Clinical Efficacy of Vector Paro With Hydroxyapatite in the Supportive Therapy of Periodontitis: a 6 Months Randomized Controlled Trial Study
Phase: NA
Conditions: Periodontal Diseases, Hypersensitivity Dentin, Hydroxyapatite
Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

 
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CONFIDENTIAL AND PROPRIETARY 
Information provided herein is the property of the University-Hospital of Brescia. Nothing herein is to be reproduced, 
published, or disclosed to others in any way without the prior expressed written permission of the University-Hospital 
of Brescia. 
 
 
Title of Study: Clinical efficacy of Vector Paro with hydroxyapatite in the supportive therapy of 
periodontitis: a 6 months Randomized Controlled Trial study  
 
Type of Study: Clinical 
 
Protocol No: PROTOCOL #PAROXY 
 
Sponsor: ASST Spedali Civili di Brescia 
 
Expected study start date: GEN, 2023 (study initiation) 
 
Study Location/Country: Brescia, Italy 
 
Study Originator(s)/ Contact (name, phone, fax): Magda Mensi, Piazzale Spedali Civili 1, 
25123 Brescia, phone: +390303995784, email: magda.mensi@unibs.it 
 
Test Products w/ PDM Numbers:  
CE marked Medical Device to be used as an adjunct therapy to standard in patients with 
moderate to severe periodontal disease (Confidential information). 
 
!
 

 
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Study Title: 
Clinical efficacy of Vector Paro with hydroxyapatite in the supportive 
therapy of periodontitis: a 6 months Randomized Controlled Trial 
study. 
 
Study sites: 
 
 
Dr. Magda Mensi (lead site) 
 
 
 
 
ASST Spedali Civili di Brescia 
 
 
 
 
University of Brescia 
 
 
 
 
Brescia, Italy. 
 
 
 
 
 
Study Phase: 
 
IV.  
 
Name of Medical Device: 
Vector and Fluid Polish (Durr Dental, Bietigheim-Bissin gen, 
Germania)   
 
Objective: 
The objective of the clinical study is to assess the efficacy of the 
addition of hydroxyapatite in the supportive therapy of periodontitis 
in terms of reduction of PD (Probing Depth). 
 
Patient Population: 
44 periodontal patients, systemically healthy, male and female 
adults (18 – 75 years), with history of periodontitis grade B or C and 
stage III or IV, with at least 2 residual sites/pockets (test sites) with 
probing depth ≥6 mm or pockets of 5 mm with bleeding on probing.  
 
Structure:                     
Split mouth: Number of treatments: 2: before a session of non-
surgical supportive therapy in one group the test sites are treated 
with a traditional handpiece (control group) in another group the test 
sites are treated with an innovative handpiece which carries 
hydroxyapatite (test group)!
                                                                                              
Duration of study: 36 months.  
"#!$%%&'($)*!
+!,&''&-./0!
 
Number of Centers:    
One. 
 
Blinding: 
Examiner and Statistician. 
 
Method of Patient Selection: Periodontal pockets: at least 4 sites (split mouth 2 – 2)  with probing 
depth ≥6 mm or pockets of 5 mm with bleeding on probing. 
 
Total Sample Size: 
44 adult subjects will be recruited (randomized) to participate in 
this study, with 40 expected to complete the study. 
 
Primary Efficacy Variable: 
Primary outcome measure will be the changing of PD in 
millimeters. 
 
 
!
 

 
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Clinical efficacy of Vector Paro with hydroxyapatite in the supportive therapy of 
periodontitis: a 6 months Randomized Controlled Trial study  
PROTOCOL #PAROXY 
____________________________________________________________!
!
 
 
Protocol Date: OCT 1, 2022 
 
 
 
 
Protocol  Approval 
 
Signature Page 
 
 
 
 
 
________________________ 
 
 
Dr. Magda Mensi 
 
 
 
 
 
 
Date 
   
 
 
 
 
 
 
 
 
!
 

 
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ADDRESSES AND RESPONSIBILITIES 
 
Addresses 
Study Centres: 
Section of Periodontics, School of Dentistry, Department of 
Surgical Specialities, Radiological Science and Public Health 
ASST Spedali Civili di Brescia 
Piazzale Spedali Civili 1  
25123, Brescia, Italy 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Magda Mensi (Principal Investigator) 
 
 
 
 
 
Tel. +390303995784 
 
 
 
 
 
Email: magda.mensi@unibs.it 
 
Study coordinator: 
 
 
Dr. Magda Mensi 
 
 
Section of Periodontics, School of Dentistry, Department of 
Surgical Specialities, Radiological Science and Public Health 
ASST Spedali Civili di Brescia 
 
 
 
 
 
 
Brescia, IT 
 
Statistician: 
 
 
 
Prof. Stefano Calza 
 
 
Unit of Biostatistics and Bioinformatics, 
 
 
 
 
 
Department of Molecular and Translational Medicine 
 
 
University of Brescia 
 
 
 
 
 
Brescia, IT 
 
 
 
 
 
 
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Responsibilities 
The principal investigator’s responsibilities are described in detail in ISO norm 14155:2011 for 
the clinical investigation of medical devices for human subjects. 
The role of the principal investigator is to implement and manage the day-to-day conduct of the 
clinical investigation as well as ensure data integrity and the rights, safety and well-being of the 
subjects involved in the clinical investigation. 
 
The principal investigator shall be qualified by education, training and experience to assume 
responsibilities for the proper conduct of the clinical investigation. In particular, the principal 
investigator is responsible for:  
- 
qualification of investigation site; 
- 
communication with Ethics Committee; 
- 
compliance with Informed Consent process; 
- 
compliance with Clinical Investigation Plan. 
Under the direct supervision of the Principal Investigator, certain duties may be delegated during 
the course of the study. These responsibilities will be documented on the transfer of responsibilities 
form maintained in the Investigator Site file. 
 
The Statistician will be responsible for: 
- 
sample size calculation; 
- 
statistical plan; 
- 
statistical section of the protocol; 
- 
statistical evaluation; 
- 
final statistical report. 
 
 
 
 
OBJECTIVE 
The study will be performed to assess the efficacy of the addition of hydroxyapatite in the supportive 
therapy of periodontitis in terms of reduction of PD (Probing Depth). 
 
INTRODUCTION 
Enamel is the most calcified tissue in the body and is composed of 92-96% by organic 
substances in particular hydroxyapatite. Hydroxyapatite nanoparticles (Vector Fluid Polish 

 
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Durr Dental) are similar to the morphology and structure of tooth enamel apatite crystals, 
and has been studied as a biomimetic material for enamel remineralization. 
Dentin hypersensitivity is a very common disorder in the adult population and it is 
characterized by short and intensive pain, in response to thermal or chemical stimuli. 
Dentin hypersensitivity can be generalized or localized, it can simultaneously affect one or 
more tooth surfaces and depends on the duration of the stimulus applied. In addition, there 
are numerous factors that can affect this condition, including gum recessions, enamel 
erosion, dentin exposure and periodontal disease. 
The Vector system (Durr Dental, Bietigheim-Bissin gen, Germany) generates ultrasonic 
vibrations at a frequency of 25 kHz, which are converted by a resonant ring in a horizontal 
oscillation that is deflected vertically. In particular, the Vector Polish handpiece with a 
solution of hydroxyapatite is activated through ultrasound and it has the ability to favor the 
occlusion of the dentinal tubules leading to a reduction in hypersensitivity. 
The tip of the handpiece moves parallel along the axis of the insert, suitable for use in 
combination with the polishing fluid containing hydroxyapatite. The presence of this fluid 
associated with ultrasonic allows the root biofilm to be broken down thanks to cavitation 
and hydrodynamic forces; furthermore, avoiding horizontal vibrations caused a lower 
hypersensitivity compared to manual instruments. 
 
STUDY OUTCOMES 
a. 
Primary outcome measure: change in PD (in mm) 
b. 
Secondary outcomes:  
• 
changes in the following clinical parameters: Pocket closure (Yes/No), REC (Clinical 
Gingival Recession, in mm), CAL (Clinical Attachment Level, in mm), BOP (Bleeding 
on Probing, Yes/No), PI (Plaque Index, %). 
• 
Changes in Hypersensitivity (observation) 
• 
Risk progression of the periodontitis and the need of periodontal surgery. 
 
STUDY POPULATION 
Forty-four (44) adults, aged 18-75 years, will be entered into study (randomized). It is expected that 
forty (40) subjects will complete the study.  

 
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Randomized subjects who deviate from the protocol (major protocol deviation) and, for this reason, 
are excluded from the analysis, will be replaced to guarantee that the sample required for the 
analysis (40) is reached. 
Patients will be treated at the Department of Surgical Specialities Radiological Science and Public 
Health, School of Dentistry, Section of Periodontics, Brescia, Italy from 01/2023. 
                
Inclusion Characteristics 
- Signed Informed Consent Form. 
- Male and female subjects, aged 18-75 years, inclusive. 
- Good general health (free of systemic diseases such as diabetes, HIV infection or genetic 
disorder, ongoing malignant disease of any type that could influence the outcome of the 
treatment and might interfere with the evaluation of the study objectives). 
- History of periodontitis staging III or IV grading B or C  
- At least 4 sites (split mouth 2 – 2) with probing depth ≥6 mm or pockets of 5 mm with bleeding 
on probing. 
- Previous periodontal non-surgical treatment at least 3 months maximum 6 months. 
- Availability for the 6-month duration of the study for an assigned subject. 
!
Exclusion Characteristics  
- Not willing to follow the agreed protocol. 
- Presence of orthodontic appliances.  
- Smokers more than 10 cigarettes per day 
- Tumors or significant pathology of the soft or hard tissues of the oral cavity. 
- Current radiotherapy or chemotherapy. 
- Pregnant women. 
- Current or past (within 3 months prior to enrollment) assumption of medications that may 
influence periodontal conditions and/or interfere with healing following periodontal treatment (i.e., 
corticosteroids, calcium channel blockers, systemic antibiotics, ...). 
 
A written informed consent will be obtained from each included patient after explanation of the risks 
and benefits of participating to this study. No change in the trial design will be made after approval 
of the Ethical Committee. 
 

 
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1. 
STUDY DESIGN 
The study design was chosen according to the current standards required by ISO, GCP and 
according to national requirements. 
a. 
A Split Mouth design. 
b. 
The RCT will be run as mono-center; 
c. 
A total of 44 subjects will be recruited to participate in the study. It is expected that all of 40 
subjects will complete the study in total; 
d. 
Admission into the study will be via rolling admission (estimated recruitment time: 12 months); 
e. 
Each subject must have at least 4 residual sites/pockets (split mouth 2 – 2) with probing depth 
≥6 mm or pockets of 5 mm with bleeding on probing; 
f. 
Each subject will follow the following treatment protocol: 
i. – Visit 1 (Screening): – consent secured; screening and entry into study; baseline data 
collection; full periodontal charting (full-mouth PD, REC, BOP, PI); identification the test 
sites. 
ii. – Visit 2 (T0 – Baseline Visit + Treatment): According to the list of randomization, the test 
sites will be allocated into one of the two group: test group receives Vector PARO 
handpiece with hydroxyapatite for 30 seconds instead the control group receives only 
ultrasonic device for 30 seconds. After the treatment of the test sites a questionnaire is 
proposed for the patient feedback. At the end all patients receive a full mouth standard 
periodontal treatment (ultrasonic + rubber cup and polish) and OHI (oral hygiene 
instruction). 
iii. – Visit 3 (T1) - 3 months: Collection of full periodontal charting (PD, REC, PI, BOP), 
treatment of test sites, questionnaire, professional oral hygiene (like Visit 2) and 
reinforcement of OHI. 
iv. – Visit 4 (T2) - 6 months: Collection of full periodontal charting (PD, REC, PI, BOP), 
treatment of test sites, questionnaire, professional oral hygiene (like Visit 2) and 
reinforcement of OHI. 
Subjects will either be entered into a routine recall system for treatment or scheduled for 
any further periodontal treatment as clinically indicated, and exit the study. 
g. 
All treatments are made by the same clinician. 
h. 
Calibration: the examiner is calibrated showing an intra-examiner reproducibility of 96% for 
duplicate measurement of probing pocket depth (PPD) with a maximum difference of 1 mm in 
5 patients. 

 
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i. 
Data collection: A PCP-UNC 15 periodontal probe is used on six sites per tooth (mesio-buccal, 
buccal, disto-buccal, mesio-lingual, lingual and disto-lingual) with a gentle probing force by the 
same clinician. Measurements are rounded to the nearest millimeter. 
j. 
Clinical assessment data will be recorded via hard copy CRFs. CRFs will be submitted to a 
data entry staff member for entry into the statistical database. At the conclusion of the study, 
such statistical database will be submitted to the statistician for the preparation of the statistical 
analysis and the final study report.  
 
2. 
TREATMENTS 
Vector Paro® and Fluid Polish® manufactured by Durr Dental Bietigheim-Bissin gen, Germany will 
be delivered to the study center prior study start.  
Concomitant Therapy 
A necessary concomitant medication or therapy is permitted as long as it is not excluded in the 
exclusion criteria. Every medication has to be reported in the CRF (Appendix 1) and in the 
Concomitant Medication form (Appendix 2). All changes during the study are to be reported in the 
CRF. Usage of prohibited therapy will lead to the exclusion of the subject. 
 
Blinding and Randomization  
Blinding: The statistician patient and the operator will be blinded to the group identification, 
defined as A and B.  Knowledge of the randomization list will be limited to the persons 
responsible for creation of the randomization list, provider of randomization numbers to study site, 
and delivery of the test/control treatment until the last subject (i.e. final examination of the last 
subject), quality control and verification of the CRFs is completed.  
Randomization and allocation concealment: The randomization of the study protocols will be 
performed by a staff member who is not further involved in this study. This will be done based on 
a computer-generated table, using a random blocks randomization algorithm for crossover 
design, that links each patient to one of the treatment combinations on each mouth side (AB or 
BA, assuming right-left side sequence). The same staff member will be responsible for blinding 
the study products. This will be done by labelling the packaging of these products with a letter 
indicating the treatment group. Additionally, the jars containing the lozenges will be identical in 
appearance and non-transparent. When a patient will be included in the study, the study 
medication will be handed out to the researcher according to group to which that patient will be 
assigned based on the patient number and the randomization list. The similarity of the packaging, 

 
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and the identical appearance, texture and taste of the study products make the double-blinding of 
the researcher and patient possible. 
Implementation: The Principal Investigator will be informed immediately of Serious Adverse 
Events (SAEs), regardless of the causality relationship between the administration of the 
investigational treatment and the SAE.  
 
3. 
PROCEDURE 
 
Screening and Selection of Subjects 
 
 
Patients visiting the Department of Dentistry at Brescia University will be asked to participate 
in this study. Subjects will report to the clinical facility and be screened by the dental examiner 
to identify those subjects who meet the inclusion/exclusion characteristics. The findings of 
this initial screening procedure will be recorded on the CRF. Subjects who meet the 
inclusion/exclusion characteristics and sign an Informed Consent Form will be entered into 
the study.  
 
 
 
 Baseline Oral Soft and Hard Tissue Assessment 
 
All subjects will receive an evaluation of their oral soft and hard tissues. This examination will 
include an evaluation of the soft and hard palate, gingival mucosa, buccal mucosa, 
mucogingival fold areas, tongue, sublingual and submandibular areas and the tonsillar and 
pharyngeal areas. The results of this evaluation will be recorded on the CRF. 
 
 
 Clinical Periodontal Evaluation 
 
All patients receiving treatment will be evaluated by the dental examiner for the following 
assessments (see Study Flow Chart): 
● Full Mouth Plaque Score (PI); 
● Bleeding on Probing (BOP);  
● Probing Pocket Depth (PD);  
● Recession (REC); 
● Clinical Attachment Level (CAL). 
 

 
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Clinical attachment level (CAL) is the measurement of the position of the soft tissue in relation 
to the cemento-enamel junction (CEJ) that is a fixed point that does not change throughout 
life. All parameters will be recorded in the CRF. 
 
  
 
 Treatment 
 
Patients who have been identified for treatment receive a test sites treatment according to 
randomization, a questionnaire, a professional oral hygiene and OHI. 
 
  Follow up 
 
Following completion of professional oral hygiene and OHI the subject discuss with the 
operator about the appropriated toothbrush and toothpaste for home use. Subjects will be 
asked to refrain from using any other adjunctive oral home care products during the study 
period.  
At 3 and 6 months the following assessments (see Study Flow Chart) will be recorded: 
● Full Mouth Plaque Score (PI); 
● Periodontal Inflammation (BOP);  
● Probing Pocket Depth (PD);  
● Recession (REC); 
● Clinical Attachment Level (CAL). 
 
Study Flow Chart 
 
 
Study phase 
Enrolment 
Treatment 
Follow-up 
Follow-up 
Study visit 
Visit 1 
Visit 2 (T0) 
Visit 3 (T2) 
Visit 4 (T3) 
Study Week 
-29 days 
0 
3 months 
6 months 
Selection criteria 
+ 
 
 
 
Informed consent 
+ 
 
 
 
Demographics, ethnics 
+ 
 
 
 
General health status 
+ 
+ 
+ 
+ 
Medical & dental history 
+ 
 
 
 
Concomitant therapy/treatment 
+ 
+ 
+ 
+ 

 
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Safety (adverse events and serious adverse events) 
 
+ 
+ 
+ 
Data collection (PD,REC, BOP, PI) 
+ 
 
+ 
+ 
Randomisation  
 
+ 
 
 
Professional oral hygiene 
 
+ 
+ 
+ 
OHI 
 
+ 
+ 
+ 
Test sites treatment 
 
+ 
+ 
+ 
 
 
4. 
STATISTICAL ANALYSIS  
 
Sample size determination 
The sample size was calculated via simulation assuming an expected average difference of 1 
mm pocket probing depth and using a linear mixed effect model considering patients as random 
effects (random intercept model). We simulated 1000 realizations of pocket probing 
depth applying the data correlation structure from a former study (AgPro): random effects 
intercept SD = 0.97; residual SD = 1.5 and assuming an average of 4 experimental sites per 
patient, 2 on each side (treatment). A sample size of 20 patients per group allowed for a power of 
at least 80.2% (lower boundary 95% confidence interval from simulation, median value 82.7%) at 
the chosen significance level of α = 0.05. Considering a dropout rate of 10%, we estimated a total 
sample size of 45 patients. The simulation was performed using R (version 4.2.1). 
 
Statistical Analysis  
Data will be described using standard summary statistics such as mean and standard deviations 
for quantitative variables, absolute counts and proportions for categorical variables. The primary 
outcome is pocket probing depth (PPD). Only the sites with PPD greater or equal to 6 mm at 
baseline were considered or PPD equal to 5 mm and BoP+. PPD will be modelled using a linear 
mixed effect model, considering patients as random effects (random intercept model). 
A similar model will be adopted for continuous secondary outcomes (CAL, REC).Generalized 
mixed models (GLMM) will be applied to categorical  (binary) outcomes, with patient as clustering 
factor, after counting the outcome variables within subject (number of sites with outcome equal 
”Yes"). A Poisson family distribution will be assumed for residuals in the GLMM. Potential 
overdispersion or zero-counts inflation will be checked and model adapted accordingly (e.g. zero-
inflation Poisson, or Negative Binomial). 

 
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Results will be expressed as estimates and relative 95% confidence intervals. A significant level 
of 5% will be used for all the comparisons and all analysis will be performed using R (version 
4.2.1 or higher). 
 
Evaluation of Safety 
The following safety variables will be used for the evaluation of safety: 
• 
Adverse events (AE); 
• 
Adverse reactions (AR). 
The total number of AEs and the total number of AEs at least possibly related to the study treatment, 
as well as the total number of patients affected by at least one adverse event will be calculated per 
treatment group.  
The type of AE classified by organ system (according to MedDRA terminology) will be tabulated. 
Serious and/or unanticipated adverse events and AEs resulting in discontinuation or 
reduction/withdrawal of the study treatment will be presented separately. 
 
Safety analysis set 
Safety summaries will be based on the safety analysis set which will consist of all patients who 
received the test/control treatment. 
 
5. 
MONITORING AND AUDIT 
Study Monitoring 
The study will be monitored by the Principal Investigator at periodic intervals during the course of 
the study to ensure that the study is being conducted according to Good Clinical Practice.  
The Investigators will be contacted by the PI on a regular basis. On this occasion, the progress of 
the study will be discussed with the Investigator and the CRFs will be checked for completeness 
and consistency and to verify compliance with the study protocol. 
 
6. 
SUBJECT TERMINATION/WITHDRAWAL PROCEDURES 
All efforts will be made to determine the reason(s) why a patient is withdrawn from the study. 
Subjects could be withdrawn from the study if any of the following occur: 
 
 
 
1. 
Subject fails to substantially comply with the protocol requirements; 

 
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2. 
Subject develops a serious adverse reaction. The Study Investigator will immediately notify 
the PI and information will be recorded on a Serious Adverse Event Form (Appendix 3); 
3. 
Subject elects to terminate participation in the study. Participation in the study is voluntary. 
A subject has the right to withdraw from the study at any time for any reason. 
 
 
The Investigator may terminate the study at any time if the risk-benefit ratio is no longer favourable. 
Before discontinuation, the Investigator should inform the PI and ask for advice. If the Investigator 
is concerned about continuation of the study, his/her concerns should be transmitted immediately 
to the PI. 
 
7. 
DOCUMENTATION AND DATA MANAGEMENT 
Data collection in the case report form (CRF) 
All study data will be recorded in the case report forms identified by the subject number. Only the 
principal investigator, co-investigators, or designated study personnel may make entries in the 
case report forms.  
The Investigator has to identify all data that were directly recorded into the CRF and to be 
considered to be source data. 
The CRFs will be checked for completeness and plausibility by the PI. The Investigator will resolve 
any queries. 
 
Investigator Site File (ISF) 
The ISF includes all documents that are required for the clinical study. During monitoring, the ISF 
will be checked regularly for completeness and actuality. After the clinical trial is finished or stopped, 
the ISF has to be stored 15 years in the study center. 
 
Data Management 
Data extraction from CRFs into a single, electronic database is performed by examiners. 
Discrepancies are to be clarified and corrected by authorized persons by means of documented 
data queries between Statistician and Investigator(s). 
After the study is finished and before data are analyzed, a blind data review meeting will be held 
between the investigator and the statistician. When the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after this procedure can 
only be made by joint written agreement among the clinical trial leader, the trial statistician, and 
the co-investigators. 

 
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8. 
ADVERSE EXPERIENCES/EVENTS 
Subjects will be informed of any possible adverse reactions which they could experience and will 
be instructed to immediately report any event to the investigator. The investigators will record any 
and all adverse reactions and report this documentation to the Principal Investigator. In the event 
of an adverse experience, emergency or other problems or questions regarding participation in this 
study, the subject can contact the following investigators: 
 
 
for Brescia Site:  Dr. Magda Mensi (Principal Investigator) – tel. +39 030 3995784. 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) are defined by the ICH Guideline 
Medical Device Directive 93/43/EEC and Guidelines on Medical Devices MEDDEVG 2.7/3rev. 3, 
May 2015 Clinical Investigations: Serious Adverse Event Reporting under Directives 90/385/EEC 
and 93/42/EEC for Good Clinical Practice (ICH GCP) as follows: 
 
An adverse event (AE) is 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 investigational medical device.  
 
With respect to intensity, adverse events are classified as follows: 
- Mild 
 
Some awareness of symptoms, but easily tolerated; 
- Moderate Symptoms causing enough discomfort to interfere with usual activity; 
- Severe 
Incapacitating event causing inability to work or to perform usual activity. 
 
Adverse events are classified as either non-serious or serious. 
 
Serious Adverse Event (SAE) is an adverse event that: 
a) led to a death; 
b) led to a serious deterioration in health of the subject, that either resulted in: 
- a life-threatening illness or injury, or 
- a permanent impairment of a body structure or a body function, or 
- in-patient hospitalization or prolongation of existing hospitalization, or 
- in medical or surgical intervention to prevent life threatening illness or 
- injury or permanent impairment to a body structure or a body function. 

 
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c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Device deficiency: inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include malfunctions, use error, or 
inadequacy in the information supplied by the manufacturer. 
 
AEs include any clinically significant deterioration of a subject’s medical status, after being enrolled 
and signing an informed consent form. The AE may involve any organs or systems and can be 
represented by the new onset or the deterioration of a disease, a syndrome, a symptom, a physical 
sign, as well as by findings and results of instrumental examinations and laboratory tests. Any 
medically relevant and untoward change from baseline, including frequency or pattern changes for 
a fluctuating condition (e.g., migraine), occurring after the administration of investigated treatments 
is an adverse event. All such occurrences must be recorded and reported accordingly, whether 
they appear causally related to the study medication, or not. 
 
Serious Adverse Device Effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse device effect which 
by its nature, incidence, severity or outcome has not been identified in the current version of the 
risk analysis report or investigator’s brochure (IB). 
 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or outcome 
has been previously identified in the risk analysis report or IB. 
 
The following events are considered reportable: 
- any SAE; 
- any Device Deficiency that might have led to a SAE if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) if circumstances had been less fortunate; 
- new findings/updates in relation to already reported events. 
 
Reportable events have to be reported by clinical investigators.  

 
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Assessment of Causality 
The following criteria are to be used for the assessment of the causal relationship to the test/control 
treatment. For classification, all criteria of one of the following categories must be met: 
related, if  
• a timely correlation exists and 
• dechallenge and/or rechallenge and 
• a biological plausibility exists and 
• other factors are clearly excluded 
• a medical report or clinical proof exists; 
 
possibly related, if  
• a timely correlation exists and 
• dechallenge and/or rechallenge and 
• a biological plausibility exists and 
• a medical report or clinical proof does not exist; 
 
unrelated, if  
• a timely correlation does not exist or is uncertain and 
• dechallenge and/or rechallenge does not exist and 
• a biological plausibility exists and 
• a medical report or a clinical proof does not exist; 
 
unknown, if 
• not enough information exists for evaluation 
• no further contact with reporter possible. 
 
Sound medical/clinical judgment will be applied when assessing the causality and seriousness of 
the adverse events. 
 
Adverse Event Reporting 
The study center will provide the study participants with emergency telephone numbers for study 
related support and feedback. The emergency telephone number is operated by either an 
investigator of the study or by a qualified person designated by the principal investigator. The 

 
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schedule of reachability of the emergency telephone number will be defined prior to start of the 
study. 
 
Serious Adverse Events 
The Investigator shall immediately after awareness (and in any event, not later than within 24 hours 
after awareness) inform the PI. The Investigator will send the SAE report to the following email 
address: magda.mensi@unibs.it. Appendix 3 has to be used for SAE reporting. Form has to be 
completed electronically and in English.  
 
Adverse Events 
Adverse events will be assessed by the investigator or designee within 24 hours for severity, 
relationship to the study product, possible etiologies, and whether the event meets the criteria as a 
serious adverse event and therefore requires immediate notification to the PI. For data collection 
purposes, the outcome of all adverse events recorded on the Adverse Reaction section of the CRF 
will be designated as of the completion of the final evaluation or examination. However, the 
investigator is responsible for following all adverse events until resolution or until no longer of 
clinical concern, and providing these data to the PI. At the end of the study, the investigator will 
report all adverse events (serious and non-serious) to the PI on CRFs. Forms have to be completed 
electronically and in English. 
 
Pregnancy 
No pregnant women (according to medical history) will intentionally be enrolled in this study. In the 
event a woman enrolled in this clinical research study becomes pregnant during the course of the 
study, participation in this study will be terminated upon the clinical staff’s notification of the event. 
The subject’s medical records used in this study will be updated to reflect the pregnancy and there 
will be follow- up contact until the end of the pregnancy to record the outcome in the clinical file.  
 
9. 
ADHERENCE TO PROTOCOL/AMENDMENT(S) 
The Investigator will be required to adhere to the final protocol. Any changes to the protocol, except 
those necessary to eliminate apparent hazards, will require prior approval by the local reviewers 
through the submission of a protocol amendment.  In the event of emergency, the Investigator shall 
engage any medical procedures that he/she deems appropriate. However, all such procedures 
must be promptly reported to the PI and Ethical Committee.  

 
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The Ethical Committee which granted approval for the study must be notified of all changes in the 
protocol and must provide written approval if changes are substantial (e.g. increase the risk to the 
subject, and/or affect the rights of the subject or validity of the investigation, change of/within study 
population, number of participants or changes of patients’ age group). 
Departures from eligibility requirements may be allowed on a case-by-case basis by the medical 
monitor or other authorized sponsor representative. Such departures must be medically and 
scientifically justified, must be pre-authorized, and must be documented in the CRF and tracked as 
official eligibility waivers. 
 
10. 
ADMINISTRATIVE ASPECTS 
Final Report 
Following the completion of the study, the PI shall prepare a final study report. The final report will 
include a general description of the conduct of the study including protocol deviations, subject 
withdrawals, discussion of any adverse events, safety and efficacy data, and statistical analysis of 
the data. This report will be shared with the Co-investigator at the Participating Centre by the 
Principal Investigator, and agreed upon parts before being sent to the Sponsor. 
 
Data Retention 
The information in this and any further document contains trade secrets and commercial 
information that are privileged or confidential and may not be disclosed unless such disclosure is 
required by law or regulations.  
In any event, persons to whom the information is disclosed must be informed that the information 
is privileged or confidential and may not be further disclosed by them. 
The files pertaining to this study will be kept by the University-Hospital of Brescia for a period of 15 
years from the day of delivery of the final report and will be available for consultation by competent 
authorities at any time. 
The Investigators will retain originals of the approved study protocol, copies of completed CRFs, 
subjects' participation agreements, relevant source documents and all other supporting 
documentation related to the study for a period of 5 years. These files must be made available for 
inspection upon reasonable request by an authorized representative of EMS or the competent 
authorities. 
 
11. 
ETHICAL ASPECTS AND REGULATIONS 
Ethical Conduct of the Study 

 
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This study is to be conducted in accordance with the ethical principles of the Declaration of Helsinki 
and according to local laws and regulations. 
 
Independent Ethics Committee (IEC) and Relevant Authorities 
Before starting the study, the study protocol will be subject to review by the Ethical Committee of 
the University-Hospital of Brescia. As required by law, the study will be notified to authorities if 
applicable. No subject should be admitted to the study before the Ethical Committees issue their 
written favourable opinion of the study. Periodic status reports must be reported to the ethics 
committee at least annually as well as notification of the completion of the study. The investigator 
must maintain an accurate and complete record of all reports and documents submitted to and 
received from the ethics committee according to the ISO 14155:2011 Clinical Investigation of 
Medical devices for human subjects. 
 
Subject information and Informed consent form 
The purpose and description of the study in lay language, possible adverse reactions, risks and 
benefits of participation and the subject’s right to withdraw without prejudice at any time must be 
explained to each subject. Each subject must read, understand and sign the informed consent form 
provided before any study-related procedure. 
 
Subject data protection and Confidentiality 
The name of the subject as well as all other personal data will be kept strictly confidential by the 
Investigator. If due to medical reasons, it is necessary to identify the subject during the study 
course, this will be done under medical secrecy.  
The subject has given his/her consent before the beginning of the study. In case of withdrawal of 
this consent subject has to leave the study. 
All subjects will agree to verify, by letter, that they participated in this study, if called upon to do so. 
 
New Findings 
Subjects will be informed of any significant new findings related to study products or procedures 
when they become known during the course of this clinical research study. Such information may 
affect the subject’s decision to continue participation in the study.