Clinical trial NCT03052842
Conditions: Dental Caries
Sponsor: Armata Pharmaceuticals, Inc.
Start date: 2017-02-09; Completion date: 2017-04-05
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Single-blind study to evaluate whether C16G2 Strip administered in multiple doses can effectively kill the bacteria in the oral cavity that cause dental caries..

Detailed description:
A single-blind, randomized, placebo-controlled, phase 2 study to evaluate oral microbiology and safety of multiple C16G2 Strip applications in male and female dental subjects 12-75 years of age.

The study will compare multiple study drug administrations of 9.2 mg, 18.4 mg, and 36.8 mg C16G2 Strip or Placebo in Study Arms 1 through 3, respectively. Enrollment of subjects in Study Arms 1 through 3 will occur sequentially in an ascending dose-escalation manner. Before dosing of study drug, eligible subjects will receive professional dental prophylaxis between Days -7 and -2. Subjects will receive 11 doses administered over approximately two weeks. Each subject will receive a single dose on Day 0, followed by 5 days of AM and PM dosing starting on Day 7. To evaluate the durability of S. mutans suppression, study subjects will be followed for microbiology for up to 1 month after the last study drug administration.

Clinic visits include Visit 1 (Screening/Days -30 to -1), Visit 2 (Prophylaxis/Day -7 to -2), Eligibility Confirmation \& Baseline Visit 3, Follow-up Visits 4-7 (Safety and Microbiology), Visits 8-17 (Study Drug Administration), Follow-up Visits 18-20 (Safety and Microbiology) and Follow-up Visits 21-22 (Microbiology only).

Arms: arm 1: Study subjects will be randomized to receive 9.2 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects). Study arm will be fully enrolled (i.e., the last subject in an arm has completed Visit 3) before enrollment is initiated in the next study arm. arm 2: Study subjects will be randomized to receive 9.2 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects). Study arm will be fully enrolled (i.e., the last subject in an arm has completed Visit 3) before enrollment is initiated in the next study arm. arm 3: Study subjects will be randomized to receive 18.4 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects). Study arm will be fully enrolled (i.e., the last subject in an arm has completed Visit 3) before enrollment is initiated in the next study arm. arm 4: Study subjects will be randomized to receive 18.4 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects). Study arm will be fully enrolled (i.e., the last subject in an arm has completed Visit 3) before enrollment is initiated in the next study arm. arm 5: Study subjects will be randomized to receive 36.8 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects). arm 6: Study subjects will be randomized to receive 36.8 mg C16G2 Strip or Placebo in a 4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects).
Interventions: intervention 1: C16G2 Strip intervention 2: Placebo Strip
Intervention descriptions: intervention 1: Antimicrobial Peptide intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
C O N F I D E N T I A L 
 
 
PROTOCOL NUMBER: 
C3J16-S205-00 
 
PROTOCOL TITLE: 
A Phase 2, Single-blind, Randomized, Placebo-controlled Study to 
Evaluate the Microbiology, Safety and Tolerability of C16G2 Strip 
Administered in Multiple Doses to Adolescent and Adult Dental 
Subjects 
 
STUDY DRUG: 
C16G2 
 
DOSAGE FORM: 
C16G2 Strip 
  
IND NUMBER: 
IND# 112,547 
 
SPONSOR: 
C3 Jian, LLC 
4503 Glencoe Avenue  
Marina del Rey, California 90292 
Contact: Siegfried Rogy, PhD 
Office: (310) 665-2928 X 232; 
Mobile: (818) 618-5774 
 
MEDICAL MONITOR: 
Marilyn R. Carlson, DMD, MD, RAC 
Agility Clinical, Inc. 
6005 Hidden Valley Road 
Carlsbad, CA 92011 
Mobile: (858) 945-7189 
 
 
DATE: 
January 25, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property of C3 Jian, LLC and is 
provided to you in confidence as an Investigator, potential Investigator, or consultant, for review by you, your staff, 
and an applicable Institutional Review Board. The information is only to be used by you in connection with authorized 
clinical study described in the protocol. You will not disclose any information to others without written authorization 
from C3 Jian, LLC. 


Protocol No. C3J16-S205-00 
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CONFIDENTIAL 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE SHEET ............................................................................................ 5 
INVESTIGATOR SIGNATURE SHEET...................................................................................... 6 
PROTOCOL SYNOPSIS FOR C3J16-S205-00 ......................................................................... 7 
ABBREVIATIONS ....................................................................................................................16 
 INTRODUCTION .................................................................................................................18 
1.1 Previous Clinical Experience ...........................................................................................18 
1.1.1 
Phase 1 ..........................................................................................................18 
1.1.2 
Phase 2 ..........................................................................................................20 
1.1.3 
Non-US Pilot Studies .....................................................................................22 
1.2 Rationale for Development of C16G2 ..............................................................................22 
1.3 Rationale for Selection of Dose & Mode of Application  ...................................................22 
1.4 Rationale for the Length of Safety Follow-up ...................................................................23 
1.5 Study Assessments and Procedures ...............................................................................24 
1.5.1 
Screening Laboratory Assessments ...............................................................24 
1.5.2 
Adverse Event Collection and Review ............................................................24 
1.5.3 
Vital Signs ......................................................................................................25 
1.5.4 
Oral Cavity Assessments & Targeted Physical Exam .....................................25 
1.5.5 
Salivary Flow Assessment .............................................................................25 
1.5.6 
Microbiology Evaluations................................................................................26 
1.6 Potential Risks to Participants .........................................................................................28 
1.7 Subject’s Duration of Participation ...................................................................................31 
 STUDY OBJECTIVES ........................................................................................................31 
 STUDY DESIGN .................................................................................................................31 
3.1 Blinding and Randomization ............................................................................................31 
3.1.1 
Randomization ...............................................................................................31 
3.1.2 
Blinding ..........................................................................................................32 
 SELECTION CRITERIA ......................................................................................................33 
4.1 Inclusion Criteria .............................................................................................................33 
4.2 Exclusion Criteria ............................................................................................................34 
 STUDY TREATMENTS .......................................................................................................35 
5.1 Study Drug ......................................................................................................................35 
5.1.1 
C16G2 Tooth Strip Formulation......................................................................35 
5.1.2 
Placebo Tooth Strip Formulation ....................................................................35 
5.1.3 
Supply, Packaging, and Labeling ...................................................................35 
5.2 Storage of Study Drug .....................................................................................................36 
5.3 Study Drug Preparation ...................................................................................................37 
5.3.1 
C16G2 or Placebo Strip Preparation ..............................................................37 
 STUDY ASSESSMENTS & PROCEDURES .......................................................................38 
6.1 Screening and Re-screening ...........................................................................................38 


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CONFIDENTIAL 
6.2 Subject Instructions .........................................................................................................38 
6.2.1 
Oral Hygiene Instructions ...............................................................................38 
6.2.2 
Diet Instructions .............................................................................................39 
6.3 Clinic Visit Schedules, Assessments & Procedures .........................................................39 
6.3.1 
Clinic Visit Schedules .....................................................................................39 
6.3.2 
Assessments & Procedures ...........................................................................39 
 ADVERSE EVENTS AND SAFETY MANAGEMENT .........................................................42 
7.1 Definition of Adverse Events ...........................................................................................42 
7.2 Assessment of Severity (Intensity) of Adverse Events .....................................................42 
7.3 Assessment of Causality (Relationship to Study Drug) ....................................................43 
7.4 Suspected Adverse Reaction (SAR) and Adverse Reaction (AR) ....................................44 
7.5 Unexpected Adverse Events ...........................................................................................45 
7.6 Withdrawal Due to Adverse Events .................................................................................45 
7.7 Serious Adverse Events ..................................................................................................45 
7.7.1 
Definition of Serious Adverse Events .............................................................45 
7.8 Procedures for Reporting and Recording Serious Adverse Events & Suspected Serious 
Adverse Reactions ..........................................................................................................46 
7.8.1 
Reporting Serious Adverse Events to the FDA and IRB .................................47 
7.8.2 
Following Adverse Events and Serious Adverse Events ................................47 
7.9 Pregnancy .......................................................................................................................47 
7.10 Management of Medical Emergency (Hypersensitivity) ................................................48 
7.11 Management of Dosing Error .......................................................................................48 
 STATISTICAL CONSIDERATIONS ....................................................................................49 
8.1 General Considerations ..................................................................................................49 
8.2 Randomization ................................................................................................................49 
8.3 Blinding ...........................................................................................................................49 
8.4 Sample Size Determination .............................................................................................49 
8.5 Analysis Sets ..................................................................................................................50 
8.6 Interim Safety Analysis ....................................................................................................50 
8.7 Statistical Analyses .........................................................................................................50 
8.7.1 
Demographics and Baseline Characteristics ..................................................50 
8.7.2 
Prior and Concomitant Medications ................................................................50 
8.7.3 
Completion of the Study and Withdrawals ......................................................50 
8.7.4 
Protocol Deviations ........................................................................................50 
8.7.5 
Safety Analysis ..............................................................................................51 
 RESPONSIBILITIES ...........................................................................................................53 
9.1 Investigator Responsibilities ............................................................................................53 
9.1.1 
Compliance with Good Clinical Practice .........................................................53 
9.1.2 
Institutional Review Board (IRB) .....................................................................53 
9.1.3 
Informed Consent ..........................................................................................53 
9.1.4 
Confidentiality ................................................................................................54 
9.1.5 
Study Files and Retention of Records ............................................................54 
9.1.6 
Study Data - Electronic Data Capture.............................................................55 
9.1.7 
Drug Accountability ........................................................................................55 
9.1.8 
Inspections .....................................................................................................55 
9.1.9 
Protocol and IRB Compliance ........................................................................55 
9.2 Sponsor Responsibilities .................................................................................................56 
9.2.1 
Protocol, Protocol Amendments, and Safety Updates ....................................56 


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CONFIDENTIAL 
9.2.2 
Monitoring of Study ........................................................................................56 
9.2.3 
Data Handling and Recording ........................................................................56 
9.2.4 
Study Report and Publication .........................................................................56 
9.3 Joint Investigator / Sponsor Responsibilities ...................................................................57 
9.3.1 
Access to Information, Quality Control and Assurance ...................................57 
9.3.2 
Withdrawal of Subjects ...................................................................................57 
9.3.3 
Study Discontinuation ....................................................................................58 
 ETHICS ...............................................................................................................................59 
10.1 Declaration of Helsinki .................................................................................................59 
10.2 Institutional Review Board ............................................................................................59 
 REFERENCES ....................................................................................................................60 
APPENDIX A: C3J16-S205-00 STUDY SCHEMATIC ..............................................................61 
APPENDIX B: SCHEDULE OF STUDY ASSESSMENTS & PROCEDURES ...........................62 
APPENDIX C: SCHEDULE OF MICROBIOLOGY ASSESSMENTS ........................................64 
APPENDIX D: CLINIC VISIT SCHEDULE ................................................................................65 
APPENDIX E: FLOSSING INSTRUCTIONS ............................................................................66 
APPENDIX F: ROUTINE MANUAL BRUSH INSTRUCTIONS .................................................67 
APPENDIX G: STUDY DRUG APPLICATION INSTRUCTIONS ..............................................68 
APPENDIX H: C16G2 AND PLACEBO STRIP APPLICATION PHOTOGRAPHIC IMAGING .69 
APPENDIX I: DECLARATION OF HELSINKI ..........................................................................72 




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CONFIDENTIAL 
INVESTIGATOR SIGNATURE SHEET 
I have read the attached protocol and agree that it contains all the necessary details for 
performing the study. 
 
I will provide copies of the protocol and the Investigator’s Brochure on the study drug, which 
was furnished to me by the Sponsor, to members of the study team responsible to me who 
participate in the study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug and the conduct of the study. 
 
Once the protocol has been approved by the Institutional Review Board (IRB), I will not modify 
this protocol without obtaining prior approval from the Sponsor and the IRB. I will submit the 
protocol modifications and/or any Informed Consent Form (ICF) and assent modifications to the 
Sponsor and the IRB, and approval will be obtained before any modifications are implemented. 
 
I understand the protocol and will work according to it, the Code of Federal Regulations, the 
principles of Good Clinical Practice (current International Conference of Harmonization [ICH] 
guidelines), and the Declaration of Helsinki (1964) including all amendments up to and including 
the Fortaleza, Brazil revision (2013). 
 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Investigator's Name and Title (print) 
 
Date 
 
 
 


Protocol No. C3J16-S205-00 
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CONFIDENTIAL 
PROTOCOL SYNOPSIS FOR C3J16-S205-00 
Protocol Number: 
C3J16-S205-00  
Protocol Title: 
A Phase 2, Single-blind, Randomized, Placebo-controlled Study to 
Evaluate the Microbiology, Safety and Tolerability of C16G2 Strip 
Administered in Multiple Doses to Adolescent and Adult Dental Subjects 
Study Design: 
A single-blind, randomized, placebo-controlled, phase 2 study to evaluate 
oral microbiology and safety of multiple C16G2 Strip applications in male 
and female dental subjects 12-75 years of age. 
The study will compare multiple study drug administrations of 9.2 mg, 
18.4 mg, and 36.8 mg C16G2 Strip or Placebo in Study Arms 1 through 3, 
respectively. Enrollment of subjects in Study Arms 1 through 3 will occur 
sequentially in an ascending dose-escalation manner. Before dosing of 
study drug, eligible subjects will receive professional dental prophylaxis 
between Days -7 and -2. Subjects will receive 11 doses administered over 
approximately two weeks. Each subject will receive a single dose on 
Day 0, followed by 5 days of AM and PM dosing starting on Day 7. To 
evaluate the durability of S. mutans suppression, study subjects will be 
followed for microbiology for up to 1 month after the last study drug 
administration. 
Clinic visits include Visit 1 (Screening/Days -30 to -1), Visit 2 
(Prophylaxis/Day -7 to -2), Eligibility Confirmation & Baseline Visit 3, 
Follow-up Visits 4-7 (Safety and Microbiology), Visits 8-17 (Study Drug 
Administration), Follow-up Visits 18-20 (Safety and Microbiology) and 
Follow-up Visits 21-22 (Microbiology only).  
Subjects enrolled in all study arms will be assessed for safety and 
microbiology parameters. For details on study schedules including dosing 
and microbiology information refer to Appendix A. Details on study 
assessments & procedures for all study arms are provided in Appendix B. 
For microbiology assessments in all study arms refer to Appendix C. 
Objectives: 
 
Primary Objectives 
 
To assess the targeted antimicrobial activity of C16G2 Strip 
administration as measured by a reduction in Streptococcus 
mutans in saliva and dental plaque  
 
To assess total bacteria in saliva and dental plaque post study drug 
administration 
Secondary Objective  
 
To evaluate the safety and tolerability of multiple C16G2 Strip 
administrations in adolescent and adult dental subjects 
Subject Population: 
Approximately 30 male and female subjects 12-75 years of age, inclusive 
at the time the Informed Consent Form or Assent is signed. 


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CONFIDENTIAL 
Duration of Study: 
Estimated duration of study from first subject in (FSI) to last subject out 
(LSO) is approximately 3.5 months. The maximum subject’s duration of 
participation will be 2.5 months. 
Study Arms / 
Treatment / 
Randomization 
The study will enroll subjects into three study arms. Approximately 
30 subjects will receive three doses of study drug (9.2 mg, 18.4 mg, 
36.8 mg C16G2 Strip or Placebo), for details see Table below. Subjects 
who do not return for assessments after study drug administration for any 
reason may be replaced at the Sponsor’s discretion. 
Study subjects will be randomized to receive C16G2 or Placebo Strip, in a 
4:1 allocation ratio (8 C16G2 Strip subjects: 2 Placebo Strip subjects) for 
each of the three study arms. Subjects will be enrolled into one of the three 
study arms and the arms will enroll sequentially. Each study arm will be 
fully enrolled (i.e., the last subject in an arm has completed Visit 3) before 
enrollment is initiated in the next study arm. 
After confirmation of study eligibility, subjects will be randomized at Visit 3 
(Day 0) by authorized study staff according to the master randomization 
schedule from the Sponsor’s study statistician. The randomization 
schedule and associated documentation will be kept in a secure location. 
C3J16-S205-00 Study Drug Schedule 
 
C16G2 
Subjects 
Placebo 
Subjects 
Mode of 
Application 
Days of 
Study Drug 
Admin. 
C16G2 
 milligram 
(mg) 
Study Arm 1 
8 
2 
Strip 
1 
9.2 
Study Arm 2 
8 
2 
Strip 
1 
18.4 
Study Arm 3 
8 
2 
Strip 
1 
36.8 
  
Blinding/Unblinding 
The study will be conducted in a single-blind, placebo-controlled manner. 
All study subjects will be blinded to the treatment assignment, while the 
Investigator, study staff/clinicians and the Sponsor’s assigned team 
members (e.g., the Clinical Monitor and the Medical Monitor) will be 
unblinded as to whether subjects are receiving C16G2 or Placebo.  
Microbiology: 
All stimulated saliva and dental plaque samples obtained in this study will 
be tested for S. mutans using mitis-salivarius bacitracin (MSB) agar plating 
and total bacteria testing using Todd Hewitt (TH) agar plating. Samples will 
be stored for S. mutans and total bacteria testing using quantitative Real-
Time Polymerase Chain Reaction (qRT-PCR) and bacterial community 
analysis. 
At the screening visit, only stimulated saliva samples will be collected and 
tested for S. mutans Colony Forming Units (CFUs) to determine the 
inclusion criterion of ≥ 1 x 105 CFU/mL at Screening using MSB agar 
plating. At all other visits both stimulated saliva and dental plaque samples 
will be obtained for microbiology assessments. Samples will be collected at 


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CONFIDENTIAL 
the following visits: Screening Visit, prior to the dental prophylaxis at Visit 
2, prior to study drug administration at Visits 3, 8-10, follow up visits 4-7 
and 18-22. For details refer to Appendix C. 
Samples will be shipped overnight to the Sponsor’s microbiology laboratory 
for analysis. Screening S. mutans results will be provided to the study 
center within 5 days of sample receipt.  
Inclusion Criteria: 
Subjects are eligible to participate if they meet the following criteria: 
1. Males and females, 12-75 years of age 
2. Adults subjects provide written informed consent and adolescent 
subjects give written or verbal assent, as appropriate, and parent(s) or 
legal guardian(s) give written informed consent 
3. Female subjects of childbearing potential must agree to use one of the 
following forms of contraception from screening through the last study 
visit: hormonal (oral, implant, or injection) begun >30 days prior to 
screening; barrier (condom, diaphragm, or cervical cap with 
spermicide); intrauterine device (IUD). Acceptable contraceptive 
options may also include abstinence, relationship with a same sex 
partner or partner who has had a vasectomy at least six (6) months 
prior to the screening visit 
4. Negative urine pregnancy test in all females of childbearing potential 
(past menarche) 
5. Male subjects of sexual activity age: willing to use contraception or 
abstain from sexual activity beginning with the first exposure to study 
drug and continuing until discharged from the study due to completion 
or Early Termination 
6. Healthy, as determined by the Investigator (in consultation with the 
Medical Monitor, as needed), based on medical and dental history, 
concurrent illnesses, laboratory results, concomitant medications, oral 
cavity assessment, and targeted physical examination (general, 
extraoral, head and neck) during Screening 
Note: Subjects on a stable dose of medication may be eligible for 
screening and will be assessed by the medical monitor on a case-by-
case basis. 
7. Have a minimum of 12 bicuspids and molars with a minimum of 
8 molars and bicuspids NOT having restorations, crowns or sealants 
8. Demonstrated ability to expectorate ≥2 mL of stimulated saliva in 
5 minutes 
9. Have a salivary S. mutans of 1.0 x 105 CFUs/mL or greater at 
Screening using MSB agar plating 
10. Willing to refrain from using non-study dentifrice and other non-study 
oral care products (oral care rinses, fluoride products, etc.) during the 
study 
11. Willing to postpone elective dental procedures (e.g., dental cleanings) 
between Screening and final post-treatment visit (End of Study or Early 
Termination) 
12. Willing and able to comply with oral hygiene and diet instructions 


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CONFIDENTIAL 
13. Able to communicate with the Investigator/study center personnel, 
understand and comply with the study requirements, and willing to 
return for protocol-specified visits at the appointed times 
Exclusion Criteria: 
Subjects are excluded from participation if any of the following apply: 
1. Advanced periodontal disease 
2. Active caries lesion(s) within 30 days prior to study drug administration 
(confirmed by comprehensive caries examination including standard 
radiographs). Subjects presenting with insipient, non-cavitated lesion(s) 
are not excluded  
Note: If radiographs are deemed appropriate for the study and taken 
within 6 months prior to the Screening visit, these may be used for 
determining eligibility and are not required to be repeated at Screening 
3. Partially erupted teeth where the entire crown is not erupted or an 
operculum is present  
4. Medical condition (e.g., artificial heart valve, history of infective 
endocarditis, cardiac transplant with valvular dysfunction, congenital 
heart disease or total joint replacement) for which antibiotics are 
recommended prior to dental visits and/or procedures  
5. Pathologic lesions of the oral cavity (suspicious or confirmed) 
6. Full dentures or permanent orthodontic appliances, e.g., braces, buccal 
or lingual brackets. Note: Partial dentures, removable retainers and 
night guards are not excluded, provided that they are cleaned regularly 
throughout the duration of the study  
7. Use of systemic antibiotics, topical oral antibiotics, or use of other 
drugs, which in the opinion of the Investigator could influence the study 
outcome, beginning 30 days prior to Screening until the end of study 
participation 
8. Medical 
history 
indicating 
the 
woman 
is 
pregnant, 
breastfeeding/lactating or has a positive urine pregnancy test 
9. Participation in a clinical trial or receipt of a non-FDA approved therapy 
within 30 days prior to study drug administration (depending on the 
specifics, participation in an observational study is not necessarily 
excluded) 
10. Presence of any condition or concurrent illness, which in the opinion of 
the Investigator, would compromise normal immune function (e.g., 
diabetes, rheumatoid arthritis, lupus, liver disease, organ transplant, 
etc.), interfere with the use of study dentifrice and oral care products, or 
interfere with the ability to comply with study requirements, or 
jeopardize the safety of the subject or the validity of the study results 
Study Assessments & 
Procedures: 
See Appendices A through D for detailed study information. 
 
Clinic Visit Schedules  
For clinic visit schedules refer to Appendix D  
 
Assessments & Procedures  
 


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CONFIDENTIAL 
Clinic Visit 1 (Screening, Days -30 to -1)  
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Informed Consent/Assent & Assign Subject ID  
o Inclusion/Exclusion 
o Medical/Surgical/Dental History and Concurrent Illnesses 
o Salivary Flow Assessment  
o Concomitant Medications 
o Demographics  
o Dental status and comprehensive caries examination including 
standard radiograph 
Note: If radiographs are deemed appropriate for the study and 
taken within 6 months prior to the Screening visit, these may be 
used for determining eligibility and not required to be repeated at 
Screening 
o Screening Laboratory Testing  
o Urine Pregnancy Test (females of childbearing potential only) 
o Oral Cavity Assessment  
o Targeted Physical Exam (general, extraoral, head & neck) 
o Vital Signs (blood pressure, heart rate, temperature)  
o Microbiology (stimulated saliva ONLY) 
Note: Screening Microbiology sample will be collected on Days  
-30 to -8 prior to Visit 2 
o Discharge   
 
Clinic Visit 2 (Prophylaxis, Day -7 to -2) 
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (Stimulated Saliva and Dental plaque collection) 
Note: Samples need to be obtained prior to oral hygiene training 
and professional dental prophylaxis 
o Professional Dental Prophylaxis (prophylaxis will include removal 
of bulk plaque and supragingival scaling)  
Note: NO fluoride treatment as part of the procedure, NO 
subgingival scaling as part of the prophylaxis 
o Oral Hygiene Training: 
 
Flossing (string): instructions are provided in Appendix E 
 
Manual toothbrush technique for routine dental hygiene 
using a manual toothbrush provided by the sponsor and 
toothpaste containing fluoride (for instructions refer to 
Appendix F) 
o Oral Hygiene Product Distribution 
o Discharge  
 
Clinic Visits 3, 8-17 (Baseline Day 0, Days 7-11) 
AM visits will be scheduled 6AM to 10AM. PM visits will be scheduled 6PM 
to 10PM. 
Subjects should not be exposed to study drug if they present with any 


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CONFIDENTIAL 
disruption or loss of integrity in the oral cavity mucosa, gingiva or have lip 
lesions, (e.g. aphthous stomatitis, active herpetic sores, cheek bites, or 
severely chapped or cracked lips, etc.). 
Pre-Dose 
o Confirmation of eligibility (Visit 3 ONLY) 
o Medical/Dental History & Concurrent Illness Update (Visit 3 
ONLY) 
o Study Arm Assignment and Randomization (Visit 3 ONLY) 
o Urine Pregnancy Test (females of childbearing potential only) 
(Visit 3 ONLY) 
o Targeted Physical Exam (Visit 3 & 8 ONLY) 
o Concomitant Medications Update 
o Oral Cavity Assessment: AM Visits 3, 8, 10, 12, 14, & 16 only 
o Vital Signs (blood pressure, heart rate, temperature taken in 
supine or sitting position) (Visits 3, 8 & 17 only) 
o Microbiology (Stimulated Saliva & Dental Plaque)  
Note: Microbiology samples will only be collected at Visits 3,  
8, 9 and 10 
o Brushing and flossing with the dental material provided by the 
Sponsor 
Study Drug Administration:  
Instructions for the application of C16G2 Strips or Placebo are provided in 
the Study Manual and in Appendix G. 
o Subjects will have C16G2 Strip (9.2 mg, 18.4 mg, or 36.8 mg in 
Study Arms 1 through 3, respectively) or Placebo applied to 
molars and bicuspids. Strips will be applied and remain on the 
subjects teeth for up to 90 minutes. Subject will not eat, swish or 
drink during study drug administration. 
 
Post-Dose 
o C16G2 and Placebo strips will remain on the subject’s teeth for 
30 minutes (do not manipulate strips during that time) 
o Remove strips that have fully self-detached starting 30 minutes 
after application 
o Remove all strips that have not fully self-detached 90 minutes 
after application  
Note: Dental strips will in most cases fully detach prior to 
90 minutes. Only remove strips that fully detach earlier than 90 
minutes after application. Subjects will not eat, swish, or drink for 
one hour after the removal of study drug 
o Photograph imaging immediately after study drug application 
(Visit 3 ONLY) 
o Oral Cavity Assessment: AM Visit 3 and PM Visits 9, 11, 13, 15, 
& 17 only  
o Vital Signs (blood pressure, heart rate, temperature) within 
20 minutes of removal of the last strip, taken in supine or sitting 
position (Visits 3, 8 & 17 only) 
Prior to Discharge 


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CONFIDENTIAL 
o Adverse Events 
o Oral Hygiene Product Distribution (as needed) 
o Discharge  
Clinic Visits 4-7 and 18-20  
On visits 7, 19 & 20 subjects will be scheduled between 6AM and 10AM. 
Remaining visits will be scheduled as appropriate, according to clinic visit 
schedule in Appendix D. 
o Concomitant Medication Update  
o Oral Cavity Assessment  
o Targeted Physical Exam (Visits 5, 18 and 20) 
o Microbiology (stimulated saliva and dental plaque collection) 
o Adverse Events 
o Discharge 
 
Clinic Visits 21 & 22  
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (stimulated saliva and dental plaque collection) 
o Discharge 
o End of Study (Visit 22 ONLY) 
 
Subject Instructions:  
Subjects enrolled in all study arms will be instructed to abstain from eating 
food and drinking beverages that contain a high sugar content (e.g., candy, 
soda with refined sugar, sugary snacks, dried fruit, fruit rolls) from 
Screening to the last day of study drug administration (Visit 17, Day 11, 
PM). While smokers are not excluded from study participation, subjects 
should abstain from using chewing tobacco or similar products throughout 
the study. 
a) Oral Hygiene Instructions  
 
Beginning at Visit 2 and during the entire study subjects will not be allowed 
to use any dental products besides the materials provided by the study 
center. Prior to attending the study center for any visit (Visits 1-22), 
subjects will not be allowed to perform oral hygiene at home. In addition, 
subjects will be advised not to use any mouth rinse for approximately 24 
hours before the Screening visit. 
 
Prior to discharge at Visit 2 (Days -7 to -2), subjects will receive a manual 
toothbrush, a regular toothpaste containing fluoride, and dental floss 
provided by the Sponsor to take home. Subjects will be instructed to use 
these dental products in the morning and evening at home during the 
remaining study duration, including the evening of Day 0. In addition, 
subjects will be resupplied with these dental products as needed. 
 
b) Diet Instructions  
 
Subjects in all study arms will be instructed as follows:  
 


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All Visits:  
• 
Do not eat for 1 hour prior to the appointment time 
• 
No liquids, other than plain water, 1 hour prior to the appointment time 
Note: Subjects will be allowed to drink water up to 10 minutes prior to 
dental plaque and saliva collection, and will be instructed not to swish 
or rinse 
Visits 3, 8-17 (Study Drug Administration Days) 
• 
Do not eat or drink anything besides plain water within 1 hour prior to 
the appointment time 
• 
Do not eat, drink anything or swish during the study drug administration 
period and for 1 hour after the removal of the strips   
 
Note: Subjects will be under the supervision of study staff to ensure that 
they do not consume any food or drink anything during and 1-hour post 
study drug administration 
 
Safety Monitoring: 
All subjects that receive study drug will be included in the safety analysis. 
Safety will be evaluated on the entire study population of 30 subjects. 
Subjects in all study arms will be followed for safety assessments for 
1 week after dosing. Safety monitoring will include vital signs, intraoral 
assessments of hard and soft tissues, targeted physical examination, and 
collection of adverse events during study visits and unscheduled telephone 
contacts. 
Subjects will be instructed to inform the Investigator and/or a member of 
the study staff of any adverse events that occur at any time during the 
study. Subjects will be asked a general health question at each clinic visit 
up to and including Visit 20 and with each unscheduled telephone contact 
to identify changes in their state of health since their last communication 
with the study center or their last study visit. All subjects will be closely 
monitored for safety for 1 week after the last administration of study drug. 
After that time point, all ongoing adverse events will be followed in 
accordance with good medical practice until resolution or the condition has 
stabilized. 
Statistical Methods: 
 
Sample Size: 
The total number of subjects planned for this study is 30. There are no 
data on which to base formal sample size calculations for this study. The 
data generated in this study will assist with ongoing clinical development of 
C16G2 Strip. Subjects’ data in the three study arms will provide information 
on the safety and microbiology of multiple administrations of C16G2 Strip 
or Placebo. Subjects may be replaced at the Sponsor’s discretion. 
Data Analysis: 
Analysis Sets: There will be two analysis sets; the safety analysis set and 
the microbiology analysis set  


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 
The safety analysis set will be defined as those subjects who 
received any amount of study drug (C16G2 Strip or Placebo) 
 
The microbiology analysis set will be comprised of two subsets, the 
saliva microbiology and dental plaque microbiology subset. These 
subsets will be based on the subjects who received study drug and 
have at least one baseline and one post-baseline dental plaque and 
saliva sample, respectively. 
Safety:  
All safety-related interventions, adverse events (AEs), and findings will be 
summarized. The incidence and duration of treatment emergent AEs 
(TEAEs) will be summarized by study arm. An AE will be considered 
treatment emergent if the onset date and time occur on or after the 
recorded clock time of the administration of study drug (C16G2 Strip or 
Placebo). Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®). The severity of each adverse event will 
be determined using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. 
All adverse events (AEs) will be classified by the relationship of the event 
to study drug as 1) None, 2) Unlikely, 3) Possible or 4) Probable. All AEs 
will be followed in accordance with good medical practice until resolved or 
fully characterized. All serious AEs (SAEs) will be followed until the 
outcome is known or the subject’s condition has stabilized. 
Other safety assessments include vital signs, oral cavity assessments, and 
targeted physical exams. These safety parameters will be presented by 
study arm using descriptive statistics. 
Microbiology: All saliva and dental plaque samples will be analyzed for 
S. mutans and total bacteria present in each sample and relative to the 
different doses in the 3 study arms. Samples will also be tested by qRT-
PCR and bacterial community analysis at appropriate time points based on 
plating assessments. Descriptive statistics utilizing mean, standard 
deviation, median and range of S. mutans and total bacteria at each time 
point for Study Arms 1 through 3 will be determined and compared to 
Baseline samples.  


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase  
AR 
adverse reaction 
AST  
alkaline phosphatase  
BMI 
body mass index 
BUN 
blood urea nitrogen  
C16G2 
antimicrobial peptide (investigational study drug) 
CFR 
Code of Federal Regulations  
CFU  
colony forming units  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae  
°C 
degrees Celsius 
ECG 
electrocardiogram 
EDC 
electronic data capture  
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
FSI 
first subject in 
HED 
HIPAA 
human equivalent dose 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization  
IRB 
Institutional Review Board  
IUD 
intrauterine device  
LLOQ 
lower level of quantitation  
LSO 
last subject out 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MSB 
mitis salivarius-bacitracin  
µM 
micromolar 
mL 
milliliter 
NCI  
National Cancer Institute  
ng 
nanogram 
NOAEL 
PHI 
no observed adverse effect level  
Protected Health Information 
PK 
pharmacokinetic 
qRT-PCR 
quantitative real-time polymerase chain reaction 


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RBC 
red blood cells  
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SAP 
Statistical Analysis Plan 
S. mutans 
Streptococcus mutans  
Sponsor 
C3 Jian, LLC (C3J) 
SSAR 
suspected serious adverse reaction 
Study Drug C16G2  or Placebo Strip 
TEAE 
treatment-emergent adverse event 
TH 
Todd Hewitt  
WBC 
white blood cells  
WHO ATC 
World Health Organization Anatomical Therapeutic Chemical  
 
 


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INTRODUCTION 
Dental caries is a chronic disease of microbiological origin that affects populations worldwide. 
Caries arises from an imbalance in the indigenous microflora of the oral cavity: upon intake of 
dietary sugars (primarily sucrose), aciduric microbes produce lactic acid that damages tooth 
structure and enables these pathogenic bacteria to become dominant in the multispecies 
biofilms found on the tooth surface (known as dental plaque). The bacterium Streptococcus 
mutans (S. mutans) has been implicated in a wide body of historical and contemporary clinical 
and nonclinical data as being the major etiological agent responsible for the majority of caries 
(Loesche 1986; Tanzer, Livingston et al. 2001; Marsh 2006; Marsh 2010). Furthermore, in 
studies examining the endpoint, caries-free individuals were found to have lower S. mutans 
compared with caries-active subjects. 
Controlling caries by reducing the total bacterial load in saliva and plaque through use of broad 
spectrum antibacterial agents can, in theory, reduce caries incidence; however, there is no 
clinical evidence supporting the long-term prevention of S. mutans re-infection and very few 
studies examining the impact on caries reduction (Tong, Dong et al. 2010; Vollmer, Papas et al. 
2010; Young, Lyon et al. 2010). The reason for lack of long-term cavity protection is the 
persistence of S. mutans within the dental plaque and the dynamic balance of the biofilm 
community between a healthy state and cariogenic state. There is a need to develop a specific 
antimicrobial therapy that can substantially reduce or eliminate the primary agent of dental 
caries, S. mutans, from the oral biofilm while leaving the remaining organisms intact. If this can 
be achieved, a healthy biofilm may be established that provides long-term caries protection. 
In response to the need for a focused S. mutans reduction, a series of novel synthetic 
molecules were designed and evaluated in vitro (Eckert, R., He J., et al., 2006; Kaplan, C. W., 
Sim, J.H., et al., 2011; Li, L. N., Guo, L. H., et al, 2010). The C16G2 antimicrobial peptide was 
shown to specifically kill S. mutans, and not other oral streptococci, in both planktonic and 
saliva-derived biofilm systems. Additionally, intact S. mutans-free biofilms created by a C16G2 
intervention were resistant to colonization from exogenous S. mutans (Li, L. N., Guo, L. H., et al, 
2010; Guo, L., McLean, J.S., et al, 2015). 
Previous studies evaluated the safety, pharmacokinetics and microbiology of single and multiple 
C16G2 doses formulated as a mouth rinse, gel and varnish. In Study C3J16-S205-00 subjects 
will receive multiple C16G2 or Placebo strip administrations to evaluate the safety and 
microbiology of this mode of application. 
1.1 
Previous Clinical Experience 
1.1.1 Phase 1 
Study C3J11-101-01, a Phase 1, randomized, double-blind, placebo-controlled, dose escalation 
study was conducted at a single study center in the US. A total of 36 healthy adult subjects were 
enrolled, of which 24 subjects received C16G2, and 12 subjects received placebo. C16G2 was 
administered in a mouth rinse formulation as a single dose of three concentrations (4 mg [50 
µM], 8 mg [100 µM] and 32 mg [400 µM]) by swishing for 40 seconds in the oral cavity and 
subsequent expectoration. 
The objectives of this study were to evaluate the safety and pharmacokinetics of C16G2 in 
healthy adult subjects and to assess the targeted antimicrobial activity of C16G2 as measured 


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by a reduction in the number of salivary S. mutans and to assess the bacterial composition in 
the oral cavity over 28 days post-study drug administration in healthy adult subjects. 
C16G2 was well-tolerated with no deaths and no other serious or severe AEs. No study 
drug-related treatment-emergent AEs were reported and no subject was discontinued due to an 
AE. No clinically significant changes in vital signs were observed in association with the 
administration of C16G2. Mean values for systolic and diastolic blood pressure and pulse 
showed only small fluctuations from baseline over the entire treatment period, and values were 
similar for the C16G2 dose cohorts and the placebo cohort. No clinically significant findings in 
the oral cavity were attributable to C16G2 administration and no clinically significant targeted 
physical exam and electrocardiogram (ECG) findings were reported. In addition, no clinically 
significant out-of-range clinical laboratory findings were observed. Immunogenicity assessments 
demonstrated that single dose C16G2 administrations up to a dose of 32 mg did not trigger the 
development of antibodies against C16G2. 
C16G2 could not be detected above the lower level of quantitation (LLOQ 10 ng/mL) in any 
pharmacokinetic (PK) sample, with a single exception, which tested just above the LLOQ and 
was most likely the result of high background signal near the LLOQ. This suggests that there is 
minimal or no systemic absorption of C16G2 into the circulation after a single C16G2 
administration up to a dose of 32 mg. 
Microbiology assessments did not demonstrate an apparent reduction or increase in S. mutans 
and other bacterial species outside of the variation observed in the placebo cohort, indicating 
that single C16G2 doses formulated as a mouth rinse did not impact the oral microbiome. 
Study C3J16-V102-00, a Phase 1, single-blind, randomized, placebo-controlled, dose-
escalation study evaluated the safety and efficacy of single 13.6 mg, 27.2 mg, 54.4 mg C16G2 
Varnish or Placebo administrations.  
The objectives of this study were to evaluate the safety and microbiology of C16G2 Varnish 
formulation in healthy adult subjects and to assess the targeted antimicrobial activity of C16G2 
as measured by a reduction in the number of salivary S. mutans. In addition, the study 
assessed the bacterial composition in the oral cavity over 28 days post single study drug 
administration in healthy adult dental subjects. 
A total of 48 adult healthy subjects were enrolled, of which 30 subjects received C16G2 and 18 
subjects received placebo. C16G2 was well-tolerated with no deaths and no other serious or 
severe AEs. No study drug-related treatment-emergent AEs were reported and no subject was 
discontinued due to an AE. No clinically significant changes in vital signs were observed in 
association with the administration of C16G2. Oral cavity assessments and targeted physical 
exams did not indicate any clinically relevant changes due to study drug administration. 
Microbiology evaluations demonstrated a significant decrease in S. mutans levels in saliva and 
plaque samples in each dose level.  The 27.2 mg dose group showed the greatest decrease in 
S. mutans compared to Placebo and the other two dose groups. Total bacteria levels did not 
change significantly post study drug administration. The clinical study report for this study is 
currently in preparation.  
 


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1.1.2 Phase 2 
To enhance the targeted S. mutans killing activity of C16G2 in dental plaque, C3 Jian 
formulated the drug product for both mouth rinse and gel application. C3J13-201-01, a double-
blind, placebo-controlled study, evaluated different combinations of multiple C16G2 Gel and/or 
C16G2 mouth rinse administrations at two dose levels. To determine the most effective mode of 
gel application, gel was applied by manual toothbrush, SonicareTM toothbrush and upper and 
lower custom dental trays. 
A total of 60 adult healthy subjects were enrolled, of which 48 subjects received C16G2, and 
12 subjects received placebo. Subjects received study drug for 7 consecutive days and were 
followed for safety and microbiology assessments for 14 days post first study drug 
administration. The C16G2 concentrations were 3.2 mg/mL (800 µM) in gel formulation and 1.6 
mg/mL (400 µM) in liquid formulation. 
C16G2 was well-tolerated with no deaths and no other serious or severe adverse events (AEs). 
A total of 43 TEAEs were reported, 38 AEs in 19 subjects receiving C16G2, 5 AEs in 3 subjects 
receiving placebo. The majority of AEs were deemed mild in severity and unrelated to study 
drug administration and study procedures. In Study Arm 3, in which subjects received gel 
administrations with a SonicareTM toothbrush, followed by a single rinse, the number of subjects 
with one or more AEs and the number of AEs was greater compared to the other three study 
arms. Since the majority of these AEs were mild irritation related to the oral cavity, use of the 
SonicareTM toothbrush for longer than recommended by the manufacturer (four minutes versus 
two) and the rinsing schedule are possible procedure-related explanations. 
Two subjects discontinued from the study due to adverse events. The first subject, a 32 year old 
Asian female, was enrolled in Study Arm 1 and randomized to C16G2 study drug. She received 
six C16G2 mouth rinses on the first day of study drug administration. She subsequently 
developed a mild rash on both arms and mild pruritus on her arms and her jaw. She withdrew 
from the study the next day. Both AEs resolved within a few hours and were assessed as 
possibly related to study drug administration and study procedures by the Investigator. The 
second subject, a 22 year old Caucasian female enrolled in Study Arm 4, developed tonsillitis 
and pyrexia at the end of the treatment period (subject completed 5 of 7 study drug 
administration days). Both AEs were assessed as moderate in severity and unrelated to study 
drug administration and study procedures by the Investigator and resolved after 5 days. 
Clinically significant findings in the oral cavity and targeted physical exam were reported as 
adverse events. No clinically significant changes in vital signs were observed in association with 
administration of C16G2. Mean values for systolic and diastolic blood pressure, pulse and 
temperature showed only small fluctuations from baseline over the entire treatment period, and 
values were similar for the four active C16G2 Study Arm groups and combined placebo group. 
The majority of subjects receiving C16G2 via a custom dental tray demonstrated an average 
1 log10 CFU/mL S. mutans reduction in saliva 1 day after the last 7-day study drug 
administration period and this reduction was maintained in some subjects 1 week after the last 
study drug administration, demonstrating the durability of effect for 7 days. The majority of 
subjects receiving C16G2 Gel via a manual toothbrush demonstrated an S. mutans reduction in 
occlusal dental plaque 1 day after the last 7-day study drug administration period, with fewer 
subjects having an impact in salivary S. mutans. At the end of the study, only a portion of 
subjects in the manual brush arm showed a substantial reduction in S. mutans occlusal dental 
plaque and the effect was less pronounced in saliva, indicating that the response observed on 
Day 7 may decrease over time post-treatment. Other modes of application (mouth rinse, gel 
administered via SonicareTM toothbrush) were less effective. 


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CONFIDENTIAL 
In the open-label study C3J14-201B-00, subjects received 400 µM and 800 µM C16G2 Gel, 
administered either by custom dental trays once daily for 5 consecutive days (Part A) or via 
manual toothbrush only compared to a combination of manual toothbrush and custom dental 
trays (Part B), with four study drug administrations on the first day of dosing followed by AM and 
PM dosing for 6 consecutive days. Results from Part A of the study demonstrated that C16G2 
administered once daily for 5 days via dental trays for up to 4 hours did not suppress S. mutans 
efficiently. Results from Part B of the study showed a 1 log10 CFU/mL suppression of S. mutans 
when C16G2 was applied via a manual toothbrush and custom dental tray combination and at 
the higher concentration (800 µM). 
Pharmacokinetic data from study C3J14-201B-00 indicated no detectable systemic levels of 
C16G2 (all samples below the LLOQ of 10 ng/mL). PK samples were obtained: 1) during and 
after a 4 hour gel tray administration of 3.2 mg/mL C16G2 in gel (C16G2 administered after 
manual brushing with conventional toothpaste without C16G2), and 2) immediately after 3 
manual brushings with C16G2 and one 30 minute tray administration with C16G2 (3.2 mg/mL 
C16G2 in gel). 
Study C3J15-202-00, a Phase 2, multi-center, randomized, double-blind, placebo-controlled 
study evaluated the safety and microbiology of C16G2 (gel formulation) in adolescent and adult 
dental subjects. The study evaluated the treatment regimen and schedule previously assessed 
in Study C3J14-201B-00, Part B and assessed the durability of S. mutans suppression over a 
longer period of time (up to 4 months compared to 7 days in previous studies), evaluated the 
safety and microbiology of two 7-day study drug administration periods, and compared 2 mL 
(Study Arm 1) versus 4 mL (Study Arm 2) 800 µM C16G2 Gel/Placebo administrations. 
A total of 64 subjects were enrolled into this study, of which 41 were randomized to receive 
active drug. A total of 104 AEs were reported in 36 subjects, with a similar distribution over the 
two study arms and the placebo group (Study Arm 1: 9 subjects; Study Arm 2: 16 subjects; 
placebo group: 11 subjects). AEs related to study drug were reported for 3 subjects receiving 
C16G2 (all in Study Arm 2) and 2 subjects treated with placebo. AEs deemed related to the 
study drug in Study Arm 2 were gingival swelling, oral discomfort, and sensitivity of teeth, all 
assessed as mild in severity. There were no serious adverse experiences (SAEs) or severe 
AEs, no deaths, and no discontinuations due to AEs.   
No clinically significant changes in vital signs were observed in association with administration 
of C16G2. Assessments of the oral cavity and body areas examined as part of the targeted 
physical exams did not reveal any treatment-related safety issues. Thus, the dosing regimens 
and modes of application evaluated in this study were safe in healthy adults and adolescents. 
Results for salivary S. mutans samples during the first and second study drug administration 
period suggest that either 2 or 4 mL volumes of 800 μM C16G2 delivered via MBGA and TGA 
over 7 days, with an intensive first day, are sufficient to suppress S. mutans for 12 hours 
following the cessation of therapy compared to placebo. 
Results for occlusal dental plaque during the first study drug administration period suggest that 
800 μM C16G2 administered as either 2 or 4 mL volumes via MBGA and TGA over 7 days, with 
an intensive first day, are sufficient to suppress S. mutans in dental plaque for up to 12 hours 
after the last dose as compared to placebo. During the second study drug administration only 
the 4 mL volume appeared sufficient to suppress S. mutans up to 12 hours in both plaque and 
saliva, while 2 mL suppressed S. mutans in saliva. 
In both study drug administration periods total bacterial loads were not reduced by study 
treatments at 1 week post last study drug administration. The magnitude of the S. mutans 


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CONFIDENTIAL 
reduction in the first study drug administration period was modest, yet selective, since there was 
no change in total bacterial levels.  
Study C3J15-203-00, a Phase 2, multi-center, randomized, double-blind and open-label, 
placebo-controlled study, evaluated the safety and microbiology of C16G2 administered in 
multiple oral gel doses to adult and adolescent dental subjects. The study evaluated different 
dosing regimens and different doses of C16G2 and Placebo Gel. There were no significant 
safety findings and the safety profile of C16G2 was consistent with previous studies and 
generally safe in majority of the subjects. Microbiology results did not show a significant durable 
response in reduction of S. mutans in stimulated saliva and dental plaque samples. The clinical 
study report for this study is currently in preparation. 
The ongoing Phase 2 study C3J16-V204-00 will evaluate the safety and microbiology of C16G2 
varnish administered in multiple doses to adolescent and adult dental subjects in a single-blind, 
randomized, placebo-controlled manner. The study is will enroll approximately 33 subjects into 
3 dose groups (13.6 mg, 27.2 mg, and 54.4 mg C16G2 Varnish or Placebo). Subjects in each 
cohort will receive three doses over one week and will be followed up for safety and 
microbiology for up to 1 month post last study drug administration.  
1.1.3 Non-US Pilot Studies  
Three C16G2 pilot studies that evaluated the safety and microbiology of C16G2 mouth rinse 
administrations were conducted in China. These studies demonstrated a safety profile similar to 
the one observed in the US clinical studies. Only one of these three studies showed a short-
term decrease in S. mutans levels that returned to baseline after 24 hours. For detailed 
information refer to the C16G2 Investigator’s Brochure. 
1.2 
Rationale for Development of C16G2 
The rationale for developing C16G2 as a product to prevent dental caries in adults, adolescents 
and younger children is based on the following: 
 
Acid production by S. mutans is implicated as a major factor in the initiation of dental caries 
and eventual cavitation of the tooth (Tanzer, Livingston et al. 2001). The selective reduction 
of S. mutans from within the oral cavity may reduce the likelihood of developing dental 
caries by reducing acid production and providing long term protection through preservation 
of the non-cariogenic oral flora that maintain protective colonization benefits. 
 
C16G2, a novel antimicrobial peptide, has demonstrated efficacy and selectivity for 
S. mutans and not other bacteria. 
Refer to the Investigator’s Brochure for additional information. 
1.3 
Rationale for Selection of Dose & Mode of Application  
In prior clinical trials using C16G2 mouth rinse and gel formulations, C16G2 was administered 
at an 400 µM (1.6 mg/mL) and 800 µM (3.2 mg/mL) dose with a maximum daily exposure of 
115.2 mg resulting in approximately 1 log10 suppression of S. mutans while study drug was 
administered. The current study is designed to evaluate a C16G2 strip formulation. The 
proposed doses of C16G2 are 9.2 mg, 18.4 mg, or 36.8 mg of C16G2 applied via 4 tooth strips 
that will extend over molars and bicuspids. Release of the peptide from the film is achieved 
through mixing of the layer of the tooth strip containing C16G2 with saliva on the tooth surface 


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CONFIDENTIAL 
resulting in a 4-fold increase in peptide release from the 9.2 to 36.8 mg dose. The strip will be 
hydrated by saliva during the administration period resulting in continuous dissolution of C16G2 
from the strip during the treatment period. In this study the tooth strips will remain on the tooth 
surface for a minimum of 30 minutes and during this timeframe it is expected that the majority of 
peptide will be released. An average salivary flow rate of 0.4 mL/min over the course of the 
30 minutes application time results in the production of approximately 12 mL of saliva and an 
average peptide concentration for the three doses from lowest to highest of 0.77, 1.53 and 
3.07 mg/mL C16G2, respectively. The highest concentration of 3.07 mg/mL is similar to a prior 
gel formulation that delivered 3.2 mg/mL in a dental tray. The three proposed doses were 
evaluated and each demonstrated a similar level of selective antimicrobial activity against 
S. mutans in a multispecies in vitro biofilm assay. Due to the well-known limitations of effective 
penetration into biofilms, the higher concentrations of C16G2 were selected to achieve a greater 
effective concentration beyond the surface of the biofilm.  
The proposed clinical program dose range, as well as the multiple dosing schedule, was not 
selected based on safety issues, but rather based on 1) a reasonable expectation that this dose 
range will cover the bactericidal potential of C16G2, 2) a product profile that targets the highest 
flexibility for C16G2 administration (at home or professional) and 3) results from prior C16G2 
clinical studies that demonstrated an unremarkable safety profile with no serious or severe 
adverse events assessed as related to study drug administration by the Investigator. 
The non-clinical toxicity and clinical safety and tolerability profile of orally administered C16G2 
mouth rinse and gel formulations is very benign, which is consistent with the peptide not being 
orally bioavailable. Pharmacokinetic and toxicokinetic studies did not detect C16G2 after oral 
administration, either by gavage to rats and dogs or buccal administration to hamsters. 
Furthermore, in vitro studies in simulated gastric and intestinal fluids show that C16G2 is quickly 
destroyed and undetectable, and thus swallowing of C16G2 is not expected to result in any 
systemic exposure. None of the ingredients in the strip formulation raise safety concerns 
because they are currently used in commercial products.  
A large safety margin exists between the proposed clinical doses and the no observed-adverse-
effect levels (NOAEL) determined after administration of C16G2 to rats and dogs by oral gavage 
daily for 14 days. The NOAELs in these nonclinical studies were at least 150 mg/kg/day in rats 
and at least 50 mg/kg/day in dogs, respectively, which converts to a human equivalent dose 
(HED) of 24 to 28 mg/kg/day. The maximum daily dose proposed in Study C3J16-S205-00 is 
1.05 mg/kg/day (assuming a 70 kg subject), which equates to 22.9 to 26.7-fold below the HED 
values at the NOAELs derived from the oral gavage toxicology studies. 
In addition, a study to assess the potential for C16G2 Gel to produce local irritation in the oral 
mucosa of hamsters did not reveal any adverse findings or delays in wound healing following 
daily buccal administration at a concentration of 16 mg/mL for up to 28 days in intact and 
abraded cheek pouches. 
1.4 
Rationale for the Length of Safety Follow-up 
Given the lack of systemic exposure at clinical doses, the short half-life, and the unremarkable 
clinical safety profile at the doses studied, safety follow-up for subjects enrolled in any study arm 
of Study C3J16-S205-00 will be 1 week after the last administration of study drug. After that 
time point, all ongoing adverse events will be followed in accordance with good medical practice 
until resolution or the adverse event or condition has stabilized. All SAEs will be followed until 
the outcome is known or the subject’s condition has stabilized. The shorter follow-up period 
compared to earlier C16G2 studies is supported by the following data:  


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CONFIDENTIAL 
The maximum daily C16G2 exposure in this study will be up to 73.6 mg, (a 36.8 mg strip applied 
twice daily), in Study Arm 3. The completed Phase 2 Study C3J13-201-01 had a maximum daily 
C16G2 exposure of 115.2 mg, and demonstrated an unremarkable safety profile with no serious 
or severe adverse events. In completed C16G2 clinical studies, the majority of adverse events 
reported were mild in severity and assessed by the investigators as unrelated to study drug. In 
addition, all adverse events that were assessed as related to study drug administration were 
assessed as mild in severity. In Study C3J14-201B-00, one serious adverse event (acute 
abdominal pain – infarcted sigmoid appendix epiploica) was reported and assessed as 
unrelated to study drug by the investigator. 
Pharmacokinetic evaluations in two clinical studies demonstrated minimal or no measurable 
systemic absorption of C16G2. In the Phase 1 Study, Protocol No. C3J11-101-01, C16G2 could 
not be detected after a single C16G2 administration of up to 32 mg with a single exception. One 
sample tested just above LLOQ, which may have been the result of high background signal 
near the LLOQ. In a Phase 2 Study (Protocol No. C3J14-201B-00), C16G2 administered at a 
concentration of 3.2 mg/mL could not be detected above the LLOQ (10 ng/mL) in any 
pharmacokinetic sample after multiple manual brush gel applications and during and after tray 
gel applications. The clinical PK evaluations are consistent with nonclinical data that 
demonstrate a lack of systemic exposure after sublingual, buccal, and oral gavage. After 
parenteral administration of C16G2 to rats and dogs for 28 days, C16G2 was rapidly cleared 
from circulation (t1/2 = 1.1 to 3.92 hours). In vitro stability studies performed with C16G2 diluted 
in human saliva indicated degradation occurs within 1 hour (t1/2 = 18.8 minutes). Furthermore, in 
vitro studies in simulated gastric and intestinal fluids demonstrated that C16G2 is quickly 
destroyed and undetectable, and thus swallowing of C16G2 is not expected to result in any 
systemic exposure. 
1.5 
Study Assessments and Procedures 
Laboratory assessments will be performed at Screening to determine eligibility. Evaluations of 
safety include oral cavity assessments, targeted physical examinations, vital sign 
measurements, and collection of adverse events as set forth in the Schedule of Study 
Assessments and Procedures in Appendix B. 
1.5.1 Screening Laboratory Assessments 
Laboratory assessments will be performed at a local laboratory to determine eligibility at 
screening. Any out-of-range hematology or chemistry test result may be repeated, in 
consultation with the Medical Monitor as needed, to evaluate eligibility. 
Hematology: White blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit, platelet 
count, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, 
and absolute basophils. 
Serum Chemistries: Sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), 
glucose, creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT). 
1.5.2 Adverse Event Collection and Review 
Adverse events (AEs) will be collected and reviewed to evaluate the safety of C16G2 or 
Placebo Strip. The safety follow-up for subjects enrolled in any study arm of Study C3J16-S205-
00 will be 1 week after the last administration of study drug. After that time point, all ongoing 


Protocol No. C3J16-S205-00 
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CONFIDENTIAL 
adverse events will be followed in accordance with good medical practice until resolution or the 
adverse event or condition has stabilized. AEs that occur after exposure to study drug will be 
classified as treatment-emergent AEs (TEAEs). 
 
All AEs, whether observed by the Investigator and/or study staff or reported by the subject, will 
be entered in the source records and electronic data capture (EDC) system. 
 
AEs will be graded according to National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0 and coded according to Medical Dictionary of 
Regulatory Activities (MedDRA). 
1.5.3 Vital Signs 
Vital signs (blood pressure [systolic and diastolic], heart rate and temperature) will be obtained 
for safety monitoring at time points specified in Section 6 and Appendix B, and will be obtained 
while the subject is in a supine or sitting position. 
1.5.4 Oral Cavity Assessments & Targeted Physical Exam 
At the scheduled time points, according to the Schedule of Study Assessments and Procedures 
in Appendix B, investigators will perform a comprehensive oral exam consisting of an evaluation 
of oral hard and soft tissue structures for each subject. Oral hard tissue assessments will be 
performed with a dental mirror on the teeth and bony structures. Oral soft tissues will be 
performed by examining each subject’s mouth and pharynx, including lips, tongue, floor of the 
mouth, palate, gingiva, alveolar mucosa, buccal mucosa, oropharynx, tonsils, uvula, and 
salivary glands using palpation techniques and visualization. Targeted extraoral examination of 
the head and neck regions will also be performed by visualization and palpation. 
At Screening and prior to the first study drug administration, any abnormal examination findings 
should be documented and evaluated for clinical significance. If, in the opinion of the 
Investigator, the findings are not clinically significant and/or do not disqualify a subject from 
participation in the study, this clinical impression should be documented and the findings should 
be adequately described to allow comparison at subsequent visits. If there are questions about 
the clinical significance of any finding(s), a discussion with the Medical Monitor is 
recommended. 
The types of abnormalities that should be recorded include, but may not be limited to, amalgam 
tattoos, bony exostoses, Fordyce granules, and extrinsic tooth stains. 
At the time of study drug administration or post-dose, should an AE be reported, the Investigator 
will determine if an oral hard/soft tissue exam should be performed. All findings will be recorded 
on the respective source document and in the EDC system. 
Any non-clinically significant and clinically significant findings, signs or symptoms that are 
present at Screening and worsen in severity or frequency during or after study drug 
administration, will be recorded as adverse events in the source record and EDC system. 
1.5.5 Salivary Flow Assessment 
Stimulated whole salivary flow rates will be used to measure salivary function. The stimulated 
whole saliva test will be administered for 5 minutes. 


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With study staff present, subjects will be instructed to chew on parafilm (a 50/50 mixture of 
paraffin wax and polyolefin) and to drain saliva into a tube which is to be held near their mouth. 
At the end of 5 minutes, subjects will be instructed to collect all remaining saliva in their mouth 
and expectorate it into the test tube. Subjects who are able to expectorate ≥2.0 mL of stimulated 
saliva within a 5 minute period are eligible to continue screening for participation in the study. 
Subjects that pass the salivary flow assessment will be instructed to continue to collect saliva 
until a minimum of 5 mL have been collected at the first screening visit. 
1.5.6 Microbiology Evaluations 
 
A dental plaque sample will be collected using an interdental brush for the analysis of microbial 
populations and for quantification of S. mutans according to the Schedule of Microbiology 
Assessments in Appendix C. 
 
Subjects will be instructed to swallow the saliva in their mouths. Subjects will be instructed to 
open their lips in a wide smile with teeth loosely together and suck in several times to remove 
bulk saliva from occlusal surfaces of the teeth. Study staff will sample the occlusal surface of 
molars and bicuspids in four quadrants of the subject’s mouth with one interdental brush used 
for each quadrant. Plaque collected from each interdental brush will be dispersed into one tube 
containing TH media. 
Immediately after collection, dental plaque samples will be stored at 2-8°C. At the end of each 
day, all samples will be placed in an insulated box with ice packs, and a temperature monitoring 
device then shipped overnight for next day early morning delivery to C3 Jian, LLC. The study 
center will provide C3 Jian with pre-notification of the upcoming shipment by supplying a sample 
inventory list via email to:  
Chris Kaplan, PhD 
Director of Product Development 
C3 Jian, LLC 
E-mail: ckaplan@c3jtherapeutics.com 
Office Phone: 310-665-2928 Ext. 207 
E-fax: 310-665-2963  
A copy of the sample inventory list should also accompany the actual shipment. A template for 
preparation of the sample inventory list is provided in the Study Manual for the study. The 
minimum required sample shipping information includes; subject number, sample description, 
sample collection date & time, and the total number of samples in the shipment. Shipments of 
stimulated saliva and dental plaque samples will be combined. 
For details on laboratory and shipping procedures refer to the Study Manual. 
Upon arrival at C3 Jian, samples will be inventoried and entered into a database for tracking 
through the analysis process. Plaque samples will then be re-suspended and aliquoted for 
immediate processing for plating. Remaining plaque samples will be aliquoted in sterile labeled 
sample tubes and stored at -80°C for qRT-PCR analysis and/or bacterial community analysis. 


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CONFIDENTIAL 
 
A stimulated saliva sample (≥ 5.0 mL) will be collected by expectoration into sterile tubes for the 
analysis of microbial populations to confirm baseline S. mutans ≥ 1.0 x 105 CFU/mL in saliva for 
study eligibility, and for quantification of S. mutans according to the Schedule of Microbiology 
Assessments in Appendix C. 
With study staff present, subjects will be instructed to chew on parafilm (a 50/50 mixture of 
paraffin wax and polyolefin) and to drain saliva into a tube which is to be held near their mouth 
until a minimum of 5 mL have been collected. 
Immediately after collection, saliva samples will be stored at 2-8°C. At the end of each day, all 
samples will be placed in an insulated Styrofoam box with ice packs, and a temperature 
monitoring device, then shipped overnight for next day early morning delivery to C3 Jian, LLC. 
The study center will provide C3 Jian, LLC with pre-notification of the upcoming shipment by 
supplying a sample inventory list via email to:  
Chris Kaplan, PhD 
Director of Product Development 
C3 Jian, LLC 
E-mail: ckaplan@c3jtherapeutics.com 
Office Phone: 310-665-2928 Ext. 207 
E-fax: 310-665-2963  
A copy of the sample inventory list should also accompany the actual shipment. A template for 
preparation of the sample inventory list is provided in the Study Manual for the study. The 
minimum required sample shipping information includes; subject number, sample description, 
sample collection date & time, sample volume, and the total number of samples in the shipment. 
Shipments of stimulated saliva and dental plaque samples will be combined. 
For details on laboratory and shipping procedures refer to the Study Manual. 
Upon arrival at C3 Jian, samples will be inventoried and entered into a database for tracking 
through the analysis process. Saliva samples will then be re-suspended and aliquoted for 
immediate processing for plating. Remaining saliva samples will be aliquoted in sterile labeled 
sample tubes and stored at -80°C for qRT-PCR analysis and/or bacterial community analysis. 
 
Dental plaque and stimulated saliva samples collected at protocol specified time points will be 
analyzed for S. mutans using mitis-salivarius bacitracin (MSB) agar plates (see Appendix C). 
Upon arrival at C3 Jian laboratories, plaque and saliva samples will be diluted in microbiology 
growth medium (TH Broth) and plated on MSB agar in triplicate. After anaerobic incubation at 
37°C for 48-72 hours, all growth on the plates will be quantified by colony count. The use of 
microbiological media containing antimicrobial agents to selectively culture bacterial groups 
from mixed bacterial community is a standard method in microbiological identification of bacteria 
present in clinical analysis. Streptococcus species present in the oral cavity have been 
traditionally isolated from oral cavity samples using MSB agar plates. The antimicrobial activity 
of crystal violet dye, high sucrose content, sodium tellurite and bacitracin effectively prevent the 
growth of all bacteria except for streptococci. Further differentiation of streptococci is 


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CONFIDENTIAL 
accomplished by observing colony morphology. S. mutans grows in large blue colonies with dry 
frosted tops or pale blue gumdrops and can be differentiated from other bacterial colonies. 
 
Upon arrival at C3 Jian laboratories, plaque and saliva samples will be diluted in bacterial 
growth medium (TH Broth) and plated on non-selective media in triplicate at protocol-specified 
time points (see Appendix C) to enumerate total bacteria present in a sample. After anaerobic 
incubation at 37°C for 24-48 hours, all growth on the plates will be quantified by colony count. 
 
The qRT-PCR method has been successfully used to quantitate bacteria present in the oral 
cavity and their association with disease states, such as dental caries and periodontitis. Dental 
plaque and saliva samples will be used for S. mutans and total bacteria testing using qRT-PCR. 
Genomic DNA will be extracted from plaque and saliva samples that will be aliquoted and stored 
at -80°C. Bacterial genomic DNA samples will be analyzed by qRT-PCR for levels of bacteria 
present. 
 
Metagenomic analysis using next-generation sequencing is a powerful tool to compare entire 
microbial communities and evaluate the bacterial community composition in healthy and 
diseased states. Genomic DNA extracted from dental plaque and saliva samples will be 
aliquoted and stored at -80°C for metagenomics analysis by next generation sequences (see 
Appendix C). 
1.6 
Potential Risks to Participants 
Potential risks to subjects participating in this study are as follows: 
 
Screening Laboratory Tests  
Venipuncture to obtain blood samples may cause some temporary discomfort. There is a 
minimal risk of surrounding nerve damage or wound infection. Some known risks, although rare, 
that can be associated with blood drawing are pain, burning, local infection, or the development 
of a bruise at the site where the needle is placed to draw the blood. 
 
Oral Examinations: 
The oral examination will involve procedures that are routinely performed in dental practice. A 
licensed dentist/hygienist will perform the procedures. The risks from the oral examination 
include minor discomfort or pain during the procedures. 
 
Biological Sample Collection: 
Dental plaque, stimulated saliva and urine (females only) will be collected. These collection 
processes confer minimal risk to the subject. 
 
 


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 
Radiographs 
Standard radiographs will be taken, unless radiographs that are deemed appropriate for the 
study and taken within 6 months prior to the screening visit are available. These may be used 
for determining eligibility and not required to be repeated at Screening. As planned, this 
procedure confers minimal risk to the subject. 
 
Photographs 
Photographs will be taken to evaluate the application of the dental strips on the subject’s molars 
and bicuspids immediately after study drug administration. The risks from taking these pictures 
include minor discomfort, and on rare occasions, minor bruising, cracking or bleeding of the lips. 
 
C16G2 Administration: 
Phase 1 
 
A total of 36 adult healthy subjects were enrolled, of which 24 subjects received C16G2, and 
12 subjects received placebo. C16G2 was administered in mouth rinse formulation as a single 
dose of three concentrations (4 mg [50 µM], 8 mg [100 µM] and 32 mg [400 µM]) by swishing for 
40 seconds in the oral cavity and subsequent expectoration. 
 
C16G2 was well-tolerated with no deaths and no serious or severe AEs. No study drug related 
treatment emergent AEs were reported and no subject was discontinued due to an AE. No 
clinically significant changes in vital signs, ECGs, clinical laboratory results, targeted physical 
examinations and oral cavity assessments were attributable to C16G2 administration. 
Immunogenicity assessments demonstrated that single dose C16G2 administrations up to a 
dose of 32 mg did not trigger the development of antibodies against C16G2. 
C16G2 was not detected above the lower level of quantitation (LLOQ 10 ng/mL) in any 
pharmacokinetic sample, with a single exception most likely related to a high background 
signal,, suggesting there is minimal or no systemic absorption of C16G2 into the circulation after 
a single C16G2 administration up to a dose of 32 mg. 
Phase 2 
In Study C3J13-201-01, a total of 60 adult healthy subjects were enrolled, of which 48 subjects 
received C16G2, and 12 subjects received placebo. Subjects received study drug for 
7 consecutive days and were followed for safety and microbiology assessments for 14 days 
post first study drug administration. The C16G2 concentrations were 3.2 mg/mL (800 µM) in gel 
formulation and 1.6 mg/mL (400 µM) in liquid formulation. 
C16G2 was well-tolerated with no deaths and no other serious or severe adverse events (AEs). 
The majority of AEs were deemed mild in severity and unrelated to study drug administration 
and study procedures. Two subjects discontinued from the study due to adverse events; one 
subject experienced a mild rash and pruritus, the other subject moderate tonsillitis and fever. All 
events resolved without sequelae. In the clinical study C3J14-201B-00, one serious adverse 
event (SAE) was reported (acute abdominal pain – infarcted sigmoid appendix epiploica 
resulting in an appendectomy), and assessed as unrelated to study drug administration by the 
investigator. 


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Pharmacokinetic data from study C3J14-201B-00 indicate no detectable systemic levels of 
C16G2 (all samples below the LLOQ of 10 ng/mL). PK samples were obtained: 1) during and 
after a 4 hour gel tray administration of 3.2 mg/mL C16G2 in gel (C16G2 administered after 
manual brushing with a conventional toothpaste without C16G2), and 2) immediately after 
3 manual brushings with C16G2 and one 15 minute tray administration with C16G2 (3.2 mg/mL 
C16G2 in gel). 
In an ongoing Study C3J15-202-00, subjects will receive 4 study drug administrations on the 
first day of dosing followed by AM and PM dosing for 6 consecutive days. 2 mL or 4 mL of 
800 µM C16G2 Gel or Placebo will be administered via manual toothbrush and custom dental 
trays. The doses, duration of application and schedule of study drug administrations in Study 
C3J15-202-00 are well supported by the safety profile established in Study C3J13-201-01, 
which also administered multiple daily doses of C16G2 for 7 consecutive days, with a maximum 
daily exposure of 115.2 mg C16G2. The maximum daily exposure in this study will be 51.2 mg, 
which is approximately half of the exposure in Study C3J13-201-01. 
In the completed Study C3J15-203-00, subjects received study drug ranging from a single day 
of dosing to 28 days of daily dosing. The C16G2 concentrations in this study will be 3.2 mg/mL 
(800 µM) and 6.4 mg/mL (1600 µM). The maximum daily exposure in this study was 102.4 mg, 
which is less than the exposure in Study C3J13-201-01. 
In an ongoing Study C3J16-V204-00 subjects will receive 13.6 mg, 27.2 mg or 54.4 mg C16G2 
Varnish or Placebo applied to all tooth surfaces. The maximum daily exposure will be 54.4 mg 
which is less than half of the exposure in Study C3J13-201-01.  
In Study C3J16-S205-00 subjects will receive study drug on multiple days of dosing. 
Approximately 9.2 mg, 18.4 mg, and 36.8 mg C16G2 Strip or Placebo will be applied to molars 
and bicuspids. The maximum daily exposure in this study will be 73.6 mg, which is less than the 
exposure in Study C3J13-201-01. 
Potential risks to subjects are minimized in this Phase 2 study by the following: 
 
Study arms will be enrolled in an ascending dose escalation manner (9.2 mg, 18.4 mg, 
and 36.8 mg C16G2 Strip or Placebo) 
 
Requirement that all women of child-bearing potential, defined as not surgically sterile or 
at least two (2) years postmenopausal, must agree to use one of the following forms of 
contraception from screening through the last study visit: hormonal (oral, implant, or 
injection) begun >30 days prior to screening; barrier (condom, diaphragm, or cervical 
cap with spermicide); intrauterine device (IUD). Acceptable contraceptive options may 
also include abstinence, relationship with a same sex partner or partner who has had a 
vasectomy at least six (6) months prior to the screening visit 
 
Requirement that women are not lactating or pregnant, as verified by urine pregnancy 
tests performed at screening and baseline 
 
Requirement for male subjects to use contraception or abstain from sexual activity 
during the study  
 
Selection of qualified Investigator and training of study personnel 
 
Monitoring by trained study staff during clinic and follow-up visits 
 
Utilizing guidelines for management of hypersensitivity and adverse events 
 
Collection of AEs 
This study is being performed in compliance with the guidelines of the International Conference 
on Harmonisation (ICH), Good Clinical Practice (GCP). 


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CONFIDENTIAL 
1.7 
Subject’s Duration of Participation 
Approximately 30 male and female subjects 12 to 75 years of age will be enrolled in the study. 
The maximum subject’s duration of participation will be 2.5 months. The estimated duration of 
the study from first subject in (FSI) to last subject out (LSO) is approximately 3.5 months. 
 
STUDY OBJECTIVES 
Primary Objectives 
 
To assess the targeted antimicrobial activity of C16G2 Strip administration as measured 
by a reduction in Streptococcus mutans in saliva and dental plaque  
 
To assess total bacteria in saliva and dental plaque post study drug administration 
Secondary Objective  
 
To evaluate the safety and tolerability of multiple C16G2 Strip administrations in 
adolescent and adult dental subjects 
 
STUDY DESIGN 
A single-blind, randomized, placebo-controlled, phase 2 study to evaluate the oral microbiology 
and safety of multiple C16G2 Strip applications in male and female dental subjects 12-75 years 
of age. 
The study will compare multiple study drug administrations of 9.2 mg, 18.4 mg, and 36.8 mg 
C16G2 Strip or Placebo in Study Arms 1 through 3, respectively. Enrollment of subjects in Study 
Arms 1 through 3 will occur sequentially in an ascending dose escalation manner. Before dosing 
of study drug, eligible subjects will receive professional dental prophylaxis between Days -7 and 
-2. Subjects will receive 11 doses administered over approximately two weeks. Each subject will 
receive a single dose on Day 0, followed by 5 days of AM and PM dosing starting on Day 7. To 
evaluate the durability of S. mutans suppression, study subjects will be followed for microbiology 
for up to 1 month after the last study drug administration. 
Clinic visits include Visit 1 (Screening/Days -30 to -1), Visit 2 (Prophylaxis/Day -7 to -2), 
Eligibility Confirmation & Baseline Visit 3, Follow-up Visits 4-7 (Safety and Microbiology), Visits 
8-17 (Study Drug Administration), Follow-up Visits 18-20 (Safety and Microbiology) and Follow-
up Visits 21-22 (Microbiology Only).  
Subjects enrolled in all study arms will be assessed for safety and microbiology parameters. For 
details on study schedules including dosing and microbiology information refer to Appendix A. 
Details on study assessments & procedures for all study arms are provided in Appendix B. For 
microbiology assessments in all study arms refer to Appendix C. 
3.1 
Blinding and Randomization  
3.1.1 Randomization 
The study will enroll approximately 30 subjects into three study arms. Approximately 10 subjects 
will receive one of three doses of study drug (9.2 mg, 18.4 mg, 36.8 mg C16G2 Strip or 
Placebo).  
Study subjects will be randomized to receive C16G2 or Placebo Strip, in a 4:1 allocation ratio 
(8 C16G2 Strip subjects: 2 Placebo Strip subjects) for each of the three study arms. Subjects 


Protocol No. C3J16-S205-00 
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CONFIDENTIAL 
will be enrolled in one of the three study arms and the arms will enroll sequentially in an 
ascending dose escalation manner. Each study arm will be fully enrolled (i.e., the last subject in 
an arm has completed Visit 3) before enrollment is initiated in the next study arm. 
After confirmation of study eligibility, subjects will be randomized at Visit 3 (Day 0) by authorized 
study staff according to the master randomization schedule from the Sponsor’s study 
statistician. The randomization schedule and associated documentation will be kept in a secure 
location. 
3.1.2 Blinding 
The study will be conducted in a single-blind manner. All study subjects will be blinded to the 
treatment assignment, while the Investigator, study staff/clinicians and the Sponsor’s assigned 
team members (e.g., the Clinical Monitor and the Medical Monitor) will be unblinded as to 
whether subjects are receiving C16G2 or Placebo. 
 
 


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CONFIDENTIAL 
 
SELECTION CRITERIA 
4.1 
Inclusion Criteria 
Subjects are eligible to participate if they meet the following criteria: 
1. Males and females, 12-75 years of age 
2. Adults subjects provide written informed consent and adolescent subjects give written or 
verbal assent, as appropriate, and parent(s) or legal guardian(s) give written informed 
consent 
3. Female subjects of childbearing potential must agree to use one of the following forms of 
contraception from screening through the last study visit: hormonal (oral, implant, or 
injection) begun >30 days prior to screening; barrier (condom, diaphragm, or cervical cap 
with spermicide); intrauterine device (IUD). Acceptable contraceptive options may also 
include abstinence, relationship with a same sex partner or partner who has had a 
vasectomy at least six (6) months prior to the screening visit 
4. Negative urine pregnancy test in all females of childbearing potential (past menarche) 
5. Male subjects of sexual activity age: willing to use contraception or abstain from sexual 
activity beginning with the first exposure to study drug and continuing until discharged from 
the study due to completion or Early Termination 
6. Healthy, as determined by the Investigator (in consultation with the Medical Monitor, as 
needed), based on medical and dental history, concurrent illnesses, laboratory results, 
concomitant medications, oral cavity assessment, and targeted physical examination 
(general, extraoral, head and neck) during Screening. 
Note: Subjects on a stable dose of medication may be eligible for screening and will be 
assessed by the medical monitor on a case-by-case basis. 
7. Have a minimum of 12 bicuspids and molars with a minimum of 8 molars and bicuspids NOT 
having restorations, crowns or sealants 
8. Demonstrated ability to expectorate ≥2 mL of stimulated saliva in 5 minutes 
9. Have a salivary S. mutans of 1.0 x 105 CFUs/mL or greater at Screening using MSB agar 
plating 
10. Willing to refrain from using non-study dentifrice and other non-study oral care products (oral 
care rinses, fluoride products, etc.) during the study 
11. Willing to postpone elective dental procedures (e.g., dental cleanings) between Screening 
and final post-treatment visit (End of Study or Early Termination) 
12. Willing and able to comply with oral hygiene and diet instructions 
13. Able to communicate with the Investigator/study center personnel, understand and comply 
with the study requirements, and willing to return for protocol-specified visits at the 
appointed times 
 
 
 
 
 


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4.2 
Exclusion Criteria 
Subjects are excluded from participation if any of the following apply: 
1. Advanced periodontal disease 
2. Active caries lesion(s) within 30 days prior to study drug administration (confirmed by 
comprehensive caries examination including standard radiographs). Subjects presenting 
with insipient, non-cavitated lesion(s) are not excluded.  
Note: If radiographs are deemed appropriate for the study and taken within 6 months prior to 
the Screening visit, these may be used for determining eligibility and are not required to be 
repeated at Screening 
3. Partially erupted teeth where the entire crown is not erupted or an operculum is present  
4. Medical condition (e.g., artificial heart valve, history of infective endocarditis, cardiac 
transplant with valvular dysfunction, congenital heart disease or total joint replacement) for 
which antibiotics are recommended prior to dental visits and/or procedures  
5. Pathologic lesions of the oral cavity (suspicious or confirmed) 
6. Full dentures or permanent orthodontic appliances, e.g., braces, buccal or lingual brackets. 
Note: Partial dentures, removable retainers and night guards are not excluded, provided that 
they are cleaned regularly throughout the duration of the study  
7. Use of systemic antibiotics, topical oral antibiotics, or use of other drugs, which in the 
opinion of the Investigator could influence the study outcome, beginning 30 days prior to 
Screening until the end of study participation 
8. Medical history indicating the woman is pregnant, breastfeeding/lactating or has a positive 
urine pregnancy test 
9. Participation in a clinical trial or receipt of a non-FDA approved therapy within 30 days prior 
to study drug administration (depending on the specifics, participation in an observational 
study is not necessarily excluded) 
10. Presence of any condition or concurrent illness, which in the opinion of the Investigator, 
would compromise normal immune function (e.g., diabetes, rheumatoid arthritis, lupus, liver 
disease, organ transplant, etc.), interfere with the use of study dentifrice and oral care 
products, or interfere with the ability to comply with study requirements, or jeopardize the 
safety of the subject or the validity of the study results 
 
 
 


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CONFIDENTIAL 
 
STUDY TREATMENTS 
Study subjects will receive a single dose of study drug on Day 0 followed by twice daily 
administrations on Days 7-11. Study drug will be administered by qualified study staff at the 
center. Study drug will be removed 90 minutes after application, unless the strips have self-
detached prior to that time point.   
 
C16G2 
Subjects 
Placebo 
Subjects 
Mode of 
Application 
Days of 
Study Drug 
Admin. 
C16G2 
(mg) 
Study Arm 1 
8 
2 
Strip 
1 
9.2 
Study Arm 2 
8 
2 
Strip 
1 
18.4 
Study Arm 3 
8 
2 
Strip 
1 
36.8 
5.1 
Study Drug 
5.1.1 C16G2 Tooth Strip Formulation 
C16G2 Tooth Strip drug product is manufactured by C3 Jian, LLC (Marina del Rey, CA) for 
administration as a dental tooth strip. The C16G2 Tooth Strip product is provided in a clear 
pouch containing 4 tooth strips at doses of 9.2, 18.4, and 36.8mg of C16G2 per set of 4 strips.  
5.1.2 Placebo Tooth Strip Formulation  
Placebo Tooth Strip drug product is manufactured by C3 Jian, LLC (Marina del Rey, CA) with 
identical excipients as the C16G2 Tooth Strips but does not contain active ingredient. To 
maintain the study blind the Placebo product is manufactured, packaged, and labeled in the 
same manner as C16G2 Tooth strips.   
5.1.3 Supply, Packaging, and Labeling 
Each kit box will contain 13 clear pouches with 4 individually pouched strips each in a white, 
light protective pouch. The dosing schedule requires 11 clear pouches for each subject. Two 
additional clear pouches are provided in each kit box in the event that replacement strips are 
needed.  
The tooth strip pouch labels will include the protocol number, caution statement “Investigational 
New Drug Limited by (US) Law to Investigational Use Only”, the kit number and the subject 
number/initials. 
Individual strip white pouches will reflect the dose of individual strips. Total dose (9.2 mg, 
18.4 mg, and 36.8 mg C16G2 or Placebo) is a total of 4 strips that will be used for a single dose 
as demonstrated in the table below.  
 
Study Arm 
Individual Strip Dose 
Total Dose (4 Strips) 
Study Arm 1 
2.3 mg 
9.2 mg 
Study Arm 2 
4.6 mg 
18.4 mg 
Study Arm 3 
9.2 mg 
36.8 mg 
 
 
 


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CONFIDENTIAL 
Sample C16G2 Strip or Placebo Strip Label 
 
 
 
 
Sample Kit Box Label 
 
 
 
The box label will include the protocol number, kit number, contents, subject number/initials, 
date of study drug administration, route of administration, storage temperature, caution 
statement “New Drug Limited by (US) Law to Investigational Use Only”, and statement 
“Manufactured by C3 Jian, LLC, Marina del Rey, CA 90292”  
 
For additional details on supply, packaging and labeling refer to the Study Manual for this study. 
5.2 
Storage of Study Drug 
All study drug material will be stored under secured conditions with limited access. Study drug 
boxes containing C16G2 or Placebo Strip will be stored at 2-8C. 
Used tooth strips are discarded at the end of each treatment event, the pouches will need to be 
retained for study drug accountability purposes. Excess tooth strips will be replaced in the study 
drug box and re-stored at room temperature or 2-8C. After dosing in the study is complete, 
box(es) will be sealed closed for future drug accountability by the authorized study staff and/or 
clinical study monitor (See Section 9.1.7). 


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5.3 
Study Drug Preparation 
5.3.1 C16G2 or Placebo Strip Preparation 
For details on study drug preparation refer to the Study Manual for this study. 
 
Study drug preparation involves the following steps: 
 
According to the randomization and study arm assignment, retrieve a study drug kit 
containing the assigned C16G2 or Placebo Strip dose 
 
Enter the subject identification and dispensation date on the appropriate study drug label 
and study records 
 
To avoid any potential damage to the strip, open the pouch on the side where the 
subject information was entered  
 
Apply one strip per quadrant  per instructions in Appendix G 
 
 
 


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STUDY ASSESSMENTS & PROCEDURES 
For details on study schedules and assessments, including dosing and microbiology information 
refer to Appendices B through D. 
6.1 
Screening and Re-screening 
Subjects will be screened, including S. mutans assessment, within 30 days of planned dosing 
with the study drug. If a subject qualifies for the study based on screening results, but cannot be 
treated within 30 days due to scheduling problems, he/she may be re-screened at the 
Investigator’s discretion. During re-screening, the following assessments will be repeated: re-
signing of the consent form (if required by the IRB), oral cavity assessment, targeted physical 
exam, salivary flow assessment, local laboratory (hematology and chemistry) and pregnancy 
test (if applicable). If the informed consent is not re-signed, all screening procedures except for 
the informed consent need to be within 30 days. During re-screening, the S. mutans 
assessment does not need to be repeated if <60 days have elapsed since the initial procedures. 
For potential subjects that do not qualify for the study based on initial screening, re-screening is 
at the discretion of the Sponsor in consultation with the Investigator on a case-by-case basis. If 
re-screened within 30 days, not all screening procedures may need to be repeated. Also, 
subjects that were successfully screened for Study C3J16-V204-00, but not enrolled, may be 
enrolled into Study C3J16-S205-00 without repeating screening assessments if these are within 
30 days of planned dosing (and within 60 days for S. mutans assessments).   
6.2 
Subject Instructions 
Subjects enrolled in all study arms will be instructed to abstain from eating food and drinking 
beverages that contain a high sugar content (e.g., candy, soda with refined sugar, sugary 
snacks, dried fruit, fruit rolls) from Screening to the last day of study drug administration (Visit 
17, Day 11, PM). While smokers are not excluded from study participation, subjects should 
abstain from using chewing tobacco or similar products throughout the study. 
6.2.1 Oral Hygiene Instructions  
During the entire study subjects will not be allowed to use any dental material besides the 
material provided by the study center. Prior to attending the study center for any visit (Visits 1-
22), subjects will not be allowed to perform oral hygiene at home. In addition, Subjects will be 
advised not to use any mouth rinse for approximately 24 hours before the Screening visit. 
 
Prior to discharge at Visit 2/Day -7 to -2, subjects will receive a manual toothbrush, a regular 
toothpaste containing fluoride, and dental floss provided by the Sponsor to take home. Subjects 
will be instructed to use these dental products in the morning and evening at home during the 
remaining study duration, including the evening of Day 0.  In addition, subjects will be resupplied 
with these dental products as needed. 
 
 
 
 
 


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6.2.2 Diet Instructions  
Subjects in all study arms will be instructed as follows:  
 
All Visits:  
• 
Do not eat for 1 hour prior to the appointment time 
• 
No liquids, other than plain water, 1 hour prior to the appointment time 
Note: Subjects will be allowed to drink water up to 10 minutes prior to dental plaque and 
saliva collection, and will be instructed not to swish or rinse 
Visits 3, 8-17 (Study Drug Administration Days) 
• 
Do not eat or drink anything besides plain water within 1 hour prior to the appointment time 
• 
Do not eat, drink anything or swish during the study drug administration period and for 1 
hour after the removal of the strips.   
 
Note: Subjects will be under the supervision of study staff to ensure that they do not 
consume any food or drink anything during and 1-hour post study drug administration.  
6.3 
Clinic Visit Schedules, Assessments & Procedures  
6.3.1 Clinic Visit Schedules  
For details on Clinic Visit Schedules refer to Appendix D. 
6.3.2 Assessments & Procedures  
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Informed Consent/Assent & Assign Subject ID  
o Inclusion/Exclusion 
o Medical/Surgical/Dental History and Concurrent Illnesses 
o Salivary Flow Assessment  
o Concomitant Medications 
o Demographics  
o Dental status and comprehensive caries examination including standard radiograph 
Note: If radiographs are deemed appropriate for the study and taken within 6 months 
prior to the Screening visit, these may be used for determining eligibility and not 
required to be repeated at Screening 
o Screening Laboratory Testing  
o Urine Pregnancy Test (females of childbearing potential only) 
o Oral Cavity Assessment  
o Targeted Physical Exam (general, extraoral, head & neck) 
o Vital Signs (blood pressure, heart rate, temperature) 
o Microbiology (stimulated saliva ONLY) 
Note: Screening Microbiology sample will be collected on Days -30 to -8 prior to Visit 2 
o Discharge   
 


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Clinic Visit 2 (Prophylaxis, Day -7 to -2) 
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (Stimulated Saliva and Dental plaque collection) 
Note: Samples need to be obtained prior to oral hygiene training and professional 
dental prophylaxis 
o Professional Dental Prophylaxis (prophylaxis will include removal of bulk plaque and 
supragingival scaling)  
Note: NO fluoride treatment as part of the procedure, NO subgingival scaling as part of 
the prophylaxis 
o Oral Hygiene Training: 
 
Flossing (string): instructions are provided in Appendix E 
 
Manual toothbrush technique for routine dental hygiene using a manual 
toothbrush provided by the sponsor and toothpaste containing fluoride (for 
instructions refer to Appendix F) 
o Oral Hygiene Product Distribution 
o Discharge  
 
Clinic Visits 3 & 8-17 (Baseline Day 0, Days 7-11 – Study Drug Administration Days) 
AM visits will be scheduled 6AM to 10AM. PM visits will be scheduled 6PM to 10PM 
Subjects should not be exposed to study drug if they present with any disruption or loss of 
integrity in the oral cavity mucosa, gingiva or have lip lesions, (e.g. aphthous stomatitis, active 
herpetic sores, cheek bites, or severely chapped or cracked lips, etc.). 
Pre-Dose 
o Confirmation of eligibility (Visit 3 ONLY) 
o Medical/Dental History & Concurrent Illness Update (Visit 3 ONLY) 
o Study Arm Assignment and Randomization (Visit 3 ONLY) 
o Urine Pregnancy Test (females of childbearing potential only) (Visit 3 ONLY) 
o Targeted Physical Exam (Visit 3 & 8 ONLY) 
o Concomitant Medications Update 
o Oral Cavity Assessment: AM Visits 3, 8, 10, 12, 14, & 16 only  
o Vital Signs (Visits 3, 8 & 17 only) 
o Microbiology (Stimulated Saliva & Dental Plaque)  
Note: Microbiology samples will only be collected at Visits 3, 8, 9 and 10 
o Brushing and flossing with the dental material provided by the Sponsor 
Study Drug Administration:  
Instructions for the application of C16G2 Strips or Placebo are provided in the Study Manual 
and in Appendix G. 
o Subjects will have C16G2 Strip (9.2 mg, 18.4 mg, or 36.8 mg in Study Arms 1 
through 3, respectively) or Placebo Strip applied to molars and bicuspids and remain 
on the subject’s teeth for up to 90 minutes. Subject will not eat, swish or drink anything 
during the study drug administration period. 
 
Post-Dose 
o C16G2 and Placebo strips will remain on the subject’s teeth for 30 minutes (do not 
manipulate strips during that time) 
o Remove strips that have fully self-detached starting 30 minutes after application 


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o Remove all strips that have not fully self-detached 90 minutes after application  
Note: Dental strips will in most cases fully detach prior to 90 minutes. Only remove 
strips that fully detach earlier than 90 minutes after application. Subjects will not eat, 
swish, or drink for one hour after the removal of study drug 
o Photographic imaging immediately after study drug application (Visit 3 ONLY) 
o Oral Cavity Assessment: AM Visit 3 and PM Visits 9, 11, 13, 15, & 17 only 
o Vital Signs (blood pressure, heart rate, temperature) within 20 minutes of removal of 
the last strip, taken in supine or sitting position (Visits 3, 8 & 17 only) 
Prior to Discharge 
o Adverse Events 
o Oral Hygiene Product Distribution (as needed) 
o Discharge  
 
Clinic Visits 4-7 and 18-20  
On visits 7, 19 & 20 subjects will be scheduled between 6AM and 10AM. Remaining visits will 
be scheduled as appropriate, according to clinic visit schedule in Appendix D 
o  Concomitant Medication Update  
o Oral Cavity Assessment  
o Targeted Physical Exam (Visits 5, 18 and 20) 
o Microbiology (stimulated saliva and dental plaque collection) 
o Adverse Events 
o Discharge 
 
Clinic Visits 21-22  
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (stimulated saliva and dental plaque collection) 
o Discharge 
o End of Study (Visit 22 ONLY) 
 
 
 
 


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ADVERSE EVENTS AND SAFETY MANAGEMENT 
7.1 
Definition of Adverse Events 
An AE is “any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.” 
For the purposes of this definition, “untoward” means unfavorable, negative, or harmful. Note 
that an AE is any event observed or reported that is associated with the use of the drug, without 
regard to causality. 
Adverse events will be collected and reviewed to evaluate the safety of C16G2 or Placebo Strip. 
All AEs will be recorded from the first exposure to study drug up to 1 week after the last 
administration of study drug. After that time point, all ongoing adverse events will be followed in 
accordance with good medical practice until resolution or the adverse event or condition has 
stabilized. AEs that occur after exposure to study drug will be classified as treatment-emergent 
AEs (TEAEs). All AEs whether observed by the Investigator and/or study staff or reported by the 
subject, will be recorded in the source records and EDC system. 
Medical or dental conditions that are present at or before the administration of study drug that 
manifest with the same intensity or frequency subsequent to administration of study drug will not 
be recorded as AEs. Similarly, signs or symptoms related to a pre-existing disease will not be 
recorded as AEs unless there is an increase in the intensity, frequency or duration of the signs 
or symptoms. These pre-existing events, signs, or symptoms will be entered in the source 
records and EDC system. 
Diagnostic and therapeutic non-invasive procedures, such as surgery, should not be reported as 
AEs. However, the medical condition for which the procedure was performed should be 
reported, if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as an AE and the resulting appendectomy 
should be recorded as treatment of the AE. 
7.2 
Assessment of Severity (Intensity) of Adverse Events 
The severity or intensity of an AE describes the degree of impact upon the subject and/or the 
need for, and the extent of medical care required to treat the AE. 
Symptoms should be graded as mild, moderate, severe, or life threatening according to the 
grading scale noted in Table 1. Please refer to Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0. 
 
 


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Table 1: Adverse Events Intensity Description 
Grade 
Description 
Mild (1) 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
Moderate (2) 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
 
Severe (3) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
 
Life Threatening (4) 
Life-threatening consequences; urgent intervention indicated  
 
Activities of Daily Living (ADL) 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly 
with subject’s usual function), but would not be classified as serious unless it met the criteria for 
an SAE (See Section 7.7). 
7.3 
Assessment of Causality (Relationship to Study Drug) 
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the study drug caused or contributed to an AE. The Investigator’s 
assessment of causality must be provided for all AEs (serious and non-serious). 
Several factors to consider when assessing the relationship of an event to the study drug: 
 
Alternative etiology - Is the event due to the underlying disorder being studied or to 
another known disorder? 
 
Known relationship - Has the event been observed before in patients treated with this 
study drug or similar products? 
 
Temporal relationship - Is there a reasonable temporal relationship between the time of 
onset of the event and the administration of the study drug? 
 
Concomitant medication - Is the event a known side effect of a concomitant medication? 


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The Investigator will document his/her opinion of AE relationship to study drug using the criteria 
outlined in Table 2 below. 
Table 2: Adverse Event Relationships Description 
Relationship 
Description 
None 
The event can be readily explained by the subject's underlying medical condition, a 
concomitant therapy or other cause and the Investigator believes no relationship 
exists between the event and study drug. In this case, the Investigator should 
document the condition, concurrent / underlying illness, medication, study 
procedure or other cause they believe to be the cause of the adverse event. 
Unlikely 
The event does not follow a reasonable temporal sequence from administration of 
study drug nor does the event follow a known or expected response pattern to study 
drug and may have another cause. In this case, the Investigator should document 
the condition, concurrent / underlying illness, medication, study procedure or cause 
they believe may have contributed to the adverse event. 
Possible 
The subject’s condition, concurrent/underlying illness, medication, or study 
procedures cannot explain the event, and there is a plausible temporal relationship 
between the event and study drug administration. 
Probable 
The temporal relationship between the administration of study drug and the adverse 
event strongly suggests a relationship, and/or the adverse event cannot be 
reasonably explained by another condition, concurrent / underlying illness, 
medication, study procedure or other cause, or the adverse event abates with 
discontinuation of study drug, and recurs with re-administration. 
For reporting purposes, AEs assigned a relationship to study drug of “Probable,” and “Possible” 
will be classified as related to study drug. AEs assigned a relationship to study drug of “Unlikely” 
and “None” will be classified as not related to study drug. 
7.4 
Suspected Adverse Reaction (SAR) and Adverse Reaction (AR) 
Suspected adverse reactions (SARs) are the subset of all AEs for which there is a reasonable 
possibility to conclude that the study drug caused the event. For the purposes of IND safety 
reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship 
between the study drug and the AE. 
An “adverse reaction” (AR) is any AE caused by a drug. ARs are a subset of all SARs for which 
there is reason to conclude that the study drug caused the event. 
An SAR implies a lesser degree of certainty about causality than an AR, which means any AE 
caused by a drug. 
For reporting purposes, AEs assigned a relationship to study drug of “Probable,” and “Possible” 
will be classified as SARs. 
AEs assigned a relationship to study drug of “Unlikely” and “None” will not be classified as 
SARs. 


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7.5 
Unexpected Adverse Events 
The Investigator's Brochure (IB) provides Investigators with information (clinical and nonclinical) 
about the study drug. The IB includes those AEs for which a causal relationship is suspected or 
confirmed (SARs or ARs), as well as adverse events that may be predicted to occur based on 
the pharmacological properties of the drug. The IB is used as the basis for the Sponsor’s 
determination of “unexpected” for reporting purposes. 
“Unexpected” SARs are AEs not currently listed in the IB. An AE or SAR may also be 
considered “unexpected” if it is not listed in the IB at the specificity or severity that has been 
observed. 
7.6 
Withdrawal Due to Adverse Events 
Withdrawal due to an AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of AE noted earlier, and entered in the source records and EDC 
system. 
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below. 
7.7 
Serious Adverse Events 
7.7.1 Definition of Serious Adverse Events 
Serious adverse events (SAEs) are defined as those AEs that meet any of the following criteria: 
 
Life threatening, that is, any event that, in the opinion of the Investigator, poses an 
immediate risk of death from that event 
 
Results in death  
 
Results in or prolongs hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
Results in congenital anomaly/birth defect 
 
Is an important medical event that may require an intervention to prevent one of the 
outcomes listed above 
 
For clarification, an AE or suspected adverse reaction (SAR) is “life-threatening”, if, in the 
view of the Investigator or the Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an AE or SAR that, had it occurred in a more severe form, 
might have caused death 
The Investigator should exercise medical and scientific judgment when deciding whether SAE 
reporting is appropriate in other situations not strictly meeting the listed criteria above. Examples 
of important medical events which may meet the definition of an SAE include: intensive 
treatment in an emergency room or at home for allergic bronchospasm, certain laboratory 
abnormalities (e.g., blood dyscrasias), convulsions that do not result in hospitalizations, or 
development of drug dependency or drug abuse. 
Pre-planned hospitalizations and/or elective surgical procedures may not be considered SAEs. 


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Hospitalization does not include the following: 
 
Rehabilitation facilities; 
 
Hospice facilities; 
 
Respite care (e.g., caregiver relief); 
 
Skilled nursing facilities; 
 
Nursing homes; 
 
Routine emergency room admissions; 
 
Scheduled or elective same day surgeries (as outpatient/same day/ambulatory 
procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself an SAE. Examples include: 
 
Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for work-up of 
persistent pre-treatment lab abnormality); 
 
Social admission (e.g., subject has no place to sleep); 
 
Administrative admission (e.g., for yearly physical exam); 
 
Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); 
 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive procedures, such as surgery, should not be reported as 
AEs. However, the medical condition for which the procedure was performed should be 
reported, if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as an AE and the resulting appendectomy 
should be recorded as treatment of the AE. 
The Investigator should contact the Sponsor's Medical Monitor immediately if there is a question 
as to whether or not an AE meets the criteria for serious. 
7.8 
Procedures for Reporting and Recording Serious Adverse Events & Suspected 
Serious Adverse Reactions 
All SAEs, irrespective of relationship to study treatment, must be reported to the Sponsor and 
the Medical Monitor as soon as possible, but no later than 24 hours from the time of notification. 
All AE/SAE information and appropriate supporting documentation must be sent electronically to 
the Medical Monitor & Sponsor. 
Medical Monitor: 
Marilyn R. Carlson, DMD, MD, RAC 
Cell Phone: 858-945-7189 
Email: mcarlson@agility-clinical.com 


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Urgent safety issues should be discussed by telephone with the Medical Monitor as soon as the 
Investigator or members of the study staff become aware of the issue. 
It is very important that the SAEs be reported as soon as possible via the EDC and the 
information be filled out as completely as possible at the time of the initial report. This includes 
the Investigator’s assessment of causality. A brief description of the event must be provided at 
the time of the initial report. After the initial SAE report has been submitted, relevant follow-up 
information should be submitted as soon as possible, preferably within one (1) business day of 
receipt. If the follow-up information changes the Investigator’s assessment of causality, this 
should also be added as follow-up information in the EDC system. 
Additional SAE-related supporting documents, such as copies of hospital reports, lab reports, 
discharge summaries, and autopsy reports, if applicable, may be requested. All subject 
identifiers, except the subject’s initials and unique study identification number, must be removed 
from documents prior to submission to the Medical Monitor and other Sponsor designees. 
Subjects’ names, personal identification numbers (i.e., medical record numbers), and 
addresses, etc., should be removed or blocked-out. 
Reporting of a suspected serious adverse reaction (SSAR) should not be delayed in order to 
obtain additional information. Any additional information, if collected, can be reported as a 
follow-up to the initial report. Any SAE that occurs at any time during the study, whether or not 
related to study drug, must be reported to the Medical Monitor within 24 hours of first awareness 
at the site. 
The Investigator is responsible for the information recorded on SAE reports. It is the 
Investigator’s responsibility to ensure that the SAE information in the EDC system and source 
documents are accurate, consistent and in agreement. The Investigator is responsible for 
continuing SAE follow-up. The results of any additional assessments of the SAE must be 
reported to the Medical Monitor as an update to the SAE as soon as possible, but no later than 
24 hours after first awareness. Details on the SAE reporting procedure are provided in the SAE 
Reporting Guidelines. Criteria for determining severity and the relationship to study drug for the 
updated SAE will be the same as those previously described in Sections 7.2 and 7.3. 
7.8.1 Reporting Serious Adverse Events to the FDA and IRB 
The Investigator will comply with the applicable regulatory requirements related to the reporting 
of SAEs to the IRB. The completed SAE report will be used by the Sponsor in regulatory filings 
and may be used by the Investigator to convey SAE information to the IRB. 
7.8.2 Following Adverse Events and Serious Adverse Events 
All AEs should be followed in accordance with good medical practice until resolution or the 
adverse event or condition has stabilized. AEs will be followed for one week post last dose in all 
Study Arms. All SAEs will be followed until the outcome is known or the subject’s condition has 
stabilized. 
7.9 
Pregnancy 
A negative urine pregnancy test result must be confirmed at Screening and Baseline visits. 


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Female subjects of childbearing potential, defined as not surgically sterile or at least two (2) 
years postmenopausal, must agree to use one of the following forms of contraception from 
screening through the last study visit: hormonal (oral, implant, or injection) begun >30 days prior 
to screening; barrier (condom, diaphragm, or cervical cap with spermicide); intrauterine device 
(IUD). Acceptable contraceptive options may also include; abstinence, monogamous 
relationship with same sex partner or partner who has had a vasectomy at least six (6) months 
prior to the screening visit. In the unlikely event a subject becomes pregnant during the study, 
the subject will be withdrawn from the study immediately upon confirmation of pregnancy. These 
subjects will be required to return to the study center to undergo early termination procedures 
(Sections 9.3.2 and 9.3.3). 
In addition, any documented pregnancy will be tracked and followed through outcome. While 
pregnancy itself is not considered an AE or an SAE, any pregnancy complications or elective 
termination of a pregnancy for medical reasons will be recorded as an AE and evaluated as a 
possible SAE. 
All pregnancies are to be reported immediately to the Medical Monitor. 
7.10 Management of Medical Emergency (Hypersensitivity)  
If a hypersensitivity reaction occurs during the administration of study drug, the Investigator will 
discontinue the administration of study drug and provide general supportive measures. If an 
adverse event occurs after administration of study drug, the Investigator will provide general 
supportive measures. 
7.11 Management of Dosing Error 
If a dosing error does occur, the Investigator will; 1) monitor the subject, 2) provide general 
supportive measures, as needed, 3) notify the Medical Monitor and the Sponsor within 24 hours, 
and, 4) report the dosing error to the IRB, per site’s policy. 
 
 


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STATISTICAL CONSIDERATIONS 
8.1 
General Considerations  
Protocol C3J16-S205-00 is a phase 2, single-blind, randomized, placebo controlled study 
designed to evaluate the safety and microbiological activity of C16G2 Strip applied directly to 
the tooth surface. Study subjects will receive a single dose of C16G2 Strip or Placebo followed 
by 5 days of twice-daily dosing 7 days post-first study drug administration. The study will 
compare 9.2 mg, 18.4 mg and 36.8 mg C16G2 Strip or Placebo administrations in Study Arms 1 
through 3, respectively. 
The objectives of the study are to assess the targeted antimicrobial activity of C16G2 Strip or 
Placebo as measured by a reduction in the number of Streptococcus mutans in saliva and 
dental plaque, and assessment of total bacteria in saliva and dental plaque, and to evaluate the 
safety of multiple C16G2 Strip or Placebo administration in adolescent and adult study subjects, 
For the summary table presentations, data will be summarized in tabular format by study arm 
and treatment group. All statistical analysis will be descriptive in nature. Descriptive summary 
statistics will include N, mean, standard deviation, median, range (minimum and maximum) for 
continuous variables, and frequency counts and percent for categorical variables. 
8.2 
Randomization 
Subjects will be sequentially assigned to one of three study arms in the order of enrollment. 
Each study arm will be fully enrolled (i.e., the last subject in an arm has completed Visit 3) 
before enrollment is initiated in the next study arm. After confirmation of study eligibility, subjects 
will be randomized at Visit 3 (Day 0) by authorized and unblinded study staff according to the 
master randomization schedule from the Sponsor’s study statistician. The randomization 
schedule and associated documentation will be kept in a secure location. 
A total of 30 subjects will receive three doses of C16G2 Strip or Placebo. Study subjects will be 
randomized to receive a single dose of study drug, C16G2 Strip or Placebo, in a 4:1 allocation 
ratio (eight C16G2 Strip subjects: two Placebo subjects) for each of the three study arms. The 
three C16G2 Strip doses planned are 9.2 mg, 18.4 mg and 36.8 mg. 
8.3 
Blinding 
The study will be conducted in a single-blind manner. All study subjects will be blinded to the 
treatment assignment, while the Investigator, study staff/clinicians and the Sponsor’s assigned 
team members (e.g., the Clinical Monitor and the Medical Monitor) will be unblinded as to 
whether subjects are receiving C16G2 or Placebo. 
To ensure blinding, study drug (C16G2 Strip or Placebo) will be prepared in an area outside the 
purview of study subjects. 
8.4 
Sample Size Determination 
The total number of subjects planned for this study is approximately 24 (n = 8 per arm). There 
are no data on which to base formal sample size calculations for this study. The data generated 
in this study will assist with ongoing clinical development of C16G2 Strip. Subjects’ data in all 
three study arms will provide information on the safety and microbiology of a single C16G2 Strip 


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CONFIDENTIAL 
or Placebo administration. Subjects who do not return for assessments after study drug 
administration for any reason may be replaced at the Sponsor’s discretion. 
8.5 
Analysis Sets 
There will be two analysis sets; the safety analysis set and the microbiology analysis set. 
The safety analysis set will be defined as those subjects enrolled and have received any 
amount of C16G2 Strip or Placebo. 
The microbiology analysis set will be comprised of two subsets, the microbiology saliva and 
microbiology dental plaque subset. These subsets will be based on the subjects who received 
study drug (C16G2 Strip or Placebo) and have at least a baseline and one post-baseline saliva 
and dental plaque sample. 
8.6 
Interim Safety Analysis 
There are no interim analyses planned; however, microbiology data will be reviewed by the 
Sponsor’s assigned team in an ongoing manner throughout the course of the study. 
8.7 
Statistical Analyses 
8.7.1 Demographics and Baseline Characteristics 
Demographic and baseline characteristics (i.e., age at screening, gender, weight, height, body 
mass index (BMI), race, ethnicity, medical history, physical examination, prior medications) will 
be listed for individual subjects and summarized by study arm / treatment group using summary 
statistics for continuous variables and frequency distributions for discrete variables. 
8.7.2 Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
and will be summarized for each study arm/treatment group by WHO Anatomical Therapeutic 
Chemical (WHO ATC) class and medication name. These summaries will present the number 
and percentage of subjects using each medication. 
8.7.3 Completion of the Study and Withdrawals 
Withdrawals and the reason for withdrawal (i.e., AE(s), protocol non-compliance, requirement 
for an unacceptable concomitant medication, lost to follow-up, failed to return, voluntary 
withdrawal, and other reasons) will be listed. The number and percentage of subjects who 
complete the study will be summarized. The number and percentage of subjects who withdraw 
from the study will be tabulated by study arm / treatment group at time of withdrawal. 
8.7.4 Protocol Deviations 
Protocol deviations will be listed and categorized (i.e., Inclusion/Exclusion Criteria, 
Randomization, Study Procedures, Missed Study Visit, Visit out of Study Window, Informed 
Consent, Safety Reporting, Study Drug Administration, Study Drug Accountability, and Other) 
and summarized based on these categories. 


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8.7.5 Safety Analysis 
Adverse events (AE) will be classified into standard terminology (preferred term and system 
organ class) using the Medical Dictionary for Regulatory Activities. The severity of each adverse 
event will be graded as 1) mild, 2) moderate, 3) severe, or 4) life-threatening, according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
In addition, all adverse events will be classified as to whether the relationship to study drug was 
1) None, 2) Unlikely, 3) Possible, or 4) Probable and followed to resolution or until the adverse 
event or condition has stabilized. 
The incidence and duration of treatment-emergent adverse events (TEAEs) will be summarized 
by study arm/treatment group according to MedDRA-preferred term and MedDRA system organ 
class term. An AE will be considered treatment emergent if the onset date and time occur on or 
after the recorded clock time of study drug administration. Tabulations of adverse events by 
severity grade and causal relationship to study drug (related, unrelated) will be provided. 
For reporting purposes, AEs assigned a relationship to study drug of “Possible” and “Probable” 
will be classified as related to study drug. AEs assigned a relationship to study drug of “Unlikely” 
or “None” will be classified as not related to study drug. 
The number and percentage of subjects with reported serious adverse experiences (SAEs) and 
subjects who withdrew due to an AE will be tabulated by study arm/treatment group. 
All adverse events will be presented in by-subject listings by reported verbatim term and 
MedDRA-preferred term, MedDRA system organ class, start and stop date and time, study day, 
duration, severity, relationship to study drug, seriousness, and outcome. All reported serious 
adverse events will also be displayed in by-subject listings. 
Oral cavity assessment (hard and soft tissues) findings will be documented at Screening and at 
each protocol-specified study visit. 
Clinically significant examination findings identified at Screening will be added to the subject's 
Medical History. 
After study drug administration clinically significant changes in the oral cavity assessment will be 
recorded as AEs and these TEAEs will be summarized by study arm / treatment group for each 
of the protocol specified assessments by calculating the number and proportion of subjects who 
develop clinically significant findings in the oral cavity after study drug administration. 
Targeted physical examination (general, extraoral, head and neck) findings will be documented 
at Baseline and at each protocol-specified study visit. 
 
Prior to administration of study drug, clinically significant examination findings will be added to 
the subject's Medical History. 


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CONFIDENTIAL 
After study drug administration clinically significant changes in the targeted physical 
examination will be recorded as AEs. 
Vital sign results (blood pressure, heart rate and temperature) will be summarized at Visit 1 
(Day -30 to Day -7), Visit 3 (Day 0) and Visit 8 (Day 7 /AM) and 17 (Day 11/PM pre- and post-
study drug administration for all study arms by calculating the mean, median, standard 
deviation, and range. Mean change from baseline will also be presented where baseline is 
defined as prior to study drug administration at Visit 3 (Day 0) for each study visit. 
Stimulated saliva and dental plaque samples will be analyzed for the number of S. mutans and 
total number of bacteria present. Samples will be analyzed by MSB and TH agar plating. 
Samples will be stored for analysis using qRT-PCR and bacterial community analysis. Bacterial 
community analysis and qRT-PCR data will be analyzed at appropriate time points based on 
plating assessments. Descriptive statistics utilizing mean, standard deviation, median and range 
of oral microbes at each time point for each study arm will be determined and compared to 
Baseline, as applicable. 
Further details regarding Microbiology analysis will be presented in the Statistical Analysis Plan 
(SAP). 
 
 
 


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RESPONSIBILITIES 
9.1 
Investigator Responsibilities 
9.1.1 Compliance with Good Clinical Practice  
The Investigator will print name and sign the Investigator Signature Sheet. 
The Investigator will ensure adherence to the basic principles of “Good Clinical Practice,” as 
outlined in the Code of Federal Regulations (CFR) 21 CFR 312, subpart D, “Responsibilities of 
Sponsors and Investigators,” 21 CFR, part 50, part 54, and part 56, as well as the International 
Conference on Harmonization (ICH) Guideline of Good Clinical Practice (ICH E6) and the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
The Investigator will ensure that this study is conducted in full compliance with the principles of 
the “Declaration of Helsinki” in Appendix I, ICH guidelines, or with the laws and regulations of 
the country in which the research is conducted, whichever affords the greater protection to the 
subject. 
9.1.2 Institutional Review Board (IRB)  
The Investigator will submit this protocol and any materials (such as advertisements, patient 
information sheets, or descriptions of the study used to obtain informed consent) to the IRB. 
Approval from the IRB must be obtained before starting the study and documented in a letter to 
the Investigator specifying the protocol number, protocol version, documents reviewed, and date 
on which the IRB granted the approval. 
The Investigator will submit all SAE reports to the IRB within the locally specified time 
requirement. The Investigator will submit any safety report from the Sponsor to the IRB within 
the locally specified time requirement. The Investigator is responsible for submitting all protocol 
amendments to the appropriate IRB prior to implementation. 
9.1.3 Informed Consent  
Informed Consent and Assent: 
The Investigator will obtain verbal or written assent, as appropriate, and written informed 
consent from one parent or legal guardian of each participant, if consistent with IRB policy and 
state law, for each individual participating in this study after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study and prior to undertaking any study-
related procedures. The Investigator will utilize IRB-approved assent and consent forms.   
Each informed consent form (ICF) will be signed and dated by the parent or legal guardian of 
the subject, and the person obtaining the informed consent. By signing the informed consent 
form or giving oral or written assent, the parent or legal guardian and the subject agree that the 
subject will complete all evaluations unless the parent, legal guardian or subject withdraws 
consent or the subject is withdrawn from the study for any reason. 
As part of the informed consent, the Investigator will obtain HIPAA compliant authorization from 
subjects to use and disclose relevant protected health information (PHI) and permission for 


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CONFIDENTIAL 
authorized representatives of C3 Jian, LLC, or regulatory authorities including the FDA, to 
review in confidence any records identifying subjects in the clinical study. 
Recruitment efforts may precede obtaining informed consent; however, informed consent must 
be obtained prior to any protocol specific procedures being performed. 
The Investigator will communicate any new information on safety to subjects who consent to 
participate in this study in accordance with IRB requirements. The ICF and assent will be 
updated, if necessary. 
9.1.4 Confidentiality 
The Investigator will assure that subjects’ anonymity will be strictly maintained and that their 
identities will be protected from unauthorized parties. Only subject initials and an identification 
code (i.e., not names) will be recorded and submitted to the Sponsor or IRB. 
The Investigator agrees that all information received from C3 Jian, LLC, including but not limited 
to the Investigator’s Brochure, this protocol, EDC data, the study drug, and any other study 
information, are the sole and exclusive property of C3 Jian, LLC. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of the 
study or as required by law) without prior written consent from C3 Jian, LLC. 
The Investigator further agrees to take all reasonable precautions to prevent the disclosure by 
any employee or agent of the study center to any third party or otherwise into the public domain. 
9.1.5 Study Files and Retention of Records 
The Investigator will maintain adequate and accurate records that fully document the conduct of 
the study and enable study data to be verified. These documents should be classified into 
separate categories: 1) Investigator’s study file and 2) subject clinical source documents. 
 
The Investigator’s study file includes the original protocol, protocol amendments, EDC data, 
and query forms, IRB approval with correspondence, approved informed consent forms, 
drug records, staff curriculum vitae (CV) and authorization forms, and other appropriate 
documents and correspondence. 
 
Subject clinical source documents include, but are not limited to, the subject’s 
medical/dental records, ECGs, pathology and special assessment reports, consultant 
letters, screening and enrollment log, as applicable. 
The Investigator will make the source documents for this study available to C3 Jian, LLC. or its 
representatives, or to regulatory or health authority inspectors. The Investigator will retain all 
study documents for at least two years after the last approval of a marketing application in an 
International Conference on Harmonization (ICH) region (i.e., United States, Europe, or Japan), 
and until there are no pending or contemplated marketing applications in an ICH region. If no 
application is filed or if the application is not approved for such indication, the Investigator will 
retain all study documents for at least two years after the investigation is discontinued and 
regulatory authorities have been notified. The Investigator may retain documents longer if 
required by applicable regulatory requirements or by agreement with C3 Jian, LLC. 


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The Investigator will notify C3 Jian, LLC prior to destroying any study records. Should the 
Investigator wish to assign the study records to another party or move them to another location, 
the Investigator must notify C3 Jian, LLC in writing in advance. If the Investigator cannot 
guarantee this archiving requirement at the study center for any or all of the documents, special 
arrangements will be made between the Investigator and C3 Jian, LLC for storage. If source 
documents are required for continued care of the subject, appropriate copies for storage off site 
will be made. 
9.1.6 Study Data - Electronic Data Capture  
The Investigator is responsible for the completeness and accuracy of information entered in the 
source records and EDC system for each individual enrolled. The Investigator will review and 
approve all EDC entries; document the reason that a subject withdraws from the study in the 
source records and EDC system and attempt to obtain termination assessments; and continue 
follow-up to document the outcome of any adverse event. 
9.1.7 Drug Accountability 
The Investigator is responsible for ensuring adequate accountability of all used and unused 
study drug, including acknowledgment of receipt of each shipment of study products (quantity 
and condition) and subject dispensing records. Dispensing records will document quantities 
received and quantities dispensed, kit or lot number (if applicable), date dispensed, Subject 
identifier number, and initials of the person dispensing study drug. 
The Investigator will make these study drug accountability records available to the study 
monitor. At the end of the study and after the Study Monitor has completed study drug 
accountability, drug supplies will be returned for destruction, unless an alternative disposition is 
arranged and approved by the Sponsor. 
Unused study drug such as partially used strip pouches and boxes must not be discarded or 
destroyed by the Investigator until requested in writing by the Sponsor and only after the Clinical 
Monitor has conducted the final investigational product accountability. At this point, the Sponsor 
may request in writing that study drug inventory be destroyed in compliance with their 
institutional requirements. 
9.1.8 Inspections 
The Investigator will make the source documents (paper and/or electronic) for this study 
available to C3 Jian, LLC or its authorized designee, or to the regulatory or health authority 
inspectors. 
9.1.9 Protocol and IRB Compliance 
The Investigator will ensure that the study is conducted in accordance with the procedures and 
evaluations described in this protocol. The Investigator will submit all amendments to the 
protocol to the IRB in accordance with local requirements. Approval by the IRB will be obtained 
before amendments are implemented. 


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9.2 
Sponsor Responsibilities 
C3 Jian, LLC is the Sponsor of this study. C3 Jian, LLC or its designee is responsible for 
selecting qualified Investigators, providing them with information needed to conduct the study 
properly, monitoring the study to ensure it is conducted in compliance with the Code of Federal 
Regulations (CFR), local/regional requirements, GCP guidelines, and the protocol, and reporting 
the new adverse events or risks to the Investigators, FDA and local regulatory authorities in a 
timely manner. 
9.2.1 Protocol, Protocol Amendments, and Safety Updates  
C3 Jian, LLC is responsible for the protocol and protocol amendments, except those intended to 
reduce immediate risk to subjects. C3 Jian, LLC is responsible for submitting the protocol and 
protocol amendments to the appropriate regulatory authorities. 
C3 Jian, LLC is responsible for providing written safety updates to the Investigator. Safety 
updates include any information that significantly bears on the subject’s risk to receive the study 
drug. 
9.2.2 Monitoring of Study 
Prior to the initiation of the study, C3 Jian, LLC or its designee will ensure the Investigator and 
study staff understands the investigational status of the product, all requirements of the protocol, 
and regulatory responsibilities as an Investigator. The Clinical Monitor will visit each clinical site 
at appropriate intervals to ensure compliance with the protocol and to verify accuracy and 
completeness of data reported, and accountability of supplies of investigational product. 
The Clinical Monitor(s) will be available for consultation with the Investigator and serve as a 
liaison between the site and the Sponsor. The Clinical Monitor or authorized representatives of 
the Sponsor may inspect all data, documents, and records required to be maintained by the 
Investigator including but not limited to, medical/dental records and pharmacy records for 
subjects participating in this study. The study center will permit access to such records. 
9.2.3 Data Handling and Recording 
C3 Jian, LLC. or its authorized designee is responsible for data processing. The Investigator is 
responsible for the accurate and timely completion of EDC entries. These entries will be 
reviewed for accuracy and completeness by the Clinical Monitor remotely on an ongoing basis 
and during study center visits. If necessary, the study center will be contacted for corrections 
and/or clarifications. All data will be entered into a study database for analysis and reporting. 
Upon completion of data entry, the database will receive a quality assurance check to ensure 
acceptable accuracy and completeness. 
9.2.4 Study Report and Publication  
C3 Jian, LLC is responsible for submitting the study report to the appropriate regulatory 
authorities and for publishing the results of this study. No results will be published without prior 
review and approval by C3 Jian, LLC. 
Within one year of the final clinical study report, the results of the entire study will be submitted 
for public disclosure in abstract, manuscript, or presentation form, under the guidance of the 


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CONFIDENTIAL 
Publication Committee. Following that disclosure, Investigators in this study may communicate, 
orally present, or publish site specific results in scientific journals or other scholarly media in 
accordance with the conditions set forth in the Clinical Study Agreement. No such 
communication, presentation, or publication will include C3 Jian’s confidential information. 
Investigator(s) will submit any proposed publication or presentation to C3 Jian, LLC at least 
45 days prior to submission of the publication or presentation. Investigator(s) will withhold 
publication or presentation for an additional 90 days in order to enable C3 Jian, LLC to obtain 
patent protection, if deemed necessary. These terms will hold except to the extent different 
period(s) may be provided for in the Clinical Study Agreement between the parties, in which 
case such different time period shall control. 
9.3 
Joint Investigator / Sponsor Responsibilities 
9.3.1 Access to Information, Quality Control and Assurance 
In accordance with International Conference on Harmonization Good Clinical Practice (ICH-
GCP) guidelines, the Clinical Monitor will have direct access to the Investigator’s source 
documentation at regular intervals throughout the study, in order to document compliance with 
the protocol and verify the completeness and accuracy of the data recorded in the source 
records and EDC system. The Investigator will cooperate with the Clinical Monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved in a reasonable 
period of time. 
Clinical Monitors will periodically audit, at mutually convenient times during and after the study, 
all EDC entries and corresponding source documents, for each subject. In addition to remote 
monitoring via the EDC system, monitoring on-site visits provide C3 Jian, LLC with the 
opportunity to evaluate the progress of the study, to verify the accuracy and completeness of 
EDC entries, to resolve any inconsistencies in the study records, and to assure that all protocol 
requirements, applicable FDA regulations, other requirements, and Investigator’s obligations are 
being fulfilled. 
9.3.2 Withdrawal of Subjects 
Any subject may choose to withdraw from the study for any reason and at any time. The 
Investigator will withdraw any subject if it is not in the subject’s best interest to continue or the 
subject is not compliant with study assessments. When a subject is withdrawn from the study 
(regardless of the reason), the date and reason will be recorded. In addition, all evaluations 
specified for the End of Study Visit 22 will be performed, if feasible. 
In addition, subjects may choose to withdraw authorization to use and disclose their protected 
health information (PHI) as defined by the Health Insurance Portability and Accountability Act of 
1996 (HIPAA). Such withdrawal of authorization must be made to the Investigator in writing. Any 
PHI collected by the Investigator or Sponsor prior to the date of such withdrawal will continue to 
be used and disclosed. 
Subjects may be removed from the study if one or more of the following events occur: 
 
Significant protocol violation on the part of the Investigator; 
 
Failure of subject to meet the study entrance criteria; 
 
Significant noncompliance on the part of the subject with study procedures; 


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CONFIDENTIAL 
 
Withdrawal of consent (refusal of the subject to continue treatment or assessments); 
 
Develops medical condition, taking a medication which could affect study outcome (e.g., 
antibiotic); 
 
Due to adverse event or unacceptable toxicity; 
 
Decision by the Investigator that termination is in the subject’s best medical interest;  
 
Unrelated medical illness or complication; 
 
Lost to follow up. 
9.3.3 Study Discontinuation 
Both the Investigator and C3 Jian, LLC reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures. In terminating 
the study, both the Investigator and C3 Jian, LLC will assure that adequate consideration is 
given to the protection of the subjects’ interests. All subjects will undergo all evaluations 
specified for the end of study (Study Visit 22), in an “exit” examination, if the study is terminated 
prematurely. 
Subject’s medical information obtained as a result of this study is considered confidential and 
disclosure to third parties other than those noted below is prohibited. Subjects will receive 
written copies of all laboratory data to bring to their health care provider. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection 
on request by FDA or other government regulatory agency auditors, C3 Jian’s Medical Monitor 
(or designee), and the Institutional Review Board (IRB). 
The information developed in this clinical study will be used by C3 Jian, LLC in the clinical 
development of the study drug. C3 Jian, LLC may disclose information to clinical Investigators, 
to other pharmaceutical companies, to the FDA and to other government agencies as required. 


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 ETHICS 
10.1  Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki (1964) including all 
amendments up to and including the Seoul, Korea revision (2008), as provided in Appendix I. 
10.2  Institutional Review Board 
The protocol, informed consent, and any materials (e.g., advertisements, subject information 
sheets, or descriptions of the study used to obtain informed consent) for this study will be 
reviewed and approved by a duly constituted IRB. 
The IRB is responsible for reviewing the protocol, informed consent, Investigator’s Brochure, all 
amendments, and periodic safety reports in accordance with current institutional, local, and 
national regulations. A letter documenting the IRB’s approval of the protocol will be provided to 
the Sponsor prior to initiation of the study. Amendments to the protocol will be subject to the 
same requirements as the original protocol. 
The Investigator will submit all periodic reports and updates that the IRB may require, including 
any final close out reports. The Investigator will inform the IRB of any reportable adverse events 
and protocol deviations. 
 
 


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 REFERENCES  
Eckert, R., J. He, et al. (2006). "Targeted killing of Streptococcus mutans by a pheromone-
guided "smart" antimicrobial peptide." Antimicrob Agents Chemother 50(11): 3651-3657. 
Kaplan, C. W., J. H. Sim, et al. (2011). "Selective membrane disruption: the mode of action of 
C16G2, a specifically-targeted antimicrobial peptide." Antimicrob Agents Chemother. 
Guo, L., J.S. McLean, et al. (2015). "Precision-guided antimicrobial peptide as a targeted 
modulator of human microbial ecology." PNAS USA 112(24):7569-7574. 
Li, L. N., L. H. Guo, et al. (2010). "Targeted antimicrobial therapy against Streptococcus mutans 
establishes protective non-cariogenic oral biofilms and reduces subsequent infection." Int J Oral 
Sci 2(2): 66-73. 
Loesche, W. J. (1986). "Role of Streptococcus mutans in human dental decay." Microbiol Rev 
50(4): 353-380. 
Marsh, P. D. (2006). "Dental plaque as a biofilm and a microbial community - implications for 
health and disease." BMC Oral Health 6 Suppl 1: S14. 
Marsh, P. D. (2010). "Microbiology of dental plaque biofilms and their role in oral health and 
caries." Dent Clin North Am 54(3): 441-454. 
Sullivan, R., P. Santarpia, et al. (2011). "Clinical efficacy of a specifically targeted antimicrobial 
peptide mouth rinse: targeted elimination of Streptococcus mutans and prevention of 
demineralization." Caries Res 45: 415-428. 
Tanzer, J. M., J. Livingston, et al. (2001). "The microbiology of primary dental caries in 
humans." J Dent Educ 65(10): 1028-1037. 
Tong, Z., L. Dong, et al. (2010). "Nisin inhibits dental caries-associated microorganism in vitro." 
Peptides 31(11): 2003-2008. 
Vollmer, W. M., A. S. Papas, et al. (2010). "Design of the Prevention of Adult Caries Study 
(PACS): a randomized clinical trial assessing the effect of a chlorhexidine dental coating for the 
prevention of adult caries." BMC Oral Health 10: 23. 
Young, D. A., L. Lyon, et al. (2010). "The role of dental hygiene in caries management: a new 
paradigm." J Dent Hyg 84(3): 121-129. 
 
 
 


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APPENDIX A: C3J16-S205-00 STUDY SCHEMATIC 
 
The schematic below is applicable for each of the three study arms,  
which will be enrolled in an ascending dose escalation manner 
SAFETY & MICROBIOLOGY FOLLOW-UP
STUDY DRUG ADMINISTRATION, SAFETY AND 
MICROBIOLOGY
CONFIRMATION OF ELIGIBILITY,
BASELINE AND FIRST STUDY DRUG ADMINISTRATION 
SAFETY & MICROBIOLOGY FOLLOW-UP
VISIT 8: Day 7 AM
VISIT 9: Day 7 PM
VISIT 10: Day 8 AM
VISIT 11: Day 8 PM
VISIT 12: Day 9 AM
VISIT 13: Day 9 PM
VISIT 14: Day 10 AM
VISIT 15: Day 10 PM 
VISIT 16: Day 11 AM
VISIT 17: Day 11 PM
Post Visit 3: 
VISIT 4: 5 ± 1 hr
Visit 5: 12 ± 1 hr
Visit 6: 24 ± 1 hr
Visit 7: 3 ± 1 day 
AM
VISIT 3 
Day 0
AM
VISIT 2
Day -7 to Day -2
AM
VISIT 1 
Day -30 to Day -1
AM
SCREENING 
DENTAL PROPHYLAXIS 
Post Visit 17: 
VISIT 18: 12 ± 2 hrs 
VISIT 19: 3  ± 1 day AM
VISIT 20: 7  ± 1 day AM
MICROBIOLOGY FOLLOW-UP
Post Visit 17: 
VISIT 21: 14 ± 2 days AM
VISIT 22: 28 ± 3 days AM
 


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CONFIDENTIAL 
APPENDIX B: SCHEDULE OF STUDY ASSESSMENTS & PROCEDURES 
STUDY ASSESSMENTS & PROCEDURES 
SCREENING 
DAY 
-30 TO -1
PROPHY 
DAY 
-7 TO -2
BASELINE 
DAY 0 
FOLLOW-UP 
5, 12, 24 ± 1 HR  
AND 
3 ± 1 DAY POST V3
DOSING 
DAYS 7-11 
FOLLOW-UP 
12 ± 2 HRS  
AND
3, 7 ± 1 DAYS POST V17
FOLLOW-UP 
14 ± 2 DAYS 
AND
28 ± 3 DAYS POST V17 
VISIT
1  
VISIT 
2 
VISIT
3 
VISITS 
4-7
VISITS 
8-17
VISITS
18-20
VISITS
21 & 22 
Informed Consent/Assent & Subject ID 
X 
Inclusion/Exclusion 
X 
Medical/Surgical/Dental History & 
Concurrent Illness 
X 
X 
Salivary Flow Assessment 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
Demographics (incl. height & weight) 
X 
Dental Status & Caries Examination a 
X 
Screening Laboratory Testing 
X 
Urine pregnancy test (females only) 
X 
X 
Oral Cavity Assessment 
X 
Xm 
X 
Xm 
X 
Targeted Physical Exam 
X 
X 
X (Visit 5 only) 
X (Visit 8 only) 
X (Visits 18 & 20 only) 
Vital Signs b 
X 
X 
X (Visit 8 and 17 only) 
Microbiology c 
Xd 
Xe 
Xf 
X 
X (Visits 8, 9 & 10 only) 
X 
X 
Professional Dental Prophylaxis g 
X 
Randomization 
X 
Training on flossing & brushing h 
X 
Study Drug Administration i 
X 
X 
Photographic imaging j 
X 
Adverse Events k 
X 
X 
X 
X 
Oral Hygiene Product Distribution l 
X 
End of Study 
X (Visit 22 only) 


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Legend: 
a Dental status and comprehensive caries examination including standard radiographs 
Note: If radiographs deemed appropriate for the study and taken within 6 months prior to the screening visit are available, these may be used for 
determining eligibility and will not be repeated at screening. 
b Vital Signs: Blood pressure, heart rate and temperature taken in sitting or supine position at Screening Visit 1, Dosing Visits 3, 8 and 17 pre- and 
post study drug administration.  
c Microbiology: For details on stimulated saliva and dental plaque sample collection schedules and microbiology assessments refer to Appendix  C. 
Subjects will not perform oral hygiene at home prior to attending the study center at Visits 1 through 22 for stimulated saliva and dental plaque 
samples collection. For details see Section 6.2 - Subject Instructions 
d Microbiology Screening Assessment: Subjects will be screened, including S. mutans assessment, within 30 days of planned dosing with the 
study drug. The stimulated saliva will be collected in a sterile fashion to confirm baseline S. mutans ≥ 1 X 105 CFUs/mL 
e Microbiology Samples at Visit 2: Stimulated saliva and dental plaque will be taken prior to performing professional dental prophylaxis and oral 
hygiene training. 
f Microbiology Samples at Visits 3 and 8-10: Stimulated saliva and dental plaque will be taken prior to oral hygiene and study drug administration. 
g Professional Dental Prophylaxis: Will include removal of bulk plaque and supragingival scaling; Note: NO fluoride treatment as part of the 
procedure, NO subgingival scaling as part of the prophylaxis. 
h Subject training on flossing and tooth brushing: Visit 2/Prophy: includes the appropriate use of dental floss per Appendix E, routine brushing with 
a manual toothbrush and a regular toothpaste containing fluoride per Appendix F. Retraining will be conducted as needed during the study. 
i Study Drug Administration: Subjects will receive C16G2 or Placebo Strips at the clinic (for details refer to Appendix A and Section 6). Subjects will 
brush and floss their teeth prior to study drug administration after microbiology samples were taken  
j Photographic imaging: Oral photographs of strip application will be taken immediately after strip application at Visit 3 
k Adverse Events: Subjects will be reminded to immediately notify the Investigator of any untoward effects up until 7 days post the last 
administration of study drug. All ongoing adverse events will be followed in accordance with good medical practice until resolution or the adverse 
event or condition has stabilized. 
l Oral Hygiene Product Distribution: After dental prophylaxis at Visit 2, subjects will receive a manual toothbrush, a regular toothpaste containing 
fluoride and dental floss to take home and will be instructed to exclusively use these dental products during the study. In addition, subjects will be 
resupplied with these dental products as needed.  
m Oral Cavity Assessments: On Screening Visit 1, Dosing Visits 3, 8 – 17 OCA will be performed.  On the first study drug administration day at 
Visit 3, OCAs will be performed prior to study drug administration and post study drug administration. At AM Visits  8, 10, 12, 14, and 16,  OCA will 
be performed prior to study drug administration, at PM Visits 9, 11, 13, 15, and 17, OCAs will be performed post-study drug administration.  


Protocol No. C3J16-S205-00         
     January 25, 2017 
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CONFIDENTIAL 
APPENDIX C: SCHEDULE OF MICROBIOLOGY ASSESSMENTS 
MICROBIOLOGY 
ASSESSMENT a 
SCREENING DAY 
-30 TO -7B 
PROPHY 
DAY -7 TO -2 
BASELINE DAY 0 
DAYS 0, 1 & 3 
DAYS 7 & 8 
DAYS 12, 14, 18,
25, 39 
VISIT 
1 
VISIT 
2 
VISIT 
3 
PRE-DOSE 
VISIT 
4-7
VISITS 
8, 9, 10 
PRE-DOSE 
VISITS 
18-22
S. mutans by MSB agar
plating
Xb 
X 
X 
X 
X 
X 
Total bacteria by TH agar 
plating  
X 
X 
X 
X 
(Visits 18-20  
& 22 only) 
a Samples will be stored for testing by qRT-PCR and bacterial community analysis at appropriate time points based on plating assessments. 
b Screening microbiology sample must be collected prior to dental prophylaxis at Visit 2. Stimulated saliva ONLY at Screening 


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CONFIDENTIAL 
APPENDIX D: CLINIC VISIT SCHEDULE 
 
*AM visits will be scheduled between 6AM and 10AM 
** PM visits will be scheduled between 6PM and 10PM 
 
 
STUDY PERIODS 
VISIT # 
SCHEDULE 
Screening 
Visit 1   
Visit 1 
Day -30 to -1 AM* 
Dental Prophylaxis 
Visit 2 
Visit 2 
Day -7 to -2 AM* 
Baseline & Study Drug 
Administration  
Visit 3 
Visit 3 
Day 0 AM* 
Safety and Microbiology 
Follow-up 
Visits 4-7 
Visit 4 
5 ± 1 hour 
Post Visit 3 
Visit 5 
12 ± 1 hour 
Visit 6 
24 ± 1 hour 
Visit 7 
3 ± 1 day  AM* 
 
 
 
 
Study Drug 
Administration 
Visits 8-17 
Visit 8 
Day 7 /  AM* 
Visit 9 
Day 7 /  PM** 
Visit 10 
Day 8 /  AM* 
Visit 11 
Day 8 /  PM** 
Visit 12 
Day 9 / AM* 
Visit 13 
Day 9 /  PM** 
Visit 14 
Day 10 /  AM* 
Visit 15 
Day 10 /  PM** 
Visit 16 
Day 11 /  AM* 
Visit 17 
Day 11 /  PM** 
Safety and Microbiology 
Follow-up 
Visits 18-20  
Visit 18 
12 ± 2 hours  
Post Visit 17 
Visit 19 
3 ± 1 day  AM* 
Visit 20 
7 ± 1 day  AM* 
Microbiology Follow-up 
Visits 21-22 
Visit 21 
14 ± 2 days  AM* 
Visit 22 
28 ± 3 day  AM* 


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CONFIDENTIAL 
APPENDIX E: FLOSSING INSTRUCTIONS  
Flossing with string will remove food particles and debris from between teeth to allow study drug 
to reach all tooth surfaces. Study staff will train the study subject using the instructions below. 
Depending on the flossing habits of the subject or preference, either rolled or pre-strung floss 
may be used. 
 
Rolled Floss Instructions: 
 
1. You will floss between all your teeth using the supplied dental floss 
2. Dispense approximately 2 feet of dental floss and wrap both ends of the dental floss 
around your index or middle finger 
3. Using your index or middle finger and thumb to hold the floss tight insert the floss 
between your teeth 
4. Press the floss against the side of one tooth and move the floss up and down 3 times. 
Repeat for the adjacent tooth surface 
5. Gently pull the floss from between the teeth and floss between all remaining teeth in the 
same manner 
 
Figure 1: Flossing 
 
 
Pre-strung Floss Instructions: 
 
1. 
You will floss between all your teeth using the supplied dental pre-strung floss 
2. 
Insert the floss between your teeth, press the floss against the side of one tooth and 
move the floss up and down 3 times. Repeat for the adjacent tooth surface 
3. 
Gently pull the floss from between the teeth and floss between all remaining teeth in 
the same manner 
 
 


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CONFIDENTIAL 
APPENDIX F: ROUTINE MANUAL BRUSH INSTRUCTIONS 
Subjects will brush their teeth at home with a manual toothbrush and a regular toothpaste 
containing fluoride (e.g., Crest Regular™) provided by the study center (see Section 6.2 - 
Subject Instructions). Subjects will dispense a routine (~ 1 mL) amount of toothpaste onto the 
toothbrush head and brush 30 seconds per quadrant, for a total of 2 minutes. 
 
Instruct the subject as follows: 
1. Hold the toothbrush handle lightly when brushing 
2. Study staff will observe you during brushing to ensure correct tooth brushing  
3. To start brushing, place the brush head on the top surface (occlusal) of the back molar 
4. Brush the occlusal surface of the first quadrant of the lower teeth for a total of 
approximately 10 seconds. Each brush stroke should move the brush head back and 
forth across the occlusal surface of several teeth. The brush should advance forward in 
the mouth with each successive brush stroke as illustrated in Figure 2, Line 1. When 
reaching the end of the quadrant continue brushing while advancing the toothbrush 
rearward to the back molars with each successive brush stroke 
5. Continue brushing the outer surface of the first quadrant of the lower teeth closest to the 
cheek as illustrated in Figure 2, Line 2 by brushing forward and backward across several 
teeth for 10 seconds 
6. Repeat for the inner surface of the first quadrant of the lower teeth closest to the tongue 
as illustrated in Figure 2, Line 3. Brush forward and backward for 10 seconds 
7. Repeat the brushing steps above for each of the remaining 3 quadrants of the mouth. 
8. If any teeth are not adequately brushed in the allotted time revisit those teeth prior to 
proceeding to other tooth surfaces 
 
Figure 2: Routine Manual Toothbrush Use  
 
 
 
 
 


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CONFIDENTIAL 
APPENDIX G: STUDY DRUG APPLICATION INSTRUCTIONS 
The tooth strip is designed with dimensions sufficient to cover the occlusal surface of the molars 
and 1 or 2 bicuspids along with the majority of the lateral tooth surfaces of these teeth. The 
anterior teeth will not be covered by the tooth strip during treatment. To achieve effective dosing 
the tooth strip is formulated with an adhesive polymer that adheres to the tooth surface on 
contact and prevents shifting during treatment. Because of the adhesive nature of the adhesive 
polymer it will be difficult to realign the tooth strip after a significant portion of the tooth strip has 
been adhered to the tooth surface. Once fully adhered to the tooth surface, tooth strip 
realignment should not be attempted. 
 
The tooth strip formulation requires hydration to achieve effective drug release. To achieve 
effective tooth strip application that results in effective release of drug the tooth strips should be 
applied to teeth covered with saliva. DO NOT dry the teeth prior to strip application.  
 
1. Prior to study drug administration subjects will be instructed to have their mouth closed 
and teeth well covered by saliva 
2. Immediately prior to application of a tooth strip, remove the release liner from the single 
strip to be applied (do not remove the release liner from other tooth strips at this time) 
Note: The side of the strip in contact with the release liner is the side containing 
study drug that will be attached to the tooth surface  
3. Subject will be instructed to swallow any excess saliva in their mouth and open their 
mouth 
4. Using cheek retractors pull back the subject’s cheeks one at a time 
5. Instruct the subject to set their tongue away from the teeth where the strips will be 
applied, or alternatively, use a tongue depressor to ensure the tongue does not come in 
contact with the strip during application 
6. Align the rear of the tooth strip to the rearmost molar and lay it down on the teeth starting 
from the rearmost molar and ending with the most proximal tooth the tooth strip covers 
(this will usually be first or second bicuspid). The side of the strip that is in contact with 
the release liner contains the active drug and should be applied to the tooth surface. The 
strip should cover the entire occlusal surface of all molars 
7. Adhere the tooth strip to the occlusal surface of the tooth using a finger tip 
8. Adhere the tooth strip to the buccal and lingual surfaces of the tooth using a finger tip 
9. The subject will be instructed to close their mouth after application of the tooth strip and 
instructed not to grind their teeth 
10. Repeat steps 1 through 7 for the remaining 3 tooth strip applications 
 
 


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CONFIDENTIAL 
APPENDIX H: C16G2 AND PLACEBO STRIP APPLICATION PHOTOGRAPHIC IMAGING 
Adapted with modifications from www.dentistrytoday.com 
 
Study staff will image the subject’s teeth as follows using the camera provided by the sponsor   
 
a. Immediately after study drug application (maxillary and mandibular occlusal view 
at Visit 3 only) 
 
NOTE: When using retractors and mirrors for imaging it is important not to disrupt the 
strip application. 
 
Shot No. 1: Maxillary Occlusal View  
For many practitioners the maxillary and mandibular occlusal shots present the most difficulty 
(Figures 1a and 1b). This photographic image is always taken with both retractors and an 
occlusal mirror. Camera settings are identical to the anterior retracted shot, although patient and 
operator positioning are different and ultimately critical to success. The patient should be 
reclined to approximately 45° and asked to raise his or her chin. The operator should be in front 
of the patient. Cheek retractors should be placed so that the lips can be pulled upward and 
outward; in some cases the medial corners of the cheek retractors will touch at the middle of the 
upper lip. If properly used, the cheek retractors will keep the buccal soft tissue and lips away 
from the teeth, allowing for proper visualization of not only the posterior teeth but the anterior 
teeth as well. Standard cheek retractors or “fork” retractors may be used. 
 
The mirror should be inserted so that the edge extends behind the most posterior tooth. It may 
sometimes rest on the tuberosity as a means of stabilization. Rotate the mirror downward so 
that the back side is touching the lower incisor teeth. In doing so, the operator can help the 
patient “open wide” but also attain the 45° angle needed to properly capture the image. Fogging 
of the mirror can again be a challenge with preventive strategies including warming the mirror, 
gentle bursts of air, or asking the patient to breathe in and hold his or her breath. 
 
The image captured should ideally include all maxillary teeth and allow visualization of incisal 
edges and embrasures. The vertical midline should be the anatomic midline of the patient, and 
the point of focus should be the premolars. In some cases the operator must allow the camera 
to focus on the premolars (e.g. hold the camera shutter button half-way, locking the focus), and 
then recompose the image to achieve better framing. If the center of the palate is used as the 
point of focus, the teeth may appear out of focus because of limited depth of field. 
 
Shot No. 2: Mandibular Occlusal View  
The mandibular occlusal shot is accomplished with the same camera settings, and similar 
positioning of the patient and operator as the maxillary occlusal (Figures 1c to 1e). The patient 
should be reclined at a minimum of 45°, and should raise the chin as far as possible (neck 
extended maximally). Standard retractors (or a fork retractor) should always be used to keep 
soft tissue and lips away from the teeth. If standard cheek retractors are used, they should be 
positioned to pull the lips downward and outward. Insert the mirror so that the end rests on soft 
tissue behind the most posterior teeth, making sure that it is not touching the teeth. Rotate the 
mirror upward so that the back of the mirror is resting against the maxillary incisor teeth; the 
image should be taken at approximately 45° to the mirror. 
 


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CONFIDENTIAL 
 
Figure 1a. Positioning of the 
patient and the operator to 
capture the maxillary occlusal 
image. Note the position of the 
cheek retractors upward and 
outward. Optimally, the angle to 
the mirror should be 45º to fully 
capture the teeth in the 
photograph. 
Figure 1b. Wide view of positioning 
to capture the maxillary occlusal 
image. Note the position of the cheek 
retractors upward and outward to pull 
the lips and soft tissue away from the 
teeth. The back of the mirror is 
behind the most posterior maxillary 
teeth. 
 
 
Figure 1c. Positioning of the 
patient and the operator to 
capture the mandibular occlusal 
image. Note the position of the 
cheek retractors pulled downward 
and outward. Optimally the angle 
to the mirror should be 45º to fully 
capture the teeth in the 
photograph. 
Figure 1d. Wide view of positioning 
to capture the mandibular occlusal 
image. Note the position of the cheek 
retractors downward and outward to 
pull the lips and soft tissue away 
from the teeth. The back of the mirror 
is behind the teeth and resting on 
soft tissue. 
 
Figure 1e. Close-up showing the 
back of the mirror touching the 
maxillary teeth when preparing to 
capture the mandibular occlusal 
photograph. 
 


Protocol No. C3J16-S205-00                           January 25, 2017 
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CONFIDENTIAL 
Too often, the patient’s tongue may prevent visualizing all of the mandibular teeth. It is 
sometimes helpful to ask the patient to “lower their tongue” having the patient practice doing so 
in a facial mirror. Other times it may be possible for the patient to move their tongue to the 
posterior, or the mirror could be used to hold the tongue out of the way. 
 
The image should be framed so that the vertical midline is the anatomic midline of the patient. 
Like the maxillary occlusal image, ideally all mandibular teeth are visible and the anterior incisal 
edges and embrasures are discernable. The point of focus for the mandibular occlusal shot are 
the premolars. Recomposition may be necessary after focusing as described for the maxillary 
photographic image. 
 
Common errors for the occlusal images include: allowing the end of the mirror to rest on the 
teeth, potentially producing a double image or viewing unreflected teeth; capturing the image at 
less than 45°, which results in unreflected teeth being seen in the image; fogging of the mirror; 
inadequate framing; and obscuring of the teeth by the tongue. 
 
Labelling and Uploading Images 
 
Image Labeling 
Label each of the two images taken with the subject identifier followed by the photograph’s 
number and the time point as follows in the examples below: 
 
For subject #V102-01-001, Photo 1 
S205-01-001 P1 
 
For subject #V102-01-001, Photo 2 
S205-01-001 P2 
 
Image Uploading 
Within the main clinical site folder (e.g. C3J16-S205-00 Site 01) there is a sub folder for “Strip 
Images”. Create a new folder for each subject within the “Strip Images” folder using the subject 
identifier (e.g. S205-01-001). Upload one image for each required photo to this folder. There will 
be a total of 2 photographic images for each subject on the first day of dosing (Visit 3). 
 
 


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CONFIDENTIAL 
APPENDIX I: DECLARATION OF HELSINKI 
 


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