The Role of a New Prosthodontics Device in Hard and Soft Tissue Changes After Subcrestal Implant Placement: 12-months, Parallel, Randomized Clinical Trial
Phase: NA
Conditions: Edentulous Alveolar Ridge
Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

PROTOCOL #NABUT 2020 
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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: The role of a new prosthodontics device in hard and soft tissue changing after 
subcrestal implant placement: 12 months parallel randomized clinical trial.   
 
Type of Study: Clinical  
 
Protocol No: PROTOCOL NABUT2020 
 
Expected study start date: September, 2020 (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 a prosthodontics device after subcrestal implant 
placement in patients with monoedentulia (Confidential information). 
 
 
 

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Study Title: 
The role of a new prosthodontics device in hard and soft tissue 
changing after subcrestal implant placement: 12 months parallel 
randomized clinical trial.   
 
 
Study sites: 
 
 
Dr. Magda Mensi (lead site) 
 
 
 
 
University-Hospital of Brescia 
 
 
 
 
Brescia, Italy. 
 
 
 
 
 
Study Phase: 
 
IV.  
 
Name of Medical Device: 
GFA® Gingival Former Abutment (Advan S.r.l. Via Linussio, 1 
33020 – Amaro (UD) Italy) 
  
 
Objective: 
The objective of the clinical study is to assess the efficacy of a new 
prosthodontics device (GFA) in hard and soft tissue changing after 
subcrestal implant placement. 
 
Patient Population: 
40 patients, systemically healthy, male and female adults (18 – 75 
years), with posterior monoedentulia at least 5 months.  
 
Structure:                     
Parallel arms: Number of treatments: 1 (test group: subcrestal 
implant placement and GFA; control group: crestal implant 
placement and healing abutment).  
                                                                                              
Duration of study: 27 months.  
 
Number of Centers:    
One. 
 
Blinding: 
Statistician 
 
Method of Patient Selection: Posterior monoedentulia intercalated with 11mm of residual bone 
 
Total Sample Size: 
40 adult subjects will be recruited (randomized) to participate in 
this study, with 34 expected to complete the study. 
 
Primary Efficacy Variable: 
Primary outcome measure will be the changing of radiographically 
MBL (marginal bone level) around implant. 
 
 
 
 

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The role of a new prosthodontics device in hard and soft tissue changing after 
subcrestal implant placement: 12 months parallel randomized clinical trial.  
PROTOCOL #NABUT 2020 
____________________________________________________________ 
 
 
 
Protocol Date: March 16, 2020 
 
 
 
 
Protocol  Approval 
 
Signature Page 
 
 
 
 
 
  
 
 
_________________________ 
 ________________________ 
 
Dr. Magda Mensi 
 
 
 
 
 
 
Date 
University-Hospital of Brescia, Italy 
   
 
 
 
 
 
 
 
 
 
 

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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 
University of 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 
 
 
University-Hospital of Brescia 
 
 
 
 
 
Brescia, IT 
 
Data Management & Monitoring: 
Dr. Magda Mensi 
 
 
Section of Periodontics, School of Dentistry, Department of 
Surgical Specialities, Radiological Science and Public Health 
 
 
University-Hospital of 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 a new prosthodontics device (GFA) in hard 
and soft tissue changing after subcrestal implant placement in terms of MBL and peri-implant 
tissues health. 
 

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INTRODUCTION 
At present there is no scientific evidence in dentistry about the origin and treatment of perimplatitis 
and mucositis. These peri-implant pathologies can be partially prevented through periodontal 
diagnosis, correct implant placement and prosthetic loading.  
In the literature, there is a physiological bone loss around implant after the placement (1 mm the 
first year and 0.2 mm each subsequent year). Different types of implants have been designed 
(laserization of the collar, platform switching..) to try to control this phenomenon with discordant 
results. Different surgical protocols for implant insertion have been created to minimize bone 
resorption: a subcrestal implant seems to partially overcome this problem even if this procedure 
increase the transmucosal tunnel: growing the risk of peri-implant soft tissue infection.  
Tissue healing around the implants is not comparable to the natural dental element: the risk of 
inflammation and consequently of infection is higher around the implants because there is no stable 
seal between the two structures (tissue and implant).  
The prosthetic structure of the GFA was created to overcome these problems: crestal bone 
reabsorption and transmucosal tunnel. Our objective is to validate or deny this claim. 
 
STUDY OUTCOMES 
a. 
Primary outcome measure: radiographically change in MBL 
b. 
Secondary outcomes changes in the following clinical parameters:  
• 
PD (Probing Depth),  
• 
REC (Clinical Gingival Recession),  
• 
BOP (Bleeding on Probing),  
• 
PI (Plaque Index). 
 
STUDY POPULATION 
Forty (40) adults, aged 18-75 years, will be entered into study (randomized). It is expected that 
forty (34) subjects will complete the study.  
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 (34) is reached. 
Patients will be treated at the Department of Surgical Specialties Radiological Science and Public 
Health, School of Dentistry, Section of Periodontics, Brescia, Italy from 09/2020. 
                

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Inclusion Characteristics 
- Comprehension and 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). 
- Good oral health (no decay, periapical or periodontal lesions, PI and BOP < 25%). 
- Patient with posterior monoedentulia: 
 
- at least 5 months, 
 
- mandibular or maxillary, 
 
- intercalated (distance between teeth more than 7.5 mm),  
- at least 11 mm of height residual bone (from bone crest to maxillary sinus or inferior 
alveolar nerve), 
- at least 5 mm of bone width (buccal – palatal/lingual). 
- Availability for the 12-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. 
- Chronic obstructive pulmonary disease and asthma. 
- Tumors or significant pathology of the soft or hard tissues of the oral cavity. 
- Current radiotherapy or chemotherapy. 
- Pregnant or lactating women. 
- Parafunctions like bruxism. 
- Previous interventions to increase bone thickness in the implant area. 
- Current or past assumption of medications that may influence surgical therapy and/or interfere 
with healing following surgical treatment.  
- Systemic diseases that constitute a contraindication to surgical therapy and/or interfere with 
healing following surgical treatment.  
 

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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. 
 
 
1. 
STUDY DESIGN 
The study design was chosen according to the current standards required by ISO, GCP and 
according to national requirements. 
a. 
A Parallel-Arm, Statistician is blinded, RCT will be established; 
b. 
The RCT will be run as mono-center; 
c. 
A total of 40 subjects will be recruited to participate in the study. It is expected that all of 34 
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 posterior monoedentulia (mandibular or maxillary) intercalated; 
f. 
Each subject will follow the following treatment protocol: 
1. Visit 1: (Screening) 
a. Screening and entry into study. 
b.  Verification of the eligibility of each subject by performing intraoral radiography. 
c.  Explanation of the research protocol. 
d.  Consent secured. 
e. Delivery of the medical request for CBCT (cone beam computed tomography) and 
for the antibiotic (Amoxicillin 1000mg 2cp/die every 12 hours for 6 days or 
Azithromycin 500mg 1cp/die every 24 hours for 6 days). 
2. When CBCT is ready the patient have to give it to the Principal Investigator to confirm the 
eligibility of each subject and to plan the surgery. Professional dental hygiene session is 
performed before surgery. 
3. Visit 2: (Treatment) 
a.  Assessment of antibiotic prophylaxis, locoregional anesthesia and opening of a 
thickness flap limited to the intervention area. 
b.  According to the list of randomization the patient will be allocated into one of the 
two arm of surgical treatment. Group A (control group): placement of the 
endosseous crestal implant through dedicated drills with 35N insertion torque and 
healing abutment. Group B (test group): placement of the endosseous subcrestal 
implant (2 mm under crestal bone) through dedicated drills with 35N insertion 

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torque and GFA (Gingival Former Abutment). Both group receive the same implant: 
TZeroâ (L= 9 mm, Æ 3,6 mm or L= 7,5 mm, Æ 4,3 mm) (Advan S.r.l. Via Linussio, 
1 33020 – Amaro (UD) Italy) 
c.  Suture. 
d.  Execution of intra-oral and post-operative X-Rays. 
After 7 days of the surgery suture removal. 
 
4. Visit 3: (after 3 months from visit 2) (Treatment) 
a.  Periodontal charting around the healing abutment or GFA (PD, BOP, PI) with 
calibrated periodontal probe. 
b.  Impression taking for prosthetic finalization. 
5. Visit 4: (after a week from Visit 3: Baseline – T0): (Treatment) 
a.  Prosthetic finalization and loading. 
b.  Periodontal charting around the new prosthetic crown (PD, BOP, PI, REC). 
c.  Take a standardized x- Ray (Bite Block). 
6. Visit 5 (6 months from baseline – T1): (Follow-up) 
a.  Control.  
b.  Periodontal charting around the prosthetic crown (PD, BOP, PI, REC). 
c.  Take a standardized x- Ray (Bite Block). 
d. Professional dental hygiene session. 
7. Visit 6 (12 months from baseline – T2): 
a. Control.  
b.  Periodontal charting around the prosthetic crown (PD, BOP, PI ,REC). 
c.  Take a standardized x- Ray (Bite Block). 
d. Professional dental hygiene session. 
g. 
All treatments are made by the same clinician; 
h. 
Data collection:  
- Standardized X- Ray: control periapical radiographs is performed using a long-cone 
paralleling technique and an individual X-ray holder (bite block) to ensure 
reproducibility. Built thanks to impression material. 
- A calibrated periodontal probe (Click-Probe™ Kerr Dental) is used on six sites per 
tooth (mesio-buccal, buccal, disto-buccal, mesio-lingual, lingual and disto-lingual) 
with a standard probing force by the same clinician. Measurements are rounded to 
the nearest millimeter; 

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j. 
Clinical and radiographical 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.  
k. 
Prosthetic finalization is given to the dental laboratory.  
 
2. 
TREATMENTS 
Implant kit, implants and every component will be delivered to the study center prior study start by 
Advan S.r.l. Via Linussio, 1 33020 – Amaro (UD) Italy: 
- Surgical Kit PRO: GKC13 
- Set countersink GFA: GKM10 
- Kit stop drills: GST11 
- Implant: TZero - T3609 (D3,6 L9,0) - T4307 (D4,3 L7,5) 
- GFA: 04GFX03 (D4,0 H3,5) - 04GFX04 (D4,0 H4,5) - 04GFX05 (D4,0 H5,5) 
- component GFA: 01GFT01 (healing stopper H1) - 01GFT03 (healing stopper H3) -01GFT05 
(healing stopper H5) - 01TGF10 (transfer pick-up) - 01AGF10 (analogo GFA) -01CGF40 (moncone 
calcinabile con base in cobalto-cromo) 
- for control group: 05OMG12 (healing abutment H2) - 05OMG13 (healing abutment H3) -
05OMG14 (healing abutment H4) - 01OTR10 (transfer pick-up) - 41CCN40 (moncone calcinabile 
con base in cobalto-cromo) 
 
Radiographically Analysis  
Specification of software analysis  
Peri-apical x-ray examinations will be performed using phosphor image plates (FONA™ Dental 
Image Plates)  and then acquired through a digital scanner device (FONA ScaNeo™).  
All radiographical images will be later analyzed by the same external examiner, which will measure 
marginal bone level parameter (MBL) around placed endosseous implants using an image analysis 
software (ImageJ™). 
In particular bone levels will be determined, both mesially and distally the dental implant, using the 
“Measure” function of the software, which records the distance between the most apical bone point 
and the most coronal bone point in 0.3 mm range from the implant. 
Measurements will be all recorded to allow the observation of bone level changes over time. 
 
Concomitant Therapy 

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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 and the patient will be blinded to the group identification. The operator will know 
the treatment allocation. 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 R package 
randomizeR) that links each patient to one of the treatment groups. Treatment allocation will be 
delivered in sealed envelopes. 
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 U.O. Odontostomatology of ASST Spedali Civili of Brescia 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.  
 
 

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 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, muco 
gingival fold areas, tongue, sublingual and submandibular areas and the tonsillar and 
pharyngeal areas. The results of this evaluation will be recorded on the CRF. 
 
   
  
  CBCT 
 
All patients receiving a CBCT to confirm the eligibility of each subject and to plan the 
surgery at Complex Operative Unit of Diagnostic Radiology 2.  
 
 
  Treatment 
 
Patients who have been identified for treatment receive an implant placement and prosthetic 
finalization will be randomized according to a randomization table generated. 
 
 
  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); 
● Periodontal Inflammation (BOP);  
● Probing Pocket Depth (PD);  
● Recession (REC); 
All parameters will be recorded in the CRF. 
 
 
 Radiographically Evaluation 
 
All patients receiving control reproducible periapical radiographs for evaluation of MBL 
(mesial and distal) (see Study Flow Chart) 
All parameters will be recorded in the CRF. 
 
  Follow up 
 
Following completion implant placement and prosthetic finalization, the study start. 
Radiographically and clinical evaluation will be done at baseline (T0), 6 and 12 months (T1 
and T2) in the test and control site. At 6 and 12 months a dental hygiene session and OHI 
will be done. 
 

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Study Flow Chart 
 
 
Study phase 
Enrolment 
Treatment 
Treatment 
Treatment 
Follow-up 
Follow-up 
Study visit 
Visit 1 
Visit 2  
Visit 3  
Visit 4 (T0) 
Visit 5 (T1) 
Visit 6 (T2) 
Study Time 
- X days 
0 
3 months 
3 months 
and 1 week 
6 months 
form visit 4 
12 months 
form visit 4 
Selection criteria 
+ 
 
 
 
 
 
Informed consent 
+ 
 
 
 
 
 
Demographics, ethnics 
+ 
 
 
 
 
 
General health status 
+ 
+ 
+ 
+ 
+ 
+ 
Medical & dental history 
+ 
 
 
 
 
 
Concomitant therapy/treatment 
+ 
+ 
+ 
+ 
+ 
+ 
Safety (adverse events and serious 
adverse events) 
 
 
+ 
+ 
+ 
+ 
Data collection (PD,REC, BOP, PI) 
+ 
 
 
+ 
+ 
+ 
X- Rays and CBCT 
+ 
+ 
+ 
+ 
+ 
+ 
Randomization  
 
+ 
 
 
 
 
Professional Oral Hygiene session 
+ 
 
 
 
+ 
+ 
Prosthetic Finalization 
 
 
+ 
+ 
 
 
Implant Placement 
 
+ 
 
 
 
 
GFA or healing abutment 
 
+ 
 
 
 
 
 
 
4. 
STATISTICAL ANALYSIS  
 
Sample size determination 
Sample size was compute assuming a two parallel groups design with balanced groups and an 
independent sample t-test. We assumed a single implant and a single measurement for patient, a 
standard deviation of 0.5 mm and an average difference of at least 0.5mm. A total sample size of 
34 patients will provide a power of at least 80% at a 5% significance level. Assuming a 15% drop-
out , the total sample size will be N=40 patients. 

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Statistical Analysis  
Data will be described using standard statistics such as, mean, median standard deviation and 
IQR for quantitative variable, and counts and percentages for qualitative variables. 
Variation in MBL will be modelled using both a simple t-test for independent samples (after 
averaging values within patients) as well as a multilevel model using GEE (Generalised 
Estimating Equations) on individual site measurements and accounting for within subject 
correlation.  
Secondary continuous outcomes will be modelled using GEE with ad hoc error distribution 
according to outcome (Gaussian for PPD, CAL, REC, binomial for BOP). 
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 
3.6.3 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.  

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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; 
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. 
 

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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. 
 
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: 
 
 
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. 

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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. 
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. 
 

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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.  
 
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 

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• 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 
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. 

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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.  
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. 

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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 
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.  

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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.