Performance and Safety of the Resorbable Collagen Membrane "Ez Cure" in Guided Tissue Regeneration and Guided Bone Regeneration Procedures
Conditions: Oral Bone Defect, Maxillofacial Bone Defect, Periodontal Bone Loss, Alveolar Bone Loss
Sponsor: Biomatlante

 
 
SA au capital de 124 586 Euros · 5 Rue Edouard Belin · ZA Les Quatre Nations · F-44360 Vigneux de Bretagne 
Tel : +33 (0)2 28 02 00 09 · Fax : +33 (0)2 28 02 00 10 · Site : www.biomatlante.com 
R.C.S Nantes 402 687 495 · SIRET 40268749500026 · APE 2013 B · N° Intracommunautaire : FR53402687495 
1/48 
 
 
 
 
CLINICAL INVESTIGATION PLAN 
PERFORMANCE AND SAFETY OF THE RESORBABLE COLLAGEN MEMBRANE “EZ 
CURETM” IN GUIDED TISSUE REGENERATION AND GUIDED BONE REGENERATION 
PROCEDURES 
 
 
 
*************************************************************************** 
 
 
 
REFERENCE 
N° ID-RCB 
2018-A03202-53 
Document type 
Clinical Investigation Plan 
Subjet_Product 
Protocol_RCM 
Version 
1.0 
Date 
13/02/2019 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
2/48 
 
PERFORMANCE AND SAFETY OF THE RESORBABLE COLLAGEN 
MEMBRANE “EZ CURETM”IN GUIDED TISSUE REGENERATION AND 
GUIDED BONE REGENERATION PROCEDURES 
 
N° ID-RCB : 2018-A03202-53 
Study reference: RE-DT04-18A 
Version N° 1.0 dated on 13/01/2019 
PROTOCOL FOR RESEARCH INVOLVING HUMAN PARTICIPANTS 
(Category 3 – Non-interventional study) 
 
SPONSOR 
BIOMATLANTE SA 
Julien DERT 
5 rue Édouard Belin – ZA Les Quatre Nations 
44360 VIGNEUX-DE-BRETAGNE - FRANCE 
Phone: 02.28.02.00.09 – Fax: 02.28.02.00.10 
E-mail: juliendert@biomatlante.com 
SCIENTIFIC CONTACT AT 
THE SPONSOR’S SITE 
Guy DACULSI 
5 rue Édouard Belin – ZA Les Quatre Nations 
44360 VIGNEUX-DE-BRETAGNE - FRANCE 
Phone: 06.21.90.58.42 – Fax: 02.28 02.00.10 
E-mail: guydaculsi@biomatlante.com 
REGULATORY CONTACT AT 
THE SPONSOR’S SITE 
Laura PAGNUCCO 
5 rue Édouard Belin – ZA Les Quatre Nations 
44360 VIGNEUX-DE-BRETAGNE - FRANCE 
Phone: 02.28.02.00.09 – Fax: 02.28 02.00.10 
E-mail: laurapagnucco@biomatlante.com 
CLINICAL INVESTIGATION 
UNIT 
Pr Assem SOUEIDAN  
1 Place Alexis-Ricordeau 
44042 NANTES - FRANCE 
Phone: 02.40.41.29.23 
E-mail: assem.soueidan@univ-nantes.fr 
COORDINATING 
INVESTIGATOR 
Dr Saïd KIMAKHE 
3 Rue Paul Ramadier  
44200 NANTES - FRANCE 
Phone: 02.40.89.70.23 
E-mail: Said.Kimakhe@univ-nantes.fr 
CONTRACT RESEARCH 
ORGANIZATION 
ATLANSTAT 
3 rue Jules Verne 
44400 REZE - FRANCE 
Phone: 02.40.63.16.60 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
3/48 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
PROTOCOL AMENDMENT HISTORY 
6 
VALIDATION AND SIGNATURES 
7 
CLINICAL INVESTIGATORS AND COLLABORATORS 
8 
CLINICAL CENTERS 
9 
LIST OF ABREVIATIONS 
10 
 
SYNOPSIS OF THE STUDY 
12 
 
SCIENTIFIC JUSTIFICATION 
16 
II.1. 
INTRODUCTION 
16 
II.2. 
CURRENT STATE OF KNOWLEDGE 
16 
II.3. 
STUDY HYPOTHESES 
20 
II.4. 
JUSTIFICATION OF METHODOLOGY CHOICES 
21 
II.5. 
EXPECTED IMPACTS 
21 
 OBJECTIVES 
21 
III.1. 
MAIN OBJECTIVE 
21 
III.2. 
SECONDARY OBJECTIVES 
21 
 STUDY DESIGN 
22 
IV.1. 
CLASSIFICATION OF THE STUDY 
22 
IV.2. 
RESEARCH PROJECT AGENDA 
22 
IV.3. 
SUMMARY TABLE OF PARTICIPANT FOLLOW-UP 
22 
IV.4. 
INFORMATION TO PARTICIPANTS 
23 
IV.5. 
FOLLOW-UP VISITS 
23 
IV.6. 
END OF RESEARCH PROJECT VISIT 
24 
 
STUDY POPULATION 
24 
V.1. 
INCLUSION CRITERIA 
24 
V.2. 
EXCLUSION CRITERIA 
24 
V.3. 
FEASIBILITY AND RECRUITMENT PROCEDURES 
25 
V.4. 
ACTIONS UPON PATIENT WITHDRAWAL 
26 
 STUDY INTERVENTION 
27 
VI.1. 
DEVICE DESCRIPTION 
27 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
4/48 
 
VI.2. 
INTENDED USE 
27 
VI.3. 
SURGICAL INTERVENTION 
27 
VI.4. 
CONTRAINDICATIONS 
28 
VI.5. 
AUTHORIZED OR FORBIDDEN TREATMENTS AND PROCEDURES 
28 
 STUDY ASSESSMENTS AND PROCEDURES 
28 
VII.1. 
MAIN EVALUATION CRITERION 
28 
VII.2. 
SECONDARY EVALUATION CRITERIA 
28 
VII.3. 
MANAGEMENT OF ADVERSE EVENTS AND NEW FACT 
29 
VII.3.1. 
DEFINITION OF ADVERSE EVENTS 
30 
VII.3.2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
30 
VII.3.3. 
CLASSIFICATION OF AN ADVERSE EVENT 
31 
VII.3.3.1. SEVERITY OF EVENT 
31 
VII.3.3.2. RELATIONSHIP TO STUDY PRODUCT 
31 
VII.3.3.3. EXPECTED ADVERSE EVENTS 
32 
VII.3.4. 
ADVERSE EVENTS REPORTING 
32 
VII.3.5. 
NEW FACTS REPORTING 
34 
 STATISTICAL ASPECTS 
34 
VIII.1. 
SAMPLE SIZE DETERMINATION 
34 
VIII.2. 
ANALYSIS SETS 
35 
VIII.3. 
MISSING VALUES AND DROP-OUT 
35 
VIII.4. 
STATISTICAL ANALYSIS 
36 
VIII.4.1. GENERAL CONSIDERATION 
36 
VIII.4.3. SAFETY ANALYSES 
37 
VIII.4.4. RADIOGRAPHIC ANALYSIS 
37 
VIII.4.5. BASELINE DESCRIPTIVE STATISTICS 
37 
VIII.4.6. RELEVANT MEDICAL AND SURGICAL HISTORIES 
38 
VIII.4.7. EXPLORATORY ANALYSES 
38 
VIII.5. 
PLANNED INTERIM ANALYSES 
38 
VIII.6. 
SUB-GROUP ANALYSES 
38 
 DATA ACCESS RIGHTS AND SOURCE DOCUMENTS 
38 
IX.1. 
ACCESS TO DATA 
39 
IX.2. 
SOURCE DATA 
39 
IX.3. 
DATA CONFIDENTIALITY 
39 
IX.4. 
PSEUDONYMIZATION PROCEDURE 
39 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
5/48 
 
 
QUALITY CONTROL AND ASSURANCE 
40 
X.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
40 
X.2. 
RESEARCH FOLLOW-UP 
41 
X.3. 
QUALITY ASSURANCE AND QUALITY CONTROL 
41 
X.4. 
DATA MANAGEMENT 
42 
X.4.1. 
DATA HANDLING 
42 
X.4.2. 
COMPUTER SYSTEMS 
42 
X.4.3. 
DATA ENTRY 
42 
X.4.4. 
MEDICAL INFORMATION CODING 
42 
X.4.5. 
DATA VALIDATION 
42 
X.5. 
PROTOCOL DEVIATION 
43 
X.6. 
AUDIT AND INSPECTION 
43 
 ETHICAL AND REGULATORY CONSIDERATIONS 
44 
XI.1. 
COMPLIANCE WITH REFERENCE TEXTS 
44 
XI.2. 
AMENDMENTS TO THE PROTOCOL 
44 
 STORAGE OF DOCUMENTS AND DATA RELATING TO THE STUDY 
45 
 RULES CONCERNING PUBLICATION 
45 
XIII.1. 
SCIENTIFIC COMMUNICATION 
45 
XIII.2. 
COMMUNICATION OF THE RESULTS TO PARTICIPANTS 
46 
XIII.3. 
DATA TRANSFER 
46 
 BIBLIOGRAPHIC REFERENCES 
47 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
6/48 
 
PROTOCOL AMENDMENT HISTORY 
 
VERSION 
DATE 
DESCRIPTION OF THE MODIFICATION 
N° 1.0 
13/02/2019 
First validated version presented to the Ethical Committee  
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
7/48 
 
VALIDATION AND SIGNATURES 
 
SPONSOR 
BIOMATLANTE SA 
Julien DERT 
CEO 
 
SCIENTIFIC 
CONTACT AT THE 
SPONSOR’S SITE 
Guy DACULSI 
Clinical expert  
 
REGULATORY 
CONTACT AT THE 
SPONSOR’S SITE 
Laura PAGNUCCO 
Regulatory Affairs Engineer 
 
COORDINATING 
INVESTIGATOR 
Dr Saïd KIMAKHE 
Dental / Maxillofacial surgeon 
 
CLINICAL 
INVESTIGATION 
UNIT 
Pr Assem SOUEIDAN 
Medical Referent – UIC11 
Odontology 
Dental / Maxillofacial surgeon 
 
CONTRACT 
RESEARCH 
ORGANIZATION 
ATLANSTAT 
Nadine GODFROID 
CEO 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
8/48 
 
CLINICAL INVESTIGATORS AND COLLABORATORS 
 
COORDINATING 
INVESTIGATOR 
Dr. Saïd KIMAKHE 
Dental / Maxillofacial surgeon 
Address: 3 Rue Paul Ramadier - 44200 
Nantes 
Phone : 02.40.89.70.23 
E-mail: Said.Kimakhe@univ-nantes.fr 
INVESTIGATOR 
Dr. Badran ZAHI 
Dental / Maxillofacial surgeon 
Address: 1 Place Alexis-Ricordeau – 
44093 Nantes 
Phone: 02.40.41.29.27 
E-mail: Zahi.Badran@univ-nantes.fr 
INVESTIGATOR 
Dr. Philippe LESCLOUS 
Dental / Maxillofacial surgeon 
Address: 1 Place Alexis-Ricordeau – 
44093 Nantes 
Phone: 02.40.41.29.40 
E-mail: Philippe.Lesclous@univ-
nantes.fr 
INVESTIGATOR 
Dr. Xavier STRUILLOU 
Dental / Maxillofacial surgeon 
Address: 1 Place Alexis-Ricordeau – 
44093 Nantes 
Phone: 02.40.41.28.15 
E-mail: Xavier.Struillou@univ-nantes.fr 
CLINICAL 
RESEARCH 
COLLABORATOR 
Mme Marjorie CHERAUD 
Clinical Investigation 
Technician 
Address: 1 Place Alexis-Ricordeau – 
44093 Nantes 
Phone: 02.40.08.73.83 
E-mail: Marjorie.CHERAUDCARPEN 
TIER@chu-nantes.fr 
CLINICAL 
RESEARCH 
COLLABORATOR 
ATLANSTAT 
Nadine GODFROID 
Clinical Operations Manager 
Address: 3 Rue Jules Verne – 44400 
Rezé 
Phone: 02.40.63.16.60 
E-mail: nadine.godfroid@atlanstat.com 
CONTRACT 
RESEARCH 
ORGANIZATION 
ATLANSTAT 
Data Management department 
Biostatistic Department 
Address: 3 Rue Jules Verne – 44400 
Rezé 
Phone: 02.40.63.16.60 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
9/48 
 
CLINICAL CENTERS 
 
CLINICAL CENTER N°01 
Dental Care Center – Nantes University Hospital 
1 Place Alexis-Ricordeau  
44093 NANTES 
FRANCE 
CLINICAL CENTER N°02 
Private dental practice – Dr S.Kimakhe  
3 Rue Paul Ramadier  
44200 NANTES 
FRANCE 
 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
10/48 
 
LIST OF ABREVIATIONS 
 
AE 
Adverse Event 
ANSM 
Agence Nationale de Sécurité du Médicament et des produits de santé 
ARS 
regional health agency 
CAL 
Clinical Attachment Level 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CPP 
Committee for Protection of Persons  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DDS 
Doctor of Dental Surgery 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full Analysis Set 
GBR 
Guided Bone Regeneration 
GTR 
Guided Tissue Regeneration 
MD 
Mean Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
NNT 
Number Needed to Treat 
OFD 
Open Flap Debridment 
PP 
Per-Protocol 
PPD 
Probing Pocket Depth 
PT 
Preferred Term 
RCM 
Resorbable Collagen Membrane 
RR 
Risk Ratio 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Events 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
11/48 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
12/48 
 
 
SYNOPSIS OF THE STUDY  
 
Title 
Performance and safety of the Resorbable Collagen Membrane “EZ CURETM” 
in Guided Tissue Regeneration and Guided Bone Regeneration procedures. 
Sponsor 
BIOMATLANTE SA 
Coordinating investigator 
Dr. Saïd KIMAKHE 
ANSM identification 
2018-A03202-53 
Justification / context 
The evaluation of the clinical data has demonstrated the conformity of the 
Resorbable Collagen Membrane (RCM), EZ CureTM, with the relevant essential 
requirements for its use in periodontal applications. The RCM is intended for 
Guided Tissue Regeneration (GTR) and Guided Bone Regeneration (GBR) 
procedures. It acts as a barrier against the migration of epithelial cells within 
the bone defect (performance) and thus complies with several surgical 
indications in the treatment of maxillofacial bone defects. It has been 
concluded that the risks associated with the use of this device are acceptable 
when weighted against the benefits to the patients.  
In order to improve the clinical data on the RCM, the manufacturer, 
Biomatlante, decided to assess that the performance and safety of the device 
are maintained until the reaching of its intended use. In this objective, the goal 
of this study will be to observe the following parameters: 
1. Tissue regeneration (mucosa health on the site of implantation) 
2. Safety (report of any adverse event) 
3. Radiographic analysis of periodontal tissues 
Studied disease 
Oral maxillofacial and periodontal defects requiring Guided Tissue 
Regeneration. 
Alveolar dental defects after tooth/teeth extraction. 
Puropose of the device 
 Treatment 
 Diagnostic 
 Supportive care 
 Prevention 
 Screening 
 Health services Research 
 Basic science 
 Other 
Study model 
 Single groupe 
 Parallel 
 Crossover 
 Factorial 
Type of data 
 Safety 
Safety/Efficacy 
 Efficacy 
 Bio-equivalence 
 Bio-availability 
 Pharmacokinetics 
 Pharmacokinetics/dynamics 
 Pharmacodynamics  
Number of arms  
1 
Medical device used 
EZ CureTM Resorbable Collagen Membrane (CE 0123) 
Studied component 
 Drug (including placebo) 
 Radiation 
 Device  
 Behavioral 
 Biological / vaccine 
 Genetic 
 Procédure / surgery 
 Dietary supplement 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
13/48 
 
 Other 
Classification of the study 
Category 3 : Non-interventional study.  
This clinical investigation is prospective, multicentric and non-comparative. 
The study is classified as category 3 according to the Jardé Law (French Law 
relative to the Clinical Research Involving Human Persons) and thus is 
qualified as “non-interventional”.  
Indeed, according to the terms of the protocol established in collaboration with 
the stakeholders, this research will be carried out on a CE-marked device (CE 
0123) and does not involve any risk or constraint since all the procedures will 
be performed and the products used in a ususal way, without any additional or 
unusual diagnostic, treatment or monitoring action. 
Intervention description 
Covering oral-maxillofacial or a periodontal defects with the Resorbable 
Collagen Membrane in order to avoid epithelial cell infiltration and to promote 
periodontal tissues healing.  
Covering alveolar bone defects after tooth-teeth extraction. 
Surgical technique 
Covering oral-maxillofacial or periodontal or alveolar bone defects with a 
RCM after filling or not the defect with a bone filling material. 
Primary outcome measure 
Evaluation of performance of the RCM in terms of periodontal tissue 
regeneration by the observation of mucosa health in terms of swelling, wound 
closure and colour of the implantation site. 
Time 
points 
at 
which 
primary outcome measure 
is assessed 
- 1 week post-surgery (± 2 days) 
- 2 weeks post-surgery (± 2 days) 
- 12 weeks post-surgery (± 1 week) 
Secondary 
outcomes 
measures 
- Evaluation of safety of the RCM by the record of any adverse event during 
follow-up, especially the one mentioned in the Instructions For Use (IFU) such 
as post-operative infections, discomfort, irritation, fever, inflammatory reaction 
and allergy. 
- Radiographic examination of periodontal tissues. 
Time points at which the 
secondary 
outcomes 
measures are assessed 
Safety data:  
From screening throught visit at 12 weeks ( ± 1 week). 
X-Rays measurements:  
- Pre-surgery 
- 12 weeks post-surgery (± 1 week) 
Inclusion criteria 
- Male or female aged from 18 to 70 
- Periodontal defects (e.g. cyst, bone tumour, crest augmentation…) 
- Alveolar bone defect after tooth (teeth) extraction  
- Non Opposition form (consent of the patient) 
- Patients affiliated to the French social security 
- Patients not under guardianship or judicial protection 
Exclusion criteria 
- Pregnancy or breastfeeding women 
- Severe smoker (>10 cigarettes per day) [13] 
- Acute infections 
- Allergies to the material (if an allergy of any kind is suspected, adequate 
exams must be carried out in advance) 
- Refusal of the patient to adhere to surgical follow-up and to the limit in 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
14/48 
 
activity level 
- Fever and/or local inflammation 
- HIV positive known  
- History of uncontrolled diabetes (untreated or not stabilized by treatment) 
- History of treatments for previous corticosteroids, long-term (more than 6 
months) and interrupted for less than 3 months 
- History of chemotherapy in progress or during the last three months 
- History of cervico-facial radiotherapy 
- History of bone disease with disorders of blood circulation which is defined 
as Albers-Schönberg disease or Paget's disease 
- Known severe hyperparathyroidism 
- History of severe immune deficiency 
Study size 
A sample size of 50 patients would give with 95% confidence interval a 
precision of ± 8.3%. 
Accounting for a maximum of 10% of dropouts or missing data, 56 patients 
should be recruited in the cohort. 
Duration of the research 
- Duration of the inclusion period: 18 months 
- Duration of follow-up per participant: 12 weeks (±1 weeks) 
- Total duration of the research project: 22 months  
Statistical analysis of the 
data 
A Statistical Analysis Plan (SAP) will be written by the Biostatistician of the 
CRO in charge of the study. This document will be approved and signed by the 
Sponsor, the Coordinating Investigator and the clinical expert before the first 
database lock. 
 
All data will be presented using descriptive statistics.  
 
An interim analysis is planned in this study protocol in order to obtain the first 
results for December 2019. 
 
Quantitative or ordinal variables will be described by the number of values 
entered, the number of missing data, the mean, the standard deviation, 95% 
confidence interval (CI) of the mean, the median, the 1st and 3rd quartiles, the 
minimum and the maximum.  
Qualitative variables will be described by the number of data filled in, the 
number of missing data, the frequency and the percentage of each modality. 
The 95% CIs of the percentages will be performed using exact confidence 
limits method. 
 
The medical and surgical histories and adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC) and Preferred Term (PT).  
 
The primary efficacy endpoint is the mucosa aspects reported by swelling, 
wound closure and colour. The composite primary endpoint will be described 
using descriptive statistics. Sensitivity will be analysed using different analyses 
sets and missing data handling as described in section “Missing values / 
dropouts”. The Per-Protocol (PP) analysis will be considered as confirmatory 
analysis. 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
15/48 
 
Adverse Events (AEs) will be classified according to period of occurrence: pre-
treatment AEs, Treatment-emergent Emergent AEs (TEAEs). 
 
TEAEs will be summarized and detailed by:  
- 
seriousness,  
- 
intensity,  
- 
action taken with trial medication,  
- 
other action taken,  
- 
relationship to study treatment,  
- 
severity according to the relationship with patient identifications 
 
The number/frequency of patients with each TEAE will be displayed by 
System Organ Class (SOC) and Preferred Term (PT) according to MedDRA 
classification.  
 
All serious adverse events (SAEs) will be listed separately with the same 
information that the TEAE. 
 
All individual data will be presented in listings. 
 
The statistical analysis will be performed using SAS® or equivalent software.  
 
No sub-group analysis is planned. 
 
The radiographic analysis of periodontal tissues will be reviewed and analyzed 
by the clinical expert and the coordinating investigator. These data will be 
recorded in the electronic case report form (eCRF). The description of the 
radiographic analyses and the presentation of these results will be in a separate 
document from the statistical report produced by the CRO. 
Expected impacts 
This study will confirm the ability of the RCM, EZ CureTM, to promote Guided 
Tissue Regeneration within 12 weeks in oral maxillo facial and periodontal 
defects, alveolar pockets after tooth (teeth) extraction and its acceptable 
benefit/risk balance. 
Keywords 
Periodontal defects, alveolar bone preservation, collagen membrane, mucosa 
healing 
 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
16/48 
 
 
SCIENTIFIC JUSTIFICATION 
II.1. INTRODUCTION 
Collagen membranes have been used worldwide for 20 years in different periodontal applications. Their 
biocompatibility has been proven thanks to in vitro, in vivo and long lasting use in clinical cases. They have 
been well described in Guided Bone Regeneration (GBR) and Guided Tissue Regeneration (GTR) procedures 
and their resorption properties lead to good tissue healing in periodontal surgery. These collagen membranes 
are safe when following manufacturers’ instructions for use.  
The Resorbable Collagen Membrane (RCM), manufactured by BIOMATLANTE SA, is an improvement of the 
generation of collagen membrane used in soft tissue wound healing management during GTR and GBR 
procedures. Its performance and safety were already assessed in GTR and GBR procedures in the case of 
periodontal and oral/maxillofacial bone defects. The clinical evidence demonstrates conformity of the RCM 
(EZ CureTM – CE0123) with the relevant essential requirements. 
In order to improve the clinical data on the device, the manufacturer decided to assess the performance and 
safety of its RCM during the post-market phase in the same indications and for the same intended use. 
II.2. CURRENT STATE OF KNOWLEDGE 
One review from Cochrane Library analysed the main strategies currently used to address the issue of guided 
tissue regeneration GTR or GBR in periodontal defects: 
“Guided tissue regeneration for periodontal infra-bony defects”. Review Intervention 
Ian Needleman, Helen V Worthington, Elaine Giedrys-Leeper, Richard Tucker 
Cochrane Oral Health Group. DOI: 10.1002/14651858.CD001724.pub2View/save citation 
 
Background 
Restoration of large bone defects remains a great issue due to the insufficient supply of horizontal and/or 
vertical bone at implant sites [1,9]. Meanwhile, the infiltration of non-osteogenic tissue at those sites also 
hinders bone regeneration process [6]. To overcome these obstacles, different approaches, including bone-
grafting techniques, alveolar distraction, and guided bone regeneration have been implemented to allow the 
implant to be fully integrated and maintained during functional loading [2, 4, 16]. Among them, utilization of 
materials to prevent the entry of non-osteogenic tissue and allow exclusively osteogenic cells to repopulate the 
defect is one of the most commonly used strategies [7, 15].  
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
17/48 
 
A barrier membrane needs to be biocompatible and acts as temporary matrice to facilitate cell proliferation, 
vascularization, and extracellular matrix deposition in addition to transport nutrition, enable bone cell 
penetration and support bone tissue formation [8, 14, 19]. The device should also possess adequate mechanical 
properties such as sufficient rigidity to endure the compression of overlying soft tissue while maintaining a 
certain degree of plasticity to adapt to the shape of defective site. Barrier membrane can be classified into two 
types including non-resorbable and resorbable membranes [9]. Comparing these two types, bioresorbable 
membranes are more advantageous since no second surgery for membrane removal is required, the cost-
effectiveness profil is suitable and the patient morbity is reduced [7].  
Conventional treatment of destructive periodontal (gum) disease arrests the disease but does not usually allow 
the recovery of the bone support or connective tissue lost in the disease process. Guided Tissue Regeneration 
(GTR) is a surgical procedure that specifically aims to regenerate the periodontal tissues when the disease is 
advanced and could overcome some of the limitations of conventional therapy. In addition of the evaluation of 
mucosa healing (clinical observation, mucosa attachment, inflammation etc...), the height of the alveolar crest 
(in periodontal disease comparison of the depth of the pocket before surgery and after several months) was also 
measured [21]. Same measurment was realized for alveolar socket after tooth (teeth) extraction.  
 
Search methods 
We conducted an electronic search of the Cochrane Oral Health Group Trials Register, MEDLINE and 
EMBASE up to April 2004. Handsearching included Journal of Periodontology, Journal of Clinical 
Periodontology, Journal of Periodontal Research and bibliographies of all relevant papers and review articles 
up to April 2004. In addition, we contacted  dental surgeons and experts/groups/companies involved in surgical 
research to find other trials or unpublished material or to clarify ambiguous or missing data and posted requests 
for data on two periodontal electronic discussion groups. 
 
Selection criteria 
Patients with periodontal defects, tooth (teeth) extraction or other maxillofacial bone defects (e.g. cyst, bone 
tumour, crest augmentation…) requiring a Guided Tissue Regeneration (mucosa and bone) with a membrane. 
Patients having good oral hygiene, and accepting the standard post-operative survey. The standard surgical 
procedure is open flap debridement for the treatment of periodontal infra-bony defects. Furcation involvements 
and studies specifically treating aggressive periodontitis were excluded. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
18/48 
 
Data collection and analysis 
Screening of possible studies and data extraction was conducted independently. The methodological quality of 
studies was assessed in duplicate using individual components and agreement determined by Kappa scores. 
Methodological quality was used in sensitivity analyses to test the robustness of the conclusions. The Cochrane 
Collaboration statistical guidelines were followed and the results expressed as mean differences (MD and 95% 
CI) for continuous outcomes and risk ratio (RR and 95% CI) for dichotomous outcomes calculated using 
random-effects models. Any heterogeneity was investigated.  
In complement, the sub group (membrane used alone), has been analyzed and compared to the second sub 
group (membrane and bone void filler used together).  
 
Main results 
The search produced 626 titles, of these 596 were clearly not relevant to the review. The full texts of 32 studies 
of possible relevance were obtained and 15 studies were excluded. Therefore, 17 studies were included in this 
review, 16 studies testing GTR alone and two testing GTR with bone substitutes (one study had both test 
treatment arms). 
No tooth loss was reported in any study although these data are incomplete where patient follow up was not 
complete. For attachment level change, the mean difference between GTR and Open Flap Debridment (OFD) 
was 1.22 mm (95% CI Random Effects: 0.80 to 1.64, Chi2 for heterogeneity 69.1 (df = 15), P < 0.001, I2 = 
78%) and for GTR with bone substitutes was 1.25 mm (95% CI 0.89 to 1.61, Chi2 for heterogeneity 0.01 (df = 
1), P = 0.91). GTR showed a significant benefit when comparing the numbers of sites failing to gain 2 mm 
attachment with risk ratio 0.54 (95% CI Random Effects: 0.31 to 0.96, Chi2 for heterogeneity 8.9 (df = 5), P = 
0.11). The number needed to treat (NNT) for GTR to achieve one extra site gaining 2 mm or more attachment 
over OFD was therefore 8 (95% CI 5 to 33), based on an incidence of 28% of sites in the control group failing 
to gain 2 mm or more of attachment. For baseline incidences in the range of the control groups of 3% and 55% 
the NNTs are 71 and 4. 
Probing depth reduction was greater for GTR than OFD: 1.21 mm (95% CI 0.53 to 1.88, Chi2 for heterogeneity 
62.9 (df = 10), P < 0.001, I2 = 84%) or GTR with bone substitutes, weighted mean difference 1.24 mm (95% 
CI 0.89 to 1.59, Chi2 for heterogeneity 0.03 (df = 1), P = 0.85). 
For gingival recession, a statistically significant difference between GTR and OFD controls was evident (mean 
difference 0.26 mm (95% CI Random Effects: 0.08, 0.43, Chi2 for heterogeneity 2.7 (df = 8), P = 0.95), with a 
greater change in recession from baseline for the control group. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
19/48 
 
Regarding hard tissue probing at surgical re-entry, a statistically significant greater gain was found for GTR 
compared with OFD. This amounted to a weighted mean difference of 1.39 mm (95% CI 1.08 to 1.71, Chi2 for 
heterogeneity 0.85 (df = 2), P = 0.65). For GTR with bone substitutes the difference was greater, with mean 
difference 3.37 mm (95% CI 3.14 to 3.61). 
Adverse effects were generally minor although with an increased treatment time for tissues regeneration. 
Exposure of the barrier membrane was frequently reported with a lack of evidence of an effect on healing. 
Concerning more specifically the rate of failure in GTR, clinical publications concerning the use of resorbable 
membrane, generally in association with bone substitute grafting for filling the defect, can be cited. Merli et al 
[12] report an analysis of 65 full text articles: they report only one publication with 396 patients and all the 
others concerned limited sample size studies. All these studies report successfull results for tissue regeneration 
at implant dehiscences and fenestration with membranes for GTR. 
Several articles specifically report a failure in tissue regeneration, with RCM covering the defect to assure 
barrier effect, cells of bacterial infiltration, promoting the mucosa regeneration and protecting the bone 
ingrowth under the membrane. The following studies report similar success : 
Publication 
Percentage of soft tissue 
healing 
Wessing et al [20] 
100 % 
De Angelis et al [3] 
88.5 % 
Felice et al [5] 
100 % 
Merli et al [11] 
100 % 
Taschieri et al [17] 
81.2 % 
Taschieri et al [18] 
89.5 % 
Meloni et al [10] 
87 % 
Table 1 Justification of the percentage of soft tissue healing 
 
Authors' conclusions 
GTR has a greater effect on probing measures of periodontal treatment than OFD, including improved 
attachment gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing 
at re-entry surgery. However there is marked variability between studies and the clinical relevance of these 
changes is unknown.  
There is therefore little value in future research repeating simple, small efficacy studies. The priority should be 
to identify factors associated with improved outcomes as well as investigating outcomes relevant to patients. 
Types of research might include large observational studies to generate hypotheses for testing in clinical trials, 
qualitative studies on patient-centred outcomes and trials exploring innovative analytic methods such as 
multilevel modelling. Open flap surgery should remain the control comparison in these studies. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
20/48 
 
Methological issues 
1. The aim of main studies was to evaluate the efficacy of the whole procedure of tissue reconstruction in 
periodontal surgery: surgery strategy + bone substitute + collagen membrane. Thus, it is quite difficult to 
certify that the obtained results can be extended to the collagen membrane alone: the success is charged to the 
whole procedure in which the collagen membrane takes its part. Knowing this limitation, all studies were used 
for the performance analysis.  
2. The articles were analyzed only if the use of a collagen membrane in these strategies was clearly indicated. 
Even if the final outcome was not to assess safety the collagen membrane per se, the absence of complications 
related to the strategy can be extended to the use of the collagen membrane as well. Thus, all studies were kept 
in the safety analysis. 
3. The minimal clinical follow up taking into account soft tissue healing was 3 months to have reliable data. 
4. Most of the studies have been conducted following the best required methodology (prospective randomized 
study, or prospective comparative study) to assess performance and safety of a product (level I). The other 
prospective and retrospective (clinical cases) studies (level II & III) are less appropriate because of the lack of 
methodological design (no comparison) and only descriptive statistics (or unique case), but the most interesting 
informations were kept in the clinical review. 
5. Split mouth approach was often used to compare different approaches within the same patient and to increase 
the number of cases in the same study. 
6. Moreover, in periodontal applications, main results concern radiological and histological assessments that are 
not clinical outcomes; it is the most usual way to address this question in these indications. 
II.3. STUDY HYPOTHESES 
Based upon previous data collected in the literature [3, 5, 10, 11, 17, 18] and previous experience with the 
Biomatlante RCM, the hypothesis that justifies this research is that 90% of the patients who will undergo GTR 
and/or GBR involving the RCM in oral/maxillofacial defects will show tissue regeneration at 12 weeks after 
surgery, as assessed by observation of : 
• 
Tissue regeneration (mucosa health on the implantation site) 
• 
Safety report on any adverse event 
• 
Height preservation of the alveolar crest 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
21/48 
 
II.4. JUSTIFICATION OF METHODOLOGY CHOICES 
Regarding: 
• 
the number of RCM units commercialized,  
• 
the ability of the centers to recruit and appropriately record follow-up data,  
• 
the previous data about the principal criterion, 
• 
the follow-up duration of the patients 
The sponsor expects that a prospective observational study will allow gathering the data required in terms of 
performance, and safety in a 22 months delay. 
II.5. EXPECTED IMPACTS 
This study will confirm the performance and safety of the RCM in periondontal defects and its acceptable 
benefit/risk balance. 
 
 
 
OBJECTIVES 
III.1. 
MAIN OBJECTIVE 
The main objective of this study is to observe performance of the RCM in terms of periodontal tissue 
regeneration by the observation of mucosa health in terms of swelling, wound closure and colour of the 
implantation site 
III.2. 
SECONDARY OBJECTIVES 
The secondary objectives are: 
• 
Evaluation of the safety of RCM by recording all the adverse events during the follow-up 
• 
Evaluation of the radiographic analysis of periodontal tissues 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
22/48 
 
 
STUDY DESIGN 
IV.1. 
CLASSIFICATION OF THE STUDY 
This clinical investigation is prospective, multicentric, single arm and non-comparative. 
The study is classified as category 3 according to the Jardé Law (French Law relative to the Clinical Research 
Involving Human Persons) and thus is qualified as “non-interventional”.  
Indeed, according to the terms of the protocol established in collaboration with the stakeholders, this research 
will be carried out on a CE-marked device (CE 0123) and does not involve any risk or constraint since all the 
procedures will be performed and the products used in a ususal way, without any additional or unusual 
diagnostic, treatment or monitoring action. 
IV.2. 
RESEARCH PROJECT AGENDA 
• 
Duration of the inclusion period: 18 months 
• 
Duration of follow-up per participant: 12 weeks (± 1 week) 
• 
Total duration of the research project: 22 months  
IV.3. 
SUMMARY TABLE OF PARTICIPANT FOLLOW-UP 
 
Pre-inclusion 
V -1 
Inclusion 
V 0 
Visit V 1 
At 1 week 
Visit V 2 
At 2 weeks 
Visit V 3 
At 12 weeks 
 
-1 month to 
Day 0 
Day 0 
± 2 days 
± 2 days 
± 1 week 
Full information and non-opposition 
✓ 
 
 
 
 
Inclusion / Exclusion criteria 
✓ 
 
 
 
 
Demographic data (a) 
✓ 
 
 
 
 
Life habits (smoker) 
✓ 
 
 
 
 
Relevant medical and surgical histories 
✓ 
 
 
 
 
Periodontal clinical examination (b) 
✓ 
 
 
 
 
PROCEDURE 
Batch 
 
✓ 
 
 
 
Clinical indication 
 
✓ 
 
 
 
Usability 
 
✓ 
 
 
 
CLINICAL EXAM 
Control of tissue regeneration (c) 
 
✓ 
✓ 
✓ 
✓ 
Membrane performance (d) 
 
 
✓ 
✓ 
✓ 
SAFETY 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
23/48 
 
 
Pre-inclusion 
V -1 
Inclusion 
V 0 
Visit V 1 
At 1 week 
Visit V 2 
At 2 weeks 
Visit V 3 
At 12 weeks 
 
-1 month to 
Day 0 
Day 0 
± 2 days 
± 2 days 
± 1 week 
Adverse events recording 
✓ <-----------------------------------------------------------> ✓ 
X-RAY 
Probing Pocket Depth (PPD) 
✓* 
✓* 
 
 
✓ 
Clinical Attachment Level (CAL) 
✓* 
✓* 
 
 
✓ 
(a) Demographic data: age, sex 
(b) Periodontal clinical examination: in accordance with the current practice (e.g. Probing Pocket Depth 
(PPD) using sensor and search for gingival inflammatory signs)  
(c) Control of tissue regeneration: swelling, wound closure, colour of the implantation site 
(d) Membrane performance: barrier effect, membrane exposition 
* X-Ray performed at pre-inclusion or inclusion visit (before the surgery) 
IV.4. 
INFORMATION TO PARTICIPANTS 
During pre-inclusion visit, the Investigator (a qualified individual) will ask the participant and/or the legal 
guardians/legal representative to participate in the research project and provide him/her/them with information 
regarding: 
• 
The objective, the description of the surgery and, 
• 
The automatic processing of participant-related data that will be collected during the research 
project, and shall also specify the participant’s right to access, object to, or rectify the data. 
The Investigator will also ensure that the eligibility criteria are met. If a person agrees to participate, he or she 
will sign the consent form included at the end of the patient information sheet. His or her non-opposition to data 
use will be recorded and stored in his or her medical file. The participant may, at any moment, oppose the use 
of his or her data as part of the research.  
IV.5. 
FOLLOW-UP VISITS 
• 
V -1, pre-inclusion visit (-1 month to Day 0): 
- 
Signature of the written consent 
- 
Inclusion / Exclusion criteria 
- 
Demographic data 
- 
Life habits: smoker 
- 
Relevant medical and surgical histories 
- 
X-Ray 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
24/48 
 
- 
Periodontal clinical examination 
• 
V 0, inclusion visit: 
- 
X-Ray (Pre-surgery, if not performed at pre-inclusion visit) 
- 
Periodontal surgery, tooth extraction, alveolar fillling  
- 
Evaluation of product stability and usability 
- 
Safety evaluation by the record of any adverse event 
• 
V 1 and V 2 at 1, 2 weeks post-surgery (± 2 days): 
- 
Control of soft tissue regeneration 
- 
Membrane performance 
- 
Safety evaluation by the record of any adverse event 
IV.6. 
END OF RESEARCH PROJECT VISIT  
• 
V 3 at 12 weeks (± 1 week): 
- 
Control of soft tissue regeneration 
- 
Membrane performance 
- 
X-Ray 
- 
Safety evaluation by the record of any adverse event 
 
 
 
STUDY POPULATION 
V.1. INCLUSION CRITERIA 
• 
Male or female aged 18 to 70 
• 
Periodontal defects (e.g. cyst, bone tumour, crest augmentation…) 
• 
Alveolar bone defect after tooth (teeth) extraction  
• 
Non Opposition form (consent of the patient) 
• 
Patients affiliated to the French social security 
• 
Patients not under guardianship or judicial protection 
V.2. EXCLUSION CRITERIA 
• 
Pregnancy or breastfeeding women 
• 
Severe smoker (>10 cigarettes per day) 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
25/48 
 
• 
Acute infections. 
• 
Allergies to the material (if an allergy of any kind is suspected, adequate exams must be carried out in 
advance) 
• 
Refusal of the patient to adhere to surgical follow-up and to the limit in activity level 
• 
Fever and/or local inflammation 
• 
HIV positive known  
• 
History of uncontrolled diabetes (untreated or not stabilized by treatment) 
• 
History of treatments for previous corticosteroids, long-term (more than 6 months) and interrupted for 
less than 3 months 
• 
History of chemotherapy in progress or during the last three months 
• 
History of cervico-facial radiotherapy 
• 
History of bone disease with disorders of blood circulation which is defined as Albers-Schönberg 
disease or Paget's disease 
• 
Known severe hyperparathyroidism 
• 
History of severe immune deficiency 
 
V.3. FEASIBILITY AND RECRUITMENT PROCEDURES 
Coordinating Investigator 
Dr. Said Kimakhe, PhD, Doctor of Dental Surgery (DDS) Associate professor Dental Faculty Nantes 
University Hospital, France. 
 
 
Other Investigators 
• 
Dr. Xavier Struillou, PhD, DDS, Associate professor Dental Faculty Nantes University Hospital, 
France. 
• 
Dr. Philippe Lesclous, PUPH, PhD, DDS, Dental Faculty Nantes University Hospital, France. 
• 
Dr Zahi Badran, PUPH, PhD, DDS, Dental Faculty Nantes University Hospital, France. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
26/48 
 
Centers involved in the clinical investigation 
Two centers will be involved in the clinical study. They already use Biomatlante RCM for GBR and GTR in 
oral/maxillofacial bone defects: 
 
 
Center n°1: 
Dental Care Center - Nantes University 
Hospital 
Center n°2 
Private Dental Practice – Saïd 
Kimakhe 
Principal Investigator 
Dr. Said Kimakhe 
Dr. Said Kimakhe 
Investigators 
Dr. Xavier Struillou 
 
Dr. Philippe Lesclous 
 
Dr Zahi Badran 
 
 
Each center will perform treatment in oral maxillofacial defects and will participate to patient recruitment 
during the whole study. The patients will be recruited during the consultations. 
V.4. ACTIONS UPON PATIENT WITHDRAWAL 
If a patient withdraws prematurely from the study, study personnel should make every effort to complete the 
full panel of assessments scheduled until the 12-week visit. The reason for patient withdrawal must be 
documented in the electronic case report form (eCRF). 
Participation of a patient in this clinical study may be discontinued for any of the following reasons: 
• 
The patient withdraws consent or requests discontinuation from the study for any reason; 
• 
Occurrence of any medical condition or circumstance that exposes the patient to substantial risk and/or 
does not allow the patient to adhere to the requirements of the protocol; 
• 
Any SAE, clinically significant adverse event, which indicates to the Investigator that continued 
participation is not in the best interest of the patient; 
• 
Pregnancy; 
• 
Patient failure to comply with protocol requirements or study-related procedures; or 
• 
Termination of the study by the Sponsor or the regulatory authority.  
In the case of patients lost to follow-up, attempts to contact the patient must be made and documented in the 
patient’s medical records. 
Withdrawn patients will not be replaced. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
27/48 
 
 
STUDY INTERVENTION 
VI.1. 
 DEVICE DESCRIPTION 
This medical device is a Resorbable Collagen Membrane intended for use in Guided Tissue Regeneration or 
Guided Bone Regeneration procedures. 
The Resorbable Collagen Membrane is crosslinked according to a controlled manufacturing process in 
accordance with current standards. Type I and III collagen fibres are extracted from the porcine epidermis and 
purified. 
The Resorbable Collagen Membrane is hydrophilic and provides a barrier function for 12 weeks to prevent 
colonization of the surgical site by cells of connective and epithelial tissues. 
The Resorbable Collagen Membrane allows the diffusion of biological fluids for a total resorption in 24 weeks. 
The Resorbable Collagen membrane is easy to handle. Flexible, it adapts perfectly to all bone geometries.  
The Resorbable Collagen Membrane is available in several dimensions: 15x25mm, 20x30mm and 30x40mm. 
VI.2. 
INTENDED USE 
The Resorbable Collagen Membrane is intended for use in Guided Tissue Regeneration or Guided Bone 
Regeneration procedures.  
The claimed performance of the Resorbable Collagen Membrane is as follows: a barrier function that prevents 
the colonization of bone defect by connective and epithelial tissues. 
VI.3. 
SURGICAL INTERVENTION 
The Resorbable Collagen Membrane is indicated for the treatment of oral and maxillofacial bone defects and in 
periodontal diseases. This membrane is exclusively reserved for adults. It has not been tested on pregnant or 
breastfeeding women. 
 
During this study, the investigators' practices will not be modified. For each type of surgery, the surgeon will 
perform all his acts in accordance with his current practice, without adding any additional procedure.  
The Resorbable Collagen Membrane should be handled in accordance with the manufacturer's recommendation 
using gloves and/or sterile instruments. This membrane can be cut to the appropriate shape and can be used 
directly or previously hydrated to facilitate its handling, especially when the surgeon intends to shape or fold 
the membrane at the implantation site. 
The Resorbable Collagen Membrane can be sutured for better immobilization. The manufacturer recommends 
that the implant site be completely closed to avoid exposure of the Resorbable Collagen Membrane. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
28/48 
 
VI.4. 
CONTRAINDICATIONS 
• 
Acute infections 
• 
Known collagen allergies (if any type of allergy is suspected, adequate tests should be performed in 
advance) 
• 
Fever and/or local inflammation 
VI.5. 
AUTHORIZED OR FORBIDDEN TREATMENTS AND PROCEDURES 
No prior or concomitant medication will be prohibited. 
 
 
 
STUDY ASSESSMENTS AND PROCEDURES 
VII.1. MAIN EVALUATION CRITERION 
This principal objective is to observe the performance of the RCM at 1, 2 and 12 weeks post surgery in terms of 
tissue regeneration. It will be assessed by the evaluation of mucose health on the implantation site at the 
different times of follow-up. The mucosa aspects that will be reported are the following: swelling, wound 
closure and colour.   
• 
Swelling is defined by the presence of one or more swellings in the wound. The total absence of 
swelling at 12 weeks will be considered as the efficacy endpoint. This swelling is assessed subjectively 
by the investigator with the naked eye or by photography.  
• 
Mucosal healing is characterized by wound closure. Complete wound closure will be considered as the 
efficacy criterion. This wound closure is assessed subjectively by the investigator with the naked eye or 
by photography. 
• 
The colour at the implantation site can take on 3 aspects: pink - identical to the surrounding mucosa - 
Red. Pink colours and identical to the surrounding mucosa will be considered as the efficacy criteria. 
This colour is assessed subjectively by the investigator with the naked eye or by photography. 
VII.2. SECONDARY EVALUATION CRITERIA 
The secondary ojectives are to evaluate the safety of the RCM during the 12 weeks follow-up and evaluate the 
radiographic analysis of periodontal tissues. 
The evaluation of the safety will be conducted by recording all the adverse events from screening throught the 
12-week visit (12 weeks ± 1 week). 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
29/48 
 
The evaluation of the radiographic analysis of periodontal tissues will by performed before the surgery and at 
the 12 weeks post-surgery visit.  
The details of this evaluation are the following :  
- 
The radiographic examination is a decisive act in the establishment of the periodontal diagnosis.  
- 
Retroalveolar plates should be used with the long cone technique.  
- 
The necessary equipment is a 70 to 90 kv (Kilovolts) generator equipped with a long cone, Rinn 
angulators to parallel the film to the major axis of the tooth and standard size films for the premolar, 
molar and pedodontic areas for the anterior areas. 
- 
A complete periodontal check-up includes 1 to 2 standard pictures for the premolar and molar areas of 
each hemiarcade, 3 to 5 pedodontic pictures for the upper and lower anterio areas and 1 to 2 “bite 
wing” pictures on each side.  
- 
The interpretation of this radiographic assessment allows to make a precise examination of dental and 
periodontal structures.  
- 
To examine and reassess a specific defect, the radiographic examination with a resin bite can be 
standardized on the Rinn angulator to reproduce the incidence.  
In this study, the radiographic examination is performed in order to:  
- 
Assess the Probing Pocket Depth (PPD): it corresponds to the distance between the top of the marginal 
gingiva and the bottom of the pocket 
- 
Assess the Clinical Attachment Level (CAL): it corresponds to the distance between the enamel-
cementum junction and the bottom of the pocket.  
 
For a better reproducibility of the results, the radiographies will be recorded in the eCRF and the analysis of the 
radiographies will be carried out by the coordinating investigator, Dr. Saïd Kimakhe in association with the 
scientific expert Guy Daculsi.  
The description of the radiographic analyses and the presentation of these results will be in a separate document 
from the statistical report produced by the CRO. 
 
VII.3. MANAGEMENT OF ADVERSE EVENTS AND NEW FACT 
The investigator records the adverse events or abnormal analysis results defined in the protocol as determinants 
for the safety assessment, keeps a documentary record and notifies the sponsor. 
The investigator informs the sponsor of all adverse events that occurred in the participants. 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
30/48 
 
VII.3.1. DEFINITION OF ADVERSE EVENTS 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient administered 
a medical device, which does not necessarily have a causal relationship with this device. An adverse event can 
therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not related to the 
investigational product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the eCRF. 
Adverse events will be monitored and documented from the time of informed consent to the end of study 
participation. Patients should be instructed to report any adverse event that they experience to the Investigator. 
Beginning with the signing of informed consent, investigators should make an assessment for adverse events at 
each visit and record the event on the adverse event on the eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and symptoms should 
be identified by the Investigator and recorded on the eCRF. However, if an observed or reported sign or 
symptom is not considered a component of a specific disease or syndrome by the Investigator, it should be 
recorded as a separate adverse event on the eCRF. Additionally, the condition that led to a medical or surgical 
procedure (e.g., surgery, endoscopy, transfusion) should be recorded as an adverse event. 
Any medical condition already present at the time of screening should not be reported as an adverse event 
unless the medical condition or signs or symptoms present at baseline changes in severity or seriousness at any 
time during the study. In this case, it should be reported as an adverse event. 
 
VII.3.2. DEFINITION OF SERIOUS ADVERSE EVENTS 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
• 
Death: AE causes or contributes to the death; 
• 
A life-threatening adverse event: AE places the subject at immediate risk of death; it does not refer to 
AE which hypothetically might have caused death if it were more severe; 
• 
Requires hospitalization or prolongation of existing hospitalizations: AE requires at least an overnight 
admission or prolongs a hospitalization beyond the expected length of stay. Hospital admissions for 
surgery planned before study entry, for social reasons, for any elective surgery (i.e. plastic surgery) or 
for normal disease management (including treatment adjustment) are NOT to be considered as SAE 
according to this criterion; 
• 
A persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal 
life functions; 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
31/48 
 
• 
A congenital anomaly/birth defect;  
• 
An important medical event: AE that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
The Investigator must continue to follow the patient until the SAE has subsided or until the condition becomes 
chronic in nature, stabilizes (in the case of persistent impairment), or the patient dies. 
 
 
VII.3.3. CLASSIFICATION OF AN ADVERSE EVENT 
VII.3.3.1. SEVERITY OF EVENT 
The severity of AEs must be assessed by the Investigator according to the following definitions. The term 
“severity” is used to describe the intensity of a specific event. This has to be distinguished from the term 
“serious”. 
• 
Mild: Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• 
Moderate: Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe: Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 
 
 
VII.3.3.2. RELATIONSHIP TO STUDY PRODUCT 
The clinician must always determine the relationship between all adverse events and the investigated medical 
device by examinating and evaluating the participant on the basis of temporal relationship between the AE and 
application of the device and his/her clinical judgment. In a clinical trial, the investigated medical device must 
always be suspected. The degree of certainty about causality will be graded using the categories below: 
• 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
32/48 
 
• 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable 
time after administration of the study intervention, is unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related: There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although 
an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the study intervention) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related: The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician 
 
VII.3.3.3. EXPECTED ADVERSE EVENTS 
The most frequent adverse events expected from RCM observed in patients are: 
• 
Post-operative infection 
• 
Discomfort 
• 
Irritation 
• 
Fever 
• 
Inflammatory reaction 
• 
Allergy 
Some side effects may be treated with medication or require reoperation. 
 
VII.3.4. ADVERSE EVENTS REPORTING 
Complete and accurate data on all AEs experienced for the duration of the reporting period, will be reported in 
the eCRF. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
33/48 
 
It is important that each AE report includes a description of the event, whether it is considered serious, its 
duration (onset and resolution dates), its severity, its relationship to the investigational product, any other 
potential causality factors, any treatment given or other action taken and its outcome. 
As defined in Article R5212-17 of the French Public Health Code, all incident or risk of incident resulting from 
the use of a medical device brought to the investigator’s attention will be the subject of a spontaneous report 
from the investigator to the local vigilance correspondent on whom he depends or, failing that, to the French 
National Agency for the Safety of Health Products (Agence Nationale de Sécurité et du Médicament = ANSM) 
in accordance with the usual procedures in force.  
These declarations should be addressed at :  
 
Direction de la surveillance – Plateforme de réception et d’orientation des signalements 
E-mail: materiovigilance@ansm.sante.fr 
Fax: 01.55.87.37.01 
 
All AEs occurring from the time of informed consent until end of study participation must also be reported to 
the Sponsor.  
All AEs that the Investigator considers related to the medical device occurring after the end of study 
participation must be reported to the Sponsor.  
To report the AE, the AE form can be filled. When the form is completed, signed and dated, it must be sent to 
the Sponsor, specifically to the vigilance contact:  
 
Vigilance contact : 
Nancy TRICHEREAU 
Quality Assurance Manager 
E-mail: materiovigilance@biomatlante.com 
Phone: 06.21.90.58.43 
 
Immediately after receiving the follow-up information, the Investigator must update the AE form and submit 
any supporting documentation (e.g., patient discharge summary or autopsy reports) to the Sponsor. 
 
For any research involving the human,where an unexpected serious adverse reaction or a new fact relevant to 
the research or product under investigation is likely to prejudice to the safety of the appropriate persons, the 
proponent and the Investigator shall take appropriate urgent safety measures. 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
34/48 
 
VII.3.5. NEW FACTS REPORTING 
A new fact is defined as any new safety data which may lead to a reassessment of the relationship between the 
benefits and risks balance of the research or the product being investigated, changes in the use of the product, 
the conduct of the research or documents relating to the search, or to suspend or interrupt or modify the 
protocol of the search or similar searches. (R.1123-46 of the French Public Health Code). 
 
In the case of a new medical fact, the Sponsor, will be responsible for reporting new facts to the authorities in 
accordance with national regulations, as follows: 
• 
Inform without delay the ANSM about the new medical fact, at the following email address: aec‐
essaiscliniques@ansm.sante.fr with the following subject: Fait nouveau / trial number/ international 
non-proprietary name (INN) or substance code and including: 
o ‐ ID-RCB N°, 
o ‐ Title of the study protocol, 
o ‐ Protocol code number, 
o ‐ Summary of the new fact and urgent safety measures implemented if necessary, 
o All relevant information for the evaluation of the new fact. 
• 
Inform without delay the director of the Agence Régionale de Santé (ARS; regional health agency) and 
the Ethical Committee (CPP). 
Any follow-up information with regards to the new safety medical fact will be reported to the regulatory 
authorities within 8 calendar days, and details regarding the urgent safety measures set up will be sent within 15 
days to the regulatory authorities. 
 
 
 
STATISTICAL ASPECTS  
VIII.1. SAMPLE SIZE DETERMINATION 
As the study is descriptive, the calculation of study size is not calculated based on considerations relating to 
formal hypothesis tests. The required number of patients is calculated to guarantee that the endpoints associated 
with the main objective of the study could be estimated with sufficient precision. 
The choice of a target of 90% of patients with tissue and bone regeneration at 12 weeks post-surgery is based 
on an estimation of the kinetics of reconstruction according to the literature (similar products resorbable 
membrane but with or without filling with different bone substitute) [3, 5, 10, 11, 17, 18, 20]. The score will be 
from 88.8% to 100% with follow-up from 4 to 12 months (due to evaluation of the bone void filler and not only 
the collagene membrane). 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
35/48 
 
For the primary endpoint of effectiveness as measured by the performance of the RCM (binary endpoint) with a 
90% target frequency (as hypothesized) and a confidence level of 95%, the following precisions can be 
achieved. The calculation was made using SAS®.  
 
Precision 
Target frequency of 
performance 
Number of patients to 
evaluate 
Number of patients to 
recruit 
8.3% 
90% 
50 
56 
6.8% 
90% 
75 
83 
5.9% 
90% 
100 
111 
5.3% 
90% 
125 
139 
5.0% 
90% 
150 
165 
Table 2 Sample size determination 
With 50 patients, a precision around 8.3% can be achieved.  
Accounting for a maximum of 10% dropouts or missing data, 56 patients should be recruited in the cohort.  
VIII.2. ANALYSIS SETS 
Four populations will be defined: 
• 
Screened population will include all patients entering the study,  
• 
Safety Set (SS) population will include all patients who received the RCM product, 
• 
Full Analysis Set (FAS) efficacy population will include all patients who received the RCM product 
and in whom at least one efficacy information has been collected after the application of the RCM, 
• 
Per-Protocol (PP) efficacy population will include all patients in FAS population without any major 
protocol deviation. 
 
Remark: according to the ICH E9 recommendations, this subset of patients corresponds to a subset of the full 
“intention-to-treat” analysis set (including all randomized patients), being the full analysis set (FAS). 
VIII.3. MISSING VALUES AND DROP-OUT 
For the primary analysis (FAS analysis), a patient with missing data on the one of primary efficacy endpoint 
(swelling, wound closure or colour of the implantation site) will be considered as non efficacy of the product 
for this patient. Sensitivity analyses will be performed according to the following scenarios: 
• 
No missing data will be imputed 
• 
The missing data for the one of primary efficacy endpoint (swelling, wound closure or colour of the 
implantation site) will be considered as efficacy of the product. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
36/48 
 
VIII.4. STATISTICAL ANALYSIS 
VIII.4.1. 
GENERAL CONSIDERATION 
A Statistical Analysis Plan will be written by the biostatistician detailing the statistical analysis. The document 
will constitute the reference document as far as statistical analyses and methodologies are concerned. This 
document will be approved and signed by the Sponsor and the Principal Investigator before the first database 
lock. 
The statistical analysis will be performed on SAS® version 9.4 or later (or equivalent statistical software). 
 
Quantitative variables will be described by the number of values entered, the number of missing data, the mean, 
the standard deviation, the 95% CIs for the means, the median, the 1st and 3rd quartiles, the minimum and 
maximum. 
Qualitative variables will be described by the number of data filled in, the number of missing data, the 
frequency and the percentage of each modality. The 95% CIs of the percentages will be performed using exact 
confidence limits method. 
 
All variable in the database will be described using descriptive statistics and all individual data will be 
presented in listings. 
 
An interim analysis is planned in this study protocol in order to obtain the first results for December 2019. 
No sub-group analysis is planned. 
 
VIII.4.2. 
ANALYSIS OF THE PRIMARY ENDPOINT 
The primary endpoint analysis will be performed on FAS population. The primary endpoint will be analyzed on 
the PP population if the difference in the number of subjects between FAS and PP is more than 10%. 
 
The primary efficacy endpoint is the mucosa aspects reported by swelling, wound closure and colour. 
The composite primary endpoint will be summarized using descriptive statistics with binary outcome.  
For patients who do not have swelling on the surgical site, with a complete wound closure on the surgical site 
and pink colour or identical colour to the surrounding mucosa on the surgical site, the investigational product 
will be considered as efficacious. If at least one of the primary endpoint performance is not satisfied, the 
investigational product will be considered ineffective for the patient. 
Sensitivity analyses using different analyses sets and missing data handling as described above will be 
performed (see section “Missing values / dropouts”). The PP analysis will be considered as confirmatory 
analysis. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
37/48 
 
VIII.4.3. 
SAFETY ANALYSES 
The safety analysis will be performed on SS population. 
Safety endpoints will be AEs and SAEs all through the study.  
AEs will be coded using MedDRA dictionary (latest version available). AEs will be classified according to 
period of occurrence: pre-treatment AEs and Treatment-Emergent AEs.  
• 
Pre-treatment AEs are defined as adverse events occurring before the introduction of the investigational 
product.  
• 
Treament-Emergent AEs are defined as an adverse who that emerges after introduction of the 
investigational product having been absent pre-treatment, or worsens relative to the pre-treatment state. 
 
AE reporting will focus on TEAEs. TEAE will be summarised and detailed using descriptive statistics by:  
• 
seriousness,  
• 
intensity,  
• 
action taken with investigational product,  
• 
other action taken,  
• 
relationship to study treatment, 
• 
severity according to the relationship with patient identifications 
 
The number/frequency of patients with each TEAE will be displayed by System Ogan Class and Preferred 
Term according to Medical Dictionary for Regulatory Activities (MedDRA) classification. 
 
All SAEs will be listed separately with the same information that the TEAE. 
 
VIII.4.4. 
RADIOGRAPHIC ANALYSIS 
The radiographic analysis of periodontal tissues will be reviewed and analysis by the clinical expert and the 
coordinating investigator.  
The radiographic data will be recorded in the eCRF. The description of the radiographic analyses and the 
presentation of these results will be in a separate document from the statistical report produced by the CRO. 
 
VIII.4.5. 
BASELINE DESCRIPTIVE STATISTICS 
Descriptive statistics of demographics and other baseline characteristics will be presented on the FAS 
population.  
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
38/48 
 
VIII.4.6. 
RELEVANT MEDICAL AND SURGICAL HISTORIES 
Relevant medical and surgical histories will be determined by the Investigator and will be describe on the FAS 
population. 
 
Relevant medical and surgical histories will be coded using MedDRA dictionary (latest version available) and 
will be describe using descriptive statistics by: 
• 
Number (percentages) of subjects with relevant medical histories 
• 
Number (percentages) of relevant medical histories by subject 
• 
Number (percentages) of relevant medical histories and number (percentages) of subjects with relevant 
medical histories by SOC 
• 
Number (percentages) of relevant medical histories and number (percentages) of subjects with relevant 
medical histories by SOC and by PT 
 
VIII.4.7. 
EXPLORATORY ANALYSES 
For exploratory purposes, factors associated with improved performance such as age, relevant medical and 
surgical histories and life habits will be investigated using logistic regression.  
VIII.5. PLANNED INTERIM ANALYSES 
One interim analysis is planned in this study protocol in order to obtain the first results for December 2019. 
This study is descriptive, no randomized, open-label and single arm, so no alpha inflation or adjusted p-value 
are to be considered. 
VIII.6. SUB-GROUP ANALYSES 
No sub-group analysis is planned 
 
 
 
DATA ACCESS RIGHTS AND SOURCE DOCUMENTS 
 
BIOMATLANTE, sponsor of the research, is identified as the data processing controller. As a result, it must be 
in compliance and ensure that the data will be processed by the various research actors, in accordance with Law 
78-17 of 6th January 1978 amended by Law 2014-344 of 17th March 2017, known as “Informatique et 
Libertés”, and the European Regulation 2016/679 of 27th April 2016 (known as “GDPR”). 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
39/48 
 
IX.1. 
ACCESS TO DATA 
Agreement to participate in the protocol means that the individuals carrying out the research will make 
documents and individual data that are strictly necessary to follow-up, quality control and audit available to the 
individuals who have a right to access these documents in accordance with applicable legal and regulatory 
provisions. 
IX.2. 
SOURCE DATA 
This includes all information contained in the original documents, or in authenticated copies of these 
documents, relating to clinical examinations, findings or other activities carried out as part of the research and 
necessary to the reconstitution and evaluation of the research. The documents in which source data are recorded 
are called source documents.  
The source documents to be used will be: 
- 
Medical patient file 
- 
Clinical picture 
- 
X-rays 
IX.3. 
DATA CONFIDENTIALITY 
In accordance with applicable legal provisions, individuals who have direct access to source data take all the 
necessary precautions to ensure the confidentiality of information relating to research, participants and 
particularly their identity, as well as the results obtained. These individuals, like the investigators and the 
person who performs data monitoring, are subject to the conditions of professional secrecy. 
During the research project or at the end of it, the collected data on participants and data transmitted to the 
sponsor by the investigators (or any other involved specialists) will be codified. The data must not, under any 
circumstances, clearly indicate the names of the participants or their address. 
Only the first letter of the name and surname of the subject will be recorded, together with a research-specific 
coded number indicating the order of inclusion of the subjects for each center. 
The sponsor will ensure that each participant of the research project will be informed about access to data 
relating to him or her and strictly necessary for quality control. 
IX.4. 
PSEUDONYMIZATION PROCEDURE 
In the context of this study, the personal data of patients will be processed in order to meet the research 
objectives.  

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
40/48 
 
For this purpose, patient’s medical data will be transmitted to the sponsor. For each patient, these data will be 
identified by the number attributed to the research center and the identification number of the patient.  
 
The number attributed to the research center is attributed as follows:  
- 
Clinical center N°01 : Dental Care Center – Nantes University Hospital 
- 
Clinical center N°02 : Private dental practice – Dr S.Kimakhe 
 
The patient identification number is attributed as follows:  
- 
Number corresponding to the order of inclusion in the research center 
- 
First letter of the patient’s first name 
- 
First letter of the patient’s name 
 
Center N°: ǁ_0 1_ǁ 
 
 
Patient N°: ǁ_0_ǁ_1_ǁ_X_ǁ_X_ǁ 
                                Inclusion N°  
 
Investigator : _________________________ 
 
Only the investigators, their collabaorators and the person responsible for the quality control of the data will 
have access to directly identifying data (name, date of birth, etc) via the correspondence table.  
 
 
 
QUALITY CONTROL AND ASSURANCE 
X.1. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
All information required by the protocol must be recorded in the electronic case report forms. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported.  
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
41/48 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording 
data for each participant enrolled in the study. Data recorded in the electronic case report form derived from 
source documents should be consistent with the data recorded on the source documents. Clinical data will be 
entered directly from the source documents. 
X.2. RESEARCH FOLLOW-UP 
A Clinical Research Associate (CRA) will ensure research follow-up. The CRA will be responsible, under the 
Coordinating Investigator, for: 
- 
Logistics and monitoring of the research;  
- 
Providing reports on its progress and sharing them with the research stakeholders (sponsor, 
Methodology and Management Centre, etc.); 
- 
Verifying the completeness of the case report forms (request for additional information, corrections, 
etc.); 
The CRA will work in accordance with standard operating procedures, in collaboration with the research 
associate delegated by the sponsor. 
X.3. QUALITY ASSURANCE AND QUALITY CONTROL 
A CRA will visit each centre, during the implementation of the research, once or several times during the 
course of the research project, according to the monitoring plan defined for the research and the frequency of 
inclusions. The elements to be reviewed during these visits are defined by the monitoring plan. All visits will be 
subject to a written monitoring report. The sponsor will be in charge of the quality survey of the study. 
Following written monitoring plan, the clinical research associate will verify that the clinical trial is conducted 
and data are generated, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Manufacturing Practices).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
42/48 
 
X.4. DATA MANAGEMENT 
X.4.1. DATA HANDLING 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The CRAs will 
verify data recorded in the electronic data capture (EDC) system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. An eCRF 
will be considered complete when all missing, incorrect, and/or inconsistent data has been accounted for. 
 
X.4.2. COMPUTER SYSTEMS 
Data will be processed using a validated computer system conforming to regulatory requirements. 
 
X.4.3. DATA ENTRY 
Data must be recorded using the EDC system as the study is in progress. All site personnel must log into the 
system using their secure user name and password in order to enter, review, or correct study data. These 
procedures must comply with Title 21 of the Code of Federal Regulations (CFR) Part 11 and other appropriate 
international regulations. All passwords will be strictly confidential. 
 
X.4.4. MEDICAL INFORMATION CODING 
For medical information, the latest version at the time of study start of the Medical Dictionary for Regulatory 
Activities (MedDRA) for medical history and adverse events will be used. 
 
X.4.5. DATA VALIDATION 
Validation checks programmed within the EDC system, as well as supplemental validation performed via 
review of the downloaded data, will be applied to the data in order to ensure accurate, consistent, and reliable 
data. Data identified as erroneous, or data that are missing, will be referred to the investigative site for 
resolution through data queries.  
The eCRFs panel for each patient will be electronically signed by the Investigator. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
43/48 
 
X.5. PROTOCOL DEVIATION 
A protocol deviation is any non-compliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or manufacturer recommendation requirements. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly. It is the 
responsibility of the site investigator to use continuous vigilance to identify deviations. All deviations must be 
reported in study source documents. 
 
Examples of protocol deviations are presented below (non-exhaustive list):  
• 
The membrane has not been installed,  
• 
Violation of inclusion/non-inclusion criteria,  
• 
Post-inclusion protocol violation, 
• 
Non compliance with visit scheduled. 
 
All protocol deviation will be listed before the data review meeting and reviewed during this meeting and 
classified as “minor” or “major".  
Number and frequency of patients with protocol deviations will be tabulated. 
X.6. AUDIT AND INSPECTION 
Individuals appointed by the sponsor and independent of those conducting the study may carry out audits at any 
moment. The audit is designed to check the safety of the participants and the respect of their rights, compliance 
with applicable regulations and data reliability. 
An inspection may also be undertaken by a competent authority (ANSM in France or EMA within the 
framework of a European study, for example). 
The audit, as well as the inspection, may be applied to any stage of the research, from protocol development to 
the publication of results and the classification of data used or produced as part of the research project. 
The investigators shall comply with the sponsor’s requirements regarding the audit and the competent 
authority’s inspection of the research. 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
44/48 
 
 
ETHICAL AND REGULATORY CONSIDERATIONS 
XI.1. 
COMPLIANCE WITH REFERENCE TEXTS  
The sponsor and the investigators undertake to ensure that the research is conducted in compliance with Law 
no. 2012-300 on research involving human participants of 5 March 2012 and the Declaration of Helsinki 
(which can be found in its entirety on the website http://www.wma.net). 
Data recorded during the course of the study will be subject to data processing at ATLANSTAT under Law no. 
78-17 on information technology, files and freedoms of 6th January 1978, amended by Law no. 2004-801 of 6th 
August 2004. 
This research project will be conducted according to the ISO 14155 : 2011 standard “Clinical Investigation of 
medical devices for human subjects – Good Clinical Practice”. 
This research project will receive the positive endorsement of the CPP (Committee for the Protection of 
Persons – French equivalent of an Ethical Committee) and will be reported to the ANSM (the French National 
Agency for the Safety of Health Products). 
This research project falls within the framework of the “Reference methodology” (MR-003). The Sponsor 
signed a commitment of compliance with this “Reference methodology”. 
The research project will be registered on the website http://clinicaltrials.gov/  
The research project will be registered in the European database EudraCT under ID-RCB number. 
XI.2. 
AMENDMENTS TO THE PROTOCOL  
Any substantial amendment, i.e. any amendment that may have a significant impact on the protection of 
persons, on the validity conditions and on the results of the research, on the quality and safety of tested 
products, on the interpretation of scientific documents that support the conduct of the research or on its conduct 
methods, is subject to a written amendment submitted to the sponsor; the latter must obtain, prior to 
implementing the amendment, a positive endorsement by the CPP. 
Non-substantial amendments, i.e. those that do not have a significant impact on any aspect of the research 
project, shall be reported to the CPP for information purposes only. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
45/48 
 
All amendments are validated by the sponsor and all of the participants affected by the amendment, prior to 
submission to the CPP. This validation may require calling a meeting of all the committees set up for the 
research project. 
All amendments to the protocol must be reported to the individuals carrying out the research, who shall commit 
to respecting their content. 
 
 
 
STORAGE OF DOCUMENTS AND DATA RELATING TO THE STUDY 
The duration of the archiving period is defined by the sponsor according to the applicable procedures and 
regulations.  
The patient data will be kept up to 2 years after the last publication of the research results, or, in absence of 
publication, until the final report of the research is written.  
In accordance with the decree of 11th August 2008 fixing the period of storage by the sponsor and the 
investigator of documents and data relating to biomedical research other than that relating to medicinal 
products for human use, they will then be archived for a minimum period of 15 years.  
 
Data processing operations of investigators and other professionals involved in the conduct of the research may 
not be stored for more than 5 years after the end of the last research in which the person participated. They will 
be then archived for a minimum period of 15 years.  
 
 
 
RULES CONCERNING PUBLICATION 
XIII.1. SCIENTIFIC COMMUNICATION 
The analysis of data provided by the centres will be carried out by ATLANSTAT (except radiographic 
analyses, which will be performed by coordinating investigator and clinical expert). The analysis will result in a 
written report, submitted to the sponsor. This report will allow for the preparation of one or more 
publication(s). 
Any written or oral communication of the results of the research project must receive prior approval of the 
investigator and, if applicable, of any committee set up for the research project. 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
46/48 
 
The publication of the main results will mention the name of the Sponsor, of all the people who included or 
followed-up research participants, of methodologists, biostatisticians and data managers who participated in the 
research, of members of the committee(s) set up for the research project. The international rules for writing and 
publishing shall be taken into account (IMCJE’s Uniform Requirements for Manuscripts, April 2010). 
XIII.2. COMMUNICATION OF THE RESULTS TO PARTICIPANTS 
Upon their request, participants will be informed of the overall results of the research projects explained in the 
patient information.  
XIII.3. DATA TRANSFER 
ATLANSTAT will ensure data management. The conditions for transferring all or part of the research database 
will be decided by the sponsor and be subject to a written agreement. The data will be transferred in a 
pseudonymized form, the study participant number will be used to identify the patient. Data transfer will be 
encrypted and no data transfer is planned outside the European Union. 
 
 
 
 

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
47/48 
 
 
BIBLIOGRAPHIC REFERENCES 
[1] Adell, R., et al., Marginal tissue reactions at osseointegrated titanium fixtures (I). A 3-ye  ar longitudinal 
prospective study. Int J Oral Maxillofac Surg, 1986. 15(1): p. 39-52.  
[2] Chiapasco, M., M. Zaniboni, and M. Boisco, Augmentation procedures for the rehabilitation of deficient 
edentulous ridges with oral implants. Clin Oral Implants Res, 2006. 17 S  uppl 2: p. 136-59.  
[3] De Angelis N et al, Guided bone regeneration with and without a bone substitute at single 
postextrativeimplants: 1 year post-loading results from a pramatic multicentre randomized controlled trial. Eur 
J Oral Implantol 2011, 4:313-25 
[4] Donos, N., N. Mardas, and V. Chadha, Clinical outcomes of implants following lateral bo  ne 
augmentation: systematic assessment of available options (barrier membranes, bone grafts, split osteotomy). J 
Clin Periodontol, 2008. 35(8 Suppl): p. 173-202.  
[5] Felice P et al, Immediate non-occlusal loading of immediate post Extractive versus delayed placement of 
single implants in preserved sockets of the anterior maxilla: 4-months post loading resuklts from a pramagtic 
multicentre randomized controlled trial. Eur J Oral Implantol 2011, 4:329-44. 
[6] Gentile, P., et al., Polymeric membranes for guided bone regeneration. Biotechnol J, 201  1. 6(10): p. 1187-
97. 
[7] Hammerle, C.H. and R.E. Jung, Bone augmentation by means of barrier membranes. Peri  odontol 2000, 
2003. 33: p. 36-53. 
[8] Kim, B.-R., et al., In Vitro and In Vivo Studies of BMP-2-Loaded PCL–Gelatin–BCP Ele ctrospun 
Scaffolds. Tissue Engineering. Part A, 2014. 20(23-24): p. 3279-3289. 
[9] Liu, J. and D.G. Kerns, Mechanisms of Guided Bone Regeneration: A Review. The Open Dentistry Journal, 
2014. 8: p. 56-65.  
[10] Meloni SM et al, One stage horizontal guided bone regeneration with autologous bone, anorganic bovine 
bone and collagen membranes: Follow-up of a prospective study 30 months after  loading.  Eur J Oral 
Implantology 2018, 11:89-95. 
[11] Merli M et al, Comparing membranes and bone sbstitutes in a one stage procedure for horizontal bone 
augmentation. A double blind randomized controlled trial. Eur J Oral Implantol 2015, 8:271-81. 
[12] Merli M. et al , Bone augmentation at implant dehiscences and fenestrations. A systematric review  of 
randomized controlled trials. Eur J Oral Implantol 2016, 9:11-32. 
[13] Papapanou PN, Sanz M, et al. J Clin Periodontol. 2018;45 (Suppl 20):S162–S170. 
[14] Polo-Corrales, L., M. Latorre-Esteves, and J.E. Ramirez-Vick, Scaffold Design for Bone Regeneration. J 
Nanosci Nanotechnol, 2014. 14(1): p. 15-56. 
[15] Rakhmatia, Y.D., et al., Current barrier membranes: titanium mesh and other membranes for guided bone 
regeneration in dental applications. J Prosthodont Res, 2013. 57(1): p.3-14.  

 
 
 
 
 
N°ID RCB : 2018-A03202-53  
 
 
 CONFIDENTIAL 
 
 
 
 
 
48/48 
 
[16] Rocchietta, I., F. Fontana, and M. Simion, Clinical outcomes of vertical bone augmentati  on to enable 
dental implant placement: a systematic review. J Clin Periodontol, 2008. 35(8 Suppl): p. 203-15. 
[17] Taschieri S et al, Guided tissue regeneration in endodontic surgery. Rev Stomatol Chir Maxillofac 2008, 
4:213-7. 
[18] Taschieri S et al, Effect of guided tissue regeneration on the outcome of surgical endodontic treatment of 
through-and-through lesions: a retrospective study at 4-years follow up. Oral Maxillofac Surg 2011, 15:153-9. 
[19] Thuaksuban, N., et al., Biodegradable polycaprolactone-chitosan three-dimensional scaffolds fabricated by 
melt stretching and multilayer deposition for bone tissue engineering: assessment of the physical properties and 
cellular response. Biomed Mater, 2011. 6(1): p . 015009. 
[20] Wessing B, Emmerich M., Bozkurt A., Horizontal ridge augmentation with a novel resorbable collagen 
membrane: a retrospective analysis of 36 consecutive patients. Int J Periodontics Restorative Dent 2016, 9:179-
87. 
[21] Wu SY et al, Comparison of clinical outcomes following guided tissue regeneration treatment with a 
polylactic acid barrier or a collagen membrane. Int J Periodontics Restorative Dent 2010 30:173-9.