Clinical trial NCT03004365
Conditions: Dental Caries
Sponsor: Armata Pharmaceuticals, Inc.
Start date: 2017-01-27; Completion date: 2017-03-29
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this single-blind study is to evaluate whether C16G2 Varnish 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 the safety and oral microbiology of C16G2 Varnish application in male and female dental subjects 12-75 years of age. This multi-center study will evaluate multiple study drug administrations of C16G2 Varnish or Placebo Varnish.

The study will enroll subjects into up to three study arms. Up to 33 subjects will receive multiple doses of study drug applied with a small brush typically used in dental varnish administration. Subjects will be enrolled in an 8:3 ratio. The Sponsor will perform unblinded microbiology review on an ongoing basis to determine whether to enroll additional 11 subjects into the next dose cohort or to terminate enrollment based on microbiology data.

Arms: arm 1: Subjects in Study Arm 1 will receive up to 1 mL of 27.2 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications. arm 2: Subjects in Study Arm 1 will receive up to 1 mL of 27.2 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications. arm 3: Subjects in Study Arm 2 will receive up to 1 mL of 13.6 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications. arm 4: Subjects in Study Arm 2 will receive up to 1 mL of 13.6 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications. arm 5: Subjects in Study Arm 3 will receive up to 1 mL of 54.4 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications. arm 6: Subjects in Study Arm 3 will receive up to 1 mL of 54.4 mg C16G2 Varnish or Placebo Varnish on day 1, followed by two additional applications a week and two weeks later, for a total of 3 study drug applications. Study drug will be administered via a small brush typically used in varnish applications.
Interventions: intervention 1: C16G2 Varnish intervention 2: Placebo Varnish
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-V204-00 
 
PROTOCOL TITLE: 
A Phase 2, Single-blind, Randomized, Placebo-controlled Study to 
Evaluate the Safety and Microbiology of C16G2 Varnish 
Administered in Multiple Doses to Adolescent and Adult Dental 
Subjects 
 
STUDY DRUG: 
C16G2 
 
DOSAGE FORM: 
C16G2 Varnish 
  
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: 
December 8, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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-V204-00 
December 8, 2016 
Page 2 of 76 
 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE SHEET ............................................................................................ 5 
INVESTIGATOR SIGNATURE SHEET...................................................................................... 6 
PROTOCOL SYNOPSIS FOR C3J16-V204-00 ......................................................................... 7 
ABBREVIATIONS ....................................................................................................................16 
 INTRODUCTION .................................................................................................................18 
1.1 Previous Clinical Experience ...........................................................................................18 
1.1.1 
Phase 1 ..........................................................................................................18 
1.1.2 
Phase 2 ..........................................................................................................19 
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 ......................................................................................................24 
1.5.4 
Oral Cavity Assessments & Targeted Physical Exam .....................................25 
1.5.5 
Salivary Flow Assessment .............................................................................25 
1.5.6 
Microbiology Evaluations................................................................................25 
1.6 Potential Risks to Participants .........................................................................................28 
1.7 Subject’s Duration of Participation ...................................................................................30 
 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 Varnish Formulation ...........................................................................35 
5.1.1 
Placebo Varnish Formulation .........................................................................35 
5.1.2 
Supply, Packaging, and Labeling ...................................................................35 
5.2 Storage of Study Drug .....................................................................................................37 
5.3 Study Drug Preparation ...................................................................................................37 
5.3.1 
C16G2 or Placebo Varnish Preparation .........................................................37 
 STUDY ASSESSMENTS & PROCEDURES .......................................................................38 


Protocol No. C3J16-V204-00 
December 8, 2016 
Page 3 of 76 
 
CONFIDENTIAL 
6.1 Screening and Re-screening ...........................................................................................38 
6.2 Subject Instructions .........................................................................................................38 
6.2.1 
Oral Hygiene Instructions ...............................................................................38 
6.2.2 
Diet Instructions .............................................................................................38 
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 .........................................................43 
7.1 Definition of Adverse Events ...........................................................................................43 
7.2 Assessment of Severity (Intensity) of Adverse Events .....................................................43 
7.3 Assessment of Causality (Relationship to Study Drug) ....................................................44 
7.4 Suspected Adverse Reaction (SAR) and Adverse Reaction (AR) ....................................45 
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 ..........................................................................................................47 
7.8.1 
Reporting Serious Adverse Events to the FDA and IRB .................................48 
7.8.2 
Following Adverse Events and Serious Adverse Events ................................48 
7.9 Pregnancy .......................................................................................................................48 
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 and Assent ........................................................................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 .................................................................................................55 


Protocol No. C3J16-V204-00 
December 8, 2016 
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CONFIDENTIAL 
9.2.1 
Protocol, Protocol Amendments, and Safety Updates ....................................56 
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-V204-00 STUDY SCHEMATIC ..............................................................61 
APPENDIX B: SCHEDULE OF STUDY ASSESSMENTS & PROCEDURES ...........................62 
APPENDIX C: SCHEDULE OF MICROBIOLOGY ASSESSMENTS ........................................64 
APPENDIX D: VISIT SCHEDULE .............................................................................................65 
APPENDIX E: FLOSSING INSTRUCTIONS ............................................................................66 
APPENDIX F: ROUTINE MANUAL BRUSH INSTRUCTIONS .................................................67 
APPENDIX G: STUDY DRUG APPLICATION INSTRUCTIONS ..............................................68 
APPENDIX H: VARNISH APPLICATION PHOTOGRAPHIC IMAGING ...................................69 
APPENDIX I: DECLARATION OF HELSINKI ..........................................................................73 




Protocol No. C3J16-V204-00 
December 8, 2016 
Page 6 of 76 
 
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-V204-00 
December 8, 2016 
Page 7 of 76 
 
CONFIDENTIAL 
PROTOCOL SYNOPSIS FOR C3J16-V204-00 
Protocol Number: 
C3J16-V204-00  
Protocol Title: 
A Phase 2, Single-blind, Randomized, Placebo-controlled Study to Evaluate 
the Safety and Microbiology of C16G2 Varnish Administered in Multiple 
Doses to Adolescent and Adult Dental Subjects 
Study Design: 
A single-blind, randomized, placebo-controlled Phase 2 study to evaluate 
the safety and oral microbiology of C16G2 Varnish application in male and 
female dental subjects 12-75 years of age. This multi-center study will 
evaluate multiple study drug administrations of C16G2 Varnish or Placebo.  
Before dosing of study drug, eligible subjects will undergo professional 
dental prophylaxis 2-7 days prior to the first study drug administration. 
Subjects will receive three study drug applications over approximately 
5 days. Study drug will be applied with a small brush typically used in dental 
varnish administration. To evaluate the durability of S. mutans suppression, 
study subjects will be followed for microbiology for 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), Visits 3-5 (Confirmation of Eligibility and Baseline 
(V3 ONLY) & Study Drug Administration), Follow-up Visits 6-8 (Safety and 
Microbiology) and Follow-up Visits 9 and 10 (Microbiology only). Dosing 
Visits 4 and 5 will occur 24-48 hours post-previous dosing visit.  
Enrolled subjects 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 
are provided in Appendix B. For microbiology assessments refer to 
Appendix C. 
Objectives: 
 
Primary Objective 
 
To evaluate the safety and tolerability of multiple C16G2 Varnish 
administrations in adolescent and adult dental subjects 
Secondary Objectives  
 
To assess the targeted antimicrobial activity of C16G2 Varnish 
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 
Subject Population: 
Approximately 33 male and female subjects 12-75 years of age, inclusive at 
the time the Assent and/or Informed Consent Form is signed. 
Duration of Study: 
All subjects will be followed for safety and microbiology for up to 1 month 
after first study drug administration. 


Protocol No. C3J16-V204-00 
December 8, 2016 
Page 8 of 76 
 
CONFIDENTIAL 
Estimated duration of study from first subject in (FSI) to last subject out 
(LSO) is approximately 3 months. 
Treatment / 
Randomization 
Approximately 11 subjects will receive multiple doses of study drug (27.2 mg 
C16G2 Varnish or Placebo) applied with a small brush typically used in 
dental varnish administration (for details see Table below and Appendix A).  
The Sponsor will perform an unblinded microbiology review on an ongoing 
basis to determine whether to enroll additional subjects into the next dose 
cohorts (13.6 mg and/or 54.4 mg C16G2 Varnish or Placebo) or to terminate 
enrollment based on microbiology data.  
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-V204-00 Study Drug Schedule 
C16G2 
Subjects 
Placebo 
Subjects 
Mode of 
Application 
Days of 
Study Drug 
Admin. 
C16G2 
(mg) 
8 
3 
Varnish 
3 
13.6 
8 
3 
Varnish 
3 
27.2 
8 
3 
Varnish 
3 
54.4 
  
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. C16G2 
Varnish and Placebo will be packaged and labeled identical to ensure 
blinding.  
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. 
Stimulated saliva and dental plaque samples taken at Visits 3 and 6 will be 
tested for total bacteria testing using Todd Hewitt (TH) agar plating. All 
dental plaque and stimulated saliva samples will be stored upon receipt 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 the 
following visits: Screening Visit 1, prior to dental prophylaxis at Visit 2, prior 
to study drug administration at Visits 3-5, follow-up Visits 6-10. For details 
refer to Appendix C. 


Protocol No. C3J16-V204-00 
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Page 9 of 76 
 
CONFIDENTIAL 
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. Adult 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 
Exclusion Criteria: 
Subjects are excluded from participation if any of the following apply: 


Protocol No. C3J16-V204-00 
December 8, 2016 
Page 10 of 76 
 
CONFIDENTIAL 
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 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, lingual 
or buccal 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 
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 


Protocol No. C3J16-V204-00 
December 8, 2016 
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CONFIDENTIAL 
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 Visit 3 (Baseline, Day 0) 
Subjects will be scheduled for this visit between 6AM and 10AM.  
Pre-Dose 
o Confirmation of eligibility  
o Medical/Dental/Surgical History & Concurrent Illness Update 
o Concomitant Medications Update 
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)  


Protocol No. C3J16-V204-00 
December 8, 2016 
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CONFIDENTIAL 
o Microbiology (stimulated saliva and dental plaque collection) 
Note: Samples need to be obtained prior to oral hygiene 
o Randomization 
o Oral Hygiene (including brushing and flossing will be conducted at 
the clinic prior to study drug administration) 
Study Drug Administration: 
Instructions for the preparation of C16G2 Varnish or Placebo are provided 
in the Study Manual. Instructions for the application of study drug are 
provided in Appendix G. 
o At Visit 3/Day 0, subjects will receive a single study drug 
administration. Subjects will have C16G2 Varnish or Placebo 
applied to all tooth surfaces.  
Note: C16G2 Varnish or Placebo will not be actively removed, but 
remain on the subject’s teeth until removed through normal wear 
and mastication after discharge 
 
Post-Dose 
o Photographic imaging immediately after study drug application 
(see instructions in Appendix H) 
o Oral Cavity Assessment (hard and soft tissues) 
o Vital Signs (blood pressure, heart rate, temperature) taken 1 hour 
± 15 minutes  post study drug administration  
o Subjects will not eat, swish, or drink anything besides plain water 
from study drug administration to one hour after study drug 
application. In addition, subjects will be advised to relax their jaws 
and to not grind their teeth. Subjects will be supervised to ensure 
compliance 
o Adverse Events 
o Discharge  
   
Clinic Visit 4 (24-48 hrs Post Visit 3) & Visit 5 (24-48 hrs Post Visit 4) 
Subjects will be scheduled for these visits between 6AM and 10AM.  
Pre-Dose 
o Concomitant Medications Update 
o Vital Signs (blood pressure, heart rate, temperature) taken in 
supine or sitting position 
o Microbiology (stimulated saliva and dental plaque collection) 
o Oral Cavity Assessment (hard and soft tissues) 
o Targeted Physical Exam (general, extraoral, head & neck) (Visit 4 
ONLY) 
o Oral Hygiene (including brushing and flossing will be conducted at 
the clinic prior to study drug administration) 
Study Drug Administration 


Protocol No. C3J16-V204-00 
December 8, 2016 
Page 13 of 76 
 
CONFIDENTIAL 
Instructions for the preparation of C16G2 Varnish or Placebo are provided 
in the Study Manual. Instructions for the application of study drug are 
provided in Appendix G. 
o Subjects will receive a single study drug application. Subjects will 
have C16G2 Varnish or Placebo applied to all tooth surfaces. 
Note: C16G2 Varnish or Placebo will not be actively removed, but 
remain on the subject’s teeth until removed through normal wear 
and mastication after discharge 
Post-Dose 
o Photographic imaging immediately after study drug application 
(see instructions in Appendix H). 
o Oral Cavity Assessment (hard and soft tissues) 
o Vital Signs (blood pressure, heart rate, temperature) taken 1 hour 
± 15 minutes post study drug application 
o Subjects will not eat, swish, or drink anything besides plain water 
for one hour after study drug application. In addition, subjects will 
be advised to relax their jaws and to not grind their teeth. Subjects 
will be supervised to ensure compliance.    
o Adverse Events 
o Discharge  
 
Clinic Visit 6-8 (24 hours, 3 days and 7 days Post Visit 5) 
Subjects will be scheduled for this visit between 6AM and 10AM 
o Concomitant Medication Update  
o Oral Cavity Assessment (Visits 6 & 8 ONLY) 
o Targeted Physical Exam  (Visits 6 & 8 ONLY) 
o Microbiology (stimulated saliva and dental plaque collection) 
o Adverse Events 
o Discharge  
 
Clinic Visits 9 & 10 (Week 2 & 4 Post Visit 5) 
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (stimulated saliva and dental plaque collection) 
o End of Study (Visit 10 only) 
 
Subject Instructions:  
Enrolled subjects 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) on the days of study drug 
administration (Visits 3-5). While smokers are not excluded from study 
participation, subjects should abstain from using chewing tobacco 
throughout the study. 
a) 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 1-10), subjects will not be allowed to perform 


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CONFIDENTIAL 
oral hygiene in the morning 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 (e.g., Crest Regular™), 
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 evenings of days of study 
drug administration (Visits 3-5). In addition, subjects will be resupplied with 
these dental products as needed. 
 
b) Diet Instructions  
 
Subjects 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 plain water up to 10 minutes prior 
to dental plaque and saliva collection, and will be instructed not to swish 
or rinse 
Visits 3-5 
• 
Do not eat, drink anything except plain water or swish from the start of 
study drug administration to 1 hour after the study drug application 
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 up to 33 subjects. 
Subjects will be followed for safety assessments for 1 week after the last 
study drug administration. 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 8 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 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 approximately 33. 
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 Varnish. Subjects’ data in this study will provide 


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information on the safety and microbiology of multiple administrations of 
C16G2 Varnish 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  
 
The safety analysis set will be defined as those subjects who 
received any amount of study drug (C16G2 Varnish 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 Varnish 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 
stabilized. 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 using 
descriptive statistics. 
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. 
Stimulated saliva and dental plaque samples taken at visits 3 and 6 will be 
tested for total bacteria testing using Todd Hewitt (TH) agar plating. Dental 
plaque and stimulated saliva samples will be stored for S. mutans and total 
bacteria testing using quantitative Real-Time Polymerase Chain Reaction 
(qRT-PCR) and bacterial community analysis. 
Descriptive statistics utilizing mean, standard deviation, median and range 
of S. mutans and total bacteria will be determined and compared to Baseline 
samples, as applicable. 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase  
AR 
adverse reaction 
AST  
alkaline phosphatase  
BP 
blood pressure 
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 
GRAS 
Generally Recognized as Safe 
FSI 
first subject in 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form  
HR 
heart rate 
hrs 
hours 
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 
MOA 
mechanism of action 
NCI  
National Cancer Institute  
ng 
nanogram 


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NOAEL 
no observed adverse effect level 
PHI 
Protected Health Information 
PK 
pharmacokinetic 
qRT-PCR 
quantitative real-time polymerase chain reaction 
RBC 
red blood cells  
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
S. mutans 
Streptococcus mutans  
Sponsor 
C3 Jian, LLC (C3 Jian) 
SSAR 
suspected serious adverse reaction 
Study Drug C16G2 Varnish or Placebo 
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 and gel. In Study C3J16-V204-00 subjects will receive 
multiple C16G2 or Placebo varnish 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 by a 


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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 10ng/mL) in any 
pharmacokinetic 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.  
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-


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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. 
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 


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(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 
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 


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CONFIDENTIAL 
doses to adult and adolescent dental subjects. The study evaluated different dosing regimens 
and different doses of C16G2 and Placebo. There were no significant safety findings and the 
safety profile of C16G2 was consistent with previous studies and generally safe in the majority of 
subjects. Microbiology results did not show a significant durable response in the reduction of 
S. mutans in stimulated saliva and dental plaque samples. Total bacteria levels did not change 
significantly post study drug administration.  Application of C16G2 (800 µM & 1600 µM) with twice 
daily tray on a single day provided a significant reduction in S. mutans although that level of 
reduction was not sustained with subsequent applications performed with a combination of brush 
and tray.  The clinical study report for this study is currently in preparation. 
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), 800 µM (3.2 mg/mL), and 1600 µM (6.4 mg/mL)  dose with a maximum 
daily exposure of 115.2 mg resulting in approximately 1 log10 suppression while study drug was 
administered. The current study is designed to evaluate a varnish formulation. The proposed dose 
concentration of C16G2 is 13.6, 27.2 and 54.4 mg of C16G2 resuspended in 1 mL of vehicle. Up 
to 1 mL of study drug may be applied to the tooth surfaces. Based on the typical application 
volume required for this study 0.4 to 0.6 mL of varnish is anticipated per study drug administration. 
Peptide release from these study drug formulations has been demonstrated. In this study, the 
study drug will remain on the tooth surface until removed through normal wear and mastication 
after discharge. The dose was evaluated for antimicrobial effect and effectively eliminated 
S. mutans from in vitro biofilms with increasing dose-dependent impact on total bacteria. The 
proposed clinical program dose, as well as the multiple dosing schedule, was not selected based 
on safety issues, but rather based on 1) a reasonable expectation that the bactericidal potential 
of this C16G2 dose is optimal to achieve a sufficient depth of kill while maintaining selectivity. The 
single dose varnish clinical trial C3J16-V102-00 evaluated three concentrations and found that 


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the 27.2 mg dose achieved the greatest depth of kill compared to the 13.6 and 54.4 mg doses.  
Applying multiple doses of the varnish may have an effect on depth of kill and selectivity of the 
drug, so each of the doses evaluated as a single dose will be evaluated in the current study, 2) a 
product profile that targets administration of C16G2 during periodic dental visits similar to current 
varnish application practices in children with severe disease, 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 benign, which is consistent with the peptide not being orally 
bioavailable. Pharmacokinetic and toxicokinetic studies did not detect C16G2 systemically 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 demonstrated 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 varnish 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-V204-00 is 0.86 mg/kg/day (assuming a 70 kg 
subject), which equates to approximately 28 to 32.5 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 Study C3J16-
V204-00 will be 1 week after dosing. 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:  
The maximum daily C16G2 exposure in this study will be up to 54.4 mg, depending on the amount 
of varnish applied. 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 


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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 Varnish or 
Placebo. 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 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. 


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CONFIDENTIAL 
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. 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. 
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 subjects mouth with one interdental brush used for each 


Protocol No. C3J16-V204-00 
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CONFIDENTIAL 
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. 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. 
 
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. 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 


Protocol No. C3J16-V204-00 
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CONFIDENTIAL 
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 Laboratory 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. 
 
A stimulated saliva sample will be collected at screening to confirm baseline S. mutans ≥ 1.0 x 
105 CFU/mL for study eligibility. Dental plaque and stimulated saliva samples will be collected 
during the study for quantification of S. mutans according to the Schedule of Microbiology 
Assessments in Appendix C.  
 
Dental plaque samples collected at protocol specified time points will be analyzed for S. mutans 
using mitis-salivarius bacitracin (MSB) agar plates. Upon arrival at C3 Jian laboratories, saliva 
samples will be aliquoted and stored at -80°C for testing using qRT-PCR and/or bacterial 
community analysis, while plaque 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 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, dental plaque 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 aliquoted and stored at -80°C for S. mutans and total bacteria testing 
using qRT-PCR. 


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CONFIDENTIAL 
 
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. 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. 
 
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 amount of study drug remaining on the subject’s teeth 
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. 
 


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CONFIDENTIAL 
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. 
In Study C3J16-V102-00 subjects received study drug on a single day of dosing. Up to 1 mL of 
13.6 mg, 27.2 mg or 54.4 mg C16G2 Varnish or Placebo was applied to all tooth surfaces. The 
maximum daily exposure in this study was 54.4 mg, which is less than half of the exposure in 
Study C3J13-201-01. Study drug was well tolerated, only two adverse events that were assessed 
as not related to study drug or study procedures were reported. 
 
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. 
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 Study C3J15-202-00, subjects received 4 study drug administrations on the first day of dosing 
followed by AM and PM dosing for 6 consecutive days. Two mL or 4 mL of 800 µM C16G2 Gel or 
Placebo was administered via manual toothbrush and custom dental trays. The doses, duration 
of application and schedule of study drug administrations in Study C3J15-202-00 were 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 was 51.2 mg, which is approximately half of 
the exposure in Study C3J13-201-01. 
In 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 were 3.2 mg/mL (800 µM) and 


Protocol No. C3J16-V204-00 
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CONFIDENTIAL 
6.4 mg/mL (1600 µM). The maximum daily exposure in this study was 102.4 mg, which was less 
than the exposure in Study C3J13-201-01. 
In the current Study C3J16-V204-00 subjects will receive a single study drug application on each 
of 3 days of dosing. Up to 1 mL of 13.6, 27.2 and 54.4 mg C16G2 Varnish or Placebo will be 
applied to all tooth surfaces. The maximum daily exposure in this study will be 54.4 mg, which is 
approximately half of the exposure in Study C3J13-201-01. 
Potential risks to subjects are minimized in this Phase 2 study by the following: 
 
Requirement that all women of child-bearing potential, defined as not surgically sterile, 
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 may not be 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). 
1.7 
Subject’s Duration of Participation 
Approximately 33 male and female subjects 12 to 75 years of age will be enrolled in the study. 
Following the subject’s first dosing with study drug, their participation in the study will be 
approximately 2 months, unless the subject is withdrawn early as specified in Section 9.3.2 or has 
a new or ongoing AE at the final safety assessment visit. 
Subjects with ongoing AEs will be followed until the AE has resolved or stabilized (see Section 
7.8.2). The estimated duration of the study from first subject in (FSI) to last subject out (LSO) is 
approximately 3 months. 
 
 
 
 
 


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CONFIDENTIAL 
 
STUDY OBJECTIVES 
Primary Objective 
 
To evaluate the safety and tolerability of multiple C16G2 Varnish administrations in 
adolescent and adult dental subjects 
Secondary Objectives  
 
To assess the targeted antimicrobial activity of C16G2 Varnish applications 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 
 
STUDY DESIGN 
A single-blind, randomized, placebo-controlled Phase 2 study to evaluate the safety and oral 
microbiology of C16G2 Varnish application in male and female dental subjects 12-75 years of 
age.  This multi-center study will evaluate multiple study drug administrations of C16G2 Varnish 
or Placebo. 
Before dosing of study drug, eligible subjects will undergo professional dental prophylaxis 2-7 
days prior to the first study drug administration. Subjects will receive five study drug applications 
over a 1-week period. Study drug will be applied with a small brush typically used in dental varnish 
administration. To evaluate the durability of S. mutans suppression, study subjects will be followed 
for microbiology for 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), Visits 3-
5 (Confirmation of Eligibility, Baseline & Study Drug Administration), Follow-up Visits 6-8 (Safety 
and Microbiology) and Follow-up Visits 9-10 (Microbiology only). 
Enrolled subjects 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 are provided in Appendix B. For microbiology assessments refer to 
Appendix C. 
3.1 
Blinding and Randomization  
3.1.1 Randomization 
The study will enroll subjects into up to three study arms. Up to 33 subjects will receive multiple 
doses of study drug (27.2 mg and/or 13.6 mg and/or 54.4 mg C16G2 Varnish or Placebo) applied 
with a small brush typically used in dental varnish administration (for details see Appendix A). 
Subjects will be enrolled in an 8:3 ratio. The Sponsor will perform unblinded microbiology review 
on an ongoing basis to determine whether to enroll additional 11 subjects into the next dose cohort 
(13.6 mg and/or 54.4 mg C16G2 Varnish or Placebo) or to terminate enrollment based on 
microbiology data. 
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 at 
the study site. 


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CONFIDENTIAL 
3.1.2 Blinding 
The study will be conducted in a single-blind, placebo-controlled manner. All study subjects, 
parents and legal guardian(s) 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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CONFIDENTIAL 
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 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 multiple doses of study drug (27.2 mg and [13.6 mg and/or 54.4 mg] 
C16G2 Varnish or Placebo). The study drug volume applied will be 1 mL or less. Study drug will 
be administered by qualified study staff at the center. C16G2 Varnish or Placebo will not be 
actively removed, but remain on the subject’s teeth until removed through normal wear and 
mastication after discharge. 
C16G2 
Subjects 
Placebo 
Subjects 
Mode of 
Application 
Days of 
Study Drug 
Admin. 
C16G2 
 (mg) 
8 
3 
Varnish 
3 
13.6 
8 
3 
Varnish 
3 
27.2 
8 
3 
Varnish 
3 
54.4 
5.1 
Study Drug 
5.1.1 C16G2 Varnish Formulation 
C16G2 Varnish drug product is manufactured by C3 Jian, LLC (Marina del Rey, CA) for 
administration as a dental varnish product. The C16G2 Varnish product is provided in two glass 
vials, their content is combined prior to application. One vial contains a lyophilized powder blend 
of C16G2 at doses of 13.6, 27.2, and 54.4 mg and other required excipients. The other vial 
contains a vehicle solution.  
5.1.1 Placebo Varnish Formulation 
Placebo Varnish is manufactured by C3 Jian, LLC (Marina del Rey, CA) and does not contain 
active ingredients. To maintain the study blind, the Placebo product is also provided in two 
glass vials, their content is combined prior to application. One vial contains a dry blend of two of 
the same excipients as the active vial but without C16G2. The other vial contains a vehicle 
solution. 
For details on the C16G2 and Placebo Varnish composition refer to the Investigators Brochure.
5.1.2 Supply, Packaging, and Labeling 
Study drug will be provided to the study centers in kits containing 1 dose of 13.6, 27.2 and 54.4 mg 
C16G2 Varnish or Placebo, 1 vial containing vehicle for reconstitution, and 4 brush applicators 
that should be sufficient for study drug mixing and application. Each subject will be assigned 3 
kits. The packaging and labeling of the C16G2 Varnish and Placebo are identical to maintain the 
blind. 
The boxes will contain the following material: 


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CONFIDENTIAL 
C16G2 Varnish or Placebo Lyophilized Powder 
1 vial containing 27.2 mg, 13.6 mg or 54.4 mg C16G2 
Varnish or Placebo lyophilized powder 
1 vial containing 1.5 mL of V301 or V302 Varnish Vehicle 
4 Brush Applicators 
 
The varnish vial 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. 
 
Sample C16G2 or Placebo Lyophilized Powder Vial Label  
  
 
 
 
 
 
 
Sample Vehicle Vial 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”  
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Kit box label sample above is for 13.6, 27.2 and 54.4 mg C16G2 or Placebo vials 
Protocol C3J16-V204-00  
13.6 mg C16G2 or Placebo 
Kit #: XXX  Subject #/Initials _______ _______ 
Caution:  New Drug Limited by (US) Law to 
Investigational Use Only. 
Protocol C3J16-V204-00  
27.2 mg C16G2 or Placebo 
Kit #: XXX  Subject #/Initials _______ _______ 
Caution:  New Drug Limited by (US) Law to 
Investigational Use Only. 
Protocol C3J16-V204-00  
54.4 mg C16G2 or Placebo 
Kit #: XXX  Subject #/Initials _______ _______ 
Caution:  New Drug Limited by (US) Law to 
Investigational Use Only. 
Protocol C3J16-V204-00  
1.5mL Varnish Vehicle 
Kit #: XXX  Subject #/Initials _______ _______ 
Caution:  New Drug Limited by (US) Law to 
Investigational Use Only. 
Protocol C3J16-V204-00 
Contents: XXX mg C16G2 Varnish or Placebo 
Kit #:  XXX 
Subject # / Initials: _____________   ____________ 
Date Dispensed: __________ 
For dental administration--Do not swallow 
Store at 2-8°C 
Caution: New Drug Limited by (US) Law to 
Investigational Use Only 
Manufactured by C3 Jian, LLC, Marina del Rey, CA, 
90292 


Protocol No. C3J16-V204-00 
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CONFIDENTIAL 
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 at the study site under secured conditions with limited access. 
Study drug boxes containing C16G2 Varnish or Placebo will be stored at 2-8C. 
Used varnish vials will be replaced in the study drug box and re-stored. Used study drug can be 
kept at room temperature. After dosing in the study is complete, box(es) will be sealed closed with 
tamper evident tape for future drug accountability by the authorized study staff and/or clinical 
study monitor (See Section 9.1.7). 
5.3 
Study Drug Preparation 
Study drug is provided in a two component system consisting of study drug and vehicle, packaged 
in a kit. Reconstitution of study drug will be performed immediately prior to application. 
5.3.1 C16G2 or Placebo Varnish Preparation 
For details on study drug preparation refer to the Study Manual for this study. 
 
Study drug preparation will be performed outside of the purview of the study subject and involves 
the following steps: 
 
Retrieve a study drug kit containing the assigned C16G2 Varnish or Placebo dose 
 
Enter the subject identification and dispensation date on the appropriate study drug label 
and study records 
 
Remove 1 lyophilized powder vial, 1 vehicle solution vial and 2 brushes from the study 
drug kit 
 
Manually remove the screw cap from the varnish vehicle vial 
 
Using a positive displacement pipet remove 1 mL of varnish vehicle from the varnish 
vehicle vial 
 
Manually remove the screw cap from the C16G2 Varnish or Placebo lyophilized powder 
 
Add the 1 mL of Varnish vehicle solution to the Varnish lyophilized powder vial 
 
Using the back end of one brush applicator quickly stir the varnish vehicle into the C16G2 
or Placebo Varnish lyophilized powder until the powder is fully resuspended and there is 
no dry powder observed in the vial 
 
Dispose of the brush applicator 
 
A second brush applicator will be used for immediate application of C16G2 Varnish or 
Placebo product 
 
The remaining 2 brushes will be used for replacements as needed 
 


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CONFIDENTIAL 
 
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. 
6.2 
Subject Instructions 
Enrolled subjects 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) on days of study drug administration (Visits 3-5). While smokers are not excluded from study 
participation, subjects should abstain from using chewing tobacco throughout the study. 
6.2.1 Oral Hygiene Instructions  
During the entire study subjects will not be allowed to use any dental products besides the 
products provided by the study center. Prior to attending the study center for any visit (Visits 1-10), 
subjects will not be allowed to perform oral hygiene in the morning 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 evenings of study drug administration (Visits 3-5). In 
addition, subjects will be resupplied with these dental products as needed. 
6.2.2 Diet Instructions  
Subjects 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 plain water up to 10 minutes prior to dental plaque and 
saliva collection, and will be instructed not to swish or rinse 
Visit 3-5 


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CONFIDENTIAL 
 
Prior to Study Drug Administration 
• 
Subjects will be instructed to not eat, drink (anything except plain water) or swish for 1 hour 
after the start of study drug administration 
• 
Subjects will also be instructed to relax their jaws and refrain from grinding their teeth  
 
Study Drug Administration  
• 
Study drug will be prepared according to instructions provided in Section 5.3 and the Study 
Manual 
• 
Study drug will be administered according to instructions provided in Appendix G and the 
Study Manual 
 
Post-Study Drug Administration 
• 
Subjects will be under the supervision of study staff to ensure that they do not consume any 
food or drink anything besides plain water for 1 hour after C16G2 Varnish or Placebo 
application. Subjects must use plastic or paper cups for water consumption, no bottles, straws 
or metal containers will be allowed. 
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) taken in supine or sitting position 
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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CONFIDENTIAL 
 
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  
 
Subjects will be scheduled for this visit between 6AM and 10AM. 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, severely 
chapped or cracked lips, etc.). 
Pre-Dose 
o Confirmation of eligibility  
o Medical/Dental and Surgical History & Concurrent Illness Update 
o Concomitant Medications Update 
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) taken in supine or sitting position 
o Microbiology (stimulated saliva and dental plaque collection) 
Note: Samples need to be obtained prior to oral hygiene 
o Randomization 
o Oral Hygiene (including brushing and flossing will be conducted at the clinic prior to 
study drug administration) 
Study Drug Administration: 
Instructions for the preparation of C16G2 Varnish or Placebo are provided in the Study Manual. 
Instructions for the application of study drug are provided in Appendix G. 
o At Visit 3/Day 0, subjects will receive a single study drug administration. Subjects will 
have C16G2 Varnish or Placebo applied to all tooth surfaces.  
Note: C16G2 Varnish or Placebo will not be actively removed, but remain on the 
subject’s teeth until removed through normal wear and mastication after discharge 
 
 
 


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CONFIDENTIAL 
Post-Dose 
o Photographic imaging immediately after study drug application (see instructions in 
Appendix H) 
o Oral Cavity Assessment (hard and soft tissues) 
o Vital Signs (blood pressure, heart rate, temperature) taken in supine or sitting position 
1 hour (± 15 minutes)  post study drug administration  
o Subjects will not eat, swish, or drink anything besides plain water from study drug 
administration to one hour after study drug application. In addition, subjects will be 
advised to relax their jaws and to not grind their teeth. Subjects will be supervised to 
ensure compliance 
o Adverse Events 
o Discharge  
 
Subjects will be scheduled for these visits between 6AM and 10AM. 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 Concomitant Medications Update 
o Vital Signs (blood pressure, heart rate, temperature) taken in supine or sitting position 
o Microbiology (stimulated saliva and dental plaque collection) 
o Oral Cavity Assessment (hard and soft tissues) 
o Targeted Physical Exam (general, extraoral, head & neck) (Visit 4 ONLY) 
o Oral Hygiene (including brushing and flossing will be conducted at the clinic prior to 
study drug administration) 
Study Drug Administration: 
Instructions for the preparation of C16G2 Varnish or Placebo are provided in the Study Manual. 
Instructions for the application of study drug are provided in Appendix G. 
o Subjects will receive a single study drug application. Subjects will have C16G2 Varnish 
or Placebo applied to all tooth surfaces. 
Note: C16G2 Varnish or Placebo will not be actively removed, but remain on the 
subject’s teeth until removed through normal wear and mastication after discharge 
Post-Dose 
o Photographic imaging immediately after study drug application (see instructions in 
Appendix H). 
o Oral Cavity Assessment (hard and soft tissues) 
o Vital Signs (blood pressure, heart rate, temperature) taken in supine or sitting position 
1 hour (± 15 minutes) post study drug application 
o Subjects will not eat, swish, or drink anything besides plain water for one hour after 
study drug application. In addition, subjects will be advised to relax their jaws and to not 
grind their teeth. Subjects will be supervised to ensure compliance.    
o Adverse Events 
o Discharge  
 


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CONFIDENTIAL 
 
Subjects will be scheduled for this visit between 6AM and 10AM 
o Concomitant Medication Update  
o Oral Cavity Assessment (Visit 6 and 8 ONLY) 
o Targeted Physical Exam (Visit 6 and 8 ONLY) 
o Microbiology (stimulated saliva and dental plaque collection) 
o Adverse Events 
o Discharge  
 
Subjects will be scheduled for this visit between 6AM and 10AM. 
o Microbiology (stimulated saliva and dental plaque collection) 
o End of Study (Visit 10 only) 
 
 
Study Visit Schedule 
 
 


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CONFIDENTIAL 
 
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. 
All AEs will be recorded beginning with the first exposure to study drug and continuing until the 
subject is discharged from the study due to completion or Early Termination. 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. 
Table 1: Adverse Events Intensity Description 
Grade 
Description 
Mild (1) 
Generally non-progressive; transient or mild discomfort; no limitation 
in activity; no medical intervention/therapy required. 
Moderate (2) 
Mild to moderate limitation in daily activity; some assistance may be 
needed; no or minimal medical intervention/therapy required. 
Severe (3) 
Marked limitation in daily activities; some assistance usually required; 
medical intervention/therapy required. 
Life Threatening (4) 
Extreme limitation in daily activities; significant assistance required; 
significant medical intervention required. 
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 


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CONFIDENTIAL 
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? 
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. 


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CONFIDENTIAL 
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. 
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 


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CONFIDENTIAL 
 
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. 
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. 


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CONFIDENTIAL 
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 
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 (SUSAR) 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. 


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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. 
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, 
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-V204-00 is a phase 2, single-blind, randomized, placebo controlled study 
designed to evaluate the safety and microbiological activity of C16G2 Varnish applied directly to 
the tooth surface. Study subjects will receive a single C16G2 Varnish or Placebo administration 
on six separate days. The study will evaluate 27.2 mg and potentially 13.6 mg and/or 54.4 mg 
C16G2 Varnish or Placebo administrations. 
The objectives of the study are to evaluate the safety of multiple C16G2 Varnish or Placebo 
administration in subjects 12-75 years of age, to assess the targeted antimicrobial activity of 
C16G2 Varnish or Placebo as measured by a reduction in the number of Streptococcus mutans 
in saliva and dental plaque, and to assess total bacteria in stimulated saliva and dental plaque. 
For the summary table presentations, data will be summarized in tabular format by 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 
The study will enroll subjects into up to three study arms. Up to 33 subjects will receive multiple 
doses of study drug (27.2 mg and 13.6 mg or 54.4 mg C16G2 Varnish or Placebo) applied with a 
small brush typically used in dental varnish administration (for details see Appendix A).  Subjects 
will be enrolled in 8:3 ratio. A microbiology review will be conducted after all subjects in Arm 1 
have completed Visit 8 (Day 14) and a determination will be made whether to enroll additional 11 
subjects into Study Arms 2 and/or 3 (13.6 mg and/or 54.4 mg C16G2 Varnish or Placebo). 
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. 
8.3 
Blinding 
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. 
Study drug (C16G2 Varnish or Placebo) will be packaged identically to ensure blinding. 
8.4 
Sample Size Determination 
The total number of subjects planned for this study is up to 33. 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 Varnish. Subjects’ data in this study will provide 
information on the safety and microbiology of multiple administrations of C16G2 Varnish or 
Placebo. Subjects may be replaced at the Sponsor’s discretion. 


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CONFIDENTIAL 
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 Varnish 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 Varnish 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 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 by treatment group and WHO Anatomical Therapeutic Chemical (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 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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CONFIDENTIAL 
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 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 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 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 -2) and Visit 3-5 pre- and post-study drug administration for each treatment group 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 3-5 for 
each study visit. 
 
All stimulated saliva and dental plaque samples obtained in this study will be tested for S. mutans 
using mitis-salivarius bacitracin (MSB) agar plating. Stimulated saliva and dental plaque samples 
taken at visits 3 & 6 will be tested for total bacteria testing using Todd Hewitt (TH) agar plating. 
Dental plaque and stimulated saliva samples will be stored for S. mutans and total bacteria testing 
using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and bacterial community 
analysis. Descriptive statistics utilizing mean, standard deviation, median and range of oral 
microbes at each time point for each treatment group will be determined and compared to 
Baseline, as applicable. 
Further details regarding the microbiology analysis will be presented in the Statistical Analysis 
Plan (SAP). 
 
 
 


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CONFIDENTIAL 
 
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 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 and Assent 
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 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, pathology and special assessment reports, x-rays, laboratory reports, screening and 
enrollment logs, 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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CONFIDENTIAL 
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 varnish vials 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. 
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, 


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CONFIDENTIAL 
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 
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. 


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CONFIDENTIAL 
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, the following 
evaluations will be performed, if feasible and if subject is withdrawn within the safety evaluation 
period defined in this protocol:  
 
Concomitant Medication Update 
 
Adverse events  
 
Oral cavity assessment 
 
Targeted physical exam 
 
Vital Signs 
 
Microbiology (dental plaque and stimulated saliva) 
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; 


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CONFIDENTIAL 
 
Significant noncompliance on the part of the subject with study procedures; 
 
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 an “exit” examination with the 
following evaluations, if the study is terminated prematurely and the subject is within the safety 
evaluation period defined in this protocol: 
 
Concomitant Medication Update 
 
Adverse events  
 
Oral cavity assessment 
 
Targeted physical exam 
 
Vital Signs 
 
Microbiology (dental plaque and stimulated saliva) 
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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CONFIDENTIAL 
 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-V204-00 STUDY SCHEMATIC 
 
 
 
 


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APPENDIX B: SCHEDULE OF STUDY ASSESSMENTS & PROCEDURES  
STUDY ASSESSMENTS & PROCEDURES 
SCREENING 
DAY 
-30 TO -1 
PROPHY 
DAY 
-7 TO -2 
BASELINE 
DAY 0 
DOSING 
DAYS 1-2 POST V3 
AND  
DAYS 1-2 POST V4 
FOLLOW-UP 
DAYS 
1, 3 AND 7± 1 DAY 
POST V5 
FOLLOW-UP 
WEEKS 
2 ± 2 DAYS &  
4 ± 3 DAYS POST V5 
VISIT  
1  
VISIT 
2 
VISIT  
3 
VISITS 
4 & 5 
VISITS  
6-8 
VISITS  
9 & 10 
Informed Consent & Subject ID 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
Medical/Surgical/Dental History & 
Concurrent Illness 
X 
 
X 
 
 
 
Salivary Flow Assessment 
X 
 
 
 
 
 
Concomitant Medications 
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 
Xm 
X (Visits 6 & 8 only) 
 
Targeted Physical Exam 
X 
 
X 
X (Visit 4 only) 
X (Visits 6 & 8 only) 
 
Vital Signs b 
X 
 
X 
X 
 
 
Microbiology c 
Xd 
Xe 
Xf 
Xf 
X 
X 
Professional Dental Prophylaxis g 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
Training on flossing & brushing h 
 
X 
 
 
 
 
Oral Hygiene 
 
 
X 
X 
 
 
Study Drug Administration i 
 
 
X 
X 
 
 
Photographic imaging j 
 
 
X 
X 
 
 
Adverse Events k 
 
 
X 
X 
X 
 
Oral Hygiene Product Distribution l 
 
X 
 
 
 
 
End of Study 
 
 
 
 
 
X (Visit 10 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, Visit 3, 4, & 5 Days 0, 1-2 Post Visit 
3  and 1-2 Post Visit 4 - Prior to study drug administration and 1 hour (± 15 minutes) after study drug application.  
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 10 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 Visit 3-5: 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 Varnish or Placebo at the clinic (for details refer to Appendix A and Section 6). 
j Photographic imaging: Oral photographs of varnish application will be taken immediately after Varnish application 
k Adverse Events: Subjects will be reminded to immediately notify the Investigator of any untoward effects until Visit 8. 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 Dosing Visits 3 to 5 OCA will be performed prior to study drug administration and post study drug administration.  
 


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APPENDIX C: SCHEDULE OF MICROBIOLOGY ASSESSMENTS 
Stimulated saliva and dental plaque samples will be tested using MSB (S. mutans) and TH agar 
plating (total bacteria). Stimulated saliva and dental plaque samples will be stored for qRT-PCR 
testing and bacterial community analysis. .  
 
MICROBIOLOGY ASSESSMENT 
VISIT 
1 
VISITS 
3 & 6 
VISITS 
2, 4, 5, 7-10 
S. mutans by MSB agar plating  
X 
X 
X 
Total bacteria by TH agar plating  
 
X 
 
qRT-PCR testing a  
X 
X 
X 
Bacterial Community Analysis a 
X 
X 
X 
a Samples will be stored for testing by qRT-PCR and bacterial community analysis 
 
 


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APPENDIX D: VISIT SCHEDULE 
 
 
 
STUDY PERIODS 
VISIT # 
SCHEDULE 
TIME 
Screening 
1 
Day -30 to -1 
Morning (6-10 AM) 
Prophylaxis 
2 
Day -7 to -2 
Morning (6-10 AM) 
Study Drug 
Administration 
3 
4 
5 
Day 0 
24-48 hrs Post Visit 3 
24-48 hrs Post Visit 4 
Morning (6-10 AM)  
Safety and Microbiology 
Follow-up 
6 
7 
8 
24 hours Post Visit 5 
3 days Post Visit 5 
7 Days ± 1 Day Post Visit 5 
Morning (6-10 AM) 
Microbiology Follow-up 
9 
10 
14 Days ± 2 days Post Visit 5 
28 Days ± 3 days Post Visit 5 
Morning (6-10 AM) 


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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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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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APPENDIX G: STUDY DRUG APPLICATION INSTRUCTIONS 
Study staff will apply study drug (C16G2 Varnish or Placebo) to each tooth surface using 
brushes provided in the study drug kits. Follow the instructions below for study drug application:  
 
1. Wipe teeth with gauze sponge or paper towel to remove excess saliva on the tooth 
surface 
2. Dry the teeth with air 
3. Use suction as necessary to remove excess saliva during study drug application 
Note: subject’s teeth must be completely dry for the varnish to adhere properly 
4. Use fingers and absorbent sponges to isolate teeth and prevent cheeks and tongue from 
rubbing against study drug prior to it setting 
5. Stir the study drug thoroughly before applying it to the teeth and between applications 
6. Dip the brush head into the study drug to collect a drop of varnish 
7. Immediately apply study drug to the tooth surface using as few strokes as necessary to 
spread out the varnish 
8. Reload the brush with study drug after coating 1 to 2 tooth surfaces 
9. Apply study drug to each tooth surface until all teeth are completely coated, including the 
lingual, buccal and occlusal surfaces with a single coating of varnish. Do not apply a 
second coat 
10. Retain remaining varnish for study drug accountability by the clinical monitor 
11. Varnish will remain on the subject’s teeth until removed through normal wear and 
mastication 
 
 
 


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APPENDIX H: VARNISH 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  
 
1. Image the subject’s teeth at the following time points:  
a. Immediately after study drug application 
 
NOTE: When using retractors and mirrors for imaging it is important not to disrupt the 
varnish application. 
 
Shot No. 1: Anterior (Frontal) View — Retracted  
To achieve the retracted anterior (frontal) view shot, the patient should ideally be seated in the 
dental chair with the operator standing in front of the patient. Figure 1a demonstrates the anterior 
view picture to be taken, while Figure 1b demonstrates the proper technique described below. 
Cheek retractors must be used with the lips retracted outward, away from the teeth. Whenever 
possible, minimize the appearance of the cheek retractors in the image as seen in Figure 1a. A 
common error during retraction is pulling the lips outward and backward; this results in the buccal 
soft tissue resting against the teeth and preventing adequate visualization of the buccal corridors. 
Use the largest set of retractors that the patient can comfortably tolerate to avoid the center of the 
upper and lower lip from showing in the photograph. The horizontal midline should be the occlusal 
plane and the vertical midline should be the anatomic midline. 
 
 
Figures 1a and 1b. Examples of anterior shot using clear plastic 
cheek retractors. 
  
Shots Nos. 2 and 3: Right and Left Buccal Views 
The right and left buccal views are accomplished using the same patient and operator position 
and same camera settings as the frontal view (Figures 2a). 
 
Place both cheek retractors and shift the retraction to the side being photographed. For example, 
if the right side is to be captured, the right retractor should be pulled out and away from the teeth, 
while the left retractor is left slack and not pulled but simply holding the lips apart. Standard adult 
cheek retractors may be used; however, it is helpful to use buccal retractors to more easily capture 
all the teeth in the image. The horizontal midline should be the occlusal plane. The vertical midline 
should be the canine, but may be variable based on the angle of view and number of teeth 
captured. Ideally, the canine and molar relationship should be visualized; however, with proper 
retraction it is usually possible to capture the entire buccal segment from second molar to incisors. 


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CONFIDENTIAL 
Figure 2a. Buccal view using clear plastic buccal 
retractor. 
 
Shot No. 4: Maxillary Occlusal View  
For many practitioners the maxillary and mandibular occlusal shots present the most difficulty 
(Figures 3a and 3b). 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. 5: 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 3c to 3e). 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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Figure 3a. 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 3b. 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 3c. 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 3d. 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 3e. Close-up showing the 
back of the mirror touching the 
maxillary teeth when preparing to 
capture the mandibular occlusal 
photograph. 
 


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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 five images taken with the subject identifier followed by the photograph’s 
number and the time point as follows in the examples below: 
 
For subject #V204-01-001, Photo 1, Day 0 
V204-01-001 P1D0 
 
Image Uploading 
Within the main clinical site folder (e.g. C3J16-V204-00 Site 01) there is a sub folder for “Varnish 
Images”. Create a new folder for each subject within the “Varnish Images” folder using the subject 
identifier (e.g. V204-01-001). Upload one image for each required photo to this folder. There will 
be a total of 5 photographic images for each subject on each day of dosing. 
 
 


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APPENDIX I: DECLARATION OF HELSINKI 
 


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