Conditions: Peri-Implantitis
Keywords: Peri-Implantitis Periodontal Diseases Chlorhexidine gluconate PerioChip Anti-Infective Agents Mouth Diseases Antiseptics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 290
Healthy volunteers: no

Brief summary:
The objective of the study is to assess the efficacy and safety of PerioChip® (Chlorhexidine gluconate chip) in the treatment of patients with Peri-implantitis.

The hypothesis of the study is that PerioChip® in adjunct to mechanical subgingival debridement is more effective in the treatment of peri-implantitis when compared to the common method of mechanical subgingival debridement alone. The primary efficacy measure will be the reduction in probing pocket depth at 6 months as measured at sites of qualifying target implant.

Detailed description:
This is a research study that uses the drug PerioChip® (active ingredient chlorhexidine gluconate) as an experimental treatment for "periimplantitis". This condition is defined an inflammation affecting the tissues (gums and bone) around an already stable implant, resulting in loss of supporting jaw bone. It is caused by many factors but current research links the condition with the presence of bacteria in the mouth which are responsible for periodontitis (gum disease). If left untreated, this can lead to decreased bone support, weakening of the implant and potential lost of the implant.

Nonsurgical treatment (deep cleaning with instruments to remove plaque) and rigorous diligent oral care at home are commonly used to treat both periimplantitis (gum disease around an implant) and periodontitis (gum disease around teeth).

The medication PerioChip® is a small dental chip (its size is smaller than a match head, and it is completely flat). The chip contains chlorhexidine gluconate, an antimicrobial agent which is not an antibiotic. The chip is inserted into the gum sulcus that is present around the tooth or implant and biodegrades naturally within 7 to 10 days while releasing the medication.

The purpose of this study is to determine the efficacy of PerioChip® in addition to a standard deep cleaning treatment regime, as compared to standard deep cleaning alone.in a large patient population, and to collect additional safety data about the treatment.

Arms:
arm 1: Treatment, 2.5 mg Chlorhexidine Gluconate chip (PerioChip®) inserted every two weeks starting at Baseline for the first 3 months, plus mechanical Subgingival Debridement at Baseline and 3 months. arm 2: Mechanical Subgingival Debridement at Baseline and 3 months.

Interventions: intervention 1: 2.5 mg Chlorhexidine gluconate chip
Intervention descriptions: intervention 1: Subgingival debridement will be carried out for each one of the target implant. Upon completion of the debridement a PerioChip® will be inserted in each one of the target implant.

Protocol document:
Prot_002.pdf: 
 
 
Dexcel Pharma Technologies Ltd. 
 
The Efficacy and Safety of Chlorhexidine Gluconate 
Chip (PerioChip®) in Therapy of Peri-implantitis 
 
Summary of Protocol Changes 
 
 
 
Protocol Number: 
CLI/016P 
 
 
NCT Number 
NCT02080403 
 
 
EudraCT Number:  
2013-000383-28 
 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
13/April/2021 
 
 
 
 


TABLE OF CONTENTS
Summary of changes from version 1 dated 02 Nov. 2013 to version 2 dated 22 Jan. 2014
Summary of changes from version 2 dated 22 Jan. 2014 to version 3 dated 13 July 2014
Summary of changes from version 3 dated 13 July2014 to version 4 dated 16 Nov. 2014
Summary of changes from version 4 dated 16 Nov. 2014 to version 6 dated 07 Oct. 2015
Summary of changes from version 5 dated 07 Oct. 2015 to version 7 dated 20 July 2017
Summary of changes from version 6 dated 07 Oct. 2015 to version 8 dated 29 Aug. 2017


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1 
Protocol No.: CLI/016P 
Protocol Title: The Efficacy and Safety of Chlorhexidine Gluconate Chip (PerioChip®) in Therapy of Peri-Implantitis  
Clinicaltrial.gov Identifier: NCT02080403 
EudraCT Number: 2013-00038-28 
Summary of changes from version 1 dated 02 Nov. 2013 to version 2 dated 22 Jan. 2014 
Page/Section 
Original Text (version 1) 
Amended Text (version 2) 
All through the 
protocol 
Number of subjects that are expected to be randomized to the study 230 
(115 at each study group) 
Number of subjects that are expected to be randomized to the study 246 
(123 at each study group) 
All through the 
protocol 
Number of subjects that are expected to be screened to the study 288 
Number of subjects that are expected to be screened to the study 336 
All through the 
protocol 
Study expected power 80% and statistical significance level 4% for all 
statistical analysis and comparisons 
Study expected power 85% and statistical significance level 5% for all 
statistical analysis and comparisons 
Page 22 - Study 
Design and 
Duration 
The duration of patient follow-up will be 25-28 weeks (including 
Screening), with interim visits at 0, 2, 4, 6, 8, 10, 12, 16 and 24 weeks 
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 
Page 40 - 
Randomization 
Code 
The randomization will be performed with stratification to study sites 
smoking habits and Baseline PD measurement in balanced blocks, each 
block containing 6 subjects. A total number of 48 blocks will be 
prepared for a total of 288 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). 
This number already includes 10 blocks for spare. 
The randomization will be performed with stratification to study sites 
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). A total 
number of 56 blocks will be prepared for a total of 336 subjects. 
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. This number already includes 10 blocks for spare. 
Page 41 – Sample 
size 
Statistical significance level was set to 4% since an Interim Analysis, 
that will use 1% of the total significance level, is planned. 
Statistical significance level for all statistical analysis was set to 4% 
since an Interim Analysis that will use 1% of the total significance level, 
is planned 5. 
Page 42 - Analysis 
population 
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 all safety 
evaluations 
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 
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Page 44 - Efficacy 
analysis and 
statistical models 
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 analysed by a Chi-square test or Fisher's exact test as is appropriate 
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 analysed by a Chi-square test or Fisher's exact test 
as is appropriate 
Page 11- Protocol 
synopsis  and 
Page 46 - Interim 
Analysis 
An interim analysis is planned when 30 patients in each group have 
completed 24 weeks of therapy. Interim analysis will include primary 
efficacy endpoint and safety assessment. The purpose of the interim 
analysis is to achieve a primary assessment for the study safety and 
efficacy endpoints. The primary efficacy endpoint will be tested using a 
0.01 significance level. 1% (0.01) of the overall type 1 error for this 
study of 5% will be used in the interim analysis. The final analyses will 
be tested with statistical significance level of 4% (0.04). The levels of 
significance will maintain an overall P value of 0.05 (Peto, Pike, 
Armitage, Breslow, Cox, Howard, et al. 1976 
An interim analysis is planned when 30 patients in each group have 
completed 24 weeks of therapy. Interim analysis will include primary 
efficacy endpoint and safety assessment. The purpose of the interim 
analysis is to achieve a primary assessment for the study safety and 
efficacy endpoints. The primary efficacy endpoint will be tested using a 
0.01 significance level. 1% (0.01) of the overall type 1 error for this 
study of 5% will be used in the interim analysis. The final analyses will 
be tested with statistical significance level of 4% (0.04). The levels of 
significance will maintain an overall P value of 0.05 (Peto, Pike, 
Armitage, Breslow, Cox, Howard, et al. 1976 
Summary of changes from version 2 dated 22 Jan. 2014 to version 3 dated 13 July 2014 
Page/Section 
Original Text (version 2) 
Amended Text (version 3) 
Page 20 - Study 
Design and 
Duration 
 
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. 
Page 39 - 
Statistical 
methods  
 
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 
(periimplantitis) and treatment regimen (frequent chip insertion) as 
appear in the current protocol 
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Page 58 - 
Reference List 
 
23. Perio Products.I. Clinical effects following subgingival 
administration of Chlorhexidine gluconate (2.5 mg) in a cross-linked 
gelatin matrix (PerioChip) in patients with periodontal disease (study 
91-011). Clinical Study Report  
24. Perio Products. II. Clinical effects following subgingival 
administration of Chlorhexidine gluconate (2.5 mg) in a cross-linked 
gelatin matrix (PerioChip) in patients with periodontal disease (study 
91-013). Clinical Study Report 
Summary of changes from version 3 dated 13 July2014 to version 4 dated 16 Nov. 2014 
Page/Section 
Original Text (version 3) 
Amended Text (version 4) 
Page 7 -  Protocol 
Synopsis; Page 22 
- Inclusion 
Criteria 
Inclusion Criteria 1 "Signed and dated informed consent"  
Inclusion Criteria 1 "Signed and dated informed consent. The patient is 
of age and is capable of understanding the nature, significance and 
implications of the clinical trial and to form a rational intention in the 
light of the facts." 
Page 8 – Protocol 
synopsis; Page 24 
- Exclusion 
Criteria 
Exclusion Criteria 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." 
Exclusion Criteria 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. In case the investigator 
advises the patient that antibiotic therapy is required during the course 
of the study, the patient should be excluded from further participation." 
Page 25 - Patient 
Discontinuation/ 
Withdrawal 
Criteria 
"Patient receives emergency dental treatment which may interfere with 
the assessment of study endpoints."  
"Patient receives emergency dental treatment including target implant 
explanation which may interfere with the assessment of study endpoints. 
Paragraph was added: "Despite participating in the study, patient, who 
in the opinion of the investigator displays an inadequate response to 
subgingival debridement and chemical disinfection during the study 
period, may be entitled to surgical therapy of peri-implantitis." 
Page 26 - 
Concomitant 
Medication 
Treatment 
 
Patients will be instructed to refrain from: 
"Any use of Chlorhexidine oral rinses/mouthwashes during the study"  
Patients will be instructed to refrain from: 
"Any use of Chlorhexidine oral rinses/mouthwashes during the study 
without consulting the Investigator in advance." 
Summary of changes from version 3 dated 13 July2014 to version 5 dated 07 Oct. 2015 
Page/Section 
Original Text (version 3) 
Amended Text (version 5) 
Page 7 - Protocol 
Synopsis 
Number of clinical sites "5 clinical sites" to "at least 5 clinical sites" 
Number of clinical sites "at least 7 clinical sites" 
Page 13; Page 28; 
Page 37 - Study 
Schedule 
Last visit number "visit 9"  
The allowance (window)of final visit “90 ±10 days from previous visit” 
Last visit number "visit 10"  
The allowance (window)of final visit “56±10 days from previous visit (8 
weeks)” 
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Summary of changes from version 4 dated 16 Nov. 2014 to version 6 dated 07 Oct. 2015 
Page/Section 
Original Text (version 4) 
Amended Text (version 6) 
Page 7 - Protocol 
Synopsis 
Number of clinical sites "5 clinical sites" to "at least 5 clinical sites" 
Number of clinical sites "at least 7 clinical sites" 
Page 13;Page 29; 
Page 38 -Study 
Schedule 
Last visit number "visit 9"  
The allowance (window)of final visit “90 ±10 days from previous visit” 
Last visit number "visit 10"  
The allowance (window)of final visit “56±10 days from previous visit (8 
weeks)” 
Summary of changes from version 5 dated 07 Oct. 2015 to version 7 dated 20 July 2017 
Lines 
Original Text (version 5) 
Amended Text (version 7) 
Headline (First Page) 
8 - 9 
Date : 07 October 2015 
Date : 02 August 2017 
8 - 9 
Version : 5 
Version : 7 
19 
Footer date: 07 October 2015 
Footer version: Protocol # CLI/016P – version 5 
Footer date: 02 August 2017 
Footer version: Protocol # CLI/016P – version 7 
Table of Contents 
39-41 
5.3 page 24;  
5.3 page 25;  
42 - 44 
5.4 page 25;  
5.4 page 26;  
45 - 80 
6. Page 26; 6.1 page 28; 6.2 page 29; 6.2.1 page 29; 6.2.2 page 32; 6.2.3 
page 34; 6.2.4 page 36; 6.2.5 page 36; 6.2.5 page 36; 6.3 page 37; 6.3.1 
page 37; 6.3.2 page 37; 6.3.3 page 37;  
6. Page 27; 6.1 page 29; 6.2 page 30; 6.2.1 page 31; 6.2.2 page 33; 6.2.3 
page 35; 6.2.4 page 37; 6.2.5 page 37; 6.2.5 page 37; 6.3 page 38; 6.3.1 
page 38; 6.3.2 page 38; 6.3.3 page 38;  
81-95 
7. Page 37; 7.1 page 37; 7.2 page 37; 7.3 page 38; 7.4 page 39;  
7. Page 38; 7.1 page 38; 7.2 page 39; 7.3 page 40; 7.4 page 40;  
96-125 
8. Page 39; 8.1 page 39; 8.2 page 40; 8.3 page 40; 8.3.1 page 40; 8.3.2 
page 40; 8.3.3 page 41; 8.4 page 41; 8.5 page 44; 8.6 page 44; 
8. Page 46; 8.1 page 40; 8.2 page 41; 8.3 page 42; 8.3.1 page 42; 8.3.2 
page 42; 8.3.3 page 42; 8.4 page 42; 8.5 page 45; 8.6 page 46; 
126-140 
9. page 45; 9.1 page 45; 9.2 page 46; 9.3 page 46; 9.4page 47;   
9. page 46; 9.1 page 46; 9.2 page 47; 9.3 page 48; 9.4 page 48;   
141-146 
10. page 48; 10.1 page 48; 
10. page 49; 10.1 page 49; 
Clinical Study Protocol - Overview 
203 
Date : 07 October 2015 
Date : 02 August 2017 
Protocol Synopsis - Number of patients 
221-224 
A total of 246 patients in at least five clinical sites will be randomized. 
123 patients for the Subgingival debridement + PerioChip® arm, and 
123 patients for Subgingival debridement alone arm 
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% 
Protocol Synopsis - Inclusion Criteria #5 
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248-254 
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 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. 
 
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. 
Protocol Synopsis - Exclusion Criteria #10 
273-276 
Patients chronically (i.e. two weeks or more) treated with non-steroidal 
anti-inflammatory drugs (NSAIDs) or any medications know to affect 
soft tissue condition (excluding treatment of Acetylsalicylic acid ≤ 100 
mg/day). 
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.  
Protocol Synopsis - Exclusion Criteria #11 (New) 
277-283 
 
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. 
Protocol Synopsis - Exclusion Criterias 12 - 16 
284-285 
11. Patients with uncontrolled diabetes, of any type, and/or patients with 
HbA1c test value >7.5% dated 3 months prior to the screening visit. 
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. 
286-287 
12. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
13. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
288-289 
13. 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. 
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. 
290 
14. Drug and alcohol abuse. 
15. Drug and alcohol abuse. 
291-292 
15. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
16. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
Protocol Synopsis – Statistical Methods – Sample Size 
315-321 
A total of 246 patients will be randomized, 123 patients for the 
A total of up to 290 patients will be randomized. At least 123 patients 
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Subgingival Debridement + PerioChip® arm and 123 patients for the 
Subgingival Debridement alone arm. 
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 336 patients will be screened in order to randomize 246 
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. 
Abbreviations 
401-402 
4 abbreviations regarding pocket aspects were not listed 
MB - Mesio-Buccal; MiB - Mid-Buccal; DB -Disto-Buccal; MiL-Mid-
Lingual 
Study Schedule 
404-413 
Evaluations/Activity Column: "dental Radiography 
SuperScript #1: Dental Radiography evaluation dated within 1 (one) 
year prior the Screening visit 
SuperScript #2: In case chips are pop-out recurrently in visits 3, 5 and 
7 a pocket examination will be conducted by the designated examiner to 
verify PD ≥ 5 mm 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm and which pocket depth at those visits is ≥5 mm" was removed 
Evaluations/Activity Column: "Periapical dental Radiography 
SuperScript #1: "Periapical Dental Radiography evaluation dated 
within 1 (one) year prior the Screening visit. 
SuperScript #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 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm 
Study Design and Duration 
621 
The same examiner will perform all the measurements during the study. 
Calibrated examiners will perform all the measurements during the 
study. 
5.1 Number of Patients 
649-657 
A total of 246 patients, with symptoms of peri-implantitis, will be 
randomized, into one of the study arms; 123 patients for the Subgingival 
debridement + PerioChip® arm and 123 patients for the Subgingival 
debridement arm alone. 
 
A total of 290 patients, with symptoms of peri-implantitis, will be 
randomized into one of the study arms; 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% 
658-663 
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 336 patients will be screened in order to randomize 246 
patients. 
 
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 
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which 246 patients will complete all required study visits. 
5.2.2 Exclusion Criteria – Exclusion Criteria #10 
708-713 
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). 
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 
Protocol Exclusion Criteria #11 (New)  
714-721 
 
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. 
Protocol Synopsis - Exclusion Criterias 12 - 16 
722-724 
11. Patients with uncontrolled diabetes, of any type, and/or patients with 
HbA1c test value >7.5% dated 3 months prior to the screening visit. 
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. 
725-726 
12. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
13. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
727-729 
13. 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. 
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. 
730 
14. Drug and alcohol abuse. 
15. Drug and alcohol abuse. 
731-732 
15. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
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 
744 
Serious Adverse Events (SAEs) which are still ongoing at the end of the 
study period must be followed up to determine the final outcome. 
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. 
5.4 Concomitant Medication Treatment 
782-785 
Any use of toothpicks and/or floss around the treated implant/s in the 24 
hours following the chip insertion. 
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. 
6. Study Plan - Treatment 1: (PerioChip®) 
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804-807 
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). 
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). 
6.1 Study Schedule 
826-834 
Evaluations/Activity Column: "dental Radiography 
SuperScript #1: Dental Radiography evaluation dated within 1 (one) 
year prior the Screening visit 
SuperScript #2: In case chips are pop-out recurrently in visits 3, 5 and 
7 a pocket examination will be conducted by the designated examiner to 
verify PD ≥ 5 mm 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm  
Evaluations/Activity Column: "Periapical dental Radiography. 
SuperScript #1: "Periapical Dental Radiography evaluation dated 
within 1 (one) year prior the Screening visit. 
SuperScript #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 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip 
6.2.1 Screening Visit and Hygienic Phase Therapy (Weeks (-3 to -1)) 
850-860 
radiographic evaluation dated within 1 (one) year prior the Screening 
visit 
periapical radiographic evaluation dated within 1 (one) year prior the 
Screening visit 
6.2.2 Baseline Visit (Week 0) 
955-961 
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 ultrasonic 
management and irrigation with Chlorhexidine ("blasting" cleaning is 
prohibited). 
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). 
980-987 
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 in the 24 hours following the chip insertion. 
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. 
990-991 
 
The period between Baseline visit and Visit 3 should not exceed 14 ± 4 
days 
6.2.3 Visits 3, 4, 5, 6, 7 and 8 (Weeks 2, 4, 6, 8, 10 and 12) 
1010 
Supragingival Scaling (at week 12 only) 
Supragingival Scaling (at week 12 (Visit 8) only). 
1012-1013 
Pocket examination and measurements (i.e. PD, R and BOP) only for 
Pocket examination and measurements (i.e. PD, R and BOP) only for 
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the target implant/s (only at weeks: 8 and 12) 
the target implant/s (only at weeks: 8 and 12 (visits 6 and 8)). 
1015-1017 
Subgingival debridement will be carried out for all the chosen target 
implant/s, regardless of the study arm randomization, (at week 12 only). 
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). 
1018-1029 
Chip/s insertion only in those target pockets which had previously 
received a chip and which pocket depth is ≥ 5 mm. 
 
 In case chips are pop-out recurrently in visits 3, 4, 5 and 7 a pocket 
examination will conducted by the designated examiner to verify PD ≥ 
5 mm. The examiner will then declare "please try to restore again" if 
PD≥ 5 mm or "do not proceed with the insertion". 
Chip/s insertion only in those target pockets which had previously 
received a chip. 
For visits 6 and 8, chip insertion will follow pocket depth verification of 
≥ 5 mm as measured during the visit. 
For visits 3, 4, 5 and 7, in case chips pop-out recurrently 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". 
1030-1037 
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 in the 24 hours following the chip insertion. 
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. 
6.2.4 Visits 9 (Week 16) 
1058-1059 
 
The allowed window for visit 9 should not exceed 28 ± 4 days from the 
previous visit. 
6.3.1 Calibration of Examiners 
1076-1078 
PD and R measurement procedures will be standardized between 
medical centres and investigators prior to study initiation, consistent 
with Good Clinical Practice (GCP). 
PD and R measurement procedures will be standardized between 
investigators within each medical centre prior to study initiation, 
consistent with Good Clinical Practice (GCP). 
7.2 Randomization Codes 
1107-1108 
A total number of 56 blocks will be prepared for a total of 336 subjects. 
Line removed 
1113 
This number already includes 10 blocks for spare 
Line removed 
7.3 Blinding 
1118-1122 
Subgingival debridement only 
Subgingival debridement alone 
8.1 Sample Size 
1133-1140 
A total of 246 patients will be randomized, 123 patients for the 
Subgingival debridement + PerioChip® arm and 123 patients for the 
Subgingival debridement alone arm. 
Based on previous phase IIa studies, the expected drop-out rate in this 
study will be between 20%-25%. Thus, it is estimated that 
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%. 
DeY~el Pharma Technologies Ltd 


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10 
 
approximately 336 patients will be screened in order to randomize 246 
patients. 
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. 
Summary of changes from version 6 dated 07 Oct. 2015 to version 8 dated 29 Aug. 2017 
Lines 
Original Text (version 6) 
Amended Text (version 8) 
Headline (First Page) 
8 - 9 
Date : 07 October 2015 
Date : 29 August 2017 
8 - 9 
Version : 6 
Version : 8 
18 
Footer date: 07 October 2015 
Footer version: Protocol # CLI/016P – version 6 
Footer date: 29 August 2017 
Footer version: Protocol # CLI/016P – version 8 
Table of Contents 
38 
5.3 page 24;  
5.3 page 25;  
45 - 47 
6.2.3 page 35 6.2.5 page 37;  
6.2.3 page 36; 6.2.5 page 38; 
52-55 
7. Page 38; 7.1 page 38; 7.2 page 38; 7.3 page 39; 
7. Page 39; 7.1 page 39; 7.2 page 40; 7.3 page 40; 
60-66 
8.3 page 40; 8.3.1 page 40; 8.3.2 page 40;  8.4 page 41; 8.6 page 44; 
8.3 page 42; 8.3.1 page 42; 8.3.2 page 42; 8.4 page 44;  8.6 page 46; 
69-73 
9.2 page 47; 9.3 page 47; 9.4page 48;   
9.2 page 48; 9.3 page 48; 9.4 page 49;   
Clinical Study Protocol – Overview 
130 
Date : October 7th 2015 
Date : August 29th 2017 
Protocol Synopsis - Number of patients 
148-151 
A total of 246 patients in at least five clinical sites will be randomized. 
123 patients for the Subgingival debridement + PerioChip® arm, and 
123 patients for Subgingival debridement alone arm 
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% 
Protocol Synopsis - Inclusion Criteria #5 
177-183 
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 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. 
 
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. 
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Protocol Synopsis - Exclusion Criteria #10 
204-207 
Patients chronically (i.e. two weeks or more) treated with non-steroidal 
anti-inflammatory drugs (NSAIDs)or any medications know to affect 
soft tissue condition (excluding treatment of Acetylsalicylic acid ≤ 100 
mg/day). 
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.  
Protocol Synopsis - Exclusion Criteria #11 (New) 
208-213 
 
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. 
Protocol Synopsis - Exclusion Criterias 12 – 16 
214-215 
11. Patients with uncontrolled diabetes, of any type, and/or patients with 
HbA1c test value >7.5% dated 3 months prior to the screening visit. 
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. 
216-217 
12. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
13. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
218-219 
13. 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. 
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. 
220 
14. Drug and alcohol abuse. 
15. Drug and alcohol abuse. 
221-222 
15. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
16. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
Protocol Synopsis – Statistical Methods – Sample Size 
245-252 
A total of 246 patients will be randomized, 123 patients for the 
Subgingival Debridement + PerioChip® arm and 123 patients for the 
Subgingival Debridement alone arm. 
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 336 patients will be screened in order to randomize 246 
patients. 
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 
DeY~el Pharma Technologies Ltd 


 - CONFIDENTIAL –  
 
 
 
12 
 
290 patients that complete all required study visits. 
Abbreviations 
332-333 
4 abbreviations regarding pocket aspects were not listed 
MB - Mesio-Buccal; MiB - Mid-Buccal; DB -Disto-Buccal; MiL-Mid-
Lingual 
Study Schedule 
336-344 
Evaluations/Activity Column: "dental Radiography 
SuperScript #1: Dental Radiography evaluation dated within 1 (one) 
year prior the Screening visit 
SuperScript #2: In case chips are pop-out recurrently in visits 3, 5 and 
7 a pocket examination will be conducted by the designated examiner to 
verify PD ≥ 5 mm 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm 
Evaluations/Activity Column: "Periapical dental Radiography 
SuperScript #1: "Periapical Dental Radiography evaluation dated 
within 1 (one) year prior the Screening visit. 
SuperScript #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 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm 
Study Design and Duration 
522 
The same examiner will perform all the measurements during the study. 
Calibrated examiners will perform all the measurements during the 
study. 
5.1 Number of Patients 
580-584 
A total of 246 patients, with symptoms of peri-implantitis, will be 
randomized, into one of the study arms; 123 patients for the Subgingival 
debridement + PerioChip® arm and 123 patients for the Subgingival 
debridement arm alone. 
 
A total of 290 patients, with symptoms of peri-implantitis, will be 
randomized into one of the study arms; 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% 
585-590 
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 336 patients will be screened in order to randomize 246 
patients. 
 
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. 
5.2.2 Exclusion Criteria – Exclusion Criteria #10 
640-645 
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). 
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 
Protocol Exclusion Criteria #11 (New) 
646-654 
 
11. Patients with any history of use of Medications known to cause 
DeY~el Pharma Technologies Ltd 


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13 
 
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. 
Protocol Synopsis - Exclusion Criterias 12 – 16 
655-657 
11. Patients with uncontrolled diabetes, of any type, and/or patients with 
HbA1c test value >7.5% dated 3 months prior to the screening visit. 
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. 
658-659 
12. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
13. Patients receiving radiation therapy to the head and neck area and/or 
receiving immunosuppressive therapy. 
660-662 
13. 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. 
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. 
663 
14. Drug and alcohol abuse. 
15. Drug and alcohol abuse. 
664-665 
15. Patient participates in any other clinical study 30 days prior to the 
start of the study and throughout the study duration. 
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 
677 
Serious Adverse Events (SAEs) which are still ongoing at the end of the 
study period must be followed up to determine the final outcome. 
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. 
5.4 Concomitant Medication Treatment 
721-723 
Any use of toothpicks and/or floss around the treated implant/s in the 24 
hours following the chip insertion. 
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. 
6. Study Plan - Treatment 1: (PerioChip®) 
742-745 
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). 
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). 
6.1 Study Schedule 
764-772 
Evaluations/Activity Column: "dental Radiography 
SuperScript #1: Dental Radiography evaluation dated within 1 (one) 
year prior the Screening visit 
SuperScript #2: In case chips are pop-out recurrently in visits 3, 5 and 
7 a pocket examination will be conducted by the designated examiner to 
Evaluations/Activity Column: "Periapical dental Radiography. 
SuperScript #1: "Periapical Dental Radiography evaluation dated 
within 1 (one) year prior the Screening visit. 
SuperScript #2: In case chips are pop-out recurrently in visits 3, 4, 5 
and 7 a pocket examination will be conducted by the designated 
DeY~el Pharma Technologies Ltd 


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14 
 
verify PD ≥ 5 mm 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip and which pocket depth at those visits is 
≥ 5 mm  
examiner to verify PD ≥ 5 mm 
SuperScript #6: Chip/s will be inserted only in target implant/s which 
had previously received a chip 
6.2.1 Screening Visit and Hygienic Phase Therapy (Weeks (-3 to -1)) 
788-798 
radiographic evaluation dated within 1 (one) year prior the Screening 
visit 
periapical radiographic evaluation dated within 1 (one) year prior the 
Screening visit 
6.2.2 Baseline Visit (Week 0) 
893-899 
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 ultrasonic 
management and irrigation with Chlorhexidine ("blasting" cleaning is 
prohibited). 
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). 
918-925 
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 in the 24 hours following the chip insertion. 
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. 
928-929 
 
The period between Baseline visit and Visit 3 should not exceed 14 ± 4 
days 
6.2.3 Visits 3, 4, 5, 6, 7 and 8 (Weeks 2, 4, 6, 8, 10 and 12) 
949 
Supragingival Scaling (at week 12 only) 
Supragingival Scaling (at week 12 (Visit 8) only). 
951-952 
Pocket examination and measurements (i.e. PD, R and BOP) only for 
the target implant/s (only at weeks: 8 and 12) 
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)). 
954-956 
Subgingival debridement will be carried out for all the chosen target 
implant/s, regardless of the study arm randomization, (at week 12 only). 
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). 
957-966 
Chip/s insertion only in those target pockets which had previously 
received a chip and which pocket depth is ≥ 5 mm. 
 In case chips are pop-out recurrently in visits 3, 4, 5 and 7 a pocket 
examination will conducted by the designated examiner to verify PD ≥ 
5 mm. The examiner will then declare "please try to restore again" if 
PD≥ 5 mm or "do not proceed with the insertion". 
Chip/s insertion only in those target pockets which had previously 
received a chip. 
For visits 6 and 8, chip insertion will follow pocket depth verification of 
≥ 5 mm as measured during the visit. 
For visits 3, 4, 5 and 7, in case chips pop-out recurrently a pocket 
examination will be conducted by the designated examiner to verify PD 
DeY~el Pharma Technologies Ltd 


 - CONFIDENTIAL –  
 
 
 
15 
 
≥ 5 mm. The examiner will then declare "please try to insert again" if 
PD≥ 5 mm or "do not proceed with the insertion". 
967-974 
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 in the 24 hours following the chip insertion. 
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. 
6.2.4 Visits 9 (Week 16) 
995-996 
 
The allowed window for visit 9 should not exceed 28 ± 4 days from the 
previous visit. 
6.3.1 Calibration of Examiners 
1013-1015 
PD and R measurement procedures will be standardized between 
medical centres and investigators prior to study initiation, consistent 
with Good Clinical Practice (GCP). 
PD and R measurement procedures will be standardized between 
investigators within each medical centre prior to study initiation, 
consistent with Good Clinical Practice (GCP). 
7.2 Randomization Codes 
1044-1045 
A total number of 56 blocks will be prepared for a total of 336 subjects. 
Line removed 
1050 
This number already includes 10 blocks for spare 
Line removed 
7.3 Blinding 
1055-1059 
Subgingival debridement only 
Subgingival debridement alone 
8.1 Sample Size 
1070-11077 
A total of 246 patients will be randomized, 123 patients for the 
Subgingival debridement + PerioChip® arm and 123 patients for the 
Subgingival debridement alone arm. 
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 336 patients will be screened in order to randomize 246 
patients. 
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. 
 
DeY~el Pharma Technologies Ltd 

SAP_003.pdf: 
 
 
Dexcel Pharma Technologies Ltd. 
 
The Efficacy and Safety of Chlorhexidine Gluconate 
Chip (PerioChip®) in Therapy of Peri-implantitis 
 
Statistical Analysis Plan 
 
 
 
Protocol Number: 
CLI/016P 
 
 
NCT Number 
NCT02080403 
 
 
EudraCT Number:  
2013-000383-28 
 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
15/August/2018 
 
 
 
 


TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN: Protocol Ref: CLI/016P_15AUG2018
Abbreviations
1. Introduction
1.1 Objectives
1.2 Design
1.3 Responsibilities
1.4 Study Populations
1.5 Primary Efficacy Endpoint
1.6 Secondary Efficacy Endpoints
1.7 Safety Analysis
1.8 Sample size
1.9 Interim Analyses
2. Statistical Methods
2.1 General
2.2 Data Summaries
2.3 Continuous
2.4 Categorical
2.5 Protocol Deviations
3. Analysis Plan
3.1 Introduction
3.1 Disposition of Subjects
3.2 Baseline Comparability
3.3 Primary Efficacy Endpoint
3.4 Secondary Efficacy Endpoints
3.5 Exploratory Analysis
3.6 Safety Analysis
4. Appendix I: Tables to be Included in the Clinical Study Report
5. Appendix II: Listings to be Included in the Clinical Study Report


STATISTICAL ANALYSIS PLAN 
Dexcel Pharma Technologies, Ltd. 
Protocol CLI/016P 
Statistical Analysis Plan 
Version: Final 
Issue Date: 15-Au -2018 
The Efficacy and Safety of Chlorhexidine Gluconate Chip (PerioChip®) in Therapy of 
Peri-implantitis 
Chlorhexidine 
(Peri0Ch1p®) 
Gluconate 
Chip 
Protocol Ref: CLl/016P 
Final Version 
Date effective: 15-Aug-2018 
Previous versions 
Draft 1: 27-Apr-14 
Draft 2: 28-May-14 
Final: 15-Aug-2018 
PROPRIETARY AND CONFIDENTIAL 
Page 1 of 19 


Medistat 
Protocol CL/1016P 
SUMMARY OF SECTIONS 
1. ABBREVIATIONS ................................................................................................................ 3 
2.INTRODUCTION ................................................................................................................... 4 
2.1 
Objectives 
4 
2.2 
Design 
4 
2.3 
Responsibilities 
6 
2.4 
Study Populations 
6 
2. 5 
Primary Efficacy Endpoint 
6 
2.6 
Secondary Efficacy Endpoints 
7 
2. 7 
Safety Analysis 
7 
2.8 
Sample size 
7 
2.9 
Interim Analyses 
8 
3. Statistical methods ............................................................................................................... 8 
3.1 
General 
8 
3.2 
Data Summaries 
9 
3.3 
Continuous 
9 
3.4 
Categorical 
9 
3.5 
Protocol Deviations 
9 
4. Analysis Plan ...................................................................................................................... 9 
4.1 
Introduction 
9 
4.1 
Disposition of Subjects 
9 
4.2 
Baseline Comparability 
10 
4.2.1 
Intent ................................................................................................................. 10 
4.2.2 
Variables Considered ........................................................................................ 10 
4.3 
Primary Efficacy Endpoint 
11 
4.3.1 
Principal Analysis .............................................................................................. 11 
4.4 
Secondary Efficacy Endpoints 
11 
4.5 
Multiplicity 
12 
4.6 
Exploratory Analysis 
12 
5. Appendix I: TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................. 15 
6. Appendix II: LISTINGS TO BE INCLUDED IN THE CLINICAL STUDY REPORT ............... 18 
Chlorhexidine 
(Peria Chip®) 
G/uconate 
Chip 
Page 2 of 19 
PROPRIETARY AND CONFIDENT/AL 


Medistat 
ABBREVIATIONS 
AE 
ATC 
BOP 
RAL 
Ch/or/Jexidine 
(PerioChip®) 
Cl 
GI 
ICH 
ITT 
Mg 
mlTT 
mm 
PD 
pp 
R 
WHO 
G/uconate 
Adverse Event 
Anatomical Therapeutic Chemical 
Bleeding on Probing 
Relative Attachment Level 
Confidence Interval 
Gingival Index 
International Conference on Harmonisation 
Intent to Treat 
Milligram 
Modified Intent to Treat 
Millimeters 
Probing Pocket Depth 
Per Protocol 
Recession 
World Health Organization 
Chip 
PROPRIETARY AND CONFIDENTIAL 
Protocol CL/1016P 
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Medistat 
1. INTRODUCTION 
1.1 
Objectives 
Protocol CL/1016P 
This document details the statistical analysis that will be performed for the Dexcel Pharma 
Technologies, Ltd. study CLl/016P. The statistical methods described in the SAP are elaboration 
of the statistical section included in the study protocol. 
The primary objective of the study is to compare the mean probing Pocket Depth (PD) reductions 
(absolute change) for the selected target implant/sat week 24 compared to baseline. 
The secondary objectives of the study are: 
• 
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 
The exploratory objectives of the study are: 
• 
PD, BOP and Relative Attachment Levels (RAL) measurements at week 24 compare to 
baseline in Responders patients. Responder 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 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. 
The safety objective of the study is to assess the safety of the PerioChip®. 
1.2 Design 
This study is a multi-center, randomized, single-blind masking, parallel, two-arm clinical study. 
The study duration will be 25-28 weeks (6 months) and will comprise a total of 1 O 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). 
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, for the first 12 weeks. 
Treatment 2 - Subgingival debridement. 
Chlorhexicline 
(Peri0Ch1j)®) 
Gluconate 
Chip 
PROPRIETARY AND CONFIDENTIAL 
Page 4 of 19 


Medistat 
Protocol CL//016P 
These 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. 
All pocket measurements (PD, BOP and R) and chip insertions will be made in the same order 
of procedures every time. 
The same examiner will perform all the measurements during the study. 
The 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). 
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. 
lmplant/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 employ 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 1 O 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. 
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. 
C/Jlor/Jexic/ine 
(PerioC/Jip®) 
Gluconate 
C/Jip 
Page 5 of 19 
PROPRIETARY AND CONFIDENTIAL 


Medistat 
Protocol CL/1016P 
The Subgingival debridement procedure will be employ twice: at baseline (visit 2) and after 3 
months, at visit 8. 
1.3 Responsibilities 
Medistat on behalf of the Sponsor (Dexcel Pharma Technologies, Ltd.) will conduct the statistical 
analysis. 
1.4 Study Populations 
Intent-to-treat (ITT) population 
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. 
Safety population 
Safety population will be the same as ITT population and will be used for safety analyses. 
Modified-Intention-to-Treat (mlTT) population 
All patients in the ITT population with no major protocol violations, used to confirm the 
assessments related to efficacy. 
Per Protocol (PP) Population 
All patients in the ITT population who completed the study according to the protocol and with no 
major protocol violations. Subjects who exceeded the time window allowed between visits as 
described in the protocol, will be excluded from the PP cohort: 
The allowances between screening (visit 1) and baseline (visit 2) should not exceed 14± 7 days 
The allowances for visits 3, 4, 5, 6, 7 and 8 should not exceed 14±4 days 
The allowances between visit 8 and visit 9 should not exceed 28±4 days 
The allowances between visit 9 and visit 1 O should not exceed 56±1 O days 
Additional PP population (PP2) will be defined, based on different time window allowances: 
No limitation for the allowances between screening (visit 1) and baseline (visit 2) 
The allowances for visits 3, 4, 5, 6, 7 and 8 should not exceed 14+7 days or 14-4 days 
The allowance between visit 8 and 9 should not exceed 28±7 days 
The allowance between visit 9 and 10 should not exceed 56+28 days or 56-14 days 
1.5 Primary Efficacy Endpoint 
At week 24, compared to baseline, the mean probing Pocket Depth (PD) reductions (absolute 
change) for the selected target implanUs will be used as the primary efficacy endpoint 
Chlorhexidine 
(PerioChip®} 
G/uconate 
Chip 
Page 6 of 19 
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Medistat 
Protocol CL/1016P 
1.6 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 Analyses 
The tertiary efficacy endpoints will include: 
• 
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 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 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. 
1.7 Safety Analysis 
Safety will be evaluated based on AEs and oral inspections recorded at each visit. 
1.8 Sample size 
A total of 290 patients will be randomized, in order to analyse at least 123 patients for the 
Subgingival debridement + PerioChip® arm and at least 123 patients for the Subgingival 
debridement alone arm. 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 Ila 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. 
The sample size is determined based on relevant literature (Machtei et al. 2012) and previous 
phase Ila study (CLl/013P) that demonstrated substantial improvement (trend toward significant, 
p = O. 07) in PD reduction between PerioChip® and Placebo chip. 
The rationale 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 !-test with a 0.05 two-
sided significance level. 
Chlorhexidine 
(Peri0Ch1p®) 
G/uconate 
Chip 
Page 7 of 19 
PROPRIETARY AND CONFIDENTIAL 


Medistat 
Statistical significance level for all statistical analysis was set to 5%. 
1.9 Interim Analyses 
No interim analyses are planned. 
2. 
STATISTICAL METHODS 
2.1 
General 
Protocol CL/1016P 
The change in efficacy parameters, PD, R and RAL during the 24 week treatment, will be 
modelled using a linear-mixed model (SAS® 9.3 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 o,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% Confidence Interval (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 implanUs measured at each visit will be analyzed by a Chi-square 
test or Fisher's exact test as is appropriate. 
Chlorhexicline 
(Peria Chip®) 
Gluconate 
Chip 
Page 8 of 19 
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Medistat 
Protocol CL/1016P 
Logistic regression will be applied for testing the above differences with adjustment to smoking 
status, Gingival Index (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, Rand RAL with time as a fixed repeated covariate will be used to 
reveal the changes of these parameters over time. 
All treatment comparison will be two-sided at the 0.05 level of significance. 
The data will be analyzed using the SAS® version 9.3 (SAS Institute, Cary North Carolina) or 
higher version. 
2.2 Data Summaries 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. 
2.3 Continuous 
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. 
2.4 Categorical 
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. 
2.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2. 
3. 
ANALYSIS PLAN 
3.1 
Introduction 
All summaries and analyses documented below will be presented in the final integrated 
statistical/clinical report and tables that will be based on the E3 guidelines published by ICH. 
However, it is noted here that no analysis plan prepared in advance of database lock can be 
absolutely definitive and so the final report may contain additional tables or statistical tests if 
warranted by the data obtained. The justification for any such additional analyses will be fully 
documented in the final report. 
3.1 
Disposition of Subjects 
The number of subjects within each analysis population will be summarized. The number of 
subjects entering each phase of the study will be tabulated along with number of subjects who 
withdraw. The calculated percentages will be based on the number of subjects in that particular 
Chlorhexidine 
{Peno Chip®) 
Gluconate 
Chip 
Page 9 of 19 
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Medistat 
Protocol CL/1016P 
phase of the study. The phase of the study, timing of withdrawal and reasons for withdrawal will 
be summarised by treatment (Table 14.1.1 ). 
3.2 Baseline Comparability 
3.2.1 
Intent 
Subject demographics and baseline characteristics will be presented for all subjects within the 
safety population. The comparability of treatment groups with respect to subject demographics 
and baseline characteristics will be assessed in a descriptive manner, but no formal statistical 
testing will be performed. 
3.2.2 Variables Considered 
Standard continuous or categorical variable summaries will be presented overall and by 
treatment group for the following variables. 
Demography (Table 14.1-3) 
• 
Age at screening visit (years) 
• 
Height and weight at screening 
• 
BMI at screening 
• 
Gender (Male, Female) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not recorded) 
• 
Race (American Indian or Alaskan Native, Asian, Black or African American, Native 
Hawaiian/Pacific Islander, White, Other, Not recorded) 
Medical History (Tables 14.1-4 to 14.1-5) 
• 
Relevant previous and ongoing medical history (Yes/No). 
• 
Tobacco use history 
Separate tabulations will be produced for previous and ongoing conditions using the MedDRA 
primary system organ class and preferred term (Version 13.1 ). 
Concomitant medications (Tables 14.3.3-11 to 14.3.3-12) 
Concomitant medications ongoing at time of first dose of study medication will be coded. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Chlorhexicline 
(PerioChip®) 
G!uconate 
Chip 
Page 10 of 19 
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Medistat 
Protocol CL/1016P 
Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. 
3.3 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. The 
analysis of the primary endpoint will be based on ITT, mlTT, PP and PP2 populations, by-pocket 
and by-patient analyses. 
3.3.1 Principal Analysis 
The change in efficacy parameters, PD, during the 24 week treatment, will be modelled using a 
linear-mixed model (SAS® 9.3 Mixed Procedure) with treatment as fixed factors. Patient and 
pocket will be entered as random effects. Interactions between treatment and the covariates 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, site and baseline measurements. The adequacy of 
the Mixed Model will be checked and if needed a normalizing transformation will be performed. 
Contrasts with 95% C.I. for the difference between the changes by week 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 Median test for independent samples (as is 
appropriate) will be applied for testing the statistical significance of the difference in the PD 
decrease from baseline between the study groups. 
Categorical analysis will be applied for PD change at week 24, using median value calculated 
overall subjects. Logistic regression will be applied for categorical PD change with adjustment 
to baseline measure, age, gender, site and smoking status. Interactions between treatment and 
the covariates will be tested and if found statistically significant, will be added to the model. 
Analysis of Variance (ANOVA) will be applied for analysing PD change at week 24, with 
adjustment to baseline measure, age, gender, site and smoking status. Interactions between 
treatment and the covariates will be tested and if found statistically significant, will be added to 
the model. 
Missing data will be handled for imputation the primary endpoint data using the MMRM model 
(Mixed-effect Model for Repeated Measures), which is based on MAR (missing at random) 
assumption. 
3.4 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
Chiorhexicline 
(Peria Chip®) 
Gluconate 
Chip 
PROPRIETARY AND CONFIDENTIAL 
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Medistat 
Protocol CL/1016P 
• 
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. 
The analysis of the secondary endpoints will be based on ITT, mlTT, PP and PP2 populations. 
Multiplicity 
The secondary efficacy 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. 
3.5 Exploratory Analysis 
• 
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. 
The statistical methods described in the subsequent paragraphs will be used for analysis of both 
primary and secondary endpoints. The change in efficacy parameters, PD, R and RAL during 
the 24 week treatment, will be modelled using a linear-mixed model (SAS® 9.3 Mixed Procedure) 
with treatment as fixed factors. Patient and pocket will be entered as random effects. The 
interactions between treatment and the covariates will be tested and if achieve statistical 
Chlor/Jexidine 
(PerioC/1ip®) 
G/uconate 
Chip 
Page 12 of 19 
PROPRIETARY AND CONFIDENTIAL 


Medistat 
Protocol CL/1016P 
significance of s5% 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 between the changes by week 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 Median test for independent samples (as is 
appropriate) will be applied for testing the statistical significance of the difference in the 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. 
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 implanUs 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, Rand RAL with time as a fixed repeated covariate will be used to 
reveal the changes of these parameters over time. 
Ch/or/Jexicline 
(PerioC/Jip®) 
G/uconate 
Chip 
Page 13 of 19 
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Medistat 
Protocol CL/1016P 
3.6 Safety analysis 
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 implantls that can be 
attributed to treatment. 
Chlorhexicline 
(PerioChip®} 
Giuconate 
Chip 
Page 14 of 19 
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Protocol CL/1016P 
4. 
APPENDIX I: TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Table 
number 
Table Title 
14.1 Demographics Data 
14.1-1 
14.1-2 
14.1-3 
14.1-4 
14.1-5 
Disposition of subjects 
Analysis population 
Demographic data and Baseline Characteristics 
Tobacco Use History 
Medical History 
14.2 Efficacy Data 
14.2-1 
14.2-2 
14.2-2.1 
14.2-2.2 
14.2-2.3 
14.2-2.4 
14.2-2.5 
14.2-2.6 
14.2-2.7 
14.2-2.8 
14.2-3 
14.2-3.1 
14.2-3.2 
14.2-3.3 
14.2-3.4 
14.2-3.5 
14.2-3.6 
14.2-3.7 
14.2-3.8 
Chlorl1exidine 
(PerioChip®) 
Summary Statistics of Pocket Depth (PD) at baseline and weeks 8, 12, 16, 
and 24 for target sites 
Primary Endpoint Analysis 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by-pocket, ITT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by-pocket, mlTT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by-pocket, PP) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by-pocket, PP2) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by-patient, ITT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by• patient, mlTT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by- patient, PP) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants (by• patient, PP2) 
Secondary Endpoint Analysis 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants, patients with PD 6-8 mm at baseline (by-pocket, ITT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants, patients with PD 6-8 mm at baseline (by-pocket, mlTT) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants, patients with PD 6-8 mm at baseline (by-pocket, PP) 
Summary Statistics of Pocket Depth (PD) Change at week 24 for target 
implants, patients with PD 6-8 mm at baseline (by-pocket, PP2) 
Summary Bleeding on Probing (BOP) Change at week 16 and 24 for target 
implants (by-pocket, ITT) 
Summary Bleeding on Probing (BOP) Change at week 16 and 24 for target 
implants (by-pocket, mlTT) 
Summary Bleeding on Probing (BOP) Change at week 16 and 24 for target 
implants (by-pocket, PP) 
Summary Bleeding on Probing (BOP) Change at week 16 and 24 for target 
implants (by-pocket, PP2) 
Gluconate 
Chip 
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Table 
number 
14.2-3.9 
14.2-3.10 
14.2-3.11 
14.2-3.12 
14.2-4 
14.2-4.1 
14.2-4.2 
14.2-4.3 
14.2-4.4 
14.2-4.5 
14.2-4.6 
14.2-4.7 
14.2-4.8 
14.2-4.9 
14.2-4.10 
14.2-4.11 
Protocol CL/1016P 
Table Title 
Summary Statistics of Pocket Depth (PD) Change at week 16 for target 
implants (by-pocket, ITT) 
Summary Statistics of Pocket Depth (PD) Change at week 16 for target 
implants (by-pocket, mlTT) 
Summary Statistics of Pocket Depth (PD) Change at week 16 for target 
implants (by-pocket, PP) 
Summary Statistics of Pocket Depth (PD) Change at week 16 for target 
implants (by-pocket, PP2) 
Exploratory Analyses 
Changes of Pocket Depth (PD) at week 24 from baseline for responder 
patients (by-pocket, ITT) 
Changes of Relative Attachment Levels (RAL) at week 24 from baseline 
for responder patients (by-pocket, ITT) 
Changes of Bleeding on Probing (BOP) at week 24 from baseline for 
responder patients (by-pocket, ITT) 
Summary statistics of Pocket Depth (PD) change at weeks 8 and 12 for 
target implants (by-pocket, ITT) 
Summary statistics of Bleeding on Probing (BOP) change at weeks 8 and 
12 for target implants (by-pocket, ITT) 
Summary of Recession (R) Changes at weeks 8, 12, 16 and 24 for target 
implants (by-pocket, ITT) 
Summary of Relative Attachment Levels (RAL) Changes at weeks 8, 12, 
16 and 24 for target implants (by-pocket, ITT) 
Summary of Pocket Depth (PD) Changes at weeks 8, 12, 16 and 24 for all 
aspects (by-pocket, ITT) 
Summary of Bleeding on Probing (BOP) Changes at weeks 8, 12, 16 and 
24 for all aspects (by-pocket, ITT) 
Summary of Relative Attachment Levels (RAL) Changes at weeks 8, 12, 
16 and 24 for all aspects (by-pocket, ITT) 
Summary of Recession (R) Changes at weeks 8, 12, 16 and 24 for all 
aspects (by-pocket, ITT) 
14.3 Safety Data 
14.3.1-1 
14.3.1-1 
14.3.1-2 
14.3.1-3 
14.3.1-4 
14.3.2 
14.3.2-1 
14.3.3 
14.3.3-1 
14.3.3-2 
Chlorhexidine 
(PerioChip®) 
Summary Incidence and Frequency of Adverse Events by Treatment (ITT) 
(Part 1 of 2) 
Summary Incidence and Frequency of Adverse Events by Treatment (ITT) 
(Part 2 of 2) 
Adverse Events by SOC and PT (ITT) 
Adverse Events by SOC, PT and relationship to study drug (ITT) 
Adverse Events by SOC, PT and severity (ITT) 
Listings of Deaths, other serious and significant AEs 
Serious Adverse Events 
Other Safety Assessments 
Oral Inspection and Treatment Results by Visit 
Pocket Examination at Screening (All pockets, by-patient) 
Gluconate 
Chip 
PROPRIETARY AND CONFIDENTIAL 
Page 16 of 19 


Medistat 
Table 
number 
14.3.3-3 
14.3.3-4 
14.3.3-5 
14.3.3-6 
14.3.3-7 
14.3.3-8 
14.3.3-9 
14.3.3-10 
14.3.3-11 
14.3.3-12 
14.3.3-13 
14.3.3-14 
C/Jlor/Jexidine 
(PerioC/Jip®) 
Protocol CL/1016P 
Table Title 
Pocket Examination at Screening (All pockets, by-implant) 
Pocket Examination at Baseline 6-8 mm in depth (All pockets, by-patient) 
Pocket Examination at Baseline 6-8 mm in depth (All pockets, by-implant) 
Plaque and Gingival Exam by visit 
Pregnancy test results by visit 
Oral Hygiene Instruction by visit 
Supra-gingival scaling, Supra-gingival plaque removal and Sub-gingival 
debridement by Visit 
Chip Insertion by visit 
Any change in AE since last visit 
Any dental change since last visit 
Any change in concomitant medication since last visit 
Any Concomitant medications 
Giuconate 
C/Jip 
PROPRIETARY AND CONFIDENTIAL 
Page 17 of 19 


Medistat 
Protocol CL/1016P 
5. 
APPENDIX II: LISTINGS TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Listing 
number 
Listing Title 
16.2.1 Subject Disposition 
Listing 16.2.1-1: Subject Disposition 
Listing 16.2.1-2: Visit dates per subject 
16.2.2 Protocol Deviations 
Listing 16.2.2-1: Inclusion Criteria 
Listing 16.2.2-2: Exclusion Criteria 
Listing 16.2.2-3: Other deviations 
16.2.3 Subjects excluded from the efficacy analysis 
Listing 16.2.3-1: Subjects excluded from the efficacy analysis 
16.2.4: Demographic data and Baseline Assessments 
Listing 16.2.4-1: Demographic Data 
Listing 16. 2.4-2: Tobacco History 
Listing 16.2.4-3: Relevant Medical History 
Listing 16.2.4-4: Eligibility Confirmation at Screening 
16.2.6 Individual Efficacy response data 
Listing 16.2.6-1 Pocket Examination 
16.2.7 Adverse Event 
Listing 16. 2. 7-1: Adverse Events 
Listing 16.2.7-2: Serious Adverse Events 
16.2.8 Listings of individual laboratory measurements and other assessments by subject 
Listing 16.2.8-1: Oral Inspection and treatment need assessment 
Listing 16.2.8-2: Plaque and Gingival Examination 
Listing 16.2.8-3: Oral Hygiene 
Listing 16.2.8-4: Supra-Gingival Scaling 
Listing 16.2.8-5: Supra-Gingival Plaque Removal 
Listing 16.2.8-6: Subgingival Debridement 
Listing 16.2.8-7: Hygienic Phase Program 
Listing 16.2.8-8: Chip Insertion 
Listing 16.2.8-9: Pregnancy, Concomitant Medication, Adverse Event, and Dental Treatment by 
visit 
Listing 16.2.8-10: Additional Comments 
Listing 16.2.8-11: Concomitant Medication 
Chforhexidine 
(PerioChip®) 
G/uconate 
Chip 
PROPRIETARY AND CONFIDENTIAL 
Page 18 of 19 


Medistat 
Titre: 
Reference: 
Version: 
Date effective: 
Author; 
Author's. signature 
Approval for Implementation of 
Statistical AnaJysls Ptan 
The Efficacy and Safety of Chlorhexfdfne 
Gluconate Chip (PerioChip5 ) In Therapy of Peri-
lmplantltis 
Cll/016P SAP 
Final 
15-Aug-2018 
2 
Reviewer 
9 
Protocol CL/1016P 
The above Statistical Analysis Plan has been reviewed and approved by the SponfJor. 
Name of Approver: 
Position: 
Signature: 
Name of Approver: 
• 
Date:------· 
Position: 
a 
' 
Signature: 
Date: 
Chlorhexidine 
(PerioChip®) 
Gluconate 
Chip 
Page 19 of 19 
PROPRIETARY AND CONFIDENTIAL 

Prot_001.pdf: 
 
 
Dexcel Pharma Technologies Ltd. 
 
The Efficacy and Safety of Chlorhexidine Gluconate 
Chip (PerioChip®) in Therapy of Peri-implantitis 
 
 
 
 
Protocol Number: 
CLI/016P 
 
 
EudraCT Number:  
2013-000383-28 
 
 
NCT Number 
NCT02080403 
 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
 
29/August/2017 
Version: 
 
8  


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 1 
Protocol # CLI/016P –version 8 
 
 
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 
 
EudraCT Number: 
2013-000383-28 
 
Sponsor: 
 
Dexcel Pharma Technologies Ltd. 
Date: 
 
29 August 2017 
Version: 
 
8  


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 2 
Protocol # CLI/016P –version 8 
 
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)) ........................ 30 
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) ........................................ 36 
6.2.4 Visits 9 (Week 16) ............................................................................................... 37 
6.2.5 Last Visit/ Early Withdrawal Visit (Week 24) ..................................................... 38 
6.3 
Other Study Considerations ........................................................................................... 38 


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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 ............................................................................... 39 
7.1 
Patient Assignment ........................................................................................................ 39 
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 ...................................................................... 43 
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 ........................................................................................ 48 
9.3 
Reporting of Serious Adverse Events ............................................................................ 48 
9.4 
Patient Removal from Study due to Adverse Events..................................................... 49 
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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 4 
Protocol # CLI/016P –version 8 
 
11.5 Monitoring ..................................................................................................................... 55 
11.6 Study Documentation and Data Storage ........................................................................ 55 
11.7 Quality Control and Quality Assurance......................................................................... 56 
12. 
REFERENCES ....................................................................................................................... 57 
 
 


CONFIDENTIAL
Chlorhexidine Gluconate Chip
PROTOCOLAPPROVALS
Dexcel Pharma Technologies Ltd.
Clinical Protocol
Protocol Title: The Efficacy and safety of Chlorhexidine Gluconate Chip
(PerioChip'") in Therapy ofPeri-implantitis
Protocol Number: CLI/O16P
Sponsor:
Dexcel Pharma Technologies Ltd.
1 Dexcel St., Or-Akiva, 3060000, Israel
Representative:
T
III
Signature:
_
Principal Investigator's Agreement:
Date:
/ have careFully read and understood the provisions of this protocol, and
/ am prepared
to Follow them in every detail in the conduct oFthis study.
Principal Investigator Name:
_
29Augus12017
Signature:
_
Page 5
Date:
_
Protocol # CLI/O16P-version 8


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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 6 
Protocol # CLI/016P –version 8 
 
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 
August 29th, 2017 
 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
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. The patient is of age and is capable of understanding 
the nature, significance and implications of the clinical trial and to form a rational intention in 
the light of the facts. 
2. 
Good general health. 


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
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 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 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. In case the 
investigator advises the patient that antibiotic therapy is required during the course of the study, 
the patient should be excluded from further participation.  
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 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 9 
Protocol # CLI/016P –version 8 
 
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. 
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 5mm 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 


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 10 
Protocol # CLI/016P –version 8 
 
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 
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. 


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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 11 
Protocol # CLI/016P –version 8 
 
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 
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.  
 
 
 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 12 
Protocol # CLI/016P –version 8 
 
 
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 
 
 
 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
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Protocol # CLI/016P –version 8 
 
 
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  


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 14 
Protocol # CLI/016P –version 8 
 
 
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 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 15 
Protocol # CLI/016P –version 8 
 
antiseptic 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-


CONFIDENTIAL  
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
Clinical Protocol 
29August2017 
Page 16 
Protocol # CLI/016P –version 8 
Jansaker, 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 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 17 
Protocol # CLI/016P –version 8 
 
reduction in periodontopathic organisms and improved clinical results. These 
results are in 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-


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 18 
Protocol # CLI/016P –version 8 
 
implantitis patients.  Given these promising results with peri-
implantitis 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-


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 19 
Protocol # CLI/016P –version 8 
 
infective treatment of 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 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 20 
Protocol # CLI/016P –version 8 
 
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 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 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 21 
Protocol # CLI/016P –version 8 
 
direction, in combination with bleeding and/or suppuration on probing and a peri-implant 
Probing Depth (PD) of 5-8 mm.  
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 study.   
The 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 5mm or PD reduction of at least 2 mm from baseline PD of 
6-8mm 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-


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 22 
Protocol # CLI/016P –version 8 
 
buccal, mid-buccal, disto-buccal and mid-lingual), surrounding the selected target 
implant/s, compared to baseline. 
 
5. STUDY POPULATION 
5.1  Number of Patients 
A total of 290 patients, with symptoms of peri-implantitis, will be 
randomized, into one of the study arms; At least 123 patients for the 
Subgingival debridement + PerioChip® arm, and at least 123 patients for the 
Subgingival debridement arm 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. The patient is of age 
and is capable of understanding the nature, significance and 


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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
implications of the clinical trial and to form a rational intention in 
the light of the facts. 
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 
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 


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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
Page 24 
Protocol # CLI/016P –version 8 
 
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. In case the 
investigator advises the patient that antibiotic therapy is required 
during the course of the study, the patient should be excluded from 
further participation.  
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), 
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 screening 
visit. 


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
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 
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.  


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
 Patient receives emergency dental treatment including target implant 
explantation which may interfere with the assessment of study endpoints. 
 Despite participating in the study, patient, who in the opinion of the 
investigator displays an inadequate response to subgingival debridement 
and chemical disinfection during the study period, may be entitled to 
surgical therapy of peri-implantitis.  
 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. 
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 Non-proprietary 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 


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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
29August2017 
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Protocol # CLI/016P –version 8 
 
Chemical classification system. 
Patients will be instructed to refrain from: 
 Any use of Chlorhexidine oral rinses/mouthwashes during the study 
without consulting the Investigator in advance.  
 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.  
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®) 


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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. 
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. 


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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 


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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.  
 
 


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6.2.1.1 Hygienic Phase Therapy 
The period between screening visit and baseline visit which 
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 


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the PD measurement. The RAL calculation will be performed 
by the Study Statistician. 
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. 


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Protocol # CLI/016P –version 8 
 
6.2.2  Baseline Visit (Week 0) 
At Baseline visit (Week 0), patients will return to the clinic for the 
following procedures: 
 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: 


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Protocol # CLI/016P –version 8 
 
 a) The deepest pocket; 
 b) Implant located between natural teeth or in edentulous ridge; 
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. 


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 Safety assessment including AEs, pregnancy assessment by 
questioning the patient (where applicable), recording of concomitant 
medications changes and dental treatment.  
 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. 
 


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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 
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 - Chip/s insertion only in those target pockets 
which had previously received a chip . 
For visits 6 and 8, chip insertion will follow pocket depth 
verification of ≥ 5 mm as measured during the visit. 
 
For visits 3, 4, 5 and 7,  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. 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 


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Clinical Protocol 
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Protocol # CLI/016P –version 8 
 
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. 
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. 


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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.  
 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. 


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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 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 


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Protocol # CLI/016P –version 8 
 
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 
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 


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Protocol # CLI/016P –version 8 
 
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. 
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. 


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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 
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 5mm or PD reduction of at least 2 mm from baseline 
PD of 6-8mm 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. 


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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. 
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 


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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. 
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% 


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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 
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 


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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. 
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 


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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, 
 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 


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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 
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. 


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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. 
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. 


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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 רפואי בלבד 
يستعمل
 
فقط  للتجارب الطبية 
Each chip blister will include the following information in English only and 
the wording "For Clinical Trial Use Only” in English, Hebrew and Arabic:  
 
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 
يستعمل
 
فقط  للتجارب الطبية 
 
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. 
 


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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 
Anweisungen zur Verabreichung sind dem Informationsblatt zur 
Dosierung und Verabreichung zu entnehmen.  
Name des Forschers:  
 
 Studienort  Nr: ____ 
Randomisierungs-Nr.:  
Screening Nr.:       Kürzel: ____ 
Lagerbedingungen: Nicht über 30 °C 
Ch.-B.: 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 
Ch.-B.: 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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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 


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assign the 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 (pp. 365-369). London: Quintessence. 
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 
dioxide surfaces with and without functionalization with Chlorhexidine. Journal 
of Biomedical Materials Research Part A, 90(4), 993-998. 
3) Briner, W.W., Grossman, E., & Buckner, R.Y., (1986). Assessment of 
susceptibility of plaque bacteria to Chlorhexidine after six months’ oral use. 
Journal of Periodontal Research, 21(Suppl 16), 53-59.  
4) Chlorhexidine Toxicity in dogs and Monkeys:  Reported Project #70S-565.  
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 
Chlorhexidine in dentistry Journal of the American Dental Association 112(6), 
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 
Journal of Dentistry, 10(2), 107-110. 
8) Goh, C.L., (1989). Sensitivity to topical antimicrobials (II).  Sensitizing potentials 
of some topical antimicrobials.  Contact Dermatitis, 21(3), 166-171. 
9) Gonzales, J.R., Harnack, L., Schmitt-Corsitto, G., Boedeker, R.H., Chakraborty, 
T., Domann, E., et al. (2011) A novel approach to the use of subgingival 
controlled-release chlorhexidine delivery in chronic periodontitis: a randomized 
clinical trial. Journal of Periodontology, 82(8), 1131-1139.   
10) Heasman, P.A., Heasman, L., Stacey, F., & McCracken, G.I. (2001). Local 
delivery of chlorhexidine gluconate (PerioChip) in periodontal maintenance 
patients. Journal of Clinical Periodontology, 28, 90-95. 
11) Houri-Haddad, Y., Halabi, A., & Soskolne, W.A. (2008). inflammatory response 
to chlorhexidine, minocycline HCI and doxycycline HCI in an in vivo mouse 
model. Journal of Clinical Periodontology, 35 (suppl. 8), 783-788.  
12) In vitro evaluation of the Perio Chip (chlorhexidine gluconate 2.5 mg):  
Chlorhexidine Release Profile, IND#35,524.  Submission Serial No. 001, 
Attachment 2, April 12, 1991. 
13) In-vivo Microbiological Mutagenesis Studies of Four Colgate Palmolive 
Compounds (Chlorhexidine Gluconate #3006).  Study No. RPA. 0024 Stanford 
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., et al. (1998). Adjunctive use of a subgingival controlled-release 
chlorhexidine chip reduces probing depth and improves attachment level 
compared with scaling and root planing alone. Journal of Periodontology, 69 (9), 
289-2997.  
15) Jeffcoat, M.K., Palcanis, K.G., Weatherford, T.W., Reese, M., Geurs, N.C., & 
Flashner, M. (2000) Use of a biodegradable Chlorhexidine chip in the treatment 
of adult periodontitis: Clinical and radiographic findings.  Journal of 
Periodontology, 71(2), 256-262. 
16) Kozlovsky, A., Artzi, Z., Moses, O., Kamin-Belsky, N., & Greenstein, R.B. 
(2006). Interaction of Chlorhexidine with smooth and rough types of titanium 
surfaces. Journal of Periodontology, 77(7), 1194-1200. 
17) Lindhe, J. & Meyle, J. (2008). Peri- implant diseases: Consensus report of the 
sixth european workshop on periodontology. Journal of Clinical Periodontology, 
35 (suppl. 8), 282-285. 
18) Löe, H. (1967). The gingival index, the plaque index and the retention index 
systems. Journal of Periodontology, 38(6), 610-616. 
19) Machtei, E.E., Frankenthal, S., Levi, G., Elimelech, R., Shoshani, E., Rosenfeld, 
O., et al. (2012). Treatment of peri-implantitis using multiple applications of 
chlorhexidine chips: a double-blind, randomized multi-centre clinical trial. 
Journal of Clinical Periodontology, 39(12), 1198-1205. 
20) Meyle, J., Ammoura, A., Hamid, H., Rolf-Hasso, B., Trinad, C., & Eugen, D. 
(2005). Sustained local delivery of chlorhexidine during initial therapy of chronic 
periodontitis. Perio, 2(2), 117-129. 
21) Morra, M., Cassinelli, C., Cascardo, G., Carpi, A., Fini, M., Giavaresi, G., et al. 
(2004). Adsorption of cationic antibacterial on collagen-coated titanium implant 
devices. Biomedicine and Pharmacotherapy, 58(8), 418- 422.  
22) Paolantonio, M., D'Angelo, M., Grassi, R.F., Perinetti, G., Piccolomini, R., Pizzo, 
G., et al.(2008). Clinical and microbiologic effects of subgingival controlled-
release delivery of chlorhexidine chip in the treatment of periodontitis: A 
multicenter study. Journal of Periodontology, 79 (2), 271-282.  
23) Perio Products.I. Clinical effects following subgingival administration of 
Chlorhexidine gluconate (2.5 mg) in a cross-linked gelatin matrix (PerioChip) in 
patients with periodontal disease (study 91-011). Clinical Study Report.  
24) Perio Products. II. Clinical effects following subgingival administration of 
Chlorhexidine gluconate (2.5 mg) in a cross-linked gelatin matrix (PerioChip) in 
patients with periodontal disease (study 91-013). Clinical Study Report. 
25) Persson, G.R., Salvi, G.E., Heitz-Mayfield, L.J., & Lang, N.P., (2006). 
Antimicrobial therapy using a local drug delivery system (Arestin) in the 
treatment of peri-implantitis. I: Microbiological outcomes. Clinical Oral Implants 
Research, 17(4), 386-393. 


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26) Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S,V, et al. 
(1976) Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient. I. Introduction and design. British Journal of Cancer, 
34(6), 585-612. 
27) Physician’s Desk Reference (PDR; 59th edition, 2005).  p. 2807 
28) Registry of Toxic Effects Chemical Substances (RTECS) (1995). 
29) Renvert S, Lessem J, Lindahl C & Svensson M. (2004), Treatment of incipient 
periimplant infections using topical minocycline microspheres versus topical 
chlorhexidine gel as an adjunct to mechanical debridement. Journal of the 
International Academy of Periodontology. 6(Suppl 4), 154-159.  
30) Renvert, S., Lessem, J., Dahle'n, G., Lindahl, C., & Svensson, M., (2006). Topical 
minocycline microspheres versus topical chlorhexidine gel as an adjunct to 
mechanical debridement of incipient peri-implant infections: A randomized 
clinical trial. Journal of Clinical Periodontology, 33(5), 362-369. 
31) Renvert, S., Roos-Jansaker, A.M., & Claffey, N., (2008). Non-surgical treatment 
of periimplant mucositis and peri-implantitis: a literature review. Journal of 
Clinical Periodontology, 35 (suppl. 8), 305-315.  
32) Renvert, S., Roos-Jansaker, A.M., Lindahl, C., Renvert, H., & Persson, G.R., 
(2007). Infection at titanium implants with or without a clinical diagnosis of 
inflammation. Clinical Oral Implants Research, 18(4), 509-516. 
33) Salvi, G.E., Persson, G.R., Heitz-Mayfield, L.J., Frei, M., & Lang, N.P., (2007). 
Adjunctive local antibiotic therapy in the treatment of peri-implantitis II: clinical 
and radiographic outcomes, Clinical Oral Implants Research, 18(3), 281-285.  
34) Schär, D., Ramseier, C.A., Eick, S., Arweiler, N.B., Sculean, A., & Salvi, G.E. 
(2013). Anti-infective therapy of peri-implantitis with adjunctive local drug 
delivery or photodynamic therapy: six-month outcomes of a prospective 
randomized clinical trial. Clinical Oral Implants Research, 24(1), 104-110.  
35) Sonis, S.T., (1998) Mucositis as a biological process: A new hypothesis for the 
development of chemotherapy-induced stomatotoxicity. Oral Oncology, 34(1), 
39-43. 
36) Sonis, S.T., & Haley, J.D., (1996). Pharmacological attenuation of chemotherapy-
induced oral mucositis. Expert Opinion on Investigational Drugs, 5(9), 1155-
1162. 
37) Stabholz, A., Sela, M.N., Friedman, M., Golomb, G., & Soskolne, A., (1986) 
Clinical and microbiological effects of sustained release chlorhexidine on 
periodontal pockets. Journal of Clinical Periodontology, 13(8), 783-788.  
38) Stabholz, A., Shapira, L., Mahler, D., Gellman, Y., Ramon, T., Dolev, E., et al. 
(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, 
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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.  
 

Prot_000.pdf: 
 
 
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  


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Clinical Protocol 
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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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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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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 
 


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
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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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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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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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Clinical Protocol 
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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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Clinical Protocol 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 14 
Protocol # CLI/016P –version 7  
 
 
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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 15 
Protocol # CLI/016P –version 7  
 
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, 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 16 
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.  


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 21 
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. 
 


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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 22 
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 


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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 
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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.  


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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. 


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02 August 2017 
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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. 


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Clinical Protocol 
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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  


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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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
 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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Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
 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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
 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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Clinical Protocol 
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Protocol # CLI/016P –version 7  
 
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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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02 August 2017 
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Protocol # CLI/016P –version 7  
 
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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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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Chlorhexidine Gluconate Chip (PerioChip®) 
 
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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 
(pp. 365-369). London: Quintessence. 
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 
dioxide surfaces with and without functionalization with Chlorhexidine. Journal of 
Biomedical Materials Research Part A, 90(4), 993-998. 
3) Briner, W.W., Grossman, E., & Buckner, R.Y., (1986). Assessment of 
susceptibility of plaque bacteria to Chlorhexidine after six months’ oral use. 
Journal of Periodontal Research, 21(Suppl 16), 53-59.  
4) Chlorhexidine Toxicity in dogs and Monkeys:  Reported Project #70S-565.  
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 
Chlorhexidine in dentistry Journal of the American Dental Association 112(6), 
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 
Journal of Dentistry, 10(2), 107-110. 
8) Goh, C.L., (1989). Sensitivity to topical antimicrobials (II).  Sensitizing potentials 
of some topical antimicrobials.  Contact Dermatitis, 21(3), 166-171. 
9) Gonzales, J.R., Harnack, L., Schmitt-Corsitto, G., Boedeker, R.H., Chakraborty, 
T., Domann, E., et al. (2011) A novel approach to the use of subgingival controlled-
release chlorhexidine delivery in chronic periodontitis: a randomized clinical trial. 
Journal of Periodontology, 82(8), 1131-1139.   
10) Heasman, P.A., Heasman, L., Stacey, F., & McCracken, G.I. (2001). Local delivery 
of chlorhexidine gluconate (PerioChip) in periodontal maintenance patients. 
Journal of Clinical Periodontology, 28, 90-95. 
11) Houri-Haddad, Y., Halabi, A., & Soskolne, W.A. (2008). inflammatory response 
to chlorhexidine, minocycline HCI and doxycycline HCI in an in vivo mouse 
model. Journal of Clinical Periodontology, 35 (suppl. 8), 783-788.  
12) In vitro evaluation of the Perio Chip (chlorhexidine gluconate 2.5 mg):  
Chlorhexidine Release Profile, IND#35,524.  Submission Serial No. 001, 
Attachment 2, April 12, 1991. 
13) In-vivo Microbiological Mutagenesis Studies of Four Colgate Palmolive 
Compounds (Chlorhexidine Gluconate #3006).  Study No. RPA. 0024 Stanford 
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., 
et al. (1998). Adjunctive use of a subgingival controlled-release chlorhexidine chip 
reduces probing depth and improves attachment level compared with scaling and 
root planing alone. Journal of Periodontology, 69 (9), 289-2997.  
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Flashner, M. (2000) Use of a biodegradable Chlorhexidine chip in the treatment of 
adult periodontitis: Clinical and radiographic findings.  Journal of Periodontology, 
71(2), 256-262. 
16) Kozlovsky, A., Artzi, Z., Moses, O., Kamin-Belsky, N., & Greenstein, R.B. (2006). 
Interaction of Chlorhexidine with smooth and rough types of titanium surfaces. 
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17) Lindhe, J. & Meyle, J. (2008). Peri- implant diseases: Consensus report of the sixth 
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(suppl. 8), 282-285. 
18) Löe, H. (1967). The gingival index, the plaque index and the retention index 
systems. Journal of Periodontology, 38(6), 610-616. 
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O., et al. (2012). Treatment of peri-implantitis using multiple applications of 
chlorhexidine chips: a double-blind, randomized multi-centre clinical trial. Journal 
of Clinical Periodontology, 39(12), 1198-1205. 
20) Meyle, J., Ammoura, A., Hamid, H., Rolf-Hasso, B., Trinad, C., & Eugen, D. 
(2005). Sustained local delivery of chlorhexidine during initial therapy of chronic 
periodontitis. Perio, 2(2), 117-129. 
21) Morra, M., Cassinelli, C., Cascardo, G., Carpi, A., Fini, M., Giavaresi, G., et al. 
(2004). Adsorption of cationic antibacterial on collagen-coated titanium implant 
devices. Biomedicine and Pharmacotherapy, 58(8), 418- 422.  
22) Paolantonio, M., D'Angelo, M., Grassi, R.F., Perinetti, G., Piccolomini, R., Pizzo, 
G., et al.(2008). Clinical and microbiologic effects of subgingival controlled-
release delivery of chlorhexidine chip in the treatment of periodontitis: A 
multicenter study. Journal of Periodontology, 79 (2), 271-282.  
23) Perio Products.I. Clinical effects following subgingival administration of 
Chlorhexidine gluconate (2.5 mg) in a cross-linked gelatin matrix (PerioChip) in 
patients with periodontal disease (study 91-011). Clinical Study Report.  
24) Perio Products. II. Clinical effects following subgingival administration of 
Chlorhexidine gluconate (2.5 mg) in a cross-linked gelatin matrix (PerioChip) in 
patients with periodontal disease (study 91-013). Clinical Study Report. 
25) Persson, G.R., Salvi, G.E., Heitz-Mayfield, L.J., & Lang, N.P., (2006). 
Antimicrobial therapy using a local drug delivery system (Arestin) in the treatment 
of peri-implantitis. I: Microbiological outcomes. Clinical Oral Implants Research, 
17(4), 386-393. 
26) Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S,V, et al. 
(1976) Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient. I. Introduction and design. British Journal of Cancer, 
34(6), 585-612. 


CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
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Protocol # CLI/016P –version 7  
 
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CONFIDENTIAL  
 
Dexcel Pharma Technologies Ltd. 
Chlorhexidine Gluconate Chip (PerioChip®) 
 
Clinical Protocol 
02 August 2017 
Page 60 
Protocol # CLI/016P –version 7