetal distress, foetal death or a congenital physical or mental
impairment or birth defect.
*Note: planned hospitalization for pre-existing condition, or a
procedure required by the CIP, without a serious deterioration of
the health status of the subject, is not considered an SAE
SADE 
Suspected Serious Device Effect.
Subjects 
SAE related to the MD and/or the comparator
Participants (i.e. Patients) that are included in a clinical
investigation.

VAS for tooth 
sensitivity 
x 
Intraoral 
pictures 
x 
x 
x 
x 
Recording 
ICDAS and 
Nyvad scores 
x 
x 
x 
x 
Professional 
cleaning of tooth 
suface  
x 
QrayCam Pro 
measurement 
x 
x 
x 
x 
Adverse events 
(incl. SAE) 
 x 
 x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
 
 
 
 
 
 
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Evaluation 
of 
Effectiveness 
of 
a 
Novel 
Remineralizing Agent: A Randomized Controlled 
Clinical Trial 
3. Study Schedule
Screening, 
Patient 
information 
Treatment, 
Intervention 
(Enrolment) 
Follow-Up (Recall) 
Visit 
1 
2 x 
3 
4 
5 
Time (hour [h], 
day [d], week 
[wk], month [mt]) 
12 mt 
1 h 
4 w 
6 mt 
12 mt 
Patient 
Information 
x 
Informed 
Consent 
x 
Medical History 
x 
In- /Exclusion 
Criteria 
x 
 x 
Tooth 
Examination 
x 
Vitality test 
x 
Study Periods