Multi-Center Phase 3 Trial of Chlorhexidine Gluconate Chip for the Use in Subjects With Peri-Implantitis.
Phase: PHASE3
Conditions: Peri-Implantitis
Sponsor: Dexcel Pharma Technologies Ltd.

 
 
Dexcel Pharma Technologies Ltd. 
 
The Efficacy and Safety of Chlorhexidine Gluconate 
Chip (PerioChip®) in Therapy of Peri-implantitis 
 
 
 
 
Protocol Number: 
CLI/016P 
 
 
NCT Number 
NCT02080403 
 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
 
02/August/2017 
Version: 
 
7  

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 1 
Protocol # CLI/016P –version 7  
 
 
Dexcel Pharma Technologies Ltd. 
 
The Efficacy and Safety of Chlorhexidine Gluconate Chip 
(PerioChip®) in Therapy of Peri-implantitis 
 
 
 
 
 
The information in this and related documents from DPT, contains trade secrets and commercial information 
that are privileged or confidential and may not be disclosed unless such disclosure is required by federal or 
other laws or regulations. Prior to such disclosure, DPT should be notified. 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. 
 
 
 
 
 
Protocol Number: 
CLI/016P 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
 
02/August/2017 
Version: 
 
7  

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
TABLE OF CONTENTS  
PROTOCOL APPROVALS .................................................................................................................. 5 
CLINICAL STUDY PROTOCOL - OVERVIEW .............................................................................. 6 
PROTOCOL SYNOPSIS ....................................................................................................................... 7 
ABBREVIATIONS .............................................................................................................................. 12 
STUDY SCHEDULE ........................................................................................................................... 13 
1. 
INTRODUCTION .................................................................................................................. 14 
1.1 
Peri-implantitis .............................................................................................................. 14 
1.2 
Chlorhexidine and Peri-implantitis................................................................................ 14 
1.3 
PerioChip® ..................................................................................................................... 16 
1.4 
Study Rationale ............................................................................................................. 17 
2. 
OBJECTIVE .......................................................................................................................... 19 
3. 
ETHICAL AND LEGAL CONSIDERATIONS ................................................................. 19 
4. 
STUDY DESIGN AND DURATION .................................................................................... 20 
5. 
STUDY POPULATION ........................................................................................................ 22 
5.1 
Number of Patients ........................................................................................................ 22 
5.2 
Entry Criteria ................................................................................................................. 22 
5.2.1 Inclusion Criteria ............................................................................................... 22 
5.2.2 Exclusion Criteria............................................................................................... 23 
5.3 
Patient Discontinuation/ Withdrawal Criteria ............................................................... 25 
5.4 
Concomitant Medication Treatment .............................................................................. 26 
6. 
STUDY PLAN ........................................................................................................................ 27 
6.1 
Study Schedule .............................................................................................................. 29 
6.2 
Study Procedures by Visit ............................................................................................. 30 
6.2.1 Screening Visit and Hygienic Phase Therapy (Weeks (-3 to -1)) ........................ 31 
6.2.2 Baseline Visit (Week 0) ....................................................................................... 33 
6.2.3 Visits 3, 4, 5, 6, 7 and 8 (Weeks 2, 4, 6, 8, 10 and 12) ........................................ 35 
6.2.4 Visits 9 (Week 16) ............................................................................................... 37 
6.2.5 Last Visit/ Early Withdrawal Visit (Week 24) ..................................................... 37 
6.3 
Other Study Considerations ........................................................................................... 38 

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Clinical Protocol 
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6.3.1 Calibration of Examiners ................................................................................... 38 
6.3.2 Dental Treatment during Study .......................................................................... 38 
6.3.3 Post-study Periodontal Therapy ......................................................................... 38 
7. 
RANDOMIZATION AND BLINDING ............................................................................... 38 
7.1 
Patient Assignment ........................................................................................................ 38 
7.2 
Randomization Codes.................................................................................................... 39 
7.3 
Blinding ......................................................................................................................... 40 
7.4 
Maintenance of the Randomization Code List .............................................................. 40 
8. 
STATISTICAL METHODS ................................................................................................. 40 
8.1 
Sample Size ................................................................................................................... 40 
8.2 
Analysis Population ....................................................................................................... 41 
8.3 
Efficacy Endpoints ........................................................................................................ 42 
8.3.1 Primary Efficacy Endpoint ................................................................................. 42 
8.3.2 Secondary Efficacy Endpoints ............................................................................ 42 
8.3.3 Exploratory Endpoints ........................................................................................ 42 
8.4 
Efficacy Analysis and Statistical Models ...................................................................... 42 
8.5 
Safety Evaluation .......................................................................................................... 45 
8.6 
Handling of Missing data .............................................................................................. 46 
9. 
HANDALING ADVERSE EVENTS .................................................................................... 46 
9.1 
Definitions ..................................................................................................................... 46 
9.2 
Recording of Adverse Events ........................................................................................ 47 
9.3 
Reporting of Serious Adverse Events ............................................................................ 48 
9.4 
Patient Removal from Study due to Adverse Events..................................................... 48 
10. 
STUDY MEDICATION ........................................................................................................ 49 
10.1 Labelling and Packaging ............................................................................................... 49 
10.2 Dosage Regimen of Study Drug .................................................................................... 53 
10.3 Disposition of Study Drug ............................................................................................. 53 
11. 
ADMINISTRATIVE OBLIGATIONS ................................................................................ 53 
11.1 Source Data ................................................................................................................... 53 
11.2 Language ....................................................................................................................... 54 
11.3 Data Collection .............................................................................................................. 54 
11.4 Data Entry ..................................................................................................................... 54 

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11.5 Monitoring ..................................................................................................................... 55 
11.6 Study Documentation and Data Storage ........................................................................ 55 
11.7 Quality Control and Quality Assurance......................................................................... 56 
12. 
REFERENCES ....................................................................................................................... 57 
 
 

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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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CLINICAL STUDY PROTOCOL - OVERVIEW 
 
STUDY NUMBER 
CLI/016P 
 
 
STUDY TITLE 
The Efficacy and safety of Chlorhexidine 
Gluconate Chip (PerioChip®) in Therapy of Peri-
implantitis 
 
CLINICAL TRIAL PHASE 
Phase III 
 
 
 
 
 
SPONSOR 
Dexcel Pharma Technologies Ltd.  
 
1 Dexcel St., 
 
Or-Akiva, 3060000 
 
Israel 
 
 
DATE OF PROTOCOL 
02 August 2017 
 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
PROTOCOL SYNOPSIS 
1. Study Title: 
The Efficacy and Safety of Chlorhexidine Gluconate Chip (PerioChip®) in Therapy of Peri-implantitis. 
2. Study Design: 
Multicenter, randomized, single blind masking, parallel, two-arm clinical study.  
3. Study Objective: 
To assess the efficacy of Chlorhexidine gluconate chip (PerioChip®) versus Subgingival debridement 
in Peri-implantitis patients. 
 
4. Study Treatments: 
Treatment 1:  Subgingival debridement + Chlorhexidine Gluconate chip (PerioChip®) inserted every 
fortnight for the first 12 weeks  
Treatment 2:  Subgingival Debridement  
5. Number of Patients: 
A total of 290 patients in at least nine clinical sites will be randomized. At least 123 patients for the 
Subgingival debridement + PerioChip® arm, and at least 123 patients for Subgingival debridement 
alone arm will complete all required study visits, considering withdrawal rate estimation of between 
12%-15% 
6. Study Duration and Visits: 
The study duration will be 25-28 weeks (6 months) and will comprise a total of 10 visits: Screening 
and hygienic phase therapy (weeks -3 to -1), Baseline (week 0), week 2, week 4, week 6, week 8, week 
10, week 12, week 16 and week 24 (follow up visit).  
7. Target Pockets: 
For each patient at least one and not more than two stable implants, with pockets depth (PD) of 5-8 
mm in the implant/s (i.e. the target pockets), will be used for either Subgingival debridement + chips 
insertion or Subgingival debridement.  
The target pocket in the selected implant/s will be treated at each visit with the same treatment arm as 
described below, initiated at the Baseline visit. 
8. Dosage: 
Chlorhexidine Gluconate chip (PerioChip®) - The dosage of a single PerioChip® contains 2.5 mg 
Chlorhexidine Gluconate; The maximum dosage for each implant is 5 mg Chlorhexidine Gluconate 
[i.e. up to 2 PerioChips can be inserted to one implant] and 10 mg of Chlorhexidine Gluconate for 
each patient per visit. The total number of PerioChips that can be inserted to one patient in one given 
visit will not exceed 4 PerioChips. 
Subgingival Debridement – twice, in baseline visit (week 0) and in visit 8 (week 12). 
9. Study Criteria 
Inclusion Criteria:  
1. 
Signed and dated Informed Consent Form. 
2. 
Good general health. 
3. 
Male or female patients aged ≥18 years old. 
4. 
Availability for the 25 to 28 weeks duration of the study. 

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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
5. 
The patient has at least one implant in the oral cavity with clinical and radiographical signs of 
peri-implantitis. In the affected implant, at least one of the four aspects measured [mesio-buccal 
(MB), mid-buccal (MiB), disto-buccal (DB) and mid-lingual (MiL)] must show radiographic 
evidence of bone loss of at least 3 mm from implant shoulder, and at least 2 mm distal and mesial 
supporting bone left from the apex to the coronal direction, in combination with bleeding and/or 
suppuration on probing and a peri-implant Probing Depth (PD) of 5-8 mm. 
6. 
The implants have been in function for more than 2 years. 
7. 
Fixed prosthetic restoration of the implant. 
8. 
Females of childbearing potential must be non-pregnant and non-lactating at entry and agree to 
use an adequate method of birth control during the study. 
Exclusion Criteria:  
1. 
Patient uses Chlorhexidine oral rinses/ mouthwashes on a regular basis. 
2. 
History of allergic reaction to Chlorhexidine. 
3. 
Horizontal inter implant distance or tooth-implant of < 2 mm (if an adjacent implant exists). 
4. 
Active Periodontitis which required definitive treatment.  
5. 
Presence of oral local mechanical factors that could (in the opinion of the Investigator) influence 
the outcome of the study.   
6. 
Presence of orthodontic appliances, or any removable appliances, that impinges on the tissues 
being assessed. 
7. 
There is technical and/or other limitation to insert a chip and/or carry out debridement or permit 
appropriate probing. 
8. 
Presence of soft or hard tissue tumours of the oral cavity.   
9. 
Patients treated with systemic antibiotic therapy or periodontal/mechanical/local delivery therapy 
within 6 weeks prior to study entry and throughout the study duration.  
10. Patients chronically (i.e. two weeks or more) treated with non-steroidal anti-inflammatory drugs 
(NSAIDs)or any medications known to affect soft tissue condition (excluding treatment of 
Acetylsalicylic acid ≤ 100 mg/day). A comprehensive list can be found in the Patient information 
sheet – list of prohibited medications. 
11. Patients with any history of use of Medications known to cause Medication related osteonecrosis 
of the jaw:  Bisphosphonates, RANKL inhibitors, Antiangiogenic agents and m-TOR inhibitors 
administered Intravenously (IV), Intramuscularly (IM) or Subcutaneously (SC).  
Patients with  a history of a one year or more of Per-Os (PO) use of the medications known to 
cause Medication related osteonecrosis of the jaw  , with  last dose being under 3 months prior to 
the screening visit, and a CTX test value of < 150 ng/ml. 
12. Patients with uncontrolled diabetes, of any type, and/or patients with HbA1c test value >7.5% 
dated 3 months prior to the screening visit. 
13. Patients receiving radiation therapy to the head and neck area and/or receiving 
immunosuppressive therapy. 
14. The presence of any medical or psychiatric condition or any other condition that, in the opinion 
of the Investigator, could affect the successful participation of the patient in the study. 
15. Drug and alcohol abuse. 
16. Patient participates in any other clinical study 30 days prior to the start of the study and 
throughout the study duration. 

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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
10. Efficacy Endpoints: 
Primary Efficacy Endpoint: 
At week 24, compared to baseline, the mean probing Pocket Depth (PD) reductions (absolute change) 
for the selected target implant/s will be used as the primary efficacy endpoint.   
Secondary Efficacy Endpoints: 
 
PD measurement at week 24 compared to baseline in patients with baseline PD measurement of 
6-8 mm inclusive. 
 
Bleeding on Probing (BOP) measurements at week 16 and 24 compared to baseline. 
 
PD measurement at week 16 compared to baseline. 
Exploratory Endpoints: 
 
PD, BOP and Relative Attachment Levels (RAL) measurements at week 24 compare to baseline 
in Responders patients. Responders patients are those patients which demonstrated at week 24 
PD reduction of at least 1 mm from baseline PD of 5 mm or PD reduction of at least 2mm from 
baseline PD of 6-8mm inclusive.    
 
PD and BOP measurements at weeks 8 and 12 compared to baseline. 
 
Recession (R) and RAL measurements at weeks 8, 12, 16 and 24 compare to baseline. 
 
PD measurement at week 12 and 16 compared to week 24. 
 
PD, BOP, RAL and R measured at weeks 8, 12, 16 and 24 for all 4 sites (mesio-buccal, mid-
buccal, disto-buccal and mid-lingual), surrounding the selected target implant/s, compared to 
baseline. 
11. Statistical Methods: 
Sample Size: 
A total of up to 290 patients will be randomized. At least 123 patients for the Subgingival Debridement 
+ PerioChip® arm and 123 patients for the Subgingival Debridement alone arm to complete all required 
study visits Based on the current drop-out rate (after randomization) of 9%, the expected drop-out rate 
(after randomization) should be between 12%-15% 
Based on previous phase IIa studies, the expected drop-out rate in this study will be between 20%-
25%. Thus, it is estimated that approximately 375 patients will be screened in order to randomize up 
to 290 patients that complete all required study visits. 
The sample size is determined based on previous phase IIa study (CLI/013P) that demonstrated 
substantial improvement (trend toward significant, p = 0.07) in PD reduction between the PerioChip® 
and Placebo chip in therapy of Peri-implantitis. 
The rational for sample size calculated is based on detecting a difference of 0.50 mm in PD reduction 
from baseline between PerioChip® and Placebo chip, with 5% statistical significance and 85% power. 
A sample size of 123 in each group will have 85% power to detect a difference in means of -0.50 mm 
(the difference between a Group 1 mean, of -2.29 and a Group 2 mean, of -1.79) assuming that the 
common standard deviation is 1.30 using a two group t-test with a 0.05 two-sided significance level. 
Statistical significance level was set to 5% for all statistical analysis and comparisons. 
 
Study Population: 
Three populations will be defined for data analysis. 
1. Intent-to-treat (ITT) population – all patients randomized for one of the treatment arms and 

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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
treated with at least one chip of study treatment or underwent Subgingival debridement will be 
used for assessments related to efficacy and all safety evaluations.  
2. Modified-Intent-to-Treat (mITT) population – all patients in the ITT population with no major 
protocol violations, will be used to confirm the assessments related to efficacy.    
3. Per Protocol (PP) population - all patients in the ITT population who completed the study 
according to the protocol and with no major protocol violations. 
All measured variables and derived parameters will be listed individually and, if appropriate, tabulated 
by descriptive statistics. For categorical variables summary tables will be provided giving sample size, 
absolute and relative frequency and 95% C.I (Confidence Interval) for proportions by study arm. For 
continuous variables summary tables will be provided giving sample size, arithmetic mean, standard 
deviation, coefficient of variation (if appropriate), median, minimum and maximum, percentiles and 
95% C.I by study arm for means of variables.  
The change in efficacy parameters, PD, R and RAL during the 24 week treatment, will be modelled 
using a linear-mixed model (SAS® 9.2 Mixed Procedure) with treatment as fixed factors. Patient and 
pocket will be entered as random effects. The model will be adjusted for smoking status Gingival 
Index (GI) and medical center. Additional potential parameters suspected as influencing the outcome 
variable will be tested at 0.10 confidence level. Parameters that will achieve statistical significance 
≤10% will be added to the model as covariates. The adequacy of the Mixed Model will be checked 
and if needed a normalizing transformation will be performed. This model will be used for the 
reduction in PD, R and for improvement in RAL for the treated peri-implant pockets. 
Contrasts with 95% C.I for the difference or ratio between the changes will be computed. 
The Paired T-test or Signed rank test for two means (paired observations) (as is appropriate) will be 
applied for testing the statistical significance of the decrease in PD at each time point within each 
study group. 
The two-sample T-test or Non-parametric Wilcoxon-Mann-Whitney Rank sum test for independent 
samples (as is appropriate) will be applied for testing the statistical significance of the difference in 
the percent PD decrease from baseline between the study groups. 
Patients may have multiple pockets being treated. All treated pockets will be taken into account to 
create a by-pocket analysis in addition to the by-patient analysis. 
Corresponding 95% C.I for the difference between treatments not including zero for linear model, or 
95% C.I for the ratios between treatments not including unity for the log-linear regression will prove 
superior to treatment with PerioChip® versus Subgingival debridement.  
Analysis for the number of pockets with at least 1 mm reduction in PD, and analysis for BOP for the 
target implant/s measured at each visit will be analyzed by a Chi-square test or Fisher's exact test as is 
appropriate. 
Logistic regression will be applied for testing the above differences with adjustment to smoking status, 
GI, medical center and other suspected confounders, if found. Odds Ratio and 95% Confidence 
Interval will be calculated using the Logistic model.   
Similar mixed models for PD, R and RAL with time as a fixed repeated covariate will be used to reveal 
the changes of these parameters over time. 
A hierarchical model will be used for analyzing the secondary endpoints (refer to section 8.4). 
Analysis will be performed by Procedure Mixed SAS® 9.2, or a higher Edition 
12. Safety Evaluation 
Safety assessments will be based on Adverse Events (AEs) and oral inspections recorded at each visit.  
All AEs will be coded using coding dictionaries MedDRA version 16.0 or higher and will be 

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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
summarized by system organ class and preferred term. AEs will be described by seriousness, onset 
and resolution dates, duration, severity, pattern, action taken, relationship to the study drug and 
outcome.    
The primary safety evaluation of the PerioChip® will be performed by comparison to the Subgingival 
debridement. Specifically, the number of AEs reported for each treatment group will be compared to 
see if there is a treatment-related difference in the appearance of the following: 
1. 
Number of dental-related AEs, such as dental or gingival pain. 
2. 
Observed changes in the clinical appearance of the tissues at each of the oral inspections relative 
to baseline. 
The number of dental-related AEs reported and the time of first occurrence of dental-related events 
will be evaluated to assess if the event is associated with the chip insertion. In addition, all other 
reported AEs will be evaluated for any treatment related effects. 
Chi-square test or Fisher’s Exact test will be applied for testing the above differences between the 
groups. 
Oral inspections will evaluate any changes from baseline in the target implant/s that can be attributed 
to treatment.  
 
 
 

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ABBREVIATIONS 
AE 
Adverse Event 
BOP 
Bleeding on Probing 
RAL 
Relative Attachment Level 
CI 
Confidence Interval 
CRF 
Case Report Form 
DPT 
Dexcel Pharma Technologies 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethic Committee 
INN 
International Nonproprietary Name 
Mg 
Milligram 
mm 
Millimeters 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PD 
Probing Pocket Depth 
Pg 
Porphyromonasgingivalis 
R 
Recession 
SAE 
Serious Adverse Event 
SD 
Source Document 
SRP 
Scaling and Root Planning 
Td 
Treponema Denticola 
Tf 
Tannerella Forsythia 
UNC 
University of North Carolina 
MB 
MiB 
DB 
MiL 
Mesio-Buccal 
Mid-Buccal 
Disto-Buccal 
Mid-Lingual 
 
 
 

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STUDY SCHEDULE 
Evaluations/Activities 
Study Visits 
Visit        
1 
Visit       
2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit 
7 
Visit 
 8 
Visit 
 9 
Visit 
10 
Week -3* 
(Screening) 
Week 0 
(Baseline) 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
16 
Week 
24 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
Relevant Past Medical 
History and Concomitant 
Diseases 
X 
 
 
 
 
 
 
 
 
 
Periapical Dental 
Radiography  
X1 
 
 
 
 
 
 
 
 
 
Oral Inspection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pocket (Site) examination2 
X3 
X4 
 
 
 
X5 
 
X5 
X5 
X5 
Selection of Eligible 
Target Pockets (Sites) 
 
X 
 
 
 
 
 
 
 
 
Plaque and Gingival 
Indices 
 
X3 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X3 
Supragingival Scaling 
X 
 
 
 
 
 
 
X 
 
 
Supragingival plaque 
removal 
 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
Oral Hygiene Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Chip Insertion** 
 
X5 
X6 
X6 
X6 
X6 
X6 
X6 
 
 
Subgingival Debridement 
 
X 
 
 
 
 
 
X 
 
 
Pregnancy Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication history and 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
The allowances (windows) between the Screening visit and the Baseline visit should not exceed 14 ± 7 days.    
The allowances (windows): For visits 3, 4, 5, 6, 7 and 8 should not exceed 14 ±4 days from the previous visit. 
For visit 9 the allowance (window) should not exceed 28 ± 4 days from the previous visit. For visit 10 the 
allowance (windows) should not exceed 56 ± 10 days from the previous visit. 
* 
Hygienic Phase Therapy - subjected to screening oral examination and treatment need assessment  
**  Only for the subgingival debridement + PerioChip® treatment group (i.e. treatment group 1) 
                                                          
1  Periapical Dental Radiography evaluation dated within 1 (one) year prior the Screening visit 
2  In case chips are pop-out recurrently in visits 3, 4, 5 and 7 a pocket examination will be conducted by the 
designated examiner to verify PD ≥ 5 mm 
3  Full mouth inspection and recording  
4  Only on implant/s which had a periodontal pocket of 5-8 mm in depth at the Screening visit 
5 Only on target implant/s 
6  Chip/s will be inserted only in target implant/s which had previously received a chip  

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1. INTRODUCTION 
1.1 
Peri-implantitis  
Peri-implantitis is an inflammatory process caused by micro-organisms 
affecting the tissues around an osseointegrated implant in function, resulting in 
a loss of supporting bone (Albrektsson & Isidor, 1994). 
The above definition was consecutively reviewed and followed by Zitzmann 
and Berglundh (2008) and the Consensus of Lindhe and Meyle (2008) was: 
"Peri-implant Mucositis and Peri-implantitis are infectious diseases. In Peri-
implantitis the inflammatory lesion affect the supporting bone and there should 
be loss of the supporting marginal bone".    
Peri-implantitis may display some or all of the following symptoms; bleeding 
on probing (BOP), increased Probing Pocket Depth (PD), mobility, suppuration 
and pain. In peri-implantitis the bio-film in the peri-implant area is dominated 
by pathogens also found in Periodontitis lesions with high levels of spirochetes 
and Gram negative rods (Zitzmann & Berglundh, 2008). 
The treatment in peri-implants infections basically used the same intervention 
protocols as in Periodontitis treatment.  The aim in both diseases is maximum 
reduction of the subgingival bacterial load presenting the deepened and 
inflamed pockets.  In peri-implant infections a greater difficulty in mechanical 
treatment is experienced because of the often rough implant surfaces and the 
screw-like morphology of many implant systems (Renvert, Roos-Jansaker, & 
Claffey, 2008). 
1.2 
Chlorhexidine and Peri-implantitis  
Chlorhexidine is active against a broad spectrum of microbes. The 
Chlorhexidine molecule, due to its positive charge, reacts with the microbial 
cell surface, destroys the integrity of the cell membrane, penetrates into the cell, 
precipitates the cytoplasm, and the cell dies. Chlorhexidine gluconate is a 
synthetic antimicrobial drug that has been in use as a broad spectrum antiseptic 

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Clinical Protocol 
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in clinical dentistry for many decades (Heasman, Heasman , Stacey & 
McCracken, 2001; Fardall, & Turnbull, 1986). For several decades it is used in 
oral rinses in various concentrations ranging from 0.02% to 0.2% (Briner, 
Grossman, & Buckner, 1986). It is applied in dentifrices, gels, toothpaste gels 
and in carriers allowing sustained delivery of the drug.  
In several in vitro and in vivo studies it has been demonstrated that 
Chlorhexidine exerts a bactericidal as well as an anti-collagenolytic effect if 
administered locally in the periodontal pockets. Recent data from animal 
experiments even suggest a beneficial action inside the body (Houri-Haddad, 
Halabi, & Soskolne, 2008).  
Several in vitro investigations have demonstrated that Chlorhexidine is 
adsorbed to the oxide layer of titanium surfaces. Recent data indicate that the 
type of oxide may influence the amount of Chlorhexidine absorbed (Barbour, 
Gandhi, el-Turki, O'Sullivan, & Jagger, 2009; Morra, Cassinelli, Cascardo, 
Carpi, Fini, Giavaresi, et al. 2004). It has also been shown that the amount 
increases with greater surface roughness and correlates positively with the 
concentration of the Chlorhexidine solution. A desorption occurs within 24 
hours and inhibits bacterial growth (Kozlovsky, Artzi, Moses, Kamin-Belsky, 
& Greenstein, 2006).  
In peri-implantitis lesions, mechanical debridement in conjunction with the 
application of a 0.2% Chlorhexidine gel resulted in clinical improvement 
including significant reduction of BOP, pocket depth (PD) reduction and 
clinical attachment gain (Salvi, Persson, Heitz-Mayfield, Frei, & Lang, 2007). 
Data collected in case series and randomized controlled clinical trials pointed 
toward the benefits of an adjunctive local antimicrobial regimen (Minocycline 
spheres) as well as a disinfective treatment with 1% Chlorhexidine gel (Persson, 
Salvi, Heitz-Mayfield, & Lang, 2006;  Renvert, Lessem, Dahle'n, Lindahl, & 
Svensson, 2006; Salvi et al. 2007). The effect of local disinfection was less 
pronounced than the local administration of antibiotics (Renvert, Lessem, 
Lindahl, & Svensson, 2004; Renvert, et al. 2006; Renvert S., Roos-Jansaker, 

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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
Lindahl, Renvert, H., & Persson, 2007). Although it might have an effect, the 
adjunctive use of antibiotics (Minocycline microspheres) to mechanical 
debridement fell to be advantages over other adjunctive therapy method (Schär, 
Ramseier, Eick, Arweiler, Sculean, & Salvi, 2013).  
1.3  PerioChip®  
PerioChip® is a small rectangular chip (rounded at one end), orange-brown, 
rigid, thin film chip that is 4.8 mm in length, about 3.8 mm wide and about 350 
m thick. It contains 2.5 mg Chlorhexidine gluconate in a cross-linked gelatin 
matrix.  The PerioChip® biodegrades within the periodontal pocket, slowly 
releasing the Chlorhexidine gluconate directly into the gingival crevicular fluid. 
Following insertion of a PerioChip®, Chlorhexidine concentrations greater than 
100 µg/mL within the periodontal pocket are achieved for a week or longer. 
Sub-gingival bacteria have been demonstrated to be suppressed for up to 11 
weeks following PerioChip® insertion.  The bio-degradable matrix of the chip 
degrades over 7-10 days, eliminating the need for a second dental appointment 
for removal. 
Studies with PerioChip® showed reductions in the numbers of the putative 
periodontopathic 
organisms 
Porphyromonas 
(Bacteroides) 
gingivalis, 
Prevotella (Bacteroides) intermedia, Bacteroides forsythus, and Campylobacter 
rectus (Wolinella recta) after insertion of the chip. No overgrowth of 
opportunistic organisms or other adverse changes in the oral microbial 
ecosystem were noted.  
A recent placebo-controlled clinical study which compared PerioChip® and 
Placebo chip found greater reduction in the number of "red complex" 
(Specifically: Pg, Tf and Td) organisms and improved clinical attachment level 
following PerioChip®  insertion (Gonzales, Harnack, Schmitt-Corsitto, 
Boedeker, Chakraborty, Domann, et al. 2011). Moreover, Meyle, Ammoura, 
Hamid, Rolf-Hasso, Trinad, & Eugen (2005), found that even in the absence of 
mechanical treatment Chlorhexidine chip demonstrated significant reduction in 
periodontopathic organisms and improved clinical results. These results are in 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 17 
Protocol # CLI/016P –version 7  
 
line with former multi-center studies which demonstrated a clinical and 
microbiological advantage for using the PerioChip® in conjunction with 
scaling and root planning (SRP) (Paolantonio, D'Angelo, Grassi, Perinetti, 
Piccolomini, Pizzo, et al. 2008).  
Jeffcoat, Bray, Ciancio, Dentino, Fine, Gordon, et al. (1998) reported a mean 
probing depth reduction of 0.95 mm after 9 months in patients treated with SRP 
+ PerioChip® compared to 0.65 mm in patients treated only with SRP. All 
pockets measured 5.0 - 8.0 mm initially. Although a 0.95 mm reduction may 
seem to be of modest clinical significance, the percentage of patients 
experiencing a decrease of more than 2.0 mm was 30.3% for the SRP + 
PerioChip® group vs. 13.5% for the SRP-only group. A reduction of 2.0 mm or 
greater is generally considered clinically significant (see also Jeffcoat, Palcanis, 
Weatherford, Reese, Geurs, & Flashner, 2000). 
The use of PerioChip® as a treatment of peri-implant disease infection, e.g. Peri-
implantitis, was recently studied in a phase IIa multi-center, randomized, 
double-blind, parallel, two-arm placebo-controlled clinical trial. The results 
showed that controlled-release chlorhexidine delivery treatment in peri-
implantitis is effective and has high safety profile without any related SAE's 
and without worsening of peri-implantitis clinical symptoms (Machtei, 
Frankenthal, Levi, Elimelech, Shoshani, Rosenfeld, et. al. 2012).    
1.4  Study Rationale 
On the basis of the information on the effectiveness of Chlorhexidine and the 
local application of sustained delivery system with Chlorhexidine gluconate 
(PerioChip®) in periodontal disease and the very recent data from a phase IIa 
study (CLI/013P) in 60 patient with Peri-implantitis, it is reasonable to expect 
that use of PerioChip® will benefit the treatment of peri-implant infections for 
several reasons: 
1. PerioChip® has been proven clinically beneficial in the treatment of 
moderate periodontitis lesions and in a small population of peri-
implantitis patients.  Given these promising results with peri-implantitis 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 18 
Protocol # CLI/016P –version 7  
 
and similarity of Periodontitis to peri-implant lesions, there is no reason 
to assume that the system will not provide similar beneficial results in 
peri-implant mucositis and peri-implantitis. 
2. Local application of Chlorhexidine at the site of infection is a more 
rational approach than rinsing with Chlorhexidine, a measure that is 
often taken for this infection.  Local application will reduce unwanted 
side effects such as staining of the teeth, a side effect that can only be 
counteracted by a time-consuming polishing treatment of the teeth. 
3. Local application of Chlorhexidine can replace the systemic use of 
antibiotics, a treatment that is often provided in cases of peri-implantitis.  
Systemic antibiotic use has several disadvantages such as side effects, 
drug interactions and development of bacterial resistance.  
4. Local application of Chlorhexidine may reduce the need for surgical 
intervention in peri-implantitis, an approach which is far more costly 
that local treatment with an antiseptic drug.  
5. The risks of local application of Chlorhexidine have shown to be 
minimal in terms of medical complications.  Apart from occasionally 
reported complaints of discomfort, the side effects of the PerioChip® are 
minimal.  
6. The slow release of PerioChip® provides long-term maintenance of 
therapeutic levels of the drug without concerns for patient compliance.  
Based on the available scientific information reported in peer reviewed studies, 
one may expect beneficial clinical and microbiological effects of local 
application of a high concentration of Chlorhexidine provided in a sustained 
delivery system such as the PerioChip® in the control of peri-implant infections.  
There is a worldwide need of adjunct antiseptic devices in the control of peri-
implant mucositis and peri-implantitis.  There is a preference of local antiseptic 
treatment of these infections over the use of systemic antibiotics.  The 
PerioChip® therefore should be investigated in the anti-infective treatment of 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 19 
Protocol # CLI/016P –version 7  
 
peri-implant lesions as a valuable adjunct to mechanical anti-infection 
measures.  
2. OBJECTIVE 
The objective of this clinical study is to assess the efficacy and the safety of Chlorhexidine 
gluconate chip (PerioChip®) versus Subgingival debridement in Peri-implantitis patients. 
3. ETHICAL AND LEGAL CONSIDERATIONS  
This study will be conducted according to globally accepted standards of International 
Clinical Harmonization Good Clinical Practice (ICH-GCP), in agreement with the revision 
of the Declaration of Helsinki (2008) and in compliance with the protocol and all applicable 
laws, guidelines and regulations of the local laws. 
It is the responsibility of the Investigator that this study will not be initiated until the 
Protocol, Investigator Brochure, the Informed Consent Form, and any study related 
document have been reviewed and approved by a duly constituted Institutional Ethics 
Committee (IEC). 
It is the responsibility of the Investigator to ensure that each patient and/or legal 
representative reads, understands, signs and dates the Informed Consent Form.  
Where the patient in the study or his legal representative cannot read the Informed Consent 
Form, an independent witness must be present throughout the explanation about the nature 
of the clinical study. After the participant or legal representative thereof has expressed their 
oral consent to participate in the trial, the witness shall sign and date the consent form. 
It is the responsibility of the Investigator to inform the patient that while personal 
information may be examined during audit or monitoring by properly authorized persons, 
personal information will be treated as strictly confidential and will not be publicly 
available. 
All revisions and/or amendments to the protocol must be approved in advance and in 
writing by the Investigator, the Sponsor's representative, and the appropriate IEC.  
Indemnification of the Investigator, co-workers and the institution is provided as specified 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 20 
Protocol # CLI/016P –version 7  
 
in the clinical study agreement. 
4. STUDY DESIGN AND DURATION 
This study is a multi-center, randomized, single-blind masking, parallel, two-arm clinical 
study.        
The duration of patient follow-up will be 25-28 weeks (including Screening and hygienic 
phase visits), with interim visits at 0, 2, 4, 6, 8, 10, 12, 16 and 24 weeks.   
During the Baseline visit, eligible patients will be randomized to one of the following 
treatment regimens: 
Treatment 1 – Subgingival debridement + Chlorhexidine Gluconate chip (PerioChip®) 
inserted every fortnight, starting at baseline, for the first 12 weeks. 
Treatment 2 – Subgingival debridement.   
The reason for preferring the above design over the Double-blind, Placebo-controlled 
design is that in previous clinical studies with PerioChip® it was evident that when used 
Placebo chips have worse clinical outcome compare to No-chip. Namely, periodontal 
pockets treated with Placebo chips showed less improvement in PD and attachment levels 
compare to No-chip treated pockets. It was also noted that at six months following the use 
of Placebo chips fewer incidences of patients were considered to have healthy pockets. The 
results of these studies suggest, that placing of the Placebo chip acting as a mechanical 
barrier preventing environmental/outside improvement in the pockets (Perio Products-I; 
Perio products-II). Due to the above mentioned findings the use of Placebo treatment arm 
is less adequate. In this case excluding the Placebo arm from the study design ultimately 
prevents the establishment of Double-blind procedure.   
The above treatments will be applied for at least 1 (one) and not more than 2 (two) implants 
in the oral cavity with clinical and radiographical signs of peri-implantitis. Peri-implantitis 
is defined as marginal bone loss of at least 3 mm from implant shoulder, and at least 2 mm 
distal and mesial supporting bone left from the apex to the coronal direction, in 
combination with bleeding and/or suppuration on probing and a peri-implant Probing 
Depth (PD) of 5-8 mm.  

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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
All pocket measurements (PD, BOP and R) and chip insertions will be made in the same 
order of procedures every time.  
Calibrated examiners will perform all the measurements during the studyThe person 
(physician/hygienist) placing the Chlorhexidine chips in the periodontal pockets or 
performing the Subgingival debridement, according to the randomization, will not be 
involved in target pockets measurements (i.e. the examiner and the physician/hygienist 
placing the chip or performing the Subgingival debridement will be two different persons). 
The primary efficacy endpoint will be the mean probing Pocket Depth (PD) reductions 
(absolute change) at week 24 compared to baseline, for the selected target implant/s.   
For secondary endpoints the following will be used: 
 PD measurement at week 24 compared to baseline in patients with baseline PD 
measurement of 6-8 mm inclusive. 
 Bleeding on Probing (BOP) measurements at week 16 and 24 compared to baseline. 
 PD measurement at week 16 compared to baseline. 
For exploratory endpoints the following will be used: 
 PD, BOP and RAL measurements at week 24 compare to baseline in Responders 
patients. Responders patients are those patients which demonstrated at week 24 PD 
reduction of at least 1 mm from baseline PD of 5 mm or PD reduction of at least 2 
mm from baseline PD of 6-8 mm inclusive. 
 PD and BOP measurement at weeks 8 and 12 compared to baseline. 
 Recession (R) and Relative Attachment Levels (RAL) measurements at weeks 8, 12, 
16 and 24 compare to baseline. 
 PD measurement at week 12 and 16 compared to week 24. 
 PD, BOP, RAL and R measured at weeks 8, 12, 16 and 24 for all 4 sites (mesio-
buccal, mid-buccal , disto-buccal  and mid-lingual), surrounding the selected target 
implant/s, compared to baseline. 
 

CONFIDENTIAL  
 
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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
5. STUDY POPULATION 
5.1  Number of Patients 
A total of 290 patients, with symptoms of peri-implantitis, will be randomized 
At least 123 patients for the Subgingival debridement + PerioChip® arm, and at 
least 123 patients for Subgingival debridement alone arm will complete all 
required study visits, considering withdrawal rate estimation of between 12%-
15%. 
 
 
Based on previous phase IIa studies, the expected drop-out rate in this study 
will be between 20%-25%. Based on updated current study data the expected 
rate of patients that are randomized and later drop out will be between 12%-
15%. Thus, it is estimated that approximately 375 patients will be screened in 
order to randomize up to 290 patients, of which 246 patients will complete all 
required study visits. 
To be eligible for this study, patients must have at Screening and Baseline visits 
at least 1 (one) implant with a loss of marginal bone of at least 3 mm from 
implant shoulder, and at least 2 mm distal and mesial supporting bone left from 
the apex to the coronal direction in combination with bleeding and/or 
suppuration on probing and a peri-implant probing depth (PD) of 5-8 mm.   
5.2  Entry Criteria 
5.2.1 Inclusion Criteria 
Patients recruited to the study must conform to the following criteria: 
1. 
Signed and dated Informed Consent Form. 
2. 
Good general health. 
3. 
Male or female patients aged ≥18 years old. 
4. 
Availability for the 25 to 28 weeks duration of the study. 
5. 
The patient has at least one implant in the oral cavity with clinical 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 23 
Protocol # CLI/016P –version 7  
 
and radiographical signs of peri-implantitis. In the affected implant, 
at least one of the four aspect measured (mesio-buccal, mid-buccal, 
disto-buccal and mid-lingual) must show radiographic evidence of 
bone loss of at least 3 mm from implant shoulder, and at least 2 mm 
distal and mesial supporting bone left from the apex to the coronal 
direction, in combination with bleeding and/or suppuration on 
probing and a peri-implant Probing Depth (PD) of 5-8 mm. 
6. 
The implants have been in function for more than 2 years. 
7. 
Fixed prosthetic restoration of the implant. 
8. 
Females of childbearing potential must be non-pregnant and non-
lactating at entry and agree to use an adequate method of birth 
control during the study. 
5.2.2 Exclusion Criteria 
Patients cannot enter the study if any of the following criteria apply: 
1. 
Patient uses Chlorhexidine oral rinses/ mouthwashes on a regular 
basis. 
2. 
History of allergic reaction to Chlorhexidine. 
3. 
Horizontal inter implant distance or tooth-implant of<2 mm (if an 
adjacent implant exists). 
4. 
Active Periodontitis which required definitive treatment. 
5. 
Presence of oral local mechanical factors that could (in the opinion 
of the Investigator) influence the outcome of the study. 
6. 
Presence of orthodontic appliances, or any removable appliances, 
that impinges on the tissues being assessed. 
7. 
There is technical and/or other limitation to insert a chip and/or carry 
out debridement or permit appropriate probing. 
8. 
Presence of soft or hard tissue tumours of the oral cavity.   
9. 
Patients 
treated 
with 
systemic 
antibiotic 
therapy 
or 

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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 24 
Protocol # CLI/016P –version 7  
 
periodontal/mechanical/local delivery therapy within 6 weeks prior 
to study entry and throughout the study duration.  
10. Patients chronically (i.e. two weeks or more) treated with non-
steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
and/or 
any 
medications known to affect soft tissue condition (excluding 
treatment of Acetylsalicylic acid ≤ 100 mg/day). A comprehensive 
list can be found in the Patient information sheet – list of prohibited 
concomitant medications. 
11. Patients with any history of use of Medications known to cause 
medication related osteonecrosis of the jaw: Bisphosphonates, 
RANKL inhibitors, Antiangiogenic agents and m-TOR inhibitors 
administered 
Intravenously 
(IV), 
Intramusculary 
(IM) 
or 
Subcutaneously (SC);  
Patients with a history of a one year or more use of the medications 
known to cause medication related osteonecrosis of the jaw, with 
last dose being under 3 months prior to the screening visit and a 
CTX value of < 150 ng/ml. 
12. Patients with uncontrolled diabetes, of any type, and/or patients with 
HbA1c test value >7.5% dated 3 months prior to screening visit. 
13. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy.  
14. The presence of any medical or psychiatric condition or any other 
condition that, in the opinion of the Investigator, could affect the 
successful participation of the patient in the study. 
15. Drug and alcohol abuse. 
16. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
5.3 
Patient Discontinuation/ Withdrawal Criteria 
Patients are free to discontinue their participation in the study at any time, for 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 25 
Protocol # CLI/016P –version 7  
 
any reason, and without prejudice to further treatment.   
When a patient decides to discontinue participation in the study, he or she 
should always be contacted in order to obtain information about the reason(s) 
for discontinuation and any Adverse Events (AEs).  When possible, every effort 
should be made to return the patient to the clinic for last visit assessments at the 
time of discontinuation, or within 14 days. All AEs occurring during the study 
period must be recorded.  The clinical course of each event should be followed 
until resolution, stabilization or until it has been determined that study treatment 
or participation is not the cause.  Serious Adverse Events (SAEs) which are still 
on-going at the end of the study period must be followed up to determine the 
final outcome. 
Patients may be dropped from the study if any of the following situations or 
protocol violations occurs: 
 Patient who was inappropriately enrolled.  
 Patient substantially fails to comply with the study schedule, or treatment 
program as described in this Protocol. 
 Patient uses prohibited concomitant medication, as detailed in this Protocol.  
 Patient receives emergency dental treatment which may interfere with the 
assessment of study endpoints. 
 Patient becomes pregnant. 
 Patient skips 2 or more sequential visits or 3 or more non sequential visits.  
 Patient skips one of the mandatory visits: screening (visit 1), baseline (visit 
2) or week 24 follow-up (visit 10). 
 Patient experiences an intolerable toxicity or change in medical condition 
which constitutes an undue risk to the patient or which would invalidate 
study observations. 
 Patient voluntarily withdraws. 

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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 26 
Protocol # CLI/016P –version 7  
 
In the event of the above mentioned protocol violations, the patient will undergo 
Week 24 (Last Visit/Early Withdrawal) assessments.  
5.4 
Concomitant Medication Treatment   
Patients will be assessed at Screening, Baseline, weeks: 2, 4, 6, 8, 10, 12, 16 
and 24 for concomitant medications (prescriptions and over-the-counter, 
including vitamins and natural food supplements). All concomitant medications 
and procedures received by the patient within 6 weeks of screening and during 
the study should be recorded in the Source Documents (SDs) and on the 
patient’s Case Report Form (CRF).  The generic name of the medication (active 
ingredient or the International Nonproprietary Name - INN) or name of the 
procedure, the indication, dose, frequency, route and the duration of use should 
be included.  
Concomitant medications will be coded using the World Health Organization 
(WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. 
Patients will be instructed to refrain from: 
 Any use of Chlorhexidine oral rinses/mouthwashes during the study.  
 Any dental treatment (including visit to dental hygienist) without consulting 
the Investigator in advance. 
 Any use of toothpicks and/or floss around the treated implant/s in the 24 
hours following the chip insertion and advised to use such interproximal 
cleaning devices only to negotiate food impaction for the following 6 days. 
 Any use of antibiotics and any chronically (i.e. two weeks or more) use of 
NSAIDs during the study which could possibly affect the periodontal 
inflammatory or healing process.  
 Any use of radiation therapy to the head and neck area and/or any 
immunosuppressive therapy or any use of medication know to affect soft 
tissue condition and which might influence the pattern of tissue response.  
There is no food restriction during the study.  

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
6. STUDY PLAN 
In each patient meeting the entrance criteria, the deepest periodontal pocket of at least 1 
(one) and no more than 2 (two) implant/s (if available) will be selected as a target pocket, 
and will be used for chip/s insertion or Subgingival Debridement and as the primary 
efficacy end-point. 
The target pocket in the selected implant/s, will be treated at each visit with the same 
treatment arm, initiated at Baseline visit, as described below. 
Implant/s which were not selected as target implant/s will be treated as per the investigators 
discretion as long as it does not affect the study inclusion/exclusion criteria (e.g. treatment 
with antibiotics or surgery next to a target implant included in the study). 
Treatment 1: (PerioChip®) 
Subgingival debridement will be carried out for each one of the target implant which its 
probing pockets depth (PD of 5-8 mm) were selected as target pockets (the Subgingival 
debridement procedure will be employed twice: at baseline (visit 2) and after 3 months, at 
visit 8).  
Upon completion of the debridement a PerioChip® will be inserted in each one of the target 
implant. 
PerioChip® contains 2.5 mg Chlorhexidine Gluconate formulated in a biodegradable cross 
linked gelatine matrix. The maximum dosage for each implant is 5 mg Chlorhexidine 
Gluconate (i.e. up to 2 PerioChips can be inserted to one implant) and 10 mg of 
Chlorhexidine Gluconate for each patient per visit. The total number of PerioChips that 
can be inserted to one patient in one given visit will not exceed 4 PerioChips.  
The number of chips inserted to one implant will be a function of the pocket width. In case 
2 chips are used in one implant, the insertion will be to the target pocket and the implant 
surface which is not adjacent to the target pocket (i.e. Buccal - Lingual or Mesial - Distal).  
The insertion place should be recorded in the Source Document. All subsequent insertion 
must be repeated to the exact place chosen in the first insertion procedure. 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 28 
Protocol # CLI/016P –version 7  
 
Treatment 2: (Subgingival Debridement) 
Subgingival Debridement will be carried out for each one of the target implant which its 
probing pockets depth (PD of 5-8 mm) were selected as target pockets.  
The Subgingival debridement procedure will be employ twice: at baseline (visit 2) and 
after 3 months, at visit 8. 

CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
6.1 
Study Schedule  
Evaluations/Activities 
Study Visits 
Visit        
1 
Visit       
2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit 
7 
Visit 
 8 
Visit 
 9 
Visit 
10 
Week -3* 
(Screening) 
Week 0 
(Baseline) 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
16 
Week 
24 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
Relevant Past Medical 
History and Concomitant 
Diseases 
X 
 
 
 
 
 
 
 
 
 
Periapical Dental 
Radiography  
X1 
 
 
 
 
 
 
 
 
 
Oral Inspection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pocket (Site) examination2 
X3 
X4 
 
 
 
X5 
 
X5 
X5 
X5 
Selection of Eligible 
Target Pockets (Sites) 
 
X 
 
 
 
 
 
 
 
 
Plaque and Gingival 
Indices 
 
X3 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X3 
Supragingival Scaling 
X 
 
 
 
 
 
 
X 
 
 
Supragingival plaque 
removal 
 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
Oral Hygiene Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Chip Insertion** 
 
X5 
X5 
X6 
X6 
X6 
X6 
X6 
 
 
Subgingival Debridement 
 
X 
 
 
 
 
 
X 
 
 
Pregnancy Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication history and 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
The allowances (windows) between the Screening visit and the Baseline visit should not exceed 14 ± 7 days.    
The allowances (windows): For visits 3, 4, 5, 6, 7 and 8 should not exceed 14 ±4 days from the previous visit. 
For visit 9 the allowance (window) should not exceed 28 ± 4 days from the previous visit. For visit 10 the 
allowance (windows) should not exceed 56 ± 10 days from the previous visit. 
* 
Hygienic Phase Therapy - subjected to screening oral examination and treatment need assessment  
**  Only for the subgingival debridement + PerioChip® treatment group (i.e. treatment group 1)
                                                          
1  Periapical Dental Radiography evaluation dated within 1 (one) year prior the Screening visit 
2  In case chips are pop-out recurrently in visits 3, 4, 5 and 7 a pocket examination will be conducted by the 
designated examiner to verify PD ≥ 5 mm 
3  Full mouth inspection and recording  
4  Only on implant/s which had a periodontal pocket of 5-8 mm in depth at the Screening visit 
5  Only on target implant/s 
6  Chip/s will be inserted only in target implant/s which had previously received a chip  

CONFIDENTIAL  
 
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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
6.2  Study Procedures by Visit 
 
6.2.1 Screening Visit and Hygienic Phase Therapy (Weeks (-3 to -1)) 
At the Screening visit (Weeks (-3 to -1)), patients will come to the 
clinical facility for screening by the examining Principal Investigator or 
delegated physician to identify those patients who meet the entrance 
criteria (inclusion/exclusion criteria). Prior to any study activities, 
patients will be asked to read an Informed Consent Form that has been 
approved previously by the IEC. Patients will be given adequate time to 
consider any information concerning the study and the opportunity to 
ask the Investigator any questions regarding potential risks and benefits 
of participation in the study.  
Written and personally signed and dated Informed Consent Form must 
be obtained from the patient prior to the patient entering the study.  The 
consenting physician must also sign and date the consent form. A copy 
of the Informed Consent Form will be given to the patient. 
Other assessments at this visit will include: 
Demographic data (including date of birth, sex, weight, height, race, and 
tobacco use history), review of the inclusion and exclusion criteria, 
relevant past medical history and concomitant diseases, pregnancy 
assessment (will be done by questioning the patient regarding 
pregnancy), concomitant medication, periapical radiographic evaluation 
dated within 1 (one) year prior the Screening visit, oral inflammation 
and infection inspection and treatment need assessment.  
In addition, number of natural teeth, implants and over all dental 
condition will be recorded and a full mouth (implant and natural teeth) 
periodontal pocket examinations, PD, R, and BOP, will be carried out 
and recorded.  
 
6.2.1.1 Hygienic Phase Therapy 
The period between screening visit and baseline visit which 

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patient, eligible to participate in the study, may undergo 
subjected to the Principal Investigator (PI) or delegated 
physician oral inspection. The hygienic phase period will be 
design to complete within the allowance window of 14 ± 7 days 
and at least 3 days prior to baseline visit. 
6.2.1.2 Probing Pocket Depth (PD) 
PD is the measurement of the distance from the coronal edge of 
the gingival margin to the base of the pocket. PD will be 
measured at four sites per implant: mesio-buccal , mid-buccal, 
disto-buccal and mid-lingual. Measurements will be taken with 
a standard 15-mm University of North Carolina (UNC) 
periodontal probe. For recording pocket depth, the probe tip will 
be placed at the bottom of the pocket and the pocket depth will 
be read directly from the millimetres markings on the probe.  
6.2.1.3 Recession (R) 
Recession is defined as the distance in millimetres that the free 
gingival margin has migrated apically from the gingival margin 
of the coronal line of the crown at the same site that PD was 
measured using a standard 15-mm UNC periodontal probe. If 
the reference point is other than the coronal line of the crown it 
should be exactly defined in the source document. 
6.2.1.4 Relative Attachment Level (RAL) 
Loss of attachment is defined as the distance in millimetres that   
the base of the pocket has migrated apically from the gingival 
margin of the coronal line crown. RAL will be calculated at the 
same site mentioned above, by adding the R measurement to the 
PD measurement. The RAL calculation will be performed by the 
Study Statistician. 

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6.2.1.5 Bleeding on Probing (BOP) 
BOP will be measured at the same site immediately after 
measuring the PD. The scoring system used for recording the 
BOP is a dichotomous one:  
 
 
0 = No bleeding 
 
 
1 = BOP at the base of the pocket 
 
Patients who qualify for the initial examination will be required to have: 
 At least 1 (one) implant in the oral cavity with clinical and 
radiographical signs of peri-implantitis. Peri-implantitis is defined as 
marginal bone loss of at least 3 mm from implant shoulder, in 
combination with bleeding and/or suppuration on probing and a peri-
implant Probing Depth (PD) of 5-8 mm. 
 The implants have been exposed to the oral environment for more than 
2 years. 
 At least 2 mm distal and mesial supporting bone left from the apex to 
the coronal direction. 
The qualified patient will undergo Supragingival scaling for all the teeth and 
implants (if not done up to 6 weeks prior the Screening visit) and in addition 
the patients will be provided with toothpaste and tooth brushes by the 
Investigator or designee for exclusive use during the course of the study. The 
Investigator or designee will give full instructions to the patient regarding the 
importance of good hygiene of the mouth. Patients will be restricted from any 
use of Chlorhexidine oral rinses/mouthwashes during the study. 
The period between Screening visit and Baseline visit should not exceed 14 ± 
7 days. 
6.2.2  Baseline Visit (Week 0) 
At Baseline visit (Week 0), patients will return to the clinic for the 
following procedures: 

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 Review of inclusion/exclusion criteria (the potential target implant/s 
from the Screening visit will be used for the inclusion criteria review 
at Baseline). 
 Oral inspection.  
 Pocket examination and measurements (i.e. PD, R and BOP) for all 
potential target implant/s (only on implant/s which had a periodontal 
pocket of 5-8 mm in depth at the Screening visit). 
 Target pockets selection - All potential target implant/s from 
Screening visit will be re-assessed as follows: 
1. In cases where no more than 2 (two) potential target implants are 
present, the deepest periodontal pocket of each implant/s (out of 
the 4 sites per implant that were measured) will be selected as a 
target pocket. 
2. In case of presence of 3 (three) or more potential target pockets, 
in three or more different implants in one side of the jaw (upper 
or lower jaw) that are identical in depth, the two deepest  pockets 
in the two implants that are furthest away from each other will be 
selected.  
3. In case of presence of 3 (three) or more potential target pockets in 
three different implants or more, that are identical in depth in both 
jaws (upper and lower jaws), the deepest potential target pocket 
from the upper and the lower jaw will be selected.  
4. In case of presence of 3 (three) or more potential target pockets in 
three implants or more, that are identical in depth in one or both 
jaws and equally distance one of the other, the following selection 
criteria should be taken by order of priority: 
 a) The deepest pocket; 
 b) Implant located between natural teeth or in edentulous ridge; 

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c) The implant with the easiest and or best accessibility;  
The selected target pocket/s must demonstrate BOP. 
 Full mouth Plaque and Gingival bleeding inspections and recording.  
 Supragingival plaque removal - only on target implant/s.  
 Subgingival debridement will be carried out for all the chosen target 
implant/s, regardless of the study arm randomization. The Subgingival 
debridement is the removal of all local irritants from the periodontal 
pockets and implant surface including the inflammatory tissue. The 
procedure will be carried out using metal based curettes and possibly 
ultrasonic management and/or irrigation with Saline .("blasting" 
cleaning is prohibited). 
 Randomization into one of the treatment arms, i.e. the Subgingival 
debridement + PerioChip® therapy group or the Subgingival 
debridement therapy only group. The randomization will be done 
according to a predetermined computer-generated randomization by 
block table. 
 PerioChip® insertion - Chip/s will be inserted only into the chosen 
target implant/s in the patients randomize to the Subgingival 
debridement + PerioChip® therapy group. Up to 2 chips will be 
inserted for each implant's site which pocket depth is 5-8. 
 
In case 2 chips are used in one implant the insertion will be to the 
target pocket and the implant surface which is not adjacent to the 
target pocket (i.e. Buccal- Lingual or Mesial- Distal). The insertion 
place should be recorded in the Source Document. All subsequent 
insertion must be repeated to the exact place chosen in the first 
insertion procedure. 
 Safety assessment including AEs, pregnancy assessment by 
questioning the patient (where applicable), recording of concomitant 
medications changes and dental treatment.  

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 Oral Hygiene instructions - The Investigator or designee will remind 
the patient of the importance of good hygiene of the mouth (if 
necessary) and of the restriction of use of Chlorhexidine oral 
rinses/mouthwashes. In addition the patient will be instructed to 
refrain from use of toothpicks and/ or floss at least for the 24 hours 
following the chip insertion, and advised to use such interproximal 
cleaning devices only to negotiate food impaction  for the following 
6 days. 
 Patients will be instructed to notify the Investigator if they feel that 
the chip has been dislodged.  
 The period between Baseline visit and Visit 3 should not exceed 14 
± 4 days 
6.2.2.1 Gingival Index (GI) 
Gingival inflammation is assessed using a modification of Löe Silness 
Gingival Index (GI) as described by Löe (1967), 4 sites per tooth/ implant 
will be assessed as follows: 
0 = No bleeding;  1 = BOP spontaneous or on probing pressure 
6.2.2.2 Plaque Index (PI) 
Plaque is assessed using a modification of O'Leary plaque control record 
as described by O'Leary, et.al. (1972). For each of the 4 sites per tooth/ 
implant a +/- marked is assign. The (-) sign indicating accumulation of 
plaque and the (+) sign indicating "No plaque". The percent of (-) signs 
from the total number of sites is computed. 
6.2.3 Visits 3, 4, 5, 6, 7 and 8 (Weeks 2, 4, 6, 8, 10 and 12)  
At weeks 2, 4, 6, 8, 10 and 12, the patients will return to the clinic for 
the following procedures: 
 Safety assessment including AEs, pregnancy assessment by 
questioning the patient (where applicable), recording of concomitant 

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medications changes and dental treatment.  
 Oral inspection. 
 Supragingival Scaling (at week 12 (Visit 8) only). 
 Supragingival plaque removal - only on target implant/s.   
 Pocket examination and measurements (i.e. PD, R and BOP) only for 
the target implant/s (only at weeks: 8 and 12 (visits 6 and 8)). 
 Gingival and Plaque inspection for the target implant/s. 
 Subgingival debridement will be carried out for all the chosen target 
implant/s, regardless of the study arm randomization, (at week 12 
(Visit 8) only).   
 PerioChip® insertion –  
o Chip/s insertion only in those target pockets which had 
previously received a chip. 
o For visits 6 and 8, chip insertion will follow pocket depth 
verification of ≥ 5 mm as measured during the visit. 
o For visits 3, 4, 5 and 7, in case chips pop-out recurrently in 
a pocket examination will be conducted by the designated 
examiner to verify PD ≥ 5 mm. The examiner will then 
declare "please try to insert again" if PD≥ 5 mm or "do not 
proceed with the insertion".   
 Oral Hygiene instructions - The Investigator or designee will remind 
the patient of the importance of good hygiene of the mouth (if 
necessary), and to refrain from use of Chlorhexidine oral 
rinses/mouthwashes. In addition the patient will be instructed to 
refrain from use of toothpicks and/ or floss at least for the 24 hours 
following the chip insertion and advised to use such interproximal 
cleaning devices only to negotiate food impaction  for the following 6 
days.Patients will be instructed to notify the Investigator if they feel 

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that the chip has been dislodged. 
In cases where the target pocket depths increased by more than 2 mm the 
patient will be withdrawn from the study. 
The allowed window for visits 3, 4, 5, 6, 7 and 8 should not exceed 14 
± 4 days from the previous visit. 
6.2.4 Visits 9 (Week 16) 
At week 16, the patients will return to the clinic for the following 
procedures: 
 Safety assessment including AEs, pregnancy assessment by 
questioning the patient (where applicable), recording of concomitant 
medications changes and dental treatment 
 Oral inspection. 
 Pocket examination and measurements (i.e. PD, R and BOP) only for 
the target implant/s 
 Gingival and Plaque inspection for the target implant/s 
 Oral Hygiene instructions - The Investigator or designee will remind 
the patient of the importance of good hygiene of the mouth (if 
necessary), and to refrain from use of Chlorhexidine oral 
rinses/mouthwashes. 
 The allowed window for visit 9 should not exceed 28 ± 4 days from 
the previous visit 
6.2.5 Last Visit/ Early Withdrawal Visit (Week 24) 
At Last Visit/ Early Withdrawal Visit (week 24), the patients will return 
to the clinic for the following procedures:  
 Safety assessment including AEs, pregnancy assessment by 
questioning the patient (where applicable), recording of concomitant 
medications changes and dental treatment.  

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 Oral inspection. 
 Full mouth Plaque and Gingival inspection and recording. 
 Pocket examination and measurements (i.e. PD, R and BOP) for the 
target implant/s only. 
 Oral Hygiene instructions - The Investigator or designee will remind 
the patient of the importance of good hygiene of the mouth.  
The allowed window for visit 10 is 56 ± 10 days from the previous visit. 
6.3 
Other Study Considerations 
6.3.1 Calibration of Examiners 
PD and R measurement procedures will be standardized between 
investigators within each medical centre prior to study initiation, 
consistent with Good Clinical Practice (GCP).  
6.3.2 Dental Treatment during Study 
If extensive crown and bridge work is planned, the Investigator should 
be notified to make sure that no periodontal landmark measurements are 
affected.  
6.3.3 Post-study Periodontal Therapy 
Upon completion of the study, patients requiring traditional methods of 
periodontal therapy will be referred for appropriate treatment. 
7. RANDOMIZATION AND BLINDING 
7.1 
Patient Assignment  
The patients accepted for the screening visit will be assigned Screening Number 
XXX, where XXX is a number beginning from 001. For each patient, the 
Investigator will add the relevant Screening Number to the labels of the 
assigned medication. 
In addition each medical center will have a site ID which will be used as an aid 

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in differentiating between patient screening numbers. 
7.2  Randomization Codes 
Eligible patients at Baseline visit will be assigned a randomization number. The 
order will start from: 101 
Each randomization number will be randomly assigned to one of the two letters 
A or B; each letter will be assigned randomly to one of the two treatments 
Subgingival debridement + PerioChip® or Subgingival debridement alone. 
The randomization will be generated using a computerized algorithm of random 
numbers by the data management Statistician using the SAS® program, prior to 
the study start.  
The randomization will be performed with stratification to smoking habits and 
Baseline PD measurement in balanced blocks, each block containing 6 subjects 
(3 per treatment Subgingival debridement + PerioChip® and 3 per treatment 
Subgingival debridement alone). Randomization blocks will be sent to the sites 
by the study data management Statistician. Each site will receive 4 types of lists 
by the defined stratification (smokers with PD 5 mm, smokers with PD 6-8 mm, 
non-smokers with PD 5 mm and non-smokers with PD 6-8 mm). Additional 
blocks will be provided to the sites according to the recruitment rate.  
One hundred and twenty three (123) chip packages, each containing 60 chips 
for one patient will be prepared for the Subgingival debridement + PerioChip® 
treatment.  
7.3  Blinding 
At the Baseline visit the patient will start receiving one of the two treatments 
(Subgingival debridement followed by insertion of PerioChip® or Subgingival 
debridement alone), since only the examiner who conducts the measurements 
is blinded to the study treatments the masking is considered "single blinding". 
In order to maintain the study blinding condition, in each visit prior to 
evaluation, the examiner will instruct the patients to refrain of bringing up 

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whether they did or did not received a PerioChip® in the previous visits. 
One set of sealed envelopes will be provided to the Investigator containing 
individual randomization codes and will be kept at the investigational site.  
7.4  Maintenance of the Randomization Code List 
The master randomization list will be kept with the Sponsor and with the study 
data management Statistician.  
8. STATISTICAL METHODS 
 
8.1 
Sample Size 
A total of up to 290 patients will be randomized, in order to analyse at least 123 
patients in the Subgingival debridement + PerioChip® arm and at least 123 
patients in the Subgingival debridement alone arm, considering expected 
patient drop-out rate estimation of between 12%-15% 
Based on previous phase IIa studies, the expected drop-out rate in this study 
will be between 20%-25%. Thus, it is estimated that approximately 375 patients 
will be screened in order to randomize  up to 290 patients, of which 246 patients 
will complete all required study visits.The sample size is determined based on 
relevant literature (Machtei et al. 2012) and previous phase IIa study 
(CLI/013P) in peri-implantitis patients that demonstrated substantial 
improvement (trend toward significant, p = 0.07) in PD reduction between 
PerioChip® and Placebo chip.  
The rational for sample size calculated is based on detecting a difference of 0.50 
mm in PD reduction from baseline between PerioChip® and Placebo chip, with 
5% statistical significance and 85% power. 
A sample size of 123 in each group will have 85% power to detect a difference 
in means of -0.50 mm (the difference between a Group 1 mean, of -2.29 and a 
Group 2 mean, of -1.79) assuming that the common standard deviation is 1.30 
using a two group t-test with a 0.05 two-sided significance level. 

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Statistical significance level for all statistical analysis was set to 5%. 
It is worth noting that although parameters used in the above calculation are 
derived from a placebo-controlled design, it is reasonable to assume this 
calculation is more conservative than if the parameter used were taken from 
previous studies where the study design included a treatment arm with no chip 
assigned, in Periodontitis patients. 
In other words, the sample size calculation is based on sound data derived from 
a study design which used the same indication (peri-implantitis) and treatment 
regimen (frequent chip insertion) as appear in the current protocol.   
8.2 
Analysis Population 
Three study populations will be defined for data analysis: 
1. Intent-to-treat (ITT) population – all patients randomized for one of the 
treatment arms and treated with at least one chip of study treatment or 
underwent Subgingival debridement will be used for assessments related to 
efficacy and all safety evaluations.  
2. Modified-Intention-to-Treat (mITT) population – all patients in the ITT 
population with no major protocol violations, used to confirm the 
assessments related to efficacy. 
3. Per Protocol (PP) population – all patients in the ITT population who 
completed the study according to the protocol and with no major protocol 
violations.    
8.3 
Efficacy Endpoints 
8.3.1  Primary Efficacy Endpoint  
At week 24, compared to baseline, the mean probing Pocket Depth (PD) 
reductions (absolute change) for the selected target implant/s will be 
used as the primary efficacy endpoint.   
8.3.2 Secondary Efficacy Endpoints 
 PD measurement at week 24 compared to baseline in patients with 

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baseline PD measurement of 6-8 mm inclusive. 
 Bleeding on Probing (BOP) measurements at week 16 and 24 
compared to baseline. 
 PD measurement at week 16 compared to baseline. 
8.3.3  Exploratory Endpoints 
 PD, BOP and RAL measurements at week 24 compare to baseline in 
Responders patients. Responders patients are those patients which 
demonstrated at week 24 PD reduction of at least 1 mm from baseline 
PD of 5 mm or PD reduction of at least 2 mm from baseline PD of 6-
8 mm inclusive. 
 PD and BOP measurements at weeks 8 and 12 compared to baseline. 
 Recession (R) and Relative Attachment Levels (RAL) measurements 
at weeks 8, 12, 16 and 24 compare to baseline. 
 PD measurement at week 12 and 16 compared to week 24. 
 PD, BOP, RAL and R measured at weeks 8, 12, 16 and 24 for all 4 
sites (mesio-buccal, mid-buccal, disto-buccal and mid-lingual), 
surrounding the selected target implant/s, compared to baseline. 
8.4 
Efficacy Analysis and Statistical Models 
All statistical analysis and consideration will be conducted in respect to a 
detailed Statistical Analysis Plan (SAP).  
All measured variables and derived parameters will be listed individually and, 
if appropriate, tabulated by descriptive statistics.  
For categorical variables summary tables will be provided giving sample size, 
absolute and relative frequency and 95% C.I. (Confidence Interval) for 
proportions by study arm. 
For continuous variables summary tables will be provided giving sample size, 
arithmetic mean, standard deviation, coefficient of variation (if appropriate), 
median, minimum and maximum, percentiles and 95% C.I. (Confidence 
Interval) by study arm for means of variables. 

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The change in efficacy parameters, PD, R and RAL during the 24 week 
treatment, will be modelled using a linear-mixed model (SAS® 9.2 Mixed 
Procedure) with treatment as fixed factors. Patient and pocket will be entered 
as random effects. The treatment-by-center interaction will be tested and if 
achieve statistical significance of ≤5% will be added to the model as covariate.  
The analysis will be adjusted to the following covariates known to have 
influence on the efficacy parameters: age, gender, smoking status and baseline 
measurements. The adequacy of the Mixed Model will be checked and if needed 
a normalizing transformation will be performed. This model will be used for 
the reduction in PD, R and for improvement in RAL.  
Contrasts with 95% C.I. for the difference or ratio between the changes will be 
computed. 
The Paired T-test or Signed rank test for two means (paired observations) (as is 
appropriate) will be applied for testing the statistical significance of the 
decrease in PD at each time point within each study group. 
The two-sample T-test or Non-parametric Wilcoxon-Mann-Whitney Rank sum 
test for independent samples (as is appropriate) will be applied for testing the 
statistical significance of the difference in the percent PD decrease from 
baseline between the study groups. 
Patients may have multiple pockets being treated. All treated pockets will be 
taken into account to create a by-pocket analysis in addition to the by-patient 
analysis. 
Corresponding 95% C.I. for the difference between treatments not including 
zero for linear model, or 95% C.I. for the ratios between treatments not 
including unity for the log-linear regression will prove superior to treatment 
with PerioChip® versus Subgingival debridement.  
Analysis for the number of pockets with at least 1 mm and at least 2 mm 
reduction in PD, and analysis for BOP for the target implant/s measured at each 
visit will be analyzed by a Chi-square test or Fisher's exact test as is appropriate. 

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Logistic regression will be applied for testing the above differences with 
adjustment to smoking status, GI, medical center and other suspected 
confounders, if found. Odds Ratio and 95% Confidence Interval will be 
calculated using the Logistic model. 
Similar mixed models for PD, R and RAL with time as a fixed repeated 
covariate will be used to reveal the changes of these parameters over time. 
A hierarchical model will be used for analysing the secondary endpoints. 
The secondary endpoints will be analysed according to pre-defined order: 
1. PD changes at 24 weeks from baseline in patients with baseline PD of 6-8 
mm inclusive. 
2. BOP changes at 24 weeks from baseline 
3. BOP changes at 16 weeks from baseline 
4. PD changes at 16 weeks from baseline 
The following stages will be applied: 
1. The 1st secondary endpoint in the ordered list will be tested at 5% 
significance level. If it achieves statistical significance then the 2nd 
secondary endpoint will be analysed (stage 2). Otherwise the other 
secondary endpoints in the list will not formally be tested.  
2. The 2nd secondary endpoint in the ordered list will be tested at 5% 
significance level. If it achieves statistical significance then the 3rd 
secondary endpoint will be analysed (stage 3). Otherwise the other 
secondary endpoints in the list will not formally be tested.  
3. The process will continue for all the secondary endpoints according to the 
list until a secondary endpoint is not significant or until all secondary 
endpoints have been found significant.  
All treatment comparison will be two-sided at the 0.05 level of significance. 
The primary time-point for all analyses will be at 24 weeks. 
The data will be analyzed using the SAS® version 9.2 (SAS Institute, Cary 

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North Carolina) or higher version. 
 
8.5 
Safety Evaluation 
Safety assessment will be based on AEs and oral inspections recorded at each 
visit.  
All AEs will be coded using coding dictionaries MedDRA version 16.0 or 
higher and will be summarized by system organ class and preferred term. AEs 
will be described by seriousness, onset and resolution dates, duration, severity, 
pattern, action taken, relationship to the study drug and outcome.    
The primary safety evaluation of the PerioChip® will be performed by 
comparison to the Subgingival debridement treatment. Specifically, the number 
of AEs reported for each treatment group will be compared to see if there is a 
treatment-related difference in the appearance of the following: 
1. Number of dental-related AEs, such as dental or gingival pain. 
2. Observed changes in the clinical appearance of the tissues at each of the oral 
inspections relative to baseline. 
The number of dental-related AEs reported and the time of first occurrence of 
dental-related events will be evaluated to assess if the event is associated with 
the chip insertion. In addition, all other reported AEs will be evaluated for any 
treatment related effects. To clarify, AEs that were reported more than once by 
a subject during the same period will be counted only once for that subject and 
period at the maximum severity. 
Chi-square test or Fisher’s Exact test will be applied for testing the above 
differences between the groups. 
Oral inspections will evaluate any changes from baseline in the target implant/s 
that can be attributed to treatment. 
8.6  Handling of Missing data 
Missing data will be handled for imputation the primary endpoint data. 

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The MMRM model (Mixed-effect Model for Repeated Measures), which is 
based on MAR (missing at random) assumption will be applied to all ITT 
subjects.  
Sensitivity analyses will be applied for testing the effect of the imputation on 
the treatment effect. This will show the influence of the imputation on the study 
results. 
9. HANDALING ADVERSE EVENTS  
9.1 
Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or 
clinical investigation patient administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  New inter current illnesses or injuries after a patient 
signs the study Informed Consent Form should be regarded as AEs.  Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality: 
 results in study withdrawal, 
 is associated with clinical signs or symptoms, 
 leads to treatment or further diagnostic tests, or 
 is considered by the Investigator to be of clinical significance. 
AEs are classified as either serious or non-serious.  A Serious Adverse Event 
(SAE) is any event that results in any of the following outcomes: 
 death, 
 are life threatening, 
 hospitalization or prolongation of existing hospitalization, 

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 persistent or significant disability or incapacity, 
 a congenital anomaly or birth defect, or malignancy 
 other important medical event. 
All AEs that do not meet any of the criteria for serious should be regarded as 
non-SAEs. 
The study period for the purpose of AE reporting is defined as the period from 
the initiation of study to the end of the follow-up period.  Although not 
considered a serious adverse event, it is the responsibility of the Investigator, or 
his designee, to report any pregnancy (spontaneously reported to them), which 
begins during the course of the study.  At that time, all study-related medication 
should be stopped and the patient discontinued from the study.  All patients who 
become pregnant must be followed up until completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of the 
infant) must also be reported by telephone to one of the individuals listed in this 
protocol. 
9.2   Recording of Adverse Events 
At each contact with the patient, the Investigator must seek information on AEs 
by specific questioning, and as appropriate, by examination.  Information on all 
AEs should be recorded in the SD and immediately on the CRF AE Form.  
All AEs occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization or until 
it has been determined that study treatment or participation is not the cause.   
9.3   Reporting of Serious Adverse Events 
All SAEs during the study period, whether or not considered to be related to 
study treatment are to be reported immediately to the Sponsor within 24 hours 
of the Investigator’s first knowledge of the event.  The report should be made 
to one of the Sponsor's representatives as detailed in the CRF SAE Form. 
SAEs which are still ongoing at the end of the study period must be followed 

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up to determine the final outcome. 
The Investigator must complete the CRF SAE Form with as much information 
as is available at the time of completion.  All clearly related signs, symptoms 
and abnormal diagnostic procedures for an event should be grouped together 
and recorded as a single diagnosis on the CRF SAE Form. 
The Investigator must complete a written follow-up report on the CRF SAE 
Form within 72 hours after receiving any additional information about the SAE 
and/or when all parameters, including laboratory values, have returned to 
normal or are otherwise explained. 
In addition, it is the responsibility of the Investigator to report SAEs to the IEC 
in accordance with the applicable local regulatory requirements and the ICH-
GCP guideline. 
9.4   Patient Removal from Study due to Adverse Events 
1.  Any patient who experiences an AE may be withdrawn at any time from the 
study at the discretion of the Investigator.  If the AE may relate to overdose 
of study treatment, the Investigator Brochure should be consulted for details 
of any specific actions to be taken.  In the event where a patient requires 
discontinuation due to an AE, the Sponsor must be notified as soon as 
possible. 
2.  Pre-treatment event or AE(s). If in the period between Screening visit and 
Baseline visit the subject has experienced a pre-treatment event or AE, 
where continued participation imposes an unacceptable risk to the subject's 
health or the subject is unwilling to continue because of the pre-treatment 
event or AE, the subject may be terminated early. 
3. Implant losses PD - In cases where the target pocket depths increased by 
more than 2 mm the patient will be withdrawn from the study. 
4. The clinical course of AE(s) occurring during the study should be followed 
until resolution, stabilization or until it has been determined that study 
treatment or participation is not the cause. 

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10. STUDY MEDICATION 
10.1   Labelling and Packaging 
For each randomized patient an individual chip package will be allocated. Each 
chip package will contain 6 aluminium blister trays containing 10 chips each. 
The blister packs will be stored in room temperature not above 30°C (storage 
temperature adequacy will be constantly monitored by the sponsor). 
The Chlorhexidine chip will be manufactured and packaged by Dexcel Pharma 
Technologies (DPT) Ltd, Israel.  Each chip package and blister will be labelled 
in accordance with the current ICH-GCP guideline, Volume 4 EU guidelines to 
GMP Annex 13: Manufacture of investigational medicinal products, CFR 21 
part 312 and the local regulatory requirements. 
 
 
 
 
For Israel: Each chip package will include the following information in English 
and the wording "For Clinical Trial Use Only” in the following languages: 
English, Hebrew and Arabic:  
Protocol No.: CLI/016P 
 
 
 
60 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket Only 
For instruction for administration, please refer to the study protocol.  
Investigator Name: 
 
 
Investigator Site No.: ____ 
Randomization No.:   
Screening No.:    
Initials:____ 
Storage condition: Not above 30°C 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel               
Telephone No.: 972-4-636400 (ext. 246) 
For Clinical Trial Use Only 
ל
שימוש ב
ניסוי רפוא
י בלבד 
الطبية فقط  للتجارب يستعمل 
Each chip blister will include the following information in English only and the 
wording "For Clinical Trial Use Only” in English, Hebrew and Arabic:  
 

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Protocol No.: CLI/016P 
 
 
 
10 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket 
Investigator Name: 
 
 
Investigator Site No.:____ 
Randomization No.:   
Screening No.:    
Initials:____ 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel  
For Clinical Trial Use Only              
ל
שימוש
 ב
ניסוי רפואי בלבד 
الطبية فقط  للتجارب يستعمل 
 
 
For the United States of America: 
 
Protocol No.: CLI/016P 
 
 
 
60 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket Only 
For instruction for administration, please refer to the study protocol.  
Investigator Name: 
 
 
Investigator Site No.:____ 
Randomization No.:   
Screening No.:    
Initials: ____ 
Storage condition: Store between 20-25°C (68-77°F) with excursion 
between 15-30°C (59-86°F) 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel               
Telephone No.: 972-4-636400 (ext. 246) 
Caution: New Drug--Limited by Federal (or United States) law to 
investigational use. 
 
 
Each of the immediate chip blisters will include the following information: 
Protocol No.: CLI/016P 
 
 
 
10 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket 
Randomization No.:   
Screening No.:    
Initials: ____ 
Storage condition: Store between 20-25°C (68-77°F) with excursion 
between 15-30°C (59-86°F) 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel  
Caution: New Drug--Limited by Federal (or United States) law to 
investigational use. 
For Germany: 
EudraCT Nr.: 2013-000383-28  Protokoll Nr.: CLI/016P 
 
60 Chips mit 2,5 mg Chlorhexidin(D-gluconat)  
Nur zum Einbringen in Parodontaltaschen 
For instruction for administration, please refer to the study protocol.  
Name des Forschers:  
 
 Studienort  Nr: ____ 
Randomisierungs-Nr.:  
Screening Nr.:       Kürzel: ____ 
Lagerbedingungen: Nicht über 30 °C 

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Batch Nr.: XXXXX  
 
Verwendbar bis: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel               
Telefon Nr.: 972-4-636400 (Durchwahl: 246) 
For Clinical Trial Use Only 
zur klinischen Prüfung bestimmt 
 
Each of the immediate chip blisters will include the following information: 
EudraCT Nr.: 2013-000383-28  Protokoll Nr.: CLI/016P 
 
10 Chips mit 2,5 mg Chlorhexidin(D-gluconat)  
Nur zum Einbringen in Parodontaltaschen 
Randomisierungs-Nr.:  
  Screening Nr.:          Kürzel: ____ 
Lagerbedingungen: Nicht über 30 °C 
Batch Nr.: XXXXX  
 
Verwendbar bis: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel  
For Clinical Trial Use Only 
zur klinischen Prüfung bestimmt 
 
 

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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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For the United Kingdom: 
EudraCT No.: 2013-000383-28 Protocol No.: CLI/016P 
 
60 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket Only 
For instruction for administration, please refer to the study protocol.  
Investigator Name: 
 
 
Investigator Site No.:____ 
Randomization No.:   
Screening No.:    
Initials: ____ 
Storage condition: Not above 30°C 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel               
Telephone No.: 972-4-636400 (ext. 246) 
For Clinical Trial Use Only 
 
Each of the immediate chip blisters will include the following information: 
 EudraCT No.: 2013-000383-28 Protocol No.: CLI/016P 
 
10 chips of 2.5 mg Chlorhexidine Gluconate  
For Insertion into Periodontal Pocket 
Investigator Name: 
 
 
Investigator Site No.:____ 
Randomization No.:   
Screening No.:    
Initials:____ 
Batch No.: XXXXX  
 
Expiry date: MM/ 20YY 
Dexcel Pharma Technologies Ltd. 10 Hakidma Street Yokneam, Israel  
For Clinical Trial Use Only              
 
In addition, 21 identical labels (3 for each visit) for weeks 0, 2, 4, 6, 8, 10 and 
12 will be prepared and attached at each visit to each of the CRF pages (original 
page and two copy pages) with information of the following in English:  
 
Protocol #: CLI/0016P 
2.5 mg Chlorhexidine Gluconate  
Visit No.: _______ 
Randomization No.:______ 
Screening No.:_______                  Initials: _______ 
Number of chips inserted: _______ 
Storage condition: Not above 30°C 
Expiry date: MM/20YY 
Dexcel Pharma Technologies Ltd.  
For Clinical Trial Use Only 
 
 

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10.2  Dosage Regimen of Study Drug 
The following procedure will be utilized for the insertion of the PerioChip® into 
peri-implant pockets assigned to this treatment. 
Using a pair of college forceps, a chip assigned to that pocket will be picked up 
so that the tapered end points are away from the forceps. The chip will then be 
carried to the pocket, which has been isolated and dried, and will be rapidly 
inserted into the pocket to its maximum depth and released. The chip can then 
be further maneuvered into position using the tips of the forceps or a flat plastic 
instrument. 
10.3 Disposition of Study Drug 
The Sponsor has ultimate responsibility for the inventory and disposition of 
study drugs. The Investigator shall keep complete records of the chips, which 
were received and used in the study, and if possible, shall return all unused or 
damaged chips and inventory records to the Sponsor upon study completion. 
The study drugs, under the supervision of the Investigator, will be stored in a 
secure, locked area 15-30°C. The Investigator is not permitted to destroy any 
of the chips.  
11. ADMINISTRATIVE OBLIGATIONS 
11.1 Source Data 
Where SDs (such as laboratory reports, medical records or Electrocardiogram 
(ECG) or laboratory databases) exist, all relevant data will be transcribed into 
the CRF, transferred electronically to the study database or entered into the 
study database directly from SDs. Where no SDs exists, data will be written 
directly into the CRF.  
The 
Investigator/Institution 
will 
permit 
study-related 
monitoring, 
audits/inspections, IEC review and regulatory inspection providing direct 
access to SDs.  

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11.2 Language 
CRFs will be in English. Generic or active ingredient or the International 
Nonproprietary Name- INN for concomitant medications should be recorded in 
the CRF whenever possible. All written material to be used by patients must 
use vocabulary that is clearly understood, and be in the language appropriate 
for the study site. 
11.3   Data Collection 
All CRFs will be completed using a black ballpoint pen, and entries must be 
legible. Errors should be crossed by a single line but not obliterated, the 
correction inserted, and the change initialled and dated by the Investigator or an 
authorised member of the investigational site team. The Investigator will sign 
and date at the indicated places of the CRF. This signature will indicate a 
thorough inspection of the data on the CRF has been made, and it will certify 
the contents of the form. 
All laboratory reports (if applicable) will be reviewed, signed and dated by the 
Investigator. 
11.4   Data Entry 
The CRFs will be logged and the data will be entered into the study database 
using double data entry with verification upon second entry. Independent 
persons will enter data into the database system, while the first entry is blind to 
the second operator to minimize bias.  
The two data entries will be compared to see if they are identical using "proc 
compare" by SAS®. 
Two data entry files are independently produced and are compared and 
corrected until they are identical by the use of a computer verification process. 
The data base will include automatic header information of the protocol 
number, the site number, subject number and initials and visit number.  
Text items/comments will be entered once and checked manually against the 

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CRFs.   
Subsequent electronic review of the data may result in queries being generated 
that will be forwarded simultaneously to the investigator or designee for prompt 
resolution. Resolutions will be sent back to the DMC in a timely fashion. All 
data modifications resulting from review or querying of the data will be 
electronically tracked.  
Any errors detected by either the study monitor or the investigator after query, 
resolution should be documented in CRF data change forms. 
In all cases the signature of an investigator or designee and of the study monitor 
will be required. 
11.5 Monitoring 
It is understood that the study monitors may contact and visit the Investigator, 
and that they will be allowed to inspect the various records of the study on 
request (CRFs and other relevant data), provided that patient confidentiality is 
maintained, and that the inspection is conducted in accordance with local 
regulations. 
It is the monitor’s responsibility to inspect the CRFs at regular intervals 
throughout the study to verify adherence to the protocol, the completeness, 
accuracy and consistency of the data, and adherence to the local regulatory 
requirements and ICH-GCP guideline.  
The Investigator agrees to cooperate with the monitor to ensure that any 
problems detected during the course of these monitoring visits are resolved. 
11.6   Study Documentation and Data Storage 
The Investigator should maintain the essential study documents as specified by 
Section 8 of the ICH-GCP guideline for no less than 15 years after the study 
completion, and should take measures to prevent accidental and premature 
destruction of these documents. 
No study document will be destroyed without prior written agreement between 
the Sponsor and the Investigator. Should the Investigator wish to assign the 

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study records to another party or move them to another location, written 
agreement must be obtained from the Sponsor. 
11.7 Quality Control and Quality Assurance 
Quality Control will be performed according to Dexcel Pharma SOPs. All 
necessary data and documents will be made available for inspection. 

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12.  REFERENCES 
1) 
Albrektsson, T. & Isidor, F. (1994). Consensus report of session IV. In: N. Lang & 
T. Karring (Eds.), Proceedings of the 1st European Workshop on Periodontology 
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2) 
Barbour, M.E., Gandhi, N., el-Turki, A., O'Sullivan, D.J., & Jagger, D.C. (2009). 
Differential adhesion of Streptococcus gordonii to anatase and rutile titanium 
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3) Briner, W.W., Grossman, E., & Buckner, R.Y., (1986). Assessment of 
susceptibility of plaque bacteria to Chlorhexidine after six months’ oral use. 
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Biodynamics, Inc., East Millstone, N.J. 00875 (1970) 
5) Cytotoxicity Assays on Perio Chip Powder and Perio Chip Matrix (Study No. 
89/PPR001/0474) Life Science Research Ltd., Suffolk, England (1989) 
6) Fardall O & Turnbull, R.S., (1986). A review of the literature on the use of 
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863-869. 
7) 
Felo, A., Shibly, O., Ciancio, S.G., Lauciello, F.R., & Ho A., (1997). Effects of 
subgingival chlorhexidine irrigation on periimplant maintenance. American 
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8) Goh, C.L., (1989). Sensitivity to topical antimicrobials (II).  Sensitizing potentials 
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Research Institute, Menlo Park, CA (1977). 

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14) Jeffcoat, M.K., Bray, K.S., Ciancio, S.G., Dentino, A.R., Fine, D.H., Gordon, J.M., 
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27) Physician’s Desk Reference (PDR; 59th edition, 2005).  p. 2807 
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Adjunctive local antibiotic therapy in the treatment of peri-implantitis II: clinical 
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(2013). Anti-infective therapy of peri-implantitis with adjunctive local drug 
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randomized clinical trial. Clinical Oral Implants Research, 24(1), 104-110.  
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Clinical and microbiological effects of sustained release chlorhexidine on 
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(2000). Using the PerioChip in treating adult periodontitis; An interim report. 
Compendium of continuing education in dentistry, 21(4), 325-328. 
39) Stanley, A., Wilson, M., & Newman, H.N. (1989). The in vitro effect of 
chlorhexidine on subgingival plaque bacteria. Journal of Clinical Periodontology, 
16(4), 259-264. 
40) Twenty Day Oral Mucosal Toxicity Study in Rats.  Sample No. 7162, 7163, and 
7173 (Sample 7173 Mouth Rinse Vehicle + 0.44% CC 17160-1 – TA 106-10-24, 
Chlorhexidine Digluconate) Report Project No. 68-355, Biodynamics, Inc. NJ 
(2/12/69).  
41) Zitzmann, N.U. & Berglundh, T. (2008). Definition and prevalence of peri- implant 
disease. Journal of Clinical Periodontology, 35 (suppl. 8), 286-291.  

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