Conditions: Plaque Regrowth
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: yes

Brief summary:
The Safety, efficacy and tolerability of an Antimicrobial Chewing Gum Formulation in Reducing Dental Plaque

Detailed description:
A Phase 2 two-armed placebo-controlled, double-blind, randomized (1:1), multiple dose, single center interventional study to evaluate the safety and proof of concept for an antimicrobial decapeptide KSL-W chewing gum formulation 3 times per day over 4 treatment days measuring dental plaque regrowth from specific regions of the upper jaw, lower jaw, buccal and lingual surfaces.

Arms:
arm 1: 3 times per day over 4 treatment days arm 2: 3 times per day over 4 treatment days

Interventions: intervention 1: KSL-W
Intervention descriptions: intervention 1: Antimicrobial KSL-W Plaque reducing chewing gum

Protocol document:
ICF_002.pdf: 
APCG Plaque Regrowth 
The Surgeon General 
IND #77532; S-16-10 
Department of the Army 
  
 
Version 0.2 (22June2016) 
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US Government Proprietary 
Informed Consent Document 
A Double-Blind, Randomized, Placebo Controlled, Clinical Trial of an Antiplaque Chewing Gum (30 
mg) - Phase 2 Proof of Concept in a Generally Healthy Patient Population 
 
Participant:  ___________________________ 
 
 
CONTACT INFORMATION: The contact information is a resource if you have questions about the 
study, your participation in the study, the study product, any adverse event that you may experience, 
possible compensation, your rights as a study participant, and the safety of this clinical trial.  
Principal Investigator (PI): (for questions about an injury related to the research study, adverse events, 
the study product, compensation due to injury, or to revoke in writing the HIPAA Authorization) 
Jeffery Milleman, DDS, MPA 
 
Salus Research                                                                                          
1220 Medical Park Dr, Bldg #4                                                                   
Fort Wayne, IN 46825                                                                         
260-755-1099;  
The contact telephone number for after work hours is: 260-413-7777 
Sub-investigator(s): (for questions relating to the research study, adverse events, or the study product) 
Kimberly R. Milleman, RDH, BSEd, MS 
 
Salus Research                                                                                          
1220 Medical Park Dr, Bldg #4                                                                   
Fort Wayne, IN 46825                                                                          
260-755-1099;  
Study Coordinator: 
Kirstin Battershell, RN, MBA 
 
Salus Research                                                                                          
1220 Medical Park Dr, Bldg #4                                                                   
Fort Wayne, IN 46825                                                                          
260-755-1099;  
Research Monitor: (for questions relating to the safety of this study) 
Armand L. Balboni, J.D., M.D., Ph.D, CPT, MS, USA  
Deputy Director, Division of Regulated Activities and Compliance (DRAC) USAMMDA 
1430 Veterans Drive  
Ft. Detrick, MD, 21702-5009 
301-619-8049 
armand.l.balboni.mil@mail.mil 


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Institutional Review Board: (for questions about your rights as a participant in research) 
U.S. Investigational Review Board, Inc.  
Chairperson: Ms. Rosa M. Fraga 
6400 S.W. 72nd Court                                                                            
Miami, Florida 33143 
786-473-3095 
E-mail: rmvf1550@aol.com 
And 
 
US Army Medical Research and Material Command ORP  
Human Research Protection Office 
ATTN: MCMR-RPH 
504 Scott Street 
Fort Detrick, MD 21702-5012 
301-619-7803 
E-mail: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil 
 
What Is Informed Consent 
You are being given the opportunity to participate in a research study to assess the safety and response to 
an anti-plaque chewing gum (APCG). The study will be conducted at Salus Research, in Fort Wayne, 
Indiana. The research study is approved by: U.S. Investigational Review Board (Central IRB) and the 
Human Research Protection Office US Army Medical Research and Material Command (HRPO 
USAMRMC). The study will be conducted at Salus Research under the direction of the Principal 
Investigator,  Dr. Jeffery Milleman.  The study is sponsored by The Surgeon General, Department of the 
Army. 
Please take your time when making your decision about participating in this study. Dr. Milleman or 
another member of the study team will explain the study to you and answer any questions you may have. 
Study personnel will wait to continue the informed consent discussion with you until you have had at 
least 24 hours to read this document. It is important that you understand what will be done and the 
possible risks to you, so please ask questions at any time. To give informed consent, you must understand 
that: 
 
You will be given detailed information about the research study. 
 
You are free to ask any questions that will enable you to understand the nature of the study. 
 
You will be asked to read, sign, and date this informed consent after you have an 
understanding of the study and decide to participate. 
 
Taking part in this study is completely voluntary. 
 
Refusal to participate will involve no penalty or loss of any benefits to which you are 
otherwise entitled. 


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 
You may withdraw from the study at any time without penalty or loss of benefits to which 
you are otherwise entitled. 
 
You will be given a signed and dated copy of this consent document to keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as 
required by US law. This website will not include information that can identify you. At most, 
the website will include a summary of the results of the study. You can search this website at 
any time. You can get information by typing the name of the investigational compound or 
protocol title into the website’s search field. 
The clinical staff will talk with you about the information in this document. The study investigators will 
encourage you to ask questions about this study at any time. You can take as much time as you need to 
review this document and take it home if you would like to discuss your study participation with your 
family, friends, and related community. 
This investigational product has not been licensed for sale by the United States of America but has been 
approved by the Food and Drug Administration (FDA) for human research. 
Why Is This Investigational Product Being Offered? 
Sometimes there are situations where daily oral hygiene (teeth brushing, flossing and mouth rinses) 
cannot be followed. This investigational product is being offered as  a chewing gum which can be used in 
place of daily oral hygiene to reduce the buildup of plaque on the teeth...  
What Is the Purpose of the Study? 
We are testing a new medication called Anti-Plaque Chewing Gum (APCG) which we think may be 
effective in helping patients reduce the amount of plaque that forms on their teeth. Poor oral hygiene and 
diet can lead to a build-up of bacteria, which then leads to a buildup of plaque on the teeth. The buildup of 
plaque on the teeth may cause tooth decay (cavities), gum disease and other oral infections. This chewing 
gum may help reduce plaque buildup on the teeth and prevent gingivitis (gum disease). 
Sometimes we don’t know which form of treatment is best. We want to know if the APCG is able to 
reduce plague buildup on the teeth and is safe to use. To find out, we will compare the APCG treatment to 
a placebo treatment.  In this case, a placebo is a chewing gum that looks exactly like the APCG, but has 
no active ingredients and has no physical effect on the patient.  In this study, patients will be put into 2 
groups. One group will get the active drug (APCG) treatment and the other group will get the inactive 
drug (placebo) treatment. 
What Is the Investigational Product? 
The investigational product is a medication that has active ingredients that kill micro-organisms or 
prevent their growth in the mouth, thus helping to prevent the buildup of plaque on the teeth that leads to 
gingivitis (gum disease) and periodontitis (diseased tissues around the teeth).   This investigational 
product has been made into a chewing gum. The active ingredient in the test gum is called KSL-W.  
How Will the Medication Be Given? 
The medication will be given as a chewing gum. Neither you nor the study staff will know whether you 
will be given the APCG test gum or the placebo gum.  This is called a double-blind treatment. You will 
chew the gum, preferably after meals three times a day for four consecutive days.  You will chew the gum 
on both sides of your mouth for 20 minutes.   
What Are the Requirements to Be in the Study?  


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To be eligible for this research study, you must meet all of the following conditions: 
    Males or females between 18 and 64 years of age (inclusive at time of screening) 
 
A negative urine pregnancy test (females of child-bearing potential only) 
 
A negative urine drug test 
 
On a reliable form of birth control for at least 30 days prior to the start of the study and 
willing to use a reliable form of contraception for the duration of the study (Females of 
childbearing potential only), with reliable contraception defined as: 
- 
Abstinence which has been the customary lifestyle of choice (acceptable only if this has 
been your usual method of contraception) 
- 
Oral contraceptive (birth control pills), either estrogen progesterone combined, or 
progesterone alone 
- 
Injectable progesterone 
- 
Implants of levonorgestrel 
- 
Estrogenic vaginal ring (containing estrogen) 
- 
Percutaneous contraceptive patches (birth control patches) 
- 
Intrauterine device (IUD) or intrauterine system 
- 
Double barrier method [condom or occlusive cap (diaphragm or cervical vault caps) plus 
spermicidal agent (foam, gel, film, cream, suppository)] 
- 
Male partner sterilization at least 6 months prior to the female subject’s entry  into the 
study, and this male is the sole partner for that subject 
- 
Post-menopausal for at least two years 
 
Good health, as determined by pertinent medical history, physical examination, and vital 
signs (heart rate, respiration rate, blood pressure and body temperature). 
 
A minimum of 20 natural teeth with 6 scorable surfaces per tooth (6=the number of 
surfaces on your tooth that the dental examiner can look at and determine the amount of 
plaque buildup) 
- 
Sufficient number of opposing posterior (back) teeth to chew on both sides of the mouth 
as determined by the examining dentist 
- 
Teeth that have gross caries (excessive decay), full crowns or extensive restorations on 
facial and/or lingual (front and/or back) surfaces, orthodontic bands (braces), and third 
molars are not included in the tooth count 
 
Subject must have refrained from all oral hygiene procedures 12 to 16 hours prior to 
screening visit. 
 
Plaque Index of 1.95 or greater {Quigley Hein Turesky Plaque Index} (Turesky et al-1970) 
(a value measured by the dental examiner to determine the amount of plaque buildup on 
your teeth) 


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 
Willing to forgo any optional dental procedures during the study period, such as dental 
prophylaxis (preventative dental procedures or teeth whitening). 
 
Ability to comprehend and a willingness to sign an informed consent, which includes the 
Authorization for the Release of Health Information (HIPPA) document. 
 
Ability to access the internet to complete the drug compliance information (electronic diary 
of when you chewed the test gum) 
 
Willingness to comply with (follow) all study procedures 
You will be excluded from the study if you are/have: 
 
Phenylketonuria (a condition in which one is unable to metabolize phenylalanine, found in 
NutraSweet® also known as Aspartame) 
 
Acute or chronic medical conditions, organ system disease, or medications that, in the 
principal investigator’s opinion, would impair the subject’s ability to participate 
 
Temporomandibular Disorders (conditions that cause pain and dysfunction of the jaw joint 
and muscles of the jaw that control movement) 
 
Self-reported allergy to sucralose or mint flavors (peppermint powder, isomalt) 
 
Self-reported use of tobacco products including e-cigarettes 
 
Use of any type of anticoagulant medications (blood thinning drugs) 
 
Routine use of proton pump inhibitors (such as Omeprazole (Prilosec®), Lansoprazole 
(Prevacid®), Dexlansoprazole, Esomeprazole (Nexium®), Pantoprazole (Protonix®), 
Rabeprazole 
 
Allergic to any component of the study drug (components include: cetylpyridinium 
chloride, isomalt, peppermint powder, sucralose, colloidal silicon dioxide or magnesium 
stearate) 
    Gross oral pathology, including widespread caries (cavities) or chronic neglect, extensive 
restoration, pre-existing gross plaque or calculus, or soft or hard tissue tumor of the oral 
cavity (mouth) 
 
Orthodontic appliances (braces) or removable partial dentures (false teeth) that will 
compromise the ability of the potential subject to participate in the study 
 
Periodontitis (gum disease) as indicated by periodontal pockets (tissues around the tooth) 
greater than 4 millimeters on more than one site  
 
Receipt of any investigational drug/test product within 30 days prior to study entry with 
study entry defined as Day 0 or currently participating in either the active or follow-up 
phase of any other Investigational Study or planning to participate in any other 
Investigational Study during participation in this trial  
 
Participation in the Phase 1/2a anti-plaque study 
 
Receipt of antibiotics within 30 days prior to study entry 
 
Need for antibiotic prophylaxis prior to invasive dental procedures  


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 
Receipt of prescription antibacterial oral products (eg products containing chlorhexidine) 
within 30 days prior to study entry 
 
Pregnant or breast-feeding female 
 
An employee of the study site directly involved with the study 
 
Inability to comply with assigned treatment regimen 
 
What Precautions Should I Take During the Study? 
The effect of this study medication on unborn babies is currently unknown. If you are a female, you 
should not breastfeed or become pregnant during the study or within 3 months after receiving the last 
dose of study drug. If you are a male, you should not have unprotected sex for at least 3 months after 
receiving the last dose of study drug. 
What is the Potential Benefit of the Study and is there an Alternative to Participating? 
There is no benefit from participating in this study other than the potential for added protection against 
gingivitis (gum disease) and periodontitis (diseased tissues around the teeth). You will receive oral 
examinations as part of the dental examination and you will have all your teeth polished at Baseline (Visit 
2). Research is designed to benefit society by gaining new knowledge. 
The alternative to participating is to choose not to participate and to practice oral hygiene as you normally 
would each day.  
What Are the Potential Risks and Discomforts?  
There are potential risks and discomforts in any medications you take. Some of the side effects that you 
may experience taking APCG are:  coated tongue, tooth discoloration, a change in taste, a loss of taste, 
tongue pigmentation (color), throat tightness, abdominal discomfort (stomach ache) and flatulence (gas). 
Study Event Schedule: 
The procedures that will be completed during the course of the study are shown in the following Table. 


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Study Events Schedule 
 
Study Visit/Day 
Visit 1 
Visit 2 
 
Visit 3 
Screening 
(-14+ 2) 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
General Procedures 
 
 
 
 
 
 
Written Informed Consent/HIPAA 
X 
 
 
 
 
 
Evaluation  Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Vital Signs (BP, HR, RR Temperature)   
X 
X 
 
 
 
X 
Physical Exam 
X 
 
 
 
 
Xa 
Urine Drug Screen 
X 
 
 
 
 
 
Urine Pregnancy Test 
Xb 
 
 
 
 
Xb 
Periodontal Examination 
Xc 
 
 
 
 
 
Intraoral Exam (OHT, OST) 
X 
X 
 
 
 
X 
Oral Hygiene Check 
Xd 
Xd 
 
 
 
Xd 
Randomization (1:1 stratified by evaluator) 
 
X 
 
 
 
 
Plaque Index Score 
X 
Xe 
 
 
 
X 
Teeth Polishing 
 
X 
 
 
 
 
Dispense Study Drug for Supervised and 
Unsupervised Use 
 
Xf 
 
 
 
 
Study Drug Administration 
 
Xg 
Xg 
Xg 
Xg 
 
Collect Used Study Drug 
 
Xh 
 
 
 
Xh 
Electronic Diary Information System 
 
Xi 
Xi 
Xi 
Xi 
 
Adverse Event Reporting 
 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
 
 
 
X 
Study Discharge 
 
 
 
 
 
X 


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Screening – Visit 1 
If you agree to take part in this study, the study staff will complete the following tests and procedures 
during a screening period to decide if you can take part in this study. You will be asked to sign a consent 
form before any tests or procedures are done. After the consent, the following assessments will occur: 
 
Study inclusion and exclusion criteria will be evaluated. 
 
Your medical history and demographic information will be collected. 
 
Your vital signs (diastolic and systolic blood pressure, respiration rate, heart rate and 
temperature) will be measured. 
 
A physical exam will be performed.  
 
A urine drug screen will be performed. 
 
If you are female and are able to become pregnant, you will take a urine pregnancy test. 
 
A periodontal exam will be performed. During this exam, the investigator will count your 
teeth, determine how many tooth surfaces and pockets depths in the tissues around your 
teeth can be measure.  
 
An intraoral examination will be performed. During this exam, the investigator will 
examine both the hard and soft tissues of your mouth. 
 
Oral hygiene check – You will be asked to confirm that you  have not performed any oral 
hygiene procedures (flossing, brushing your teeth, using any mouth wash rinse) for 12 to 
16 hours prior to the screening visit. 
 
The amount of plaque buildup on your teeth will be measured by the dental examiner. 
The dental examiner will rate your plaque buildup using a scoring system called the 
Quigley Hein Turesky Plaque Index. (A red food dye will be used to disclose (show) the 
plaque deposits on your teeth.) 
 
You will be asked to provide a list of any additional medications you may be taking. 
 
BP-blood pressure, HIPAA-Health Insurance Portability and Accountability Act, HR-heart rate, RR-respiration rate, OHT-oral hard tissue, OST – oral soft tissue, 
QHT-Quigley-Hein Turesky Plaque Index 
a Brief symptom oriented physical exam (based upon reported adverse events) 
b Pregnancy test for females of childbearing potential 
c Includes determination of number of teeth, score-able surfaces and pocket depths around teeth 
d Confirm subject has refrained from all oral hygiene procedures (flossing, brushing of teeth, mouth wash rinse) for 12 to 16 hours prior to Screening and Day 0 
(Baseline).  On Day 4, confirm subject has refrained from all oral hygiene procedures since chewing their last dose on Day 3  
e Measured after randomization, but before teeth polishing 
f Subject will be allocated 14 tablets of gum for the 4 day study period 
g Subject will chew one tablet of gum for 20 minutes preferable after a meal (breakfast, lunch, dinner) or every 4 to 6 hours for a maximum of 3 chews per day. 
Chewing will be balanced as equally as possible between both sides of the mouth.  The first tablet will be given under supervision in the clinic. Oral hygiene is not 
allowed at any time during the 4 day treatment. Oral hygiene cannot resume until after the determination of the Plaque Index Score on Day 4 
h After each chewing period, the gum is disposed of in individual labeled bags.  Subject records time/date of gum disposal on each bag 
i Subject records all start /stop times of gum chewing via the internet using the electronic diary information system (ePRO).  
 


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Study Day 0 (Baseline) – Visit 2   
After the screening period, if you are eligible to participate, you will be scheduled to return to the clinic 
for Visit 2 (Day 0 baseline) to begin treatment.  The following assessments will occur at Visit 2: 
 
The study inclusion and exclusion criteria will be re-checked 
 
Your vital signs (blood pressures, respiration rate, heart rate and temperature) will be measured 
 
Intraoral exam (OHT and OHT) will be conducted. During this exam, the investigator will 
examine both the hard and soft tissues of your mouth. 
 
Oral hygiene check: You will be asked to confirm that you did not perform any oral hygiene 
procedures (flossing, brushing your teeth, using any mouth wash rinse) for 12 to 16 hours prior to 
the visit  
 
You will be assigned to a chewing gum group. You will be assigned to receive either active 
ACPG (containing 30 mg KSL-W) or to receive placebo gum. There is an equal chance that you 
will be assigned to either chewing gum group. (You will be assigned to a treatment group 
according to a randomization schedule and neither you nor the investigators will know whether 
you will receive active ACPG or placebo during the study). 
 
The amount of plaque buildup on your teeth will be measured by the dental examiner. The dental 
examiner will rate your plaque buildup using a scoring system called the Quigley Hein Turesky 
Plaque Index. (A red food dye will be used to disclose (show) the plaque deposits on your teeth.) 
 
A licensed dental hygienist will polish your teeth. 
 
You will chew your first piece of study gum while you are at the clinic.  You will be instructed to 
chew one tablet of gum for 20 minutes and to balance your chewing on both sides of your mouth 
as equally as possible.  
 
After chewing the gum for the 20 minutes, you will be given a used product collection bag to 
store the chewed gum.  The evaluator will tell you how to label this bag with the time and date 
that you chewed the gum. 
 
After the chewing gum is stored in the used product collection bag, you will enter the time you 
started and completed chewing the gum into the electronic diary information system. You will 
enter this information while in the clinic with assistance from the staff if necessary. 
 
Before leaving the clinic, you will be provided with the study medication to take home for  
unsupervised use.  You will receive:   
- 
13  tablets of gum along with 13 individual used product collection bags. (Note: this 
includes two 2 extra pieces of gum and used-product collection bags in case you 
mistakenly lose or misplace one of your doses. If you need more than 2 additional doses 
of gum, you will need to contact the study center). 
- 
You will be given the following instructions for chewing the gum as follows:  
a. Chew the gum for 20 minutes preferably after a meal or every 4 to 6 hours (3 times a 
day). Balance chewing as equally as possible between both sides of your mouth.  Do 
not chew more than 3 pieces of gum each day. 


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b. After chewing a piece of gum for 20 minutes, place  the used gum in its own used 
product collection bag that you were provided. 
c. Label each used product collection bag with the date and time that you chewed the 
gum. (You must use a separate bag for each chew). 
d. After each chew, record the start and stop time of the chew on the electronic diary 
information system.  
e. You must bring all of the used product collection bags (containing your chewed gum) 
back to the clinic for Visit 3, 4 days later. You must also return any of the chewing 
gum tablets you did not chew. 
 
You will be told that no oral hygiene procedures of any kind (teeth brushing, flossing or using 
mouth wash rinse) are allowed while you are on study treatment (Day 0, 1, 2, 3 and 4).   
 
You will be asked about any adverse events that you may experience after your first gum chew. 
 
You will be asked about any other medications that you are taking. 
 
Unsupervised Treatment, Study Days 0, 1, 2, and 3   
After the first supervised chew is completed, you will be released from the clinic. Over the next 4 days, 
outside of the clinic, you will chew a total of 11 pieces of gum.  You will chew one tablet of gum (study 
medication) for 20 minutes every 4 to 6 hours, preferably after a meal, for a maximum of 3 chews per day 
according to the schedule in the table below. 
Schedule for Unsupervised Chews: 
Time* 
Day 0 
Day 1 
Day 2 
Day 3 
After Breakfast** 
N/A 
1 
1 
1 
After Lunch 
1 
1 
1 
1 
After Dinner 
1 
1 
1 
1 
Total Chews per Day 
2 
3 
3 
3 
* Chew gum for 20 minutes, preferably after a meal or every 4 to 6 hours 
for a maximum of 3 chews per day. Balance chewing as equally as 
possible between both sides of your mouth. 
** You will chew your first tablet of gum at the clinic under staff 
supervision.  
 
 
After completing each 20 minute chew, you will place the used gum in one of the used product collection 
bags provided to you. You will record the date and time of that you chewed the gum on the used-product 
collection bag.  A separate bag will be used for each chew.  You will record your  chewing gum start and 
stop times on the electronic diary system after each chew. You will log onto the internet to enter in this 


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information. The study staff will explain how to do this after your first chew and before you leave the 
clinic. If you need help, contact Dr. Milleman at 260-755-1099 or after work hours at 260-413-7777. 
 
Treatment, Study Day 4 – Visit 3 
After 4 days of treatment, you will return to the clinic for Visit 3.  The following events will occur at Visit 
3: 
 
You will return all used product collection bags and any unused gum 
 
Your vital signs (blood pressure, respiration rate, heart rate and temperature) will be measured 
 
A brief, symptom-oriented physical examination will be performed 
 
If you are female and are able to become pregnant, you will take a urine pregnancy test 
 
You will be asked to confirm that you did not perform any oral hygiene procedures (flossing, 
brushing your teeth, using any mouth wash rinse) for 12 to 16 hours prior to the visit 
 
An intraoral examination will be performed. During this exam, the investigator will examine both 
the hard and soft tissues of your mouth. 
 
The amount of plaque buildup on your teeth will be measured by the dental examiner. The dental 
examiner will rate your plaque buildup using a scoring system called the Quigley Hein Turesky 
Plaque Index. (A red food dye will be used to disclose (show) the plaque deposits on your teeth.) 
 
You will be asked about any adverse experiences you had while taking the study medication 
(chewing gum). 
 
You will be asked about any other medications that you took since your last visit to the clinic. 
 
You will be dismissed from the study and paid a gratuity. (You will be allowed to brush your 
teeth just prior to leaving the research center.) 
 
What Happens if I Get Sick?  
If you get sick, you should call Dr. Milleman and your Primary Doctor for instructions.   
What Happens if I Am Injured as a Result of Taking Part in This Treatment Protocol? 
If you are injured and are affiliated with the Department of Defense: The US Department of Defense 
is funding this research study. If you are hurt or get sick because of this research study, you can receive 
medical care at an Army hospital or clinic free of charge even if you are a contracted employee. You will 
be treated for injuries that are directly caused by the research study only. The Army will not pay for your 
transportation to and from the hospital or clinic. If you believe you have received a research-related 
injury, or if you pay out-of-pocket expenses for medical care elsewhere for injuries caused by this 
research study, contact Dr. Milleman. If you still are not satisfied, contact the US Army Medical Research 
and Materiel Command (USAMRMC) Office of the Staff Judge Advocate (legal office) (301-619-
7663/2221). 
Requests for other benefits are processed independent of this research study. Military members retain the 
right to pursue military disability benefits, and federal civilian employees retain the right to pursue relief 
through established workers’ compensation processes; however, neither military disability benefits nor 


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workers’ compensation benefits are guaranteed. This is not a waiver or release of your legal rights. You 
should discuss this issue thoroughly with the Principal Investigator before you sign the informed consent 
to participate in the study. 
If you are injured and are not affiliated with the Department of Defense: Your participation in this 
protocol is being provided as a service by the US Department of Defense under an agreement with 
another institution or agency. Only short-term acute or emergent medical care will be available at the 
clinic for illness or injury associated with participation in this protocol. However, if care for your 
research-related illness or injury is needed beyond that provided at the clinic, you are entitled to free 
medical care for such illness or injury at an Army hospital or clinic. It cannot be determined in advance 
which Army hospital or clinic will provide care. Transportation to and from Army hospitals or clinics will 
not be provided. 
You may choose to seek care under your own health insurance, and it is also possible that you may have 
workers’ compensation/disability coverage that applies to your injury. No reimbursement is available if 
you incur medical expenses to treat research-related injuries. No compensation is available for research-
related injuries. If you believe you have sustained a research-related injury, please contact the PI. You 
should understand that this does not constitute a waiver or release of legal rights. 
What Happens if I Want to Leave the Study? 
Your participation in this research study is completely voluntary. You may choose not to take part at all, 
or you may choose to stop your participation at any time after you have begun the research study. If you 
stop participating in this research study, you will not be penalized or lose any benefits to which you are 
otherwise entitled. 
You may refuse to participate in or may withdraw from this study at any time without penalty or loss of 
benefits to which you are otherwise entitled. If you decide to leave this study early, we ask that you notify 
the PI or a designee as soon as possible. You may be asked to schedule a clinic visit. 
What Are the Safeguards for My Protection? 
All study procedures will be performed by qualified, trained personnel. 
Volunteer Registry Data Sheet: USAMRMC requires that data sheets (Volunteer Registry Data Sheet, 
Form 60-R) be completed for entry into the Command’s Volunteer Registry Database for all individuals 
participating in research trials. This information includes the volunteer’s name, address, Social Security 
Number, study identity, and dates of participation. The intent of this database is twofold: first, to readily 
answer questions about an individual’s participation in research sponsored by USAMRMC; and second, 
to ensure that USAMRMC can exercise its obligation to ensure that all research study participants are 
adequately warned (duty to warn) of risks and to provide new information as it becomes available. This 
information will be stored at USAMRMC for a minimum of 75 years and is kept confidential. The 
Volunteer Registry Data Base is separate from and not linked to the study database. 
Will I Be Compensated for My Participation in the Study? 
You will be compensated for participation in the study.  You will be given a $25 gift card for the 
screening visit.  If you are eligible for participation in the study and receive treatment you will receive gift 
cards worth $200.  Total compensation will be $225 in gift cards. 
What About My Confidentiality? 


APCG Plaque Regrowth 
The Surgeon General 
IND #77532; S-16-10 
Department of the Army 
  
 
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Confidentiality: All data and medical information obtained about you as an individual will be considered 
privileged and held in confidence. We may need to request your medical or hospital records to monitor 
your safety. You will not be identified by name in any published report or in any presentation of the 
results. Information bearing on your health may be required to be reported to appropriate medical or 
command authorities. Representatives from other regulatory agencies, such as the FDA, USAMRMC, and 
its subordinate commands, and study personnel are eligible to review research records as part of their 
responsibility to protect human participants in research and to carry out their obligations relating to the 
study. Representatives from the US Army Medical Material Development Activity may review your 
research record. By signing this consent document, you agree to such inspection and disclosure. 
HIPAA Authorization: The Federal Health Insurance Portability and Accountability Act (HIPAA) 
requires that researchers obtain the participant’s permission (called an Authorization) to use and disclose 
protected health information (PHI) about the participant that is either created by or used in connection 
with this research. This Authorization has no expiration date. By signing this consent form, you are 
agreeing to the use and disclosure of your PHI by the PI and the research staff, including results of 
physical exams, blood tests, and other diagnostic and medical procedures as well as vaccination and 
medical history. Your PHI may also be viewed and used by other regulatory and medical representatives, 
including but not limited to representatives from FDA and USAMRMC. 
Your PHI may also be used by others who do not necessarily work under HIPAA rules. Subject records 
are maintained permanently. 
If you choose not to authorize these uses and disclosure of your PHI by signing this form, you will not be 
eligible to participate in this research study. However, your decision not to sign this consent form will not 
affect any other treatment, payment, or enrollment in health plans or eligibility for benefits. You may also 
change your mind and cancel this Authorization at any time by sending a written notice to the PI. 
Cancellation of this Authorization will not alter disclosure of PHI that has already been collected; 
however, no further PHI about you will be collected by or disclosed to the researcher for this study. 
 
Consent for Participation in the Research Study 
Your signature on this form indicates that you have read this consent form, that the research study has 
been explained to you and your questions have been answered, and that you agree to take part in this 
study. You will receive a copy of this form. 
 
SIGNATURES 
 
 
 
 
Printed Full Name of Study Participant 
 
 
 
 
 
 
Signature of Study Participant 
 
Date 
 
 
 
 
 
 


APCG Plaque Regrowth 
The Surgeon General 
IND #77532; S-16-10 
Department of the Army 
  
 
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Permanent Address of Study Participant 
 
 
 
 
 
 
 
Printed Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion and Obtaining 
Informed Consent 
 
Date 
 
 
 
 

Prot_000.pdf: 
APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
A Double-Blind, Randomized, Placebo Controlled, Clinical Trial of an Antiplaque Chewing Gum (30 mg) -
Phase 2 Proof  of Concept in a Generally Healthy Patient Population 
Sponsor 
The Surgeon General, Department ofthe Army
Sponsor’s Representative 
US Army Medical Research and Materiel Command (USAMRMC)
1430 Veterans Drive, Ft. Detrick, MD 21702-5009
301 -619-0317; DSN :  343-0317 
,
Fax: 301-619-0197
Email: usarmy.detrick.medcom -usammda.mbx.usamrmc -regulatory-
affairs@mail.mil 
Research Monitor 
Armand L. Balboni, J.D., M.D., PhD. CPT, MS, USA
Deputy Director, Division of Regulated Activities and Compliance
(DRAC) USAMMDA
1430 Veterans Drive
Ft. Detrick, MD 21702
301-619-8049 (Office) 413-923-8775 (cell)
Email: armand.l.balboni.mil@mail.mil
Principal Investigator 
Jeffery L. Milleman, DDS, MPA
Salus Research
1220 Medical Park Dr, Bldg #4
Fort Wayne, IN 46825
Telephone: 260-755-1099
Fax: 260-755-1128
Email: Milleman@SalusResearch.us
Sub-investigator 
Kimberly R. Milleman, RDH, BS Ed, MS (Examiner)
1220 Medical Park Dr, Bldg #4
Fort Wayne, IN 46825
Telephone: 260-755-1099
Fax: 260-755-1128
Email: KMilleman@SalusResearch.us
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APCG Plaque Regrowth
IND #77532; S-16-10
Clinical Trial Site
Qualified Physician Responsible 
for All Trial-Site-Related Medical 
Decisions:
The Surgeon General
Department of the Army
Salus Research
1220 Medical Park Drive, Bldg #4
Fort Wayne, IN 46825
260-755-1099 
Fax:260-755-1128
Email: Milleman@SalusRes
Dominick Acquaro, MD
7806 W. Jefferson Blvd. Sui
Fort Wayne, IN 46804
260-459-0087
Fax: 260-969-8514
Site Investigational Product 
Accountability 
earch.us
te E
Clinical Laboratories and Other Departments/Institutions Involved in the Trial
Jack L. Lowe, BS
Clinical Research Assistant, Salus Research
1220 Medical Park Dr. Bldg #4, Fort Wayne, IN 46825
260-755-1099
Fax: 260-755-1128
Email: Lowe@SalusResearch.us ~
Clinical Laboratory 
None Required ~  
Michael Miller, PhD
VI:h
ClinSmart CRO
2080 Cabot Blvd West, Suite 201
Langhorne, PA 19047
215-710-3220
Fax : 215-702 -2899 wv-v
Email: mmiller@clinsmart.com
Mary Hallmark, Clinical Data Manager
ClinSmart CRO
2080 Cabot Blvd West, Suite 201
Langhorne, PA 19047
215-710-3213 
/
FAX: 215-702-2899
Email: mhallmark@clinsmart.com
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Statistician 
Data Management 
COPY


APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
Institutional Review Board for 
Site of Study Conduct 
U.S. Investigational Review Board, Inc.
6400 S.W. 72nd Court
Miami, Florida 33143
786-473-3095 (Ms. Rosa Fraga, Chairperson)
Fax: 305-374-1789
Email: rmvf1550@aol.com
AND
Institutional Review Board for
Army - USAMRMC Office of
Research Protections 
Email: usarmy.detrick.medcom -usamrmc.other.hrpo@mail.mil ~
 
Human Research Protection Office
US Army Medical Research and Materiel Command,
ATTN: MCMR-RPH
504 Scott Street
Fort Detrick, MD 21702-5012 ~
 
Fax: 301-619-7803
Telephone: 301-619-2165
FOR OFFICIAL USE ONLY
Information and data included in this document contain privileged and/or proprietary information, which is the
property of the United States Army. No person is authorized to make it public without express written permission of
the United States Army. These restrictions on disclosure will apply equally to all future information, which is
indicated as privileged or proprietary.
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
Investigator’s Agreement 
A Double-Blind, Randomized, Placebo Controlled, Clinical Trial of an Antiplaque Chewing Gum (30 mg) -
Phase 2 Proof  of Concept in a Generally Healthy Patient Population 
“I have read this protocol and agree to conduct the study as outlined herein in accordance with
International Conference on Harmonization Good Clinical Practice Guideline and FDA, DoD,
and United States Army Regulations.”
Jeffrey Milleman, DDS, MPA 
Date
Principal Investigator
Salus Research
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
Emergency Contact Information 
Table 1: 
Emergency Contact Information
Role in Study
24-hour Emergency Contact Number:
Name 
Jeffery Milleman, DDS, MPA 
Address and Telephone 
Number 
260-413-7777
Principal Investigator:
Sub-investigator:
Study Coordinator
Research Monitor
Jeffery Milleman, DDS, MPA 
Kimberly R. Milleman, RDH, 
BSEd, MS
Armand L. Balboni, J.D., M.D.,
Ph.D, CPT, MS, USA Deputy
Director, Division of Regulated
Activities and Compliance
(DRAC)
Kirstin Battershell, RN, MBA 
Salus Research
1220 Medical Park Drive Bldg
#4 Fort Wayne, IN 46825
Telephone: 260-755-1099 ~
FAX; 260-755-1128 
Email:
Milleman@SalusResearch.us 
Salus Research
1220 Medical Park Drive Bldg
#4 Fort Wayne, IN 46825
Telephone: 260-755-1099
FAX; 260-755-1128
Email:
KMilleman@SalusResearch.us 
Salus Research
1220 Medical Park Drive Bldg
#4 Fort Wayne, IN 46825
Telephone: 260-755-1099
FAX; 260-755-1128
Email:
Battershell@SalusResearch.us
USAMMDA
1430 Veterans Drive
Ft. Detrick, MD 21702-5009
Fax: 301-619-7790
Telephone: 301-619-8049
Email:
armand.l.balboni.mil@mail.mil
USAMMDA Clinical Services Support 
Division
Carrie Laurencot, PhD
Acting Director, CSSD
USAMMDA USAMRMC
USAMMDA
1430 Veterans Drive
Ft. Detrick, MD 21702-5009
Fax: 301-619-0197
Telephone: 301-619-0317
carolyn.m.laurencot.civ@mail.m
il
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
Address and Telephone 
Role in Study 
Name 
Number 
Sponsor’s Representative 
Kenneth A. Bertram, MD, PhD 
USAMRMC
Principal Assistant for Acquisition 1430 Veterans Drive
USAMRMC 
Ft. Detrick, MD 21702-5009
301-619-0317
usarmy.detrick.medcom -
usammda.mbx.usamrmc -
regulatory-affairs@mail.mil
'
Institutional Review Board for Site of
Study Conduct
U.S. Investigational Review Board 6400 S.W. 72nd Court,
Miami, Florida 33143
Rosa Fraga, Chairperson
786-473-3095
305-374-1789
rmvf1550@aol.com
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
2. 
Synopsis 
b
Name of Sponsor: 
The Surgeon General, Department of the Army
Name of Investigational Product: 
Anti-Plaque Chewing Gum (APCG)
Name of Active Ingredient: 
KSL-W (30 mg)
Title of Study: A Double-Blind, Randomized, Placebo Controlled, Clinical Trial of an Antiplaque Chewing
Gum (30 mg) - Phase 2 Proof of Concept in a Generally Healthy Patient Population
Study Center: 
«
Salus Research
1220 Medical Park Dr, Bldg #4
Fort Wayne, IN 46825
Principal Investigator: 
Jeffery L. Milleman, DDS, MPA
Sub-Investigator: 
Kimberly R. Milleman, RDH, BSEd, MS (Examiner)
Study Period (years): 
Phase of development: 2
Estimated date first subject enrolled: August 2016
Estimated date last subject completed: August 2016
Objectives: 
-
Primary: 
• To assess the safety and tolerability of KSL-W (30 mg dose) delivered in a chewing gum formulation
compared to a placebo gum formulation
Seconda  ry  :  
.
• To assess the proof of concept change in plaque regrowth from baseline in the Quigley Hein-Turesky Plaque
Index (QHT) of KSL-W (30 mg dose) compared to a placebo gum formulation
• To evaluate the proof of concept of KSL-W (30 mg) in change in plaque regrowth based on sub-scores from
specific regions of the upper jaw, lower jaw, buccal and lingual surface based on the QHT
Methodology: This study is a Phase 2 two-armed placebo-controlled, double -blind, randomized (1 :1), multiple
dose, single center study to evaluate the safety and proof of concept of 30 mg KSL-W administered in a chewing
gum formulation 3 times per day over 4 treatment days. Oral hygiene (teeth brushing, flossing and/or mouth
wash rinse) is prohibited throughout the trial beginning 12 to 16 hours before both the screening and Baseline
(Day 0) visits, during the 4 days of treatment (Days 0, 1, 2, and 3) and ending after the periodontal examination
and plaque assessment on Day 4. The ability of KSL-W to reduce existing supragingival plaque will be assessed.
The oral soft (OST) and oral hard tissues (OHT) will be examined. Changes from baseline, such as soft tissue
erythema, ulceration and sloughing, will be noted.
Estimated Number of Subjects Screened: 
35
Estimated Number of Subjects Enrolled: 
26
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
Data from physical examinations and vital signs will be summarized for each evaluation time point. Any
abnormal physical examination findings noted at the end-of-study exam on Day 4 will be tabulated as a listing.
For vital signs, change from baseline to the end-of-study evaluation time points will be summarized.
Two proof of concept (efficacy) endpoints will be assessed. The first, will use the QHT whole mouth scores from
the full analysis set (FAS) and will be based on the mean change from baseline to Day 4. The QHT whole mouth
average will be the average of scores only from surfaces evaluable for QHT, The QHT score is based on each
subject having at least 20 teeth with 6 evaluable surfaces per tooth .  
- -
An analysis of covariance (ANCOVA) model will be used to compare 30 mg KSL-W with placebo. The model
will include the baseline score and study arm (KSL-W, placebo). Sensitivity assessments will be employed to
determine whether the effects of treatment on the slope of the baseline covariate, and the effect of evaluator on
the treatment placebo comparison can be ignored .  KV 
-
While a formal p-value comparison based on the final primary ANCOVA model will be generated and
summarized, this will not be the primary evaluation since this study has not been powered for detection of a
minimally clinically important improvement in QHT. The primary proof of concept summaries for this study will
include the estimated difference, KSL-W minus placebo, in the mean (QHT) change from baseline, and the
estimated error standard deviation from the primary ANCOVA model. This information will be critical to assess
the chances for a successful demonstration of KSL-W efficacy in future phase 3 studies utilizing QHT
evaluations, as a function of the sample size of these studies.
Similar ANCOVA models will be used for the per protocol (PP) population, and secondary mean scores (FAS
and PP), and the results from each model will be summarized.  
.
The second proof of efficacy endpoint will assess the reduction in plaque based on sub-scores from specific
regions of the upper jaw, lower jaw, buccal and lingual surface.
Descriptive and inferential summaries for FAS and PP will be presented for all scores by study arm overall, and
by study arm and evaluator. The summaries will include the mean, standard error, minimum, 25th percentile,
median, 75th percentile, and maximum, for baseline, Day 4, and change from baseline to Day 4. P-values will be
given for study arm comparisons but will not be adjusted for multiple comparisons.
Missing data will not be imputed. A missing QHT score w ill occur if there are insufficient numbers of surfaces
evaluable for QHT. A subject will be considered lost to follow-up if their Day 4 morning evaluation occurs more
than 24 hours after the scheduled time. ~
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APCG Plaque Regrowth
IND #77532; S-16-10
The Surgeon General
Department of the Army
3. 
Table of Contents, List of Tables, and List of Figures 
Table of Contents 
1. 
Title Page ............................................................................................................................... 1  
2. 
Synopsis ................................................................................................................................. 7
3. 
Table of Contents, List of Tables, and List of Figures ........................................................ 10
4. 
List of Abbreviations and Definitions of Terms .................................................................. 16
5. 
Introduction ......................................................................................................................... 18
5.1 Military Relevance ................................................................................................. 18
5.2 Rationale for Study ................................................................................................. 18
5.3 Background ............................................................................................................ 18
5.4 Name and Description of the Investigational Product ............................................ 20
5.5 Summary of Nonclinical and Clinical Trials .......................................................... 20
5.5.1 Nonclinical Studies.................................................................................... 20
5.5.2 Clinical Studies.......................................................................................... 21
5.5.3 Rationale for Four Day Proof of Concept Study…………………………22
5.6 Known and Potential Risks and Benefits to Human Subjects ................................ 23
5.6.1 Risks/Discomfort to Subjects and Precautions to Minimize Risk ............. 23
5.6.1.1 Local Reactions...................................................................... 23
5.6.1.2 Systemic Reactions ................................................................ 23
5 .6. 1 .3 
- Pregnancy .............................................................................. 23
5.6.1.4 Lactation ................................................................................ 24
~ 5.6.1.5 Allergic Reaction ................................................................... 24
5.6.1.6 Unknown Risks ...................................................................... 24
5.6.2 Alternatives to this IND Product or Study ................................................ 24
5.6.3 Intended Benefit for Subjects .................................................................... 24
5.6.4 Risks to the Study Personnel and the Environment ................................... 24
5.7 Route of Administration, Dosage Regimen, Treatment Period, and Justification .. 24
5.8 Compliance Statement ............................................................................................ 25
5.9 Study Population .................................................................................................... 25
5.10 Study Site ............................................................................................................... 25
6 
Trial Objectives and Purpose ............................................................................................... 26
6.1 Primary Objectives ................................................................................................. 26
6.2 Secondary Objective ............................................................................................... 26
7 
Design ......................................................................................................................... 27
Study Measurements (Endpoints) ........................................................................... 27
Overall Study Design ............................................................................................. 27
Measures Taken to Minimize/Avoid Bias .............................................................. 31
7.3.1 Randomization........................................................................................... 31
7.3.2 Blinding ..................................................................................................... 31
7.3.3 Unblinding ................................................................................................. 32
7.3.4 Calibration Exercise and Repeatability of Plaque Assesments ................. 32
7.4 Investigational Product ........................................................................................... 33
7.4.1 Investigational Product Packaging and Labeling ...................................... 33
7.4.2 Investigational Product Storage ................................................................. 34
7 .4. 3 
Investigational Product Preparation.  ......................................................... 34
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IND #77532; S-16-10 
The Surgeon General
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7.4.4 Investigational Product Accountability ..................................................... 35
7.5 Duration of Subject Participation ........................................................................... 36
7.6 Dose-adjustment Criteria ........................................................................................ 36
7.6.1 Safety Criteria for Dose Adjustment or Stopping Doses ........................... 36
7.6.2 Pharmacokinetic Criteria for Dose Adjustment or Stopping Doses .......... 36
7.6.3 Study Termination Criteria ........................................................................ 36
7.7 Trial Treatment Randomization Codes .................................................................. 36
7.8 Identification of Data to be Recorded on the Case Report Forms .......................... 37
8 
Selection and Withdrawal of Subjects ................................................................................. 38
8.1 Recruitment of Subjects ......................................................................................... 38
8.2 Eligibility Screening ............................................................................................... 38
8.3 Subject Inclusion Criteria ....................................................................................... 38
8.4 Subject Exclusion Criteria ...................................................................................... 39
8.5 Subject Withdrawal Criteria ................................................................................... 40
8.5.1 When and How to Withdraw Subjects ...................................................... 40
8.5.2 Data Collected for Withdrawn Subjects .................................................... 41
8.5.3 Replacement of Subjects ........................................................................... 41
8.5.4 Follow-up for Withdrawn Subjects ........................................................... 41
9 
Treatment of Subjects .......................................................................................................... 42
9.1 Study Visits ............................................................................................................ 42
9.1.1 Screening (Day -14+2) – Visit 1   ............................................................... 42
9.1.2 Supervised Treatment, Study Day 0 (Baseline) –Visit 2 .......................... 42
9.1.3 Unsupervised Treatment, Study Days 0, 1, 2, and 3 ................................. 43
9.1.4 Treatment, Study Day 4 – Visit 3 .............................................................. 43
9.4 Concomitant Medications ....................................................................................... 45
9.5 Procedures for Monitoring Subject Compliance .................................................... 45
10 Proof of Concept Assessments ......................................................................................................... 46
10.1 Supragingival Plaque .............................................................................................. 46
10.1.1 Primary Proof of Concept Measurement (Endpoint) ................................ 46
10. 1  .2 Secondary Proof of Concept Measurement (Endpoint)Error! Bookmark not defined.
10.2 Methods/Timing for Assessing, Recording, and Analyzing Proof of Concept
Measurements (Endpoints) ..................................................................................... 46
Safety Assessment ............................................................................................................... 47
Specification of Safety Measurements (Endpoints) ............................................... 47
11.1.1 Vital Signs ................................................................................................. 47
11.1.2 Physical Examination ................................................................................ 47
11.1.3 Intraoral Examination ................................................................................ 47
11.1.3.1 Oral Soft Tissue Examination ......................................................... 47
11 
.11 
.3 .2 Oral Hard Tissue Examination ........................................................ 47
IND Safety Reporting ............................................................................................. 48
11.2.1 Adverse Event or Suspected Adverse Reaction ........................................ 48
11.2.2 Solicited Adverse Event ............................................................................ 48
11.2.3 Serious Adverse Event or Serious Suspected Adverse Reaction .............. 48
11.2.4 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 49
11.2.5 Unanticipated Problems Involving Risks To Subjects Or Others ............. 49
11.3 Relationship to Investigational Product.................................................................. 50
11.3.1 Severity Assessment .................................................................................. 50
11.4 Recording Adverse Events ..................................................................................... 51
11 
11.1 
11.2 
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IND #77532; S-16-10 
The Surgeon General
Department of the Army
11.4.1 Methods/Timing for Assessing, Recording and Analyzing Safety
Measurements (Endpoints) ........................................................................ 51
11.4.2 Duration of Follow-Up of Subjects after Adverse Events ......................... 52
11.5 Reporting Adverse Events ...................................................................................... 52
11.5.1 Reporting Serious and Unexpected Adverse Events ................................. 52
11.5.1.1 Reporting to the Sponsor ....................................................... 53
11.5.1.2 Reporting to the IRB .............................................................. 54
11.5.1.3 Reporting to ORP HRPO ....................................................... 54
11.5.2 Reporting Additional Immediately Reportable Events to the Sponsor’s
Safety Office and IRB of Record and/or the USAMRMC ORP ............... 55
11.5.2.1 Pregnancy .............................................................................. 55
11.5.2.2 AE-related Withdrawal of Consent ........................................ 56
11.5.2.3 Pending Inspections/Issuance of Reports............................... 56
11.5.3 IND Annual Report to the FDA ................................................................ 56
11.5.4 Final Report ............................................................................................... 56
12 
Statistics............................................................................................................................... 58
12.1 Description of Statistical Methods ......................................................................... 58
12.1.1 Analysis Addressing the Primary Study Objective ................................... 59
12.1.2 Multiple Endpoints .................................................................................... 60
12.1.3 Analysis Addressing the Secondary Study Objective ............................... 60
12.1.4 Subgroup Analysis .................................................................................... 61
12.2 Planned Enrollment and Reason for Sample Size .................................................. 61
12.3 Level of Significance to be Used  ............................................................................ 61
12.4 Statistical Criteria for the Termination of the Trial ................................................ 61
12.5 Interim Analysis and Stopping Rules ..................................................................... 61
12.6 Accounting for Missing, Unused, and Spurious Data ............................................ 61
12.7 Procedures for Reporting Deviations from the Original Statistical Plan ................ 62
12.8 Selection of Subjects to be Included in Analyses ................................................... 62
13 
Direct Access to Source Data/Documents ........................................................................... 63
13.1 Study Monitoring ................................................................................................... 63
13.2 Audits and Inspections ........................................................................................... 63
13.3 Institutional Review Boardi ..................................................................................... 63
14 
Quality Control and Quality Assurance............................................................................... 65
15
.
Ethics ................................................................................................................................... 66
15.1 Ethics Review ......................................................................................................... 66
15.1.1 Review/Approval of Study Protocol ......................................................... 66
15.1.2 Protocol Modifications .............................................................................. 66
15.1.3 Protocol Deviation Procedures .................................................................. 67
15.2 Ethical Conduct of the Study .................................................................................. 67
15.2.1 Confidentiality ........................................................................................... 67
15.2.2 Compensation for Participation ................................................................. 68
15.2.3 Medical Care for Research-Related Injury ................................................ 68
15.3 Written Informed Consent ...................................................................................... 68
16 
Data Handling and Recordkeeping ...................................................................................... 70
16.1 Inspection of Records ............................................................................................. 70
16.2 Retention of Records .............................................................................................. 70
17 
Publication Policy ................................................................................................................ 72
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IND #77532; S-16-10 
The Surgeon General
Department of the Army
18 
List of References ................................................................................................................ 73
19 
Appendices .......................................................................................................................... 77
Appendix A. Study Personnel Roles and Responsibilities – Salus Research ........................................... 78
Appendix B. Quigely Hein Index and Calculation Example .................................................................... 79
Appendix C. Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials ................................................. 82
Appendix D. ePRO Electronic Diary Information .................................................................................... 83
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IND #77532; S-16-10
The Surgeon General
Department of the Army
List of Tables 
Table 1: 
Emergency Contact Information ........................................................................................... 5
Table 2: 
Abbreviations ...................................................................................................................... 16
Table 3: 
Study Design ....................................................................................................................... 28
Table 4: 
Study Events Schedule ........................................................................................................ 29
Table 5: 
Description of Investigational Product and Placebo ............................................................ 33
Table 6: 
Schedule for Unsupervised Chews: ..................................................................................... 44
Table 7: 
Quigley Hein-Turesky Plaque Index Scores ....................................................................... 46
Table 8: 
Severity Assessment Scale .................................................................................................. 51
Table 9: 
Study Contacts for Reporting Serious Adverse Events ....................................................... 53
Table 10: SAE Information to be Reported to the Sponsor's Safety Office ........................................ 54
Table 11: Compensation for Study Subjects ....................................................................................... 68
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List of Figures 
Figure 1  : Example Label for Blinded Product Vials  ............................Error! Bookmark not defined.
Figure 2: Representative Antiplaque Chewing Gum Vial Label: KSL-W .......................................... 33
Figure 3: Antiplaque Chewing Gum Vial Label: Placebo .................................................................. 34
Figure 4: Example Label for Used Product Bags................................................................................ 36
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4. 
List of Abbreviations and Definitions of Terms
The following abbreviations are used in this study protocol.
Table 2: 
Abbreviations 
Abbreviation 
Explanation 
AE
Adverse event
APCG
Antiplaque chewing 
ANCOVA
Analysis of Covarian
AR
Army Regulation
C 
Celsius
CPC 
Cetylpyridinium chlo
CFR
Code of Federal Regulation
cm
Centimeter
CSSD
Clinical Services Support Division, USAMMDA
DA
Department of the Army
4
DoD
Department of Defense
eCRF
Electronic Case Report Form
F 
Fahrenheit
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Processes
HA
Hydroxyapatite
HIPAA
Health Insurance Portability Accountability Act
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
mg
Milligram
mL
Milliliter
mm
Millimeter
OHT
Oral hard tissue
OST
Oral soft tissue
gum
ìce
oride
OHRP
Office for Human Research Protections, Department of Health and
Human Services
ORP, 
 of Research Protections, Human Research Protection Office
PIPlaque Index
POC 
Proof of Concept
PP 
Per Protocol Population
PT 
Preferred Term
PSSB 
Product Safety Surveillance Branch , CSSD, USAMMDA
QHT 
Quigley-Hein Turesky Plaque Index
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Abbreviation
SAE
SAP
SOC
SOP
TMD
TSG-DA
USAMMDA
USAMRMC
Explanation 
Serious adverse event
Statistical analysis plan
System organ class
Standard operating procedure
Temporomandibular disorder
The Surgeon General, Department of the Army
United States Army Medical Material Development Activity
United States Army Medical Research and Material Command
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5. 
Introduction 
5.1 
Military Relevance 
Dental caries and periodontal disease pose threats to operational readiness. The effects of poor
oral hygiene and diet of deployed soldiers can lead to the uncontrolled accumulation of oral
bacteria in dental plaque. Dental plaque is associated with caries, gingivitis, and other oral
infections. Dental emergencies requiring soldiers to seek treatment and resulting in lost duty time
occur at a rate of approximately 150 per 1000 deployed service members with an overwhelming
number of these (approximately 40%) due to caries and approximately 5% due to periodontal
diseases such as acute gingivitis (  Allen and Smith-1992; Chaffin et al-2001; Deutsch and
Simecek-1996; Dunn et al-2004; Mahoney and Coombs-2000; Moss-2002). There is a need for a
product that is capable of arresting and preventing dental plaque build-up and augmenting and
replenishing host defense, and is suitable for inclusion in a health package.
5.2 
Rationale for Study 
*
The emergence of resistance to conventional antibiotics observed in oral pathogens strongly
suggests the need to develop new and safe antimicrobial agents for the treatment and/or
prevention of oral infections (Davies-1994; Koeleman et al-2001; Leng et al-1997; Lynch and
Zhanel-2005; Okamoto et al-2001; Schutze et al-1994; Stein-2005). The use of a novel
antimicrobial peptide (KSL-W) in a chewing gum formulation to help control plaque growth is
the primary goal of this capability development. KSL-W exhibits selective bactericidal activity
against cariogenic bacteria (Streptococcus mutans, S. sobrinus, and Lactobacillus acidophilus)
and early colonizers (Actinomyces naeslundii) (Na et al-2007) but shows little effect on some of
the members ofthe normal oral flora ( S.  mitis and S.  oralis) (unpublished data). Furthermore, per
in vitro data, the peptide is degraded in gastrointestinal environments; therefore, suggesting it has
no deleterious effect on the resident intestinal flora (unpublished data). The use of chewing gum
formulations has additional beneficial effects on oral health by stimulating saliva flow and
thereby promoting remineralization of tooth enamel. The peptide exhibits significant adsorption
to hydroxyapatite (HA) (tooth-like material), an important characteristic for an antiplaque agent
(Faraj et al-2007; Na et al-2007).
The most common methods for removing supragingival plaque are daily tooth brushing, flossing
and/or use of antimicrobial mouthwash ( Haps et al-2008). Inability for daily practice of good
oral hygiene due to poverty, military deployment or general lack of compliance, are further
reasons for the development of a chewing gum that would assist with daily oral care and
reduction of oral plaque.
5.3 ~ Background ~
The discovery of a large number of naturally occurring invertebrate and vertebrate antimicrobial
peptides has resulted in the emergence of alternative classes of peptide antimicrobials that
exhibit selectivity for prokaryotes and minimize problems of inducing microbial resistance
(Boman-1998; Gilmore et al-2009; Hancock and Chapple-1999; Hancock and Lehrer-1998;
Hancock and Sahl-2006; Nizet et al-2001; Zasloff-2002; Zhang and Falla-2009). In general,
antimicrobial peptides are cationic amphiphilic molecules that can be categorized into different
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structural groupings (Hancock-1997; Hancock et al-1995; Hancock and Lehrer-1998; Henderson
et al-1998):
• Cysteine-rich, amphiphilic β-sheet peptides (α- and β-defensins, protegrins, and
tachyplesins) 
• Cysteine-disulfide ring peptides with or without amphiphilic tails (bactenecin,
ranalexin, and brevinins)
• Amphiphilic α-helical peptides without cysteine (magainins and cecropins)
• Linear peptides (Bac 5, Bac 7, PR39, and indolicidin) with 1or 2 predominant amino
acids (proline or tryptophan)
While more potent antibiotics exist, antimicrobial peptides exhibit pronounced cidal activity
against some significant antibiotic-resistant bacterial pathogens found in medical treatment *
facilities (eg Pseudomonas aeruginosa , Acinetobacter baumannii, methicillin-resistant
Staphylococcus aureus, and vancomycin-resistant Enterococci). Bacterial killing by
antimicrobial peptides is thought to begin when the positively charged peptides interact with the
negatively charged components of microbial membranes including lipopolysaccharides in gram-
negative bacteria and teichoic acid in gram-positive bacteria as a result of electrostatic
interactions. The bound peptides then cause membrane destabilization through pore/channel 
formation or by exerting a detergent-like action. This destabilization is followed by subsequent
changes of membrane permeability and the loss of membrane integrity leading to cell death
(Hancock-1997; Hancock and Chapple-1999; Hancock and Lehrer-1998; Koczulla and Bals-
2003; Patrzykat and Douglas-2005; Yount and Yeaman-2005; Zasloff-2002).
In other cases, peptides can enter the cell without damaging the membranes (ie the non-
membrane effects of cationic peptides). Once within the cell, they may disturb intracellular
bacterial functions such as DNA and/or protein synthesis or interfere with vital housekeeping
cell functions such as chaperone-assisted protein folding (Otvos et al-2000; Patrzykat and
Douglas-2005; Patrzykat et al-2002). Further, some of these peptides also possess other biologic
activities that can impact cell proliferation, immune induction, cytokine release, chemotaxis, and
tissue repair (Bateman et al-1991; Elsbach-2003; Koczulla and Bals-2003; Koczulla et al-2003).
Acquired resistance toward antimicrobial peptides is uncommon (Boman-1998; Hancock and
Chapple-1999; Hancock and Lehrer-1998; Koczulla and Bals-2003; Nizet et al-2001; Yeaman
and Yount-2003; Zasloff-2002), though some bacterial strains are naturally resistant to certain
antimicrobial peptides (Peschel et al-1999). Resistance mechanisms, if developed, may include:
reductions in transmembrane potential with a concomitant decrease in the attraction of cationic
peptide antimicrobials (Yeaman et al-1998), sequestration of peptide antimicrobials by cell
surface-associated anionic exopolysaccharides (Friedrich et al-1999), microbial degradation of
peptides (Guina et al-2000), modification of the cytoplasmic membrane by a decrease in anionic
phospholipid levels (Dorrer and Teuber-1977), and efflux of peptide antimicrobials (Bengoechea
and Skurnik-2000). However, the fact that naturally occurring antimicrobial peptides have been
conserved and remained functional throughout evolution is a strong testament to their efficacy
and importance as effectors of innate defense (Peschel et al-1999; Yount et al-2006; Yount and
Yeaman-2005).
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Many synthetic analogs have been created in attempts to improve the antimicrobial activity of
some of the naturally occurring antibacterial peptides. Some such as Dhvar 5, an analog of
histatin 5, one of the antimicrobial histatin peptides derived from saliva (Helmerhorst et al-1999;
Mickels et al-2001) and IB-367, an analog of protegrins, the antimicrobial peptides that were
isolated from porcine leukocytes, are more effective in inhibiting bacterial growth and are easier
to synthesize than their native counterparts.
5.4 
Name and Description of the Investigational Product 
The drug product, Antiplaque Chewing Gum (APCG), contains the active ingredient, KSL-W
which is a cationic antimicrobial decapeptide. (KSL-W is C68H10631810). The KSL-W dose
formulation of the APCG being used in this clinical trial is 30 mg (active). 
. 4.
Other components of the APCG are cetylpyridinium chloride (CPC) as an additive, isomalt as a
bulk sweetener, peppermint powder for flavoring, sucralose as an intense sweetener, colloidal
silicon dioxide as a flow enhancer, magnesium stearate as a process aid, and the proprietary gum
base formulation produced by Fertin Pharma A/S.
KSL-W is synthesized by standard solid-phase procedures using 9-fluorenylmethoxycarbony1
(Fmoc) chemistry on a semi-automatic peptide synthesizer. The synthetic peptides are purified
by reverse-phase high-performance liquid chromatography using a reverse phase C18 media. The
bulk drug substance is stored in lyophilized form at -20°C until formulation of APCG (KSL-W
IB 2016).
Refer to section 7.4 for additional information. ~ ~
 
5.5 
Summary of Nonclinical and Clinical Trials 
5.5.1 
Nonclinical Studies 
~
The following studies, with study numbers in parentheses, were conducted by or sub-contracted
through WIL Research Laboratories, LLC to evaluate the toxicity potential of KSL-W, when co-
administered with CPC in non-clinical laboratory studies .  The ratio of 8 :1(KSL-W :CPC) was
selected for the animal studies because it demonstrated the most effective bactericidal activity in
pre-formulation and bactericidal experiments. Where appropriate, the studies included separate
KSL-W and CPC groups.
• A 5-Day Repeated-Dose Oral (Gavage) Toxicity Range Finding Study of in Rats
(WIL-485012) 
, t
• A 28-Day Oral (Gavage) Toxicity Study in Albino Rats (WIL-485005)
• A 5-Day Oral (Gavage) Repeated Dose Study in Beagle Dogs (WIL-485003)
• A 28-Day Oral (Gavage) Toxicity Study in Beagle Dogs (WIL-485006)
• A 7-Day Repeated-Dose Gingival Mucosal Tolerance Study in Beagle Dogs (WIL-
485016)
• Genetic toxicology testing (WIL-485007)
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- Ames Test (WIL-485007-l) 
- Mouse Lymphoma Assay (WIL-485007-2) 
- Chromosome Aberration (CA) Assay (WIL-485007-3) 
- Micronucleus Test (WIL-485007-4)
• Immunogenicity Testing (WIL-485008)
• KSL-W Bioanalytical method validation (WIL-485009) 
• CPC Bioanalytical method validation (WIL-485010)
• Method validation for determination of KSL-W and CPC in aqueous formulations
(WIL-485011 )
F.
The highlights from these studies are as follows: I~A
• KSL-W, when tested in the presence of CPC at a ratio of 8:1 
 was not genotoxic in
four different tests (Ames test, mouse lymphoma assay, CA, and micronucleus test).
• KSL-W was found not to be immunogenic. Efforts at developing an assay for anti-
KSL-W antibodies were eventually ceased.  .
• KSL-W was found to degrade very rapidly even in chilled plasma; as a result, efforts
at developing a bioassay for the presence of KSL-W in plasma were eventually
dropped. As a decapeptide, it can be anticipated that KSL-W would be rapidly
degraded by natural enteric digestion. When administered in a slow release buccal
preparation, such as a chewing gum, it can be anticipated that the systemic exposure
to KSL-W would be very low, if not non-existent.
• No gross evidence of irritation was observed when KSL-W and CPC were applied to
the gingival tissue ofbeagle dogs 
'.
• In a 28-day rat study, the No Observed Adverse Effect Level (NOAEL) was 32/6.4
mg/kg/day (KSL-W/CPC), while at 320/64 mg/kg/day (KSL-W/CPC) potential
adverse effects were characterized by rales, slightly decreased body weight gain and
small changes in clinical pathology. In a 28-day dog study, the NOAEL was found to
be 60/7.5 mg/kg/day (KSL-W/CPC), while effects at 200/25 mg/kg/day (KSL-
W/CPC) were characterized by excessive salivation, abnormal excreta, slightly lower
body weight gain, and minor non-adverse clinical pathology findings. Given that
there was no systemic exposure to KSL-W in these studies, while there was proven
systemic exposure to CPC, it can be assumed that all the relatively minor findings in
the mammalian toxicity studies were due to CPC and not to the KSL-W.
In general, the studies conducted thus far indicate that KSL-W, when administered in the
presence of CPC, is not genotoxic, is not antigenic, does not cause localized buccal irritation and
is not systemically observed to any appreciable extent.
5.5.2 Clinical Studies 
Oral Health Research Institute Indiana University School of Dentistry in Indianapolis, Indiana
conducted the first APCG trial in humans entitled: “A Double-Blind, Randomized, Controlled,
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Dose Escalation Clinical Trial of an Antiplaque Chewing Gum - Phase 1Safety and Tolerability
and Phase 2a Safety, Tolerability and Proof of Concept in a Gingivitis Population.” The study
was a 2-part trial with 9 dosing cohorts in Phase 1(2- 100 mg) and 7 dosing cohorts in Phase 2a
(4 -75 mg). Dosing began with 2 mg and increased sequentially. The safety of each dose was
evaluated prior to administering the next higher dose. Subjects in the Phase 1portion of the study
received a single dose of the study medication. Subjects in the Phase 2a portion of the study
received multiple oral doses over 28 days .  
..
The proof of concept analyses in the Phase 2a portion of the study indicate APCG efficacy
against plaque formation after 2-4 weeks of active treatment. Results regarding gingivitis were
not as consistent across the active treatment doses.
No deaths or other serious adverse events (SAEs) occurred in either the placebo- controlled,
single dose escalating (2,4,6,10,20, 30, 50, 75, or 100 mg) phase or the placebo- controlled,
28 day, multiple-dose (4, 6, 10, 20, 30, 50, or 75 mg) phase ofthe study.  
-
All 71subjects enrolled in the escalating, single-dose phase completed the study. A total of 10
adverse events (AEs) were reported: [6 in the APCG group (abdominal discomfort, dyspepsia,
mouth swelling, increase in blood pressure, headache and throat irritation) and 4 in the placebo
group (mouth ulceration, muscle strain, oral mucosal erythema, musculoskeletal stiffness). All
AEs in both groups were considered mild. 
-
Sixty-four subjects were enrolled in the 28-day, multiple-dose Phase 2a study and 58 subjects
completed the study per protocol. For the active treatment group, 5 of 45 subjects who received
at least one of the active treatment doses withdrew or were withdrawn from the study. The
reasons for withdrawal of these 5 subjects were :  lost to follow-up ( 1 ), protocol violation (1-
antibiotic use), and subjects’ request [change ofjob (1), need to be out of town 
 (1) and religious
purposes (1)]. For the placebo group, 1of the 19 subjects receiving placebo treatment withdrew, 
due to a family emergency.  
./
There were a total of 54 AEs in the multiple-dose study phase of which 45 were considered mild,
9 were considered moderate, and none were considered severe. AEs reported once for the lower-
dose active treatment groups (4 mg, 6 mg, 10 mg, 20 mg, 30 mg) included: abdominal
discomfort, dyspepsia, flatulence, food poisoning, gingival ulceration, mouth hemorrhage, mouth
ulceration, oral pain, ear infection, sinusitis, mouth injury, muscle strain, thermal burn, increase
in blood glucose, glucose in urine, headache and oropharyngeal pain. In addition, oral mucosal
erythema and nasopharyngitis were reported twice for the lower-dose active treatment groups.
The higher dose treatment groups (50 mg, 75 mg) had 3 reports of tongue coated with 50 mg,
and 2 reports of tooth discoloration with both the 50 and the 75 mg doses. The 50 mg dose also
had 2 reports of dysgeuia, 
,  ,
1report of food poisoning and 1report of arthropod bite. The 75 mg dose had 3 reports of
nasopharyngitis and dysgeuia as well as 1report of abdominal discomfort, coating in mouth,
tongue pigmentation, ageusia and throat tightness.
From a review of all the AEs reported in Phase 2a, the following types of AEs were found to be
possibly, probably or definitely related to study drug: abdominal discomfort, tongue coated,
tooth discoloration, flatulence, dysgeusia, tongue pigmentation, throat tightness and ageusia. All
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of these AEs were mild in intensity with the exception of 1incidence of tongue coated which
was deemed moderate in intensity.
The clinical findings of altered taste perception, signs of teeth staining and brown coating on the
dorsum of the tongue reported at the higher doses of 50 mg and 75 mg are mainly of esthetic
concern and are commonly observed with the extended use of currently marketed antimicrobial
mouth rinses and are not considered to be a health risk.  
. 4
There were no study-related laboratory findings, notable vital signs, or physical examination
findings, or other observations that were considered to be of clinically signification in either the
single-dose or multiple-dose phases of the study (Clinical Study Report #S-11-14, Listing 19).
5.5.3 
Rationale for Four Day Proof of Concept Study --7'IA.
The primary objectives for the Phase 1/2a study were to evaluate the safety and tolerance to the
active gum. In the Phase 2a study, the proof of concept efficacy assessment for plaque
accumulation and changes of gingivitis conditions were included and the assessments occurred
on Days 0 (baseline), 14, 28 and 34 (follow-up). The rationale for conducting a 4-day treatment
study is to determine if the active gum (vs. placebo gum) can reduce plaque regrowth during
early time points (4 days). 44
5.6 
Known and Potential Risks and Benefits to Human Subjects 
5.6.1 
Risks/Discomfort to Subjects and Precautions to Minimize Risk
Outlined below are anticipated and unexpected adverse reactions, and a brief description of
procedures to ameliorate risks and symptoms. All known risks and precautions described here
are explained in detail in the informed consent.  
.
5.6.1.1 Local Reactions 
Subjects participating in this study are at risk for local reactions such as: coated tongue, tooth
discoloration, dysgeusia, tongue pigmentation, throat tightness and ageusia. Subjects with known
TMD will not be enrolled in the study, and subjects will receive oral examinations throughout
the study. In the first Phase 1/2a trial, altered taste perception, brown coating on dorsum of the
tongue and teeth staining were noted at the higher doses of 50 mg and 75 mg.
5.6.1.2 Systemic Reactions 
Based on review of the nonclinical data, no direct systemic AEs from administration of the study
drug are expected. Review of the clinical data indicates that subjects participating in this study
may experience: abdominal discomfort and flatulence. Subjects will be asked at each visit to
report any new symptoms or concomitant medications used.
5.6.1.3 Pregnancy ~
Risks to unborn babies are unknown at this time. Pregnant females will be excluded from this
study. Female subjects should not become pregnant for at least 3 months after receiving the last
dose of investigational product. Male subjects should not have unprotected sex for at least 3
months after receiving the last dose of investigational product.
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5.6.1.4 Lactation 
Risks to nursing infants are unknown at this time; breastfeeding females will be excluded from
this study. Lactating females must agree not to breast feed while on the study and for 3 months
after the last dose of investigational product.
5.6.1.5 
Allergic Reaction 
As with any Investigational New Drug (IND), product administration, no matter what
precautions are taken, there is always the risk of a serious, or even life-threatening, allergic
reaction. Medical emergency equipment is available on site at Salus Research to handle
emergencies, such as anaphylaxis, angioedema, bronchospasm, and laryngospasm.
5.6.1.6 Unknown Risks 
-
Furthermore, as with all research there is the remote possibility of risks that are unknown or that
cannot be foreseen based on current information. 1
5.6.2 
Alternatives to this INDProduct or Study
The alternative to using this IND Product is to not participate in the study and for the subject to
practice normal oral hygiene procedures. 
5.6.3 
Intended Benefit for Subjects 
There is no intended benefit to the subjects in this research study; however, subjects will receive
oral soft tissue (OST) and oral hard tissue (OHT) examinations as part of the periodontal
examination and all subjects will have their teeth polished following randomization.
5.6.4 
Risks to the Study Personnel and the Environment 
The principal risk in the clinical setting is similar to those in any medical or dental clinic.
Adherence to standard operating procedures (SOPs) for working with dental patients and
universal precautions will reduce the risk of exposure to blood.
There are no known risks to the environment other than those associated with the generation of
biohazardous waste attendant to dental procedures in humans. All biohazardous waste will be
disposed of as stipulated by local, state, and Federal regulations and in accordance with study
site SOPs.
5.7 í Route of Administration, Dosage Regimen, Treatment Period, and Justification 
A total of 26 subjects will participate in the study in order to obtain 24 completers. Thirteen (13)
subjects will receive KSL-W and 13 subjects will receive placebo in accordance to the
randomization schedule. Subjects will receive 30 mg multiple oral doses of KSL-W chewing
gum or placebo chewing gum in tablet form over the course of 4 days. The 30 mg dose was
selected based on the “Day 14 change in plaque index” data from the “Phase1/2a Dose
Escalation Study of an Antiplaque Chewing Gum Study.” Each dose consists of 1 piece of gum
in tablet form. Subjects who drop out of the study will not be replaced.
Subjects will receive the first dose of chewing gum under supervision in the clinic. The
remaining 11 doses will be self-administered and unsupervised. These unsupervised gum chews
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should occur preferably after a meal or at 4-6 hour intervals 3 times a day for a total of 4 days.
The gum will be chewed for 20 minutes and chewing will be balanced as equally as possible
between both sides of the mouth. The maximum dose of KSL-W in a 24 hour period is three 30
mg chewing gum tablets (90 mg total). Subjects will be instructed to use the same chewing
procedure for each self-administered, unsupervised chew.
5.8 
Compliance Statement 
The study will be conducted according to the protocol and in compliance with International
Conference on Harmonization (ICH) Good Clinical Practice (GCP), Belmont Principles, and
other applicable regulatory and Department of Defense (DoD) requirements. All identified study
personnel will be trained to perform their roles and will carry out their responsibilities in
accordance with ICH GCP guideline and clinical site SOPs. Roles and responsibilities of study
staff are presented in Appendix A.
5.9 
Study Population 
It is anticipated that approximately 35 subjects will be screened for study participation. The
study population will be comprised of 26 males and females (on contraceptives or
postmenopausal) between the ages of 18 and 64 (inclusive). Subjects will be generally healthy,
without organ system diseases. Refer to Section 12.2 for a justification of the sample size.
5.10 
Study Site
The study will be conducted at Salus Research located at 1220 Medical Park Drive, Bld#4, Fort
Wayne, IN 46825. The Fort Wayne, Indiana Metropolitan Statistical Area (MSA) is a federally
designated metropolitan area consisting of three counties in northeastern Indiana (i.e. Allen,
Wells and Whitley counties), anchored by the city of Fort Wayne. As of the 2010 census, the
MSA had a population of 416,257. The Fort Wayne metropolitan area is part of the Northern
Indiana region where approximately 2.2 million people live (Fort Wayne 2016). This region is
considered part of the Great Lakes Megalopolis with an estimated population of 59 million
people. Study subjects will be recruited from the Salus Research Categorized Database.
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6 
Trial Objectives and Purpose
6.1 
Primary Objectives 
The primary objective of this study is:
• to assess the safety and tolerability of KSL-W (30 mg dose) delivered in a chewing gum
formulation compared to a placebo formulation.
:pt (efficacy) of:  
6.2 
Secondary Objectives 
The secondary objectives are to assess the proof of conce
• KSL-W (30 mg dose) delivered in a chewing gum formulation compared to a placebo
formulation in the change in plaque regrowth from baseline based on the QHT
• KSL-W (30 mg) in change in plaque regrowth based on sub-scores from specific regions
of the upper jaw, lower jaw, buccal and lingual surface based on the QHT.
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7 Trial Design 
7.1
Study Measurements (Endpoints) 
The primary endpoint is:
• Incidence of AEs including change from baseline in vital signs
The secondary endpoints are:
• Change from baseline in QHT (Day 4 QHT minus baseline QHT)
• QHT based on sub-scores from designated regions of the mouth (upper jaw, lower jaw,
buccal and lingual surface
it.
7.2 
Overall Study Design
This is a Phase 2, double-blind, two-armed, placebo-controlled, randomized, single-center,
multiple dose study to evaluate the safety and proof of concept of KSL-W administered as a
chewing gum formulation (APCG) 3 times per day over 4 treatment days. The study will
evaluate the ability of APCG to reduce existing supragingival plaque. Plaque will be assessed
using the QHT (Turesky et al- 1970). 
A
The OST and OHT will be examined. Changes from baseline, such as soft tissue erythema,
ulceration and sloughing, will be noted and assessments will be made by the principal
investigator or designee as to whether these events are related to treatment with APCG.
The study design is illustrated in Table 3 and is detailed below. The Study Event Schedule is
presentedl in Table 4l.
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Table 3: 
Study Design 
Treatment 
Dosage * 
# of Chews
Day
KSL-W / Placebo
Placebo  per
per Day **
Day 0 
30 mg / 0 mg 
3
Day 1  
30 mg / 0 mg 
3
Day 2 
30 mg / 0 mg 
3 
-
Day 3 
30 mg / 0 mg 
3
* Subjects randomized to either KSL -W or placebo
**Each dose taken preferably after each meal
(breakfast, lunch and dinner) or every 4-6 hours for
a maximum of 3 chews per day
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IND #77532; S-16-10
Table 4: Study Events Schedule 
Study Visit/Day
Visit 1 
Visit 2 
Visit 3
Screening 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4
(-16 to -1)
General Procedures 
Written Informed Consent/HIPAA 
X
Evaluation Inclusion/ Exclusion Criteria 
X 
X
Demographic Data 
X
Medical History 
X
Vital Signs (BP, HR, RR Temperature) 
X 
X 
X
Physical Exam 
X 
Xa
Urine Drug Screen 
X
Urine Pregnancy Test 
Xb 
Xb
Periodontal Examination 
Xc
Intraoral Exam (OHT, OST) 
X 
X 
X
Oral Hygiene Check 
Xd 
Xd 
Xd
Randomization (1:1)X
 
Plaque Index Score 
X 
Xe 
X
Teeth PolishingX
 
Dispense Study Drug for Supervised andX
 
Unsupervised Use
f
Study Drug Administration 
Xg 
Xg 
Xg 
Xg
Collect Used Study Drug 
Xh 
Xh
Electronic Diary Information System 
Xi 
Xi 
Xi 
Xi
Adverse Event Reporting 
X 
X
Concomitant Medications 
X 
X 
X
Study DischargeX
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IND #77532; S-16-10
BP-blood pressure, HIPAA-Health Insurance Portability and Accountability Act, HR-heart rate, RR-respiration rate, OHT-oral hard tissue, OST – oral soft tissue,
QHT-Quigley-Hein Turesky Plaque Index
Brief symptom oriented physical exam (based upon reported adverse events)
b Pregnancy test for females of childbearing potential
c Includes determination of number of teeth, score-able surfaces and pocket depths around teeth
d Confirm subject has refrained from all oral hygiene procedures (flossing, brushing of teeth, mouth wash rinse) for 12 to 16 hours prior to Screening and Day 0
(Baseline). On Day 4, confirm subject has refrained from all oral hygiene procedures since chewing their last dose on Day 3
Measured after randomization, but before teeth polishing
f Subject will be allocated 14 tablets of gum for the 4 day study period 
.I--..-~  
g  Subject will chew one tablet of gum for 20 minutes preferably after a meal (breakfast, lunch, dinner) or every 4 to 6 hours for a maximum of 3 chews per day.
Chewing will be balanced as equally as possible between both sides of the mouth. The first tablet will be given under supervision in the clinic. Oral hygiene is not
allowed at any time during the 4 day treatment. Oral hygiene cannot resume until after the determination of the Plaque Index Score on Day 4
h After each chewing period, the gum is disposed of in individual labeled bags. Subject records time/date of gum disposal on each bag. Subject will return all
used/unused bags to the site on Day 4.
i Subject records all start /stop times of gum chewing via the internet using the electronic diary information system (ePRO).
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IND #77532; S-16-10
The Surgeon General
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7.3 
Measures Taken to Minimize/Avoid Bias
7 .3.1 
Randomization 
,~
The random assignment of subjects to the 2 study arms will be 1:1.There will be 2 evaluators at
the study site to assess the QHT scores, and the evaluator assigned to each subject will remain
with that subject throughout the study. The randomization schedule will be generated by an
independent biostatistician not involved in any way with the conduct and analysis of the study.
The randomization schedule will be provided to designated study personnel for preparation of
the blinded product and for emergency unblinding for safety reasons if necessary.
7.3.2 
Blinding 
-.-I--
For this double-blind study, the investigator, study biostatistician, staff not involved in product 
preparation and study subjects will be blinded to the treatment assignments throughout the
duration of the study. A study specific procedure explaining the blinding and unblinding plan
will be developed and maintained by appropriate study team members.
Salus Research will receive the investigational gum product directly from Fertin Pharma.
Authorized product preparation staff at Salus Research will repackage the product into blinded
individual opaque plastic vials in accordance with the randomization schedule. The product
preparation staff will have no other responsibilities or involvement in the study. No other
personnel are permitted in the preparation room during preparation of the blinded product.
The product preparation staff will receive a randomization schedule from the unblinded
independent biostatistician. Each unique subject identification number will be assigned a
treatment and this list will be used by the product preparation staff to prepare the blinded
product. The blinded product will be labeled as shown in Figure 1. Salus Research will be
provided with individually sealed envelopes identifying each subject’s specific treatment
assignment. Salus Research will store these envelopes in a secure location accessible to the
principal investigator in the event that the blind needs to be broken. The randomization,
repackaging and labeling of the study product will be performed as per approved procedures in
place at Salus Research.
Figure 1: Example Label for Blinded  Product Vials 
Subject ID Number:  
'.
Directions for Subject: Chew 1tablet for 20 minutes balanced equally on
both sides of the mouth. Each dose should be taken preferably after each
meal (breakfast, lunch and dinner) or every 4-6 hours for a maximum of 3
chews per day.  
.-'
Storage Instructions: Material to be stored at ambient room temperature, out
of direct sunlight. Do not expose to extreme heat or cold.
Caution: New Drug – Limited by Federal (or U.S) law for investigational
use.
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IND #77532; S-16-10
The Surgeon General
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Distributed by: Salus Research
Phenylketonurics: Contains Phenylalanine
KEEP  OUT OF REACH OF CHILDREN 
Dr. Jeffrey Milleman, Principal Investigator Study S-16-10
Emergency Phone #: 260 -413-7777
Non-emergency Phone #: 260-755-1099
7.3.3 Unblinding 
Emergency unblinding of a subject should only be done in the case of a medical emergency, or in
the event of a serious medical condition, when knowledge of the investigational study product is
essential for the clinical management or welfare of the subject. In such an emergency situation,
the Principal Investigator may unblind a subject’s treatment without first discussing with the
Sponsor’s Safety Physician. While it is recommended to discuss with the Sponsor’s safety
physician prior to unblinding, the safety of the subject is the highest priority. The Sponsor will
be notified by the Principal Investigator when emergency unblinding has occurred. Only the
Principal Investigator or Sponsor can authorize emergency unblinding. The reason for unblinding
should be clearly specified in the source documentation. ~
The individual treatment codes for each subject will be given to Salus Research in sealed
envelopes. Each individual envelope will contain the subject identification number and their
specific treatment assignment. These envelopes will be stored in a secure location accessible to
the Principal Investigator in the event that the blind needs to be broken for emergency unblinding
or individual emergency safety unblinding. 
Contact Information for Emergency Unbli
Responsible person: ..A  
• Salus Research: Dr. Jeffrey Milleman,
Phone: 260-755-1099
Army: Carrie Laurencot, PhD Acting-Director, Clinical Services Support Division
Phone: 301 -619-0317 /
7 .3 .4 Calibration Exercise and Repeatability of Plaque Assessments by Evaluator 
The dental examiners (evaluators) must have completed the standard calibration exercise and
repeatability procedure on the QHT prior to the conduct of this study. The statistical report
containing the results of this exercise and procedure will be written prior to conduct of the study
and maintained on file as documentation that all evaluators can conduct the QHT scoring in a
consistent manner and any differences between evaluators would be negligible.
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IND #77532; S-16-10
The Surgeon General
Department of the Army
Figure 3: Representative Bulk Antiplaque Chewing Gum Vial Label: Placebo 
Antiplaque Chewing Gum (APCG), Placebo, 20 pcs
Lot Number: 3925-267
Contains: 0 mg KSL-W 
Storage: 2-8°C
Caution: New Drug – Limited by Federal (or United States) law to investigational use.
MFG Date: 19Nov2012
Manufactured by: Fertin Pharma, Vejle, Denmark
7.4.2 
Investigational Product Storage 
The study drug is manufactured in accordance with Good Manufacturing Practices (GMP) by
Fertin Pharma. Fertin Pharma will ship the product to Salus Research under refrigeration (2-8°C
or 35.6 - 46.4°F) in opaque plastic vials (Activ-Vial®). At the site, the gum will be stored at 2-
8°C or 35.6 - 46.4°F). A Temperature log will be maintained at the site and checked during site
visits by the sponsor’s clinical study monitor.
The product may be removed from the temperature-controlled environment and maintained at
room temperature conditions, defined as the prevailing temperature in a working area
(approximately 20-25°C or 68-77°F), during certain periods during the study: preparation of dose
administration at the clinical site, and packaging and storage for unsupervised doses while in the
subjects’ possession (unsupervised chews). - ~
7.4.3 *f Investigational Product Preparation 
Each of the APCG and placebo products will be provided as a ready-to-use piece of gum from
the manufacturer. The product will be repackaged into a new vial for each subject. Each blinded
vial will contain 14 pieces of gum, either active or placebo that will be prepared according to the
randomization schedule in order to maintain the double-blind nature of the study. Preparation of
the subject’s vials with their assigned doses will be performed ahead of time at room temperature
and then returned to refrigeration (2-8°C or 35.6 - 46.4°F) for storage until dispensed to the
subject.  
.
Approximately one (1) 
 hour prior to dispensing, the subject’s vial of blinded study product will
be removed from refrigerated storage to allow time for the product to come to room temperature.
For the first chew, the assigned study product will be dispensed to the subjects by designated
study staff for supervised use at the site. For unsupervised use, enough investigational product
will be dispensed to each subject for self-administration during the 4 day study period. Subjects
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IND #77532; S-16-10
The Surgeon General
Department of the Army
will be given 2 additional chewing gum tablets, to use if the product is inadvertently lost or
misplaced. If the subject needs additional product (ie. more than 2 tablets) they will need to
contact Salus Research. The subjects will be instructed on proper storage of the study product.
7.4.4 
Investigational Product Accountability 
The sponsor’s representative is responsible for distributing the investigational product to the
study site and has ultimate responsibility for accountability of study drug. The sponsor’s
representative has delegated the drug accountability responsibility for this product to the
Principal Investigator. The Principal Investigator may delegate in writing this responsibility to
another individual, but the Principal Investigator is ultimately responsible for the investigational
product and its proper storage from the time the investigational product arrives at the study site
until it is returned to the sponsor’s representative or designee or is destroyed, as directed by the
sponsor’s representative. Drug accountability will be conducted once the site receives the
investigational product. The Principal Investigator or designee, will maintain logs of storage,
drug accountability by subject, including dispensed product, and product remaining before final
disposition within Salus Research. In the event of a temperature excursion, the Principal
Investigator should contact the Sponsor Representative, who will make the determination of the
product’s integrity and use.
Used investigational product will be collected by study staff during the supervised time (first
chew) at the site on Day 0. For each of the unsupervised doses, subjects will be instructed to
collect the used product in individually labeled bags (Figure 4) and return them to the site at
Visit 3 (Day 4). A total of 11 bags of used investigational product will be returned at Visit 3. If a
subject forgets to return the used product, they will be asked to make arrangements to return the
used product bags to the site. Subjects will also be instructed to return any unused product
resulting from missed doses. Unreturned used and unused product (missed dose) will be
considered protocol deviations.
Used product and unused product will be verified by the sponsor’s study monitor and then
destroyed in accordance with site SOPs for destruction of study drug as directed by the sponsor’s
representative and as stipulated by institutional, state, and Federal regulations. 
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IND #77532; S-16-10
The Surgeon General
Department of the Army
Figure 4: Example Label for Used Product Bags
Subject Number:
Date and Time of Chew:
Caution: New Drug - Limited by Federal (or United States) law to investigational use.
Distributed by Salus Research
Phenylketonurics: Contains Phenylalanine
KEEP OUT OF REACH OF CHILDREN
Dr. Jeffrey Milleman, Principal Investigator Study S
Emergency Phone #: 260-413-7777
Non-Emergency Phone #: 260-755-1099
-16-10
7.5 
Duration of Subject Participation 
Each subject will participate for up to 21days; screening, 4 days of treatment followed by 1day
for dental evaluation and end of study activities.
7.6 
Dose-adjustment Criteria
For this study, dose adjustments will not be made other than to discontinue the use of study
medication ifthe situation warrants.  
i .*/1 . 0.
7.6.1 
Safety Criteria for Dose Adjustment or Stopping Doses
This section is not applicable.
7.6.2 
Pharmacokinetic Criteria for Dose Adjustment or Stopping Doses 
This section is not applicable.
7.6.3
Study Termination Criteria 
The Principal Investigator, research monitor, sponsor’s representative, the IRB and/or the United
States Army Medical Research and Material Command (USAMRMC) Office of Research
Protections, Human Research Protection Office or the FDA may stop or suspend the use of this
product at any time.
7.7 
Trial Treatment Randomization Codes
Subject ID numbers will be assigned in ascending numerical order as each subject signs the
consent form. The Subject ID numbers will be assigned from one centrally located pre-printed
list.
Each subject who meets the inclusion and exclusion criteria and is deemed fully eligible will be
assigned a unique randomization number. The randomization numbers will be on the
randomization list, generated by the independent unblinded  biostatistician. The randomization
numbers will be assigned to subjects sequentially as they are randomized at Visit 2.
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IND #77532; S-16-10
The Surgeon General
Department of the Army
7.8 
Identification of Data to be Recorded on the Case Report  Forms
All eCRF data will be transcribed from subject’s source records. For more information on data
. 
.l 
r• 
.  
../
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IND #77532; S-16-10
The Surgeon General
Department of the Army
8 Selection and Withdrawal  of Subjects 
8.1 
Recruitment of Subjects 
Salus Research is located in Fort Wayne, Indiana. Salus Research expects to recruit from a
subject population in the surrounding Fort Wayne area. Based on the site’s vast experience with
dental trials and database of potential participants, it is estimated that 35 subjects will need to be
screened in order to obtain 26 subjects eligible for randomization.  
».
The staff at Salus Research will be trained on the details of the protocol and will have the
responsibility to identify potential study participants .  A recruitment plan based on the ,~  
inclusion/exclusion criteria of the study will be developed and submitted to the U.S. ~
Investigational Review Board for approval. Salus Research will recruit subjects from their Salus
Research Categorized Database of past study participants. After the IRB has approved the
protocol and the study initiation visit has been completed, prospective subjects will be contacted
by the study staff via telephone. These prospective subjects will be provided the study dates and,
if interested, the inclusion and exclusion criteria from the protocol will be reviewed. Once this is
complete and they are still interested, they will be scheduled for the Screening Visit.
8.2 
Eligibility Screening 
Each subject must satisfy all inclusion and exclusion criteria. During screening, the following
assessments will be conducted: physical examination, urine drug screen, medical history,
periodontal examination, OHT and OST examinations, oral hygiene check, plaque index
measurement and vital sign measurements. Females of child-bearing potential must have a
negative urine pregnancy test result at screening (14+2 days prior to randomization) in order to
participate and must agree to use a reliable form of birth control throughout the duration of the
study. The Principal Investigator or designee will make the final decision regarding the eligibility
of the subject. Only eligible subjects will be given the investigational product.
8.2.1 
Subject Inclusion Criteria .
 
Subjects must meet all of the following criteria to be included in the study:
I01Males or females between 18 and 64 years of age (inclusive at time of
screening) 
'/
I02 A negative urine pregnancy test (females of childbearing potential only)
I03 A negative urine drug test
I04 On a reliable form of birth control for at least 30 days prior to the start of the
study and willing to use a reliable form of contraception for the duration of the
study (Females of childbearing potential only), with reliable contraception defined
as : 
*.
- Abstinence which has been the customary lifestyle of choice
- Oral contraceptive, either estrogen progesterone combined, or progesterone alone
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IND #77532; S-16-10
The Surgeon General
Department of the Army
- Injectable progesterone 
- Implants of levonorgestrel
- Estrogenic vaginal ring
- Percutaneous contraceptive patches
- Intrauterine device or intrauterine system
- Double barrier method [condom or occlusive cap (diaphragm or cervical vault
caps) plus spermicidal agent (foam, gel, film, cream, suppository)]
- Male partner sterilization at least 6 months prior to the female subject’s entry into
the study, and this male is the sole partner for that subject
- Post-menopausal for at least twc) years IA
I05 Good health, as determined by pertinent medical history, physical examination,
and vital signs.
I06 A minimum of 20 natural teeth with 6 scorable surfaces per tooth
- Sufficient number of opposing posterior teeth to chew on both sides of the mouth
as determined by the examining dentist
<
l crowns or extensive
st rat i
on 
fands
, and third molars are not included
iI
procedures 12 to
 
1Y
- Teeth that have gross caries, fulcial and/or
lingual surfaces, orthodontic ban
 
 the tooth
count
107 Subject16 
hours
prior to screening visit.  
b .
Index of 1 .95 or greater (Turesky
al-19
to forgo any optional dental procedures
dhylaxis
or teeth whitening . 
0d
a willingness
signhe
Release ofHealth
Inet
to complete the 
druth
all study procedures
108 Plague 
70)
109 Willinguring the study period, such as
dental prop
1  
 an informed consent, which
nformation document.
g compliance information
8.2.2 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study:
~
EO1 
Phenylketonuria10
udes
I012
Willin02 Acute  or chronic  medical 
that, in the pri nci pal 
investigatparticipateE03
TMD
conditions, organ system disease, or medications
or's opinion, would impair the subject's ability to
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IND #77532; S-16-10
The Surgeon General
Department of the Army
E04 Self-reported allergy to sucralose or mint flavors
E05 Self-reported use of tobacco products including e-cigarettes
E06 Use of any type of anticoagulant medications (eg clopidogrel)
E07 Routine use of proton pump inhibitors
E08 Allergic to any component of the study drug
E09 Gross oral pathology, including widespread caries or chronic neglect, extensive
restoration, pre-existing gross plaque or calculus, or soft or hard tissue tumor of the
oral cavity
E010Orthodontic appliances or removable partial dentures that will compromise the
ability of the potential subject to participate in the study
E011Periodontitis as indicated by periodontal pockets greater than 4 millimeters on
more than one site 
,
E012 Receipt of any investigational drug/test product within 30 days prior to study
entry with study entry defined as Day 0, or currently participating in either the
active or follow-up phase of any other investigational study or planning to
participate in any other investigational study during participation in this trial
E013 Participation in the Phase 1/2a antiplaque study
E014 Receipt of antibiotics within 30 days prior to study entry
E015 Need for antibiotic prophylaxis prior to invasive dental procedures
E016 Receipt of prescription antibacterial oral products (eg products containing
chlorhexidine) within 30 days prior to study entry
E017Pregnant or breast-feeding female I
E018 An employee of the study site directly involved with the study
E019 Inability to comply with assigned treatment regimen
8.3 
Subject Withdrawal Criteria 
A subject may withdraw consent at any time during the study without penalty. The PI may
discontinue the subject’s activity without the subject’s consent if any of these criteria is met:
A subject fails to comply with study procedures
A subject’s safety or health may be compromised by further participation
8.3.1 When and How to Withdraw Subjects 
A subject may end his or her participation in the study at any time. If a subject withdraws, the
Principal Investigator will make a reasonable effort to determine the reason for the withdrawal
from the study and to complete termination procedures as described in section 8.5.2 and section
8.5.4. Telephone calls, registered letters, and email correspondence are considered reasonable
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IND #77532; S-16-10
The Surgeon General
Department of the Army
effort. For subjects leaving the study, a targeted examination may be performed, if medically
indicated and if permitted by the subject.
A subject may be withdrawn for an AE or SAE resulting in a safety concern. When a subject
withdraws due to an AE or is withdrawn by the principal investigator due to an AE, the sponsor’s
safety office, the USAMRMC Clinical Services Support Division (CSSD), Product Safety
Surveillance Branch (PSSB), must be notified within 72 hours (usarmy.detrick.medcom-
usammda.mbx.sae-reporting@mail.mil). The Principal Investigator must follow specific policy
regarding the timely reporting of AEs and SAEs to the US Investigational IRB as the IRB of
record (section 11.5.1.2). In all cases, the Principal Investigator will make a reasonable effort to
complete study termination  procedures.
If a subject meets withdrawal conditions for a concomitant medication violation or ~
noncompliance, this should clearly be stated in the source document and the study termination
eCRF.
V
8.3.2 
Data Collected for Withdrawn Subjects 
All data collected up to the time of withdrawal will be reported. The reason for withdrawal will
be specified in the eCRF.
8.3.3 
Replacement of Subjects 
Subjects who withdraw from the study will not be replaced.
8.3.4 
Follow-up for Withdrawn Subjects 
Salus Research will attempt to contact any subject who withdraws from the study in an effort to
determine the reason for withdrawal as well as to schedule a visit to conduct the study
termination procedures (Visit 3). Reasonable effort will be made to complete final study
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IND #77532; S-16-10
The Surgeon General
Department of the Army
• Licensed dental hygienist will polish teeth.
• The first chew will be administered under supervision in the clinic. The subject will be
instructed to chew one tablet of gum for 20 minutes. Chewing should be balanced as
equally as possible between both sides of the mouth.
• After chewing the gum for the designated time, the subject will be given a used product
bag to store the chewed gum. The evaluator will inform the subject to label this bag with
the time and date of the chew.
• After the chewing gum is stored in the used product bag, the subject will complete the
start and stop times for chewing gum on the electronic diary information system (ePRO).
The subject will enter this information while in the clinic.
• The study drug will be dispensed for unsupervised use. The subject will receive:
- 13 gum tablets for their unsupervised use along with 13 individual used product
collection bags.  
• 4 
4
- Subjects will be given instructions for chewing the gum.
a. The gum will be chewed for 20 minutes preferably after a meal or every 4 to 6
hours (3 times a day). Chewing will be balanced as equally as possible
between both sides of the mouth for a maximum of 3 chews per day.
b. After completing each 20 minute chew, subjects will store the used gum in the
used product collection bags provided to them.
c. Subjects will label each used product collection bag with the date and time of
chew. (A separate bag will be used for each chew).
d. After each chew, subjects will record the start and stop time of the chew on
the electronic diary information system - ePRO (Instructions provided in
Appendix D ) 
.'
e. Subjects will be informed that they must bring all of the used product
collection bags back to the clinic for Visit 3
• Subjects will be told that no oral hygiene procedures of any kind (teeth brushing, flossing
~ or mouth wash rinse) will be allowed while on study treatment (Day 0, 12, 3 and 4).
• AEs from first chew will be collected.
Concomitant medication will be recorded.
9.1 .3 4 Unsupervised Treatment, Study Days 0, 1, 2, and 3
After the first supervised chew is completed, the subjects will be released from the clinic. There
will be a total of 11 unsupervised, self-administered chews. The subjects will chew one tablet of
the gum (study drug) for 20 minutes every 4 to 6 hours, preferably after a meal, for a maximum
of 3 chews per day according to the schedule in Table 6.
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IND #77532; S-16-10
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Table 6: 
Schedule for Unsupervised Chews: 
Time~
Time~
Time~
Time~
Day 0 Day 1 Day 2 Day 3
After Breakfast b 
N/A 
1  
1  
1  
After Lunch 
1  
1  
1  
1  
After Dinner 
1  
1  
1  
1  
Total Chews per Day 
2 
3 
3 
3
a Gum will be chewed for 20 minutes preferably after a meal or every 4 to
6 hours for a maximum of 3 chews per day. Chewing will be balanced as
equally as possible between both sides of the mouth. ~ ~
b First chew takes place in the clinic.
After completing each 20 minute chew, the subject will store the used gum in the used product
collection bags provided to them. The subject will record the date and time of chew on the
individual collection bags as instructed. A separate bag will be used for each chew. Subjects
will record their chewing gum start and stop times on the electronic diary system (ePRO) after
each chew .  
AM - VIAY.
9.1.4 
Treatment, Study Day 4 – Visit 3 ~
After 4 days of treatment, subjects will return to the clinic for Visit 3. The following procedures
will occur at Visit 3 : . - 
'.
• Subjects will return all used product bags and any unused product. Site Staff will
collected used/unused product bags.
%-
• Vital signs (diastolic and systolic blood pressures, heart rate, respiration rate and
/ temperature) will be measured.  
• A brief, symptom-oriented physical examination will be performed
~ • Females of child-bearing potential will take a urine pregnancy test
• Subjects will be asked to verify that he/she has refrained from all oral hygiene procedures
~ (teeth brushing, flossing or mouth wash rinse) since their last chew.
• An intraoral exam (OST and OHT) will be performed.
• Supragingival plaque will be assessed using the QHT. (A red, food dye will be used to
disclose plaque deposits on the teeth).
• AEs will be assessed.
• Concomitant medications will be recorded.
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• Subject will be discharged from the study. (Subject will be allowed to brush their teeth
just prior to leaving the research center is discharged from the study.)
9.4 Concomitant Medications 
This protocol places no restrictions on rescue medications.
9.5 
Procedures for Monitoring Subject Compliance 
The first chew will be administered by the study staff and the chewing will be supervised at the
clinic. Subject compliance will be monitored through supervision of the first dose, controlled
distribution ofproduct and collection ofused product.  
.
For unsupervised dosing, each subject will be provided with bags to collect the used product.
Each bag will contain the used product of one chew. The bags (11total) will be labeled to record
product usage. Subjects will return the used product bags to the research center at Visit 3.
Subjects will record the start and stop time of each chew on the electronic diary information
system.
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10 Proof  of Concept Assessments 
10.1 Supragingival Plaque
Supragingival plaque will be assessed at screening, Day 0 (baseline) and Day 4 using the QHT
(Turesky et al-1970). The scoring index is shown below in Table 7 and the calculation is
provided in Appendix B.
Table 7: 
Quigley Hein-Turesky Plaque Index Scores 
Score
0
1  
2
3
4
5
Description 
No plaque
Separate flecks of plaque at the cervical margin of the tooth
A thin continuous band of plaque (up to one mm) at the cervical margin of the tooth
A band of plaque wider than one mm but covering less than one-third of the crown of the tooth
Plaque covering at least one-third but less than two thirds of the crown of the tooth
Plaque covering two-thirds or more of the crown of the tooth
10.1.1 Proof  of Concept Measurement (Endpoints) 
Two proof of concept endpoints will be assessed based on the QHT. The change in plaque
regrowth from baseline as well as the change in plaque regrowth based on sub-scores from
specific regions of the upper jaw, lower jaw, buccal and lingual surface.
10.2 
Methods/Timing for Assessing, Recording, and Analyzing Proof of Concept 
Measurements (Endpoints) 
The QHT will be measured on Day 0 after randomization. The Day 0 score will be designated as
the baseline score. The QHT is measured again on Day 4 after the subjects have completed 4
days of treatment with study drug. The change from baseline to Day 4 in the QHT will be
defined as the difference , KSL-W minus placebo. ,
Proof of concept measurements will also include the change from baseline in plaque regrowth
based on sub-scores from specific regions of the upper jaw, lower jaw, buccal and lingual surface
based on the QHT .  
*.4
Refer to Section 12 for statistical details.
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11 
Safety Assessment 
*
Safety monitoring will be conducted throughout  the study; therefore safety concerns will be
identified by continuous review of the data by the Principal Investigator, clinical staff, the
Sponsor’s Clinical Monitor, Research Monitor, and United States Army Medical Material
Development Activity (USAMMDA) Clinical Services Support Division (CSSD) Product Safety
Surveillance Branch (PSSB). The following data will be monitored: vital signs, physical
examinations, and intraoral (OHT and OST) examination.  
,
Study Safety Management: The IRB , Research Monitor, and Principal Investigator will review
any safety concern. A data safety monitoring board (DSMB) is not required for this study.
Research Monitor: The Research Monitor will function as an independent safety advocate for
subjects per AR 70-25 and DoD Instruction 3216.02. An independent Research Monitor is
required to review all unanticipated problems involving risk to subjects or others, SAEs, and all
subject deaths associated with the protocol and provide an unbiased written report of the event.
At a minimum the Research Monitor should comment on the outcomes of the event or problem
and, in the case of a SAE or death, comment on the relationship to participation in the study. The
Research Monitor should also indicate whether he/she concurs with the details of the report
provided by the Principal Investigator. Reports for events determined by either the Principal
Investigator or Research Monitor to be possibly or definitely related to participation and reports
of events resulting in death should be promptly forwarded to US Investigational Review Board
and/or USAMRMC ORP and USAMRMC CSSD PSSB (sponsor safety office).
USAMMDA Clinical Services Support Division: CSSD is responsible for coordinating and
integrating the review of safety data regarding The Surgeon General (TSG)-sponsored products.
The PSSB reviews each SAE report for medical consistency, accuracy, and completeness and
follows each event until it is satisfactorily resolved. USAMMDA Safety Pharmacovigilance
(PVG) physician, as delegated by the Sponsor, evaluates all safety cases and provides the final
determination on relatedness to the product, and whether expedited reporting is warranted, per
current FDA regulation and guidance .  
»,
11.1 ~ Specification of Safety Measurements (Endpoints) 
11.1.1 Vital Signs
Vital sign measurements include: blood pressure (systolic and diastolic), heart rate, respiration
rate and body temperature. These measurements will be collected after the subject has been
seated for at least 5 minutes during screening and on Day 0 and Day 4.
11.1.2 Physical Examination 
During the screening visit a physical examination will be performed. A brief symptom-oriented
physical exam will be performed on Day 4 and will involve observation of the physical
appearance of the subject. Any unexpected abnormalities or changes from baseline will be
assessed and documented. Findings that are considered to be of clinical significance will be
recorded as AEs.
11.1.3 Intraoral 
n
Examination 
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11.1.3.1 Oral Soft Tissue Examination 
The OST examination will be performed by visually inspecting the oral cavity and perioral area
using a dental light, dental mirror, periodontal probe and gauze. Any abnormalities at baseline 
will be recorded in order to detect changes such as the development of erythema, ulceration, or
tissue sloughing should they occur during the four day study period.
The structures examined will include the labial mucosa (including lips), buccal mucosa,
mucogingival folds, gingival mucosa, hard palate, soft palate, tonsillar area, pharyngeal area,
tongue, sublingual area, submandibular area, salivary glands, temporomandibular joint, and any
other area as deemed necessary by the investigator. The same examiner will conduct the
-
subject’ s OST during the study.  
.
4
OST observations will be listed as “Normal” or “Abnormal.” Abnormal observations will be
documented and described in the subject’s study records. Any changes will be recorded, severity
assessed according to standard dental examination procedures, and a decision made with respect
to whether or not these changes are related to treatment with the study drug. New or worsened
OST findings occurring after the first use of the study product will be recorded as AEs.
11.1.3.2 
Oral Hard Tissue Examination '
The OHT examination will assess irregularities in tooth enamel, tooth fracture, decay, faulty
restorations and implants. OHT observations will be listed as “Absent” or “Present” and any
“Present” observations will be described.
11.2 
INDSafety Reporting
The following terms, as defined by 21FR 312.32, apply to IND safety reporting.
11.2.1 Adverse Event or Suspected Adverse Reaction
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether
or not considered drug related.
Suspected adverse reaction means any AE for which there is a reasonable possibility that the
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” means
there is evidence to suggest a causal relationship between the drug and the AE. Suspected
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which
means any AE caused by a drug.
11.2.2 Solicited Adverse Event
This section is not applicable. ~
11.2.3 Serious Adverse Event or Serious Suspected Adverse Reaction
An AE or suspected adverse reaction is considered “serious” if, in the viewo 
 f either the
investigator or sponsor, it results in any of the following outcomes:
• Death
• Life-threatening AE
• In-patient hospitalization or prolongation of existing hospitalization
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• Persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions
• Congenital anomaly/birth defect.
An AE or suspected adverse reaction is considered “life-threatening” if, in the viewof either the
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form,
might have caused death.  
/4
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical judgment, they
may jeopardize the patient or subject and may require medical or surgical intervention to prevent
one of the outcomes listed in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias
or convulsions that do not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.  
A..' 
)
4  
11.2.4 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an
investigator brochure is not required or available, is not consistent with the risk information
described in the general investigational plan or elsewhere in the current application, as amended.
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of
greater specificity) if the investigator brochure listed only cerebral vascular accidents.
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated
from the pharmacological properties of the drug, but are not specifically mentioned as occurring
with the particular drug under investigation.
.4
11.2.5 Unanticipated Problems Involving Risks To Subjects Or Others 
Federal regulations require that unanticipated problems that are serious adverse events involving
risks to subjects or others be promptly reported to the IRB within 5 business days of the
investigator becoming aware of the event. Any other unanticipated problem should be reported to
the IRB within 10 days of the investigator becoming aware of the problem. These events
encompass a broader category of events than SAEs and may include issues such as problems
with loss of control of subject data or the investigational product; adverse psychological
reactions; or breach of confidentiality. Risks to others (e.g., program personnel) must also be
reported.   4 
v
Unanticipated problems involving risks to subjects or others are any incident, experience, or
outcome that meets all of the following criteria:
• Unexpected (in terms of nature, severity, or frequency) given (a) the procedures that
are described in the protocol, investigators brochure or informed consent document;
and (b) the characteristics of the subject population; 
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• Related or possibly related to a subject’s participation in the study; and
• Suggests that the study places subjects or others at a greater risk of harm than was
previously known or recognized.  
*4
The IRB and/or the ORP will evaluate the Principal Investigator’s and Research Monitor’s
reports to determine whether a given incident, experience or outcome constitutes an
unanticipated problem involving risk to subjects or others and, in coordination with USAMRMC 
CSSD, ensure reporting of the unanticipated problems involving risk to subjects or others to the
appropriate regulatory offices, as applicable.
11.3
11.3
11.3
11.3 
Relationship to Investigational Product 
The investigator must assign a relationship of each AE to the receipt of the investigational
product.  The investigator will use clinical judgment in conjunction with the assessment of a *
plausible biologic mechanism, a temporal relationship between the onset of the event in relation
to receipt of the investigational product, and identification of possible alternate etiologies
including underlying disease, concurrent illness or concomitant medications. The following
guidelines should be used by the investigator to assess the relationship of an AE to study product
administration.  ONLY A DENTIST/PHYSICIAN CAN MAKE THIS DETERMINATION.
Not related : Relationship to investigational product .  Applies to those events for which
evidence exists that there is an alternate etiology.
Unlikely: Likely unrelated to the investigational product.  Likely to be related to factors
other than investigational product, but cannot be ruled out with certainty.
Possible: An association between the event and the administration of investigational
product cannot be ruled out. There is a reasonable temporal association, but there may also
be an alternative etiology such as the subject’s clinical status or underlying factors including
other therapy.  
, 
'.
Probable: There is a high degree of certainty that a relationship to the investigational
product exists. There is a reasonable temporal association, and the event cannot be explained
by known characteristics of the subject’s clinical state or factors including other therapy.
Definite: An association exists between the receipt of investigational product and the event .  
An association to other factors has been ruled out.
11.3.1 Severity 
nt
Assessment 
All AEs will be assessed for severity by the investigator. Inherent in this assessment is the
medical and clinical consideration of all information surrounding the event including any
medical intervention required. Each event will be assigned one of the following categories: mild,
moderate, severe, or potentially life-threatening as defined in Table 8. Refer to the FDA
guidance for Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in
Preventive Vaccine Clinical Trials in Appendix C for further guidance in the assignment of
severity.
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Table 8: 
Severity Assessment Scale 
Category 
Grade 
Description 
-
Mild 
1  
Mild symptoms: No interference with
routine activities (Minimal level of
discomfort)
Moderate 
2 
Moderate symptoms: Moderate
interference with the patient’s routine
activities (Moderate level of discomfort)
Severe 
3 
Severe Symptoms: Considerable ~ ~
interference with the patient’s daily
activities, unable to perform routine
activities
(Significant level of discomfort )
Potentially Life-threatening 
4 
Urgent intervention indicated
Hospitalization or ER visit for potentially
life-threatening event
The severity assessment criteria may be used for any symptom not included in the grading scale.
Any grade 4 (potentially life-threatening) AE must be reported as an SAE. The eCRF for AEs
will reflect only the highest severity for continuous days an event occurred. The criteria in Table
8 will be followed; however, if a subject is evaluated in an emergency room setting for nonlife
threatening illness or symptoms (ie, visits emergency department on weekend for mild problems
because the physician’s office is closed), the information from that visit will be reviewed and
severity of the AE will be assessed according to the subject’s clinical signs and symptoms.
As defined by the ICH guideline for GCP, the term “severe” is often used to describe intensity
(severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event
itself however, may be of relatively minor medical significance (such as severe headache). This
is not the same as “serious”, which is based on subject/event outcome 
or action criteria usually
associated with events that pose a threat to a subject’s life or functioning. Seriousness (not
severity) serves as a guide for defining regulatory reporting obligations.
11.4 4 Recording Adverse Events
11.4.1 Methods/Timing for Assessing, Recording and Analyzing Safety Measurements 
1 (Endpoints) 4
AEs and SAEs will be assessed at each study visit and documented in the source records. All
AEs will be recorded on the eCRFs using accepted medical terms and/or the diagnoses that
accurately characterizes the event. SAEs will be documented using the SAE paper form. It
should be noted that the form for collection of SAE information is not the same as the AE eCRF.
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Where the same data are collected on both forms, the forms must be completed in a consistent
manner. For example, the same event term should be used on both forms.
When a diagnosis is known, the AE term recorded on the eCRF will be the diagnosis rather than
a constellation of symptoms. The investigator will assess and record for all AEs/SAEs: a
description of the event (if the event consists of a cluster of signs and symptoms, a diagnosis
should be recorded rather than each sign and symptom): onset date and time, and resolution date
and time: intensity (recorded as mild, moderate or severe): relationship to study drug (recorded
as unrelated, unlikely related, possibly related, probably related and definitely related): outcome
(recorded as recovered, recovering, resolved with sequelae, not resolved, fatal, ongoing (end of
study) or unknown if applicable): action taken with the study product (recorded as no action
taken, dose reduced, interrupted, discontinued). When an event has not resolved by study
closure, it will be documented on the AE eCRF as “ongoing”.
The timeframe for the collection of AEs and SAEs for each subject begins at the first ~IV
administration of investigational product (Visit 2 - Day 0) through Visit 3 - Day 4.
11.4.2 Duration of Follow-Up of Subjects after Adverse Events
Investigators are required to follow SAEs to resolution, even if this extends beyond the
prescribed reporting period. Resolution is the return to baseline status or stabilization of the
condition with the probability that it will become chronic. The SAE outcomes will be reported to
the sponsor’s representative using the Serious Adverse Event Report Form.
Investigators are not obligated to actively seek SAEs in former subjects; however, if a SAE,
considered to be related to the investigational product is brought to the attention of the
investigator at any time following completion of the study , the event will be reported to the
sponsor’s safety office as defined in section 11.5.1.1. ~
11.5
11.5
11.5
11.5
Reporting Adverse Events 
~
The Principal Investigator will report all AEs to the sponsor’s safety office (USAMRMC CSSD)
and the U.S. Investigational Review Board/or the USAMRMC ORP in the appropriate safety,
annual, and/or final reports. After appropriate data cleaning and query resolution between the
clinical site, sponsor’s clinical monitor, and clinical data manager, SAEs from the clinical
database will be reconciled with the sponsor’s SAE database. Annual and final study report data
will be provided by the ClinSmart Data Management Group.
11.5.1 Reporting Serious and Unexpected Adverse Events
Contact information for reporting SAEs is provided in Table 9.
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Table 9: 
Study Contacts for Reporting Serious Adverse Events 
Sponsor’s Safety Office 
US Army Medical Research & Material Command
ATTN: MCMR-UMR
1430 Veterans Drive
Fort Detrick, MD 21702-5009
Fax: 301-619-7790
.A
Telephone: 301-619-1106 
Email: usarmy.detrick.medcom -usammda.mbx.sae-
reporting@mail.mil
Institutional Review Board 
U.S. Investigational Review Board
6400 S.W. 72nd Court
Miami, Florida 33143
Telephone: 786-473-3095
Fax: 305-374-1789
Email: rmvf1550@aol.com
AND
USAMRMC Office of Research Protections 
Human Research Protection Office
Research Monitor 
US Army Medical Research and Material Command,
ATTN: MCMR-RPH
504 Scott Street
Fort Detrick, Maryland 21702-5012
Fax: 301-619-7803
Telephone: 301-619-2165
Email: usarmy.detrick.medcom -
usamrmc.other.hrpo@email.mil
Armand L. Balboni, JD, MD, PhD CPT, MS, USA
Deputy Director, Division of Regulated Activities and
Compliance (DRAC) USAMMDA
1430 Veterans Drive
Fort Detrick. MD 21702
Telephone: 301-619-2956
Fax: 301-619-2304
Email: armend.l.balboni.mil@mail.mil
11.5.1.1 
Reporting to the Sponsor 
All SAEs and unexpected AEs must be reported promptly (within 24 hours) to the sponsor’s
representative as per 21CFR 312.64, whether or not the event is considered related to study
product. All notification will be provided to the sponsor’s safety office, the PSSB, Clinical
Services Support Division (CSSD), USAMMDA, USAMRMC. Further, the investigator should
comply with relevant study site SOPs on reporting SAEs.
The information that the investigator will provide to the USAMRMC CSSD, PSSB is specified
in Table 10. The sponsor’s representative may request additional information for purposes of the
study.
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Table 10: SAE Information to be Reported to the Sponsor's Safety Office 
Notification Method Information to be Provided 
Email or Telephone 
(within 24 hours) 
IND number, sponsor study number, name of the investigational product, and
investigator name and contact number
Subject identification number
SAE term, description, onset date, date of investigational product administration,
severity, relationship, and subject’s current status
AND
Email or Fax 
Cover sheet or letter
Adverse event case report form
Sponsor approved Serious Adverse Event Report Form 
~
 
Concomitant medication case report form or a list of concomitant medications V
Medical record progress notes including medical history/pertinent laboratory/diagnostic
test results
NOTE: When submitting SAE reports via email, the subject line of each email notification will read as follows:
SAFETY REPORT – IND # _____, Sponsor Study #_____, Subject# _____, Event term: _____
In order to comply with regulations mandating sponsor notification of specified SAEs to the
FDA within 7 calendar days, investigators must submit additional information as soon as it is
available on the SAE electronic Case Report Form/SAE Report Form. The sponsor’s
representative will report unexpected SAEs associated with the use of the drug to the FDA as
specified at 21 CFR 312.32 (c).
Investigators must follow all relevant regulatory requirements as well as specific policy
regarding the timely reporting of SAEs to the research monitor and US Investigational Review
Board and/or the USAMRMC ORP .  
.
Reporting to the sponsor’s representative does not fulfill the investigator’s duty to report all
unanticipated problems involving risk to human subjects or others to the IRB. The Principal
Investigator will notify US Investigational Review Board and/or the USAMRMC ORP, and the
Research Monitor.  
i
11.5.1.2 Reporting to the IRB
Unanticipated problems involving risk to subjects or others, SAEs related to participation in the
study, and all subject deaths should be promptly reported by telephone, email, or fax to US
Investigational Review Board and/or USAMRMC ORP. The IRB contact information is
provided in Table 9. A complete written report should follow the initial notification.
Investigators are required to forward safety information provided by the sponsor’s representative
to the IRB .   -ä~=a ,
11.5.1.3 Reporting to ORP HRPO
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The Principal Investigator must comply with the following minimum reporting requirements.
Specific reporting requirements for the protocol will be included in the HRPO Approval
Memorandum.  Failure to comply could result in suspension of funding. 04
1. Substantive modifications to the research protocol and any modifications that could
potentially increase risk to subjects must be submitted to the HRPO for approval prior to
implementation. The USAMRMC ORP HRPO defines a substantive modification as a
change in Principal Investigator, change or addition of an institution, elimination or
alteration of the consent process, change to the study population that has regulatory
implications (E.G. adding children, adding active duty population, etc.), significant
change in study design (i.e. would prompt additional scientific review) or a change that
could potentially increase risks to subjects.
2. All unanticipated problems involving risk to subjects or others must be promptly reported
by telephone (301-619-2165), by email (usarmy.detrick.medcom- 
-
usamrmc.other.hrpo@mail,mil ), or by facsimile (301-619-7803) to the HRPO. A
complete written report will follow the initial notification. In addition to the methods
above, the complete report can be sent to the U.S. Army Medical Research and Material
Command, ATTN: MCMR-UMR, 1430 Veterans Drive, Fort Detrick, Maryland 21702-
5009.
3. Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by
US Investigational Review Board (IRB), Salus Research, the Sponsor, or regulatory
agencies will be promptly reported to the USAMRMC ORP HRPO.
4. A copy of the continuing review approval notification by the US Investigational Review
Board (IRB of Record) must be submitted to the HRPO as soon as possible after receipt.
For greater than minimal risk research, a copy of the continuing review report approved
by the IRB must also be provided. Please note that the HRPO also conducts random
audits at the time of continuing review. Additional information and documentation may
be requested at that time.
5. The final study report, including any acknowledgement documentation and supporting
documents, must be submitted to the HRPO when available.
6. The knowledge of any pending compliance inspection/visit by the FDA, DHHS Office of
Human Protections (OHRP), or other government agency concerning this research, the
issuance of Inspection Reports, FDA Form 483, warning letters or actions taken by any
regulatory agencies including legal or medical actions and any instances of serious or
continuing noncompliance with the regulations or requirements, must be promptly
reported to the HRPO .  Þ  .
11.5.2 Reporting Additional Immediately Reportable Events to the Sponsor’s Safety 
Office and IRB of Record and/or the USAMRMC ORP
11.5.2.1 Pregnancy ~
Each pregnancy must be reported within 72 hours of identification by completing and
submitting the Sponsor approved Pregnancy Report Form (paper) via email or fax to the
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sponsor’s safety office (CSSD, Product Safety Surveillance Branch). Report the incident to US
Investigational Review Board and/or the USAMRMC ORP in accordance with IRB policy.
Subjects who become pregnant after Day 0 will be followed to term, and the following
information will be gathered, documented, and reported on the follow-up Pregnancy Report
Form for outcome, date and type of delivery, Apgar scores, health status of the mother and child
including the child’s gender, height and weight.Complications and or abnormalities should be
reported including any premature terminations. A pregnancy is reported as an AE or SAE only
when there is suspicion that the investigational product may have interfered with the
effectiveness of contraception or there was a serious complication in the pregnancy including a
spontaneous abortion or an elective termination for medical rationale.
11.5.2.2 AE-related Withdrawal of Consent -
Any AE-related withdrawal of consent during the study must be reported immediately (within 
72 hours of identification) by email or fax to the sponsor’ s representative.  Report the
withdrawal to US Investigational Review Board (IRB of Record) and/or the USAMRMC ORP in
accordance with IRB policy. 
~
 
11.5.2.3 
Pending Inspections/Issuance of Reports 7
The knowledge of any pending compliance inspection/visit by the FDA, Office for Human
Research Protections (Department of Health and Human Services), or other government agency
concerning clinical investigation or research, the issuance of Inspection Reports, FDA Form 483,
warning letters, or actions taken by any regulatory agency including legal or medical actions and
any instances of serious or continuing noncompliance with the regulations or requirements will
be reported immediately to US Investigational Review Board and/or the USAMRMC ORP
HRPO and the sponsor’s representative.
11.5.3 INDAnnual Report  to the FDA
The Principal Investigator will be responsible for the preparation of a detailed annual synopsis of
clinical activity, including AEs, for submission to the sponsor’s representative (USAMMDA).
Each annual report will summarize IND activity for 1year beginning approximately 3 months
before the IND FDA anniversary date. The sponsor’s representative will notify the Principal
Investigator of the due date with sufficient time for the Principal Investigator to assemble the
required information.
11.5.4 Final Report
A final study report will be prepared in accordance with “Guidance for Industry: Submission of
Abbreviated Reports and Synopses in Support of Marketing Applications” and ICH E3 Guideline
“Structure and Content of Clinical StudyReports” and provided to the sponsor’s representative
for review and approval. The sponsor’s representative will use this report to prepare the final
clinical study report for submission to the FDA.
The principal investigator will report all AEs to the sponsor’s safety office (USAMRMC CSSD,
PSSB) and the IRB of Record (US Investigational Review Board) in the appropriate safety,
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annual, and/or final reports. After appropriate data cleaning and query resolution between the
clinical site, sponsor’s clinical monitor, and clinical data manager, SAEs from the clinical
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12 Statistics 
~
Detailed statistical procedures, listings, table shells and figures will be provided in a separate
statistical analysis plan (SAP) written shortly after protocol approval but before any subject
enrollment. The SAP will be finalized before study close-out and database lock. The following
key statistical components will be considered and a detailed description will be documented in
the SAP:
• Primary and secondary measurements and how they will be measured,
• Statistical methods and tests that will be used to analyze the measurements,
• Strategy that will be used if the statistical test assumptions are not satisfied,
• Indication of whether  the comparisons will be one-tailed or two-tailed (with
justification of the choice) and the level o
sig ficance to be used
stments to the significance level
t e
any planned or unplanned subgroup an
analy es and a statement with which c
.
•í
justif icat on of their im portance,
andical
just ification a nd support from with
• Identification ofwhether any adju 
 overall p-
value will be made to account foralyses or
multiple testing,
• Specification of potential adjustedovariates
or factors will be included,
• Planned exploratory analyses and
• Any subgroup effects with biologin 
and
outside the study.
12.1 
Description of Statistical Methods 
The primary objective of this Phase 2 study is:
• to assess the safety and tolerability of KSL-W (30 mg dose) delivered in a chewing
gum formulation compared to placebo after multiple doses over a 4 day treatment
, ¥R\SA. . 
\
secondary proof of concept (efficacy) o
•
change in plague
regro~
to assess the treatment related
changdose
) compared to placebo after mul
study will evaluate the following 
:•
KSL-W and placebo adverse
eve~
displayed side by side by
affectedrug
,•
The estimated mean difference C  
regrowth from baselineto Day 4
these reductions
Thebjectives are:
t 
wth from baseline in the WHT of KSL-W (30 mg
~es
 
 from baseline using the sub-scores ofthe QHT.
tiple doses over a 4 day treatment period
The
nt frequencies, incidences and rate estimates will be
d body system, severity and relationship to study
KSL-W minus placebo) in the change in plague
in the QHT and the estimated standard deviation of
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• The estimated means, standard deviations of the total score and sub-scores of the
QHT, by visit (baseline, Day 4), and by study arm (KSL-W, placebo)
• The estimated effect of evaluator on the QHT index 
~
Two evaluators will be used for this study and each subject’s randomly assigned evaluator will
stay with that subject throughout the study. The randomization to the study arm (KSL-W,
placebo) will be 1:11. 
 The study biostatistician will remain blinded until database lock.
Summaries of continuous variables will include the sample size, mean, median, standard
deviation, and the minimum and maximum scores. Summaries of categorical variables will
include the number and percentage of subjects that presented each value of the variable. Unless
specifically noted to the contrary in the SAP, all analyses will be based on data as observed, with
no imputation of missing data. Analyses will be performed using SAS, release 9.3 or later.
12.1.1 Analysis Addressing the Primary and Secondary Study Objectives 
12.1.1.1 Sa  fe  ty
Sa  fe  ty
Sa  fe  ty
Sa  fe  ty (P  rimary
P  rimary
P  rimary
P  rimary)  ..
All AEs will be presented in by-subject data listings. Treatment-emergent AEs will be tabulated
where treatment-emergent is defined as any AE that occurs after administration of the first dose
of study treatment or any medical or dental condition that is present at baseline but worsens in
intensity subsequent to the administration of the first dose of study treatment.
k-
In addition to the subject listings, summaries by study arm, noting severity and relationship to
study treatment, will include AE incidence proportions and rates by system organ class (SOC)
and by preferred term (PT) within SOC. Verbatim AE terms will be shown in a table listing.
Incidence rates (in events per patient-week) will be estimated as the number treatment emergent
AEs divided by the total number of patient-weeks of follow-up. AE incidence proportion will be
estimated based on the number of subjects having at least one AE of a particular type divided by
the number of subjects exposed.  Il... 
..,di..*4
12.1.2.1 Proof  of Concept Analyses (Secondary) 
The QHT whole mouth average, determined at baseline and Day 4, will be the average of scores
from surfaces evaluable for QHT. In order to qualify for this study each subject must have at
least 20 teeth with 6 evaluable surfaces per tooth.
An analysis of covariance (ANCOVA) model will be applied to each subject's change in plaque
regrowth from baseline in the QHT score (baseline minus Day 4) for subjects in the primary
analysis population (FAS defined in section 12.8 below). The primary model will include study
arm (KSL-W, placebo) and the baseline QHT score.
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Estimates and 95% confidence bounds on all model parameters will be summarized, and the
estimated mean study arm difference from the final ANCOVA  model will be presented along
with its standard error and 95% confidence bound. A 2-tailed p-value for this difference will
also be presented as a further descriptive summary.
The estimated mean difference together with the error standard deviation from the primary
ANCOVA model will be used to forecast success of future studies based on the average power
for detecting a KSL-W improvement in the QHT reduction as a function of the future study
sample size.  
----*4-
Secondary analyses involving the change in plaque regrowth will include a full model with the
baseline QHT score, study arm, evaluator and all interactions of these terms. This model will be
used to assess the overall effect of evaluator on the results, and any study arm difference in the
slope terms of the baseline QHT score. ~
In addition to the model interaction evaluations described above, the assumption of equal error
variance across the design will be checked using scatter plots and the estimated study arm
standard deviations. The linearity assumption of mean reduction in QHT versus baseline QHT
will be checked using scatter plots .  ..rt
12.1.2 
Multiple Endpoints 
There will be only one primary assessment for this study.
12.1.3 
Other Analyses 
~~
Demographic assessments will be summarized by study arm. Frequencies and proportions will
be presented for categorical scales. Sample means, sample standard deviations, minima, maxima
will be presented for continuous scales. -1
Descriptive summaries (sample means, sample standard deviations, minimum, maximum) of the
total score and sub-scores of the QHT, by visit (baseline, Day 4), and by study arm (KSL-W,
placebo) will be summarized using both the FAS and .per-protocol subjects cohorts.
Data from physical examinations and vital signs will be summarized for each evaluation time
point. Any abnormal physical examination findings noted at the end of study exam on Day 4 will
be tabulated as a listing. For vital signs, change from baseline to end of study evaluation time
points will be summarized .  
-I
The efficacy analyses described for the analysis in section 12.1.1will also be performed using
the per protocol population defined in section 12.8.
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12.1.4 
Subgroup Analysis 
There are no planned subgroup analyses for this study.
12.2 
Planned Enrollment and Reason for Sample Size
A sample size of at least 12 subjects per study arm (KSL-W, Placebo) yields at least a posterior
94% chance of observing any KSL-W improvement in the sample mean QHT scores, and at least
an 81% posterior chance (given that an improvement was observed) that the projected sample
size for a similar, later phase, confirmatory study, using a 2-tailed p = 0.05, power = 90%
criterion, is no more than 100 per study arm. This is based on the results of the phase 2a trial at
Day 14, where for the 30 mg dose the observed QHT mean change from baseline was -0.31with
n= 7 subjects, and for the placebo subjects the QHT mean change from baseline was -0.03 with n
= 16. The observed QHT error standard deviation was 0.22. It was assumed that these Day 14
results from the phase 2a study will apply to this study having 4 treatment days.
12.3
12.3
12.3
12.3
Level of Significance to be Used
While formal p-value comparisons of the study arms based on the ANCOVA model results will
be generated and summarized (2 tailed, p = 0.05), these will be considered only as descriptive
summaries since this study has not been powered for detection of a minimally clinically
important improvement in QHT. The primary summaries for this study will include the
estimated difference, KSL-W minus placebo, in the mean (QHT) reduction from baseline, and
the estimated error standard deviation from the final ANCOVA  model. This information will be
critical to assess the chances for a successful demonstration of KSL-W efficacy from future
phase 3 studies, utilizing QHT as a function of the sample size of these studies.
12.4 
Statistical Criteria for the Termination of the Trial
There are no statistical criteria for study termination in this clinical trial.
12.5
12.5
12.5
12.5 
Interim Analysis and Stopping Rules
No interim analyses are planned.
12.6 
Accounting for Missing, Unused, and Spurious Data
Non-analyzable data will be documented.
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12.7
12.7
12.7
12.7 
Procedures for Reporting Deviations from the Original Statistical Plan
Any deviation(s) from the original statistical plan as indicated in the protocol will be described in
an amendment to the protocol and the SAP. Deviations from the SAP will be documented in
accordance with study site SOPs. Non-analyzable data will be documented.
12.8
12.8
12.8
12.8 
Selection of Subjects to be Included in Analyses 
The Full Analysis Set (FAS) is defined as all randomized subjects having Baseline and Day 4
QHT evaluations, with the Day 4 evaluation occurring on the morning following the last
chewing gum treatment from the previous day. The FAS population will be analyzed according
to their randomized treatment assignment.  
.
The Per Protocol Population (PP) is a subset of FAS and consists of all subjects with no major
protocol violations such as: failure to obtain valid informed consent, accidental distribution of
incorrect study medication, not following the inclusion/exclusion criteria, evidence that study
medication was not taken, and the performance of oral hygiene other than chewing the study
gum during the study period. Analysis of the PP will be according to the treatment actually
received by the subject.  
. 4,
The Safety Population consists of all randomized subjects receiving at least one dose of study
medication, and summarized on the basis of treatment received. All AE summaries will be based
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13 Direct Access to Source Data/Documents 
~
Subjects will be identified on eCRFs by a unique subject identification number and on source
documents by name and date of birth. No personal identifier will be used in any publication or
communication used to support this research study. The subject identification number will be
used if it becomes necessary to identify data specific to a single subject. Representatives of
USAMRMC, the sponsor’s representative, the IRB of Record and/or the USAMRMC ORP, and
the FDA are eligible to review medical and research records related to this study as a part of their
responsibility to protect human subjects in clinical research. Personal identifiers will be removed
from photocopied medical and research records.
13.1 Study Monitoring 
Study monitoring will be the responsibility of ClinSmart CRO with oversight by USAMRMC
CSSD Clinical Oerations Branch. Upon successful approval of the protocol and establishment of
the regulatory file, ClinSmart CRO will establish a clinical monitoring plan. To ensure that the
investigator and the study staff understand and accept their defined responsibilities, the clinical
monitor will maintain regular correspondence with the site and may be present during the course
of the study to verify the acceptability of the facilities, compliance with the investigational plan
and relevant regulations, and the maintenance of complete records. As needed, the clinical
monitor may witness the informed consent process or other applicable study procedures to assure
the safety of subjects and the investigators’ compliance with the protocol and GCPs.
Monitoring visits will be scheduled to take place at the initiation of the study, during the study at
appropriate intervals, and after the last subject has completed the study. A report of monitoring
observations will be provided to the Principal Investigator (for corrective actions) and
USAMRMC CSSD. USAMRMC CSSD Operations Branch may conduct co-monitoring and/or
sponsor monitoring visits as part of their oversight.
13.2 Audits and Inspections 
Authorized representatives of the sponsor, the FDA, the independent ethics committee or IRB
may visit the site to perform audits or inspections, including source data verification. The
purpose of the audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data
were recorded, analyzed, and accurately reported according to the protocol, GCP guideline of the
ICH, and any applicable regulatory requirements.
The investigator should contact the sponsor’s representative and ORP HRPO immediately if
contacted by a regulatory agency about an inspection.
13.3 Institutional Review Board
As the IRB of record, U.S Investigational Review Board along with ORP HRPO will serve as the
responsible IRBs and will review the protocol, informed consent, and progress reports on a
continuing basis in accordance with all applicable regulations, including Title 21 
 Code of
Federal Regulations (CFR), Parts 50 and 56. The ORP HRPO will provide a second review.
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The Principal Investigator must obtain IRB approval for the study. Initial IRB approval and all
materials approved by the IRB for this protocol, including the patient consent form and
recruitment materials, must be maintained by the protocol physician and made available for
inspection.  
.
The Principal Investigator will be responsible for preparing and submitting continuing review
reports per institution and IRB requirements. The Principal Investigator or a designee will submit
the approved continuing review reports and the US Investigational Review Board approval
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14 Quality Control and Quality Assurance 
4
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor’s
representative may conduct quality assurance audits. Refer to section 13.2 for more details
regarding the audit process.  
.
Auditing of the clinical trial may be conducted at any time during the study to ensure continued
compliance with regulations, policies and procedures. Auditing will be undertaken, as needed, by
independent personnel designated by the Quality Office, USAMMDA. Audit findings will be
documented in a formal audit report that will detail the conduct of the audit and summarize the
observations noted.
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15 Ethics
15.1 
cs
Ethics 
w
Review 
This study will be conducted under an IRB approved protocol. The study is to be conducted by
scientifically and medically qualified persons. The IRB will determine whether the benefits of
the study are in proportion to the risks. The rights and welfare of the subjects will be respected;
the physicians conducting the study will ensure that the hazards do not outweigh the potential
benefits; the results to be reported will be accurate; subjects will give their informed consent and
will be competent to do so and not under duress; and all study staff will comply with the ethical
principles in 21CFR Part 50 and the Belmont Principles.
15. 1. 1  Review/Approval of Study Protocol 
 0
Before a clinical study can be initiated, the study protocol and other required documents will be
submitted to the following departments in the order listed for review and/or approval, with the
final review by the FDA:
• Integrated Product Team
• Sponsor’s Representative Team (Senior Regulatory Affairs Advisor; Division of
Regulated Activities and Compliance, USAMMDA)
• Commander, Subordinate Command, if applicable
• IRB
• Office of Research Protections, Human Research Protection Office (ORP HRPO)
• Sponsor’s Representative (acting for The Office of the Surgeon General of the
Army) .. 
'.
• USAMRMC Commanding General, if applicable
Enrollment in this protocol may not begin until all approvals have been obtained and the formal
authorization letter is received by the Principal Investigator from the sponsor’s representative.
15. 1.2 Protocol Modifications -v~1
All modifications to the protocol and supporting documents (informed consent, study-specific
procedures, SOPs, recruitment materials, etc) must be reviewed and approved prior to
implementation. Any protocol amendment will be agreed upon and approved by the sponsor’s
representative prior to submission to the IRB and/or the ORP and prior to implementation of said
change or modification. Any modification that could potentially increase risk to patients must be
submitted to the FDA prior to implementation. The informed consent document must be revised
to concur with any amendment as appropriate and must be reviewed and approved with the
amendment. Any patient already enrolled in the program will be informed about the revision and
asked to sign the revised informed consent document if the modification directly affects the
individual’s participation in the program. A copy of the revised, signed, and dated informed
consent document will be given to the patient. All original versions of the informed consent
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No personal identifier will be used in any publication or communication used to support this
research study. The subject’s identification number will be used in the event it becomes
necessary to identify data specific to a single subject.
15.2.2 Compensation for Participation 
The compensation for participation amounts are provided in Table 11.
Table 11: Compensation for Study Subjects 
Visit(s) 
Amount Per Visit ($)*
Screening 
- 
25-
Each Randomized Subject
200-
Total Compensation
225-
*Compensation will be given in the form of gift cards.
15.2.3 Medical Care for Research-Related Injury
All non-exempt research involving human subjects shall, at a minimum, meet the requirement of
32 CFR 219.116(a)(6).
If a subject is injured because of participation in this research and is a DoD healthcare
beneficiary (eg, active duty in the military, military spouse or dependent), the subject is entitled
to medical care for that injury within the DoD healthcare system, as long as the subject remains a
DoD healthcare beneficiary. This care includes, but is not limited to, free medical care at Army
hospitals or clinics .  
.
If a subject is injured because of participation in this research and is not a DoD healthcare
beneficiary, the subject entitled to medical care for that injury at an Army hospital or clinic;
medical care charges for care at an Army hospital or clinic will be waived. The subject is also
entitled to care for that injury, but such care for that injury at other DoD (non-Army) hospitals or
clinics may be limited by time, and the subject’s insurance may be billed. It cannot be
determined in advance which Army or DoD hospital or clinic will provide care. If the subject
obtains care for research-related injuries outside of an Army or DoD hospital or clinic, the
subject or the subject’s insurance will be responsible for medical expenses.
15.3 Written Informed Consent 
The informed consent process and document will be reviewed and approved by US
Investigational Review Board, USAMRMC ORP and Sponsor’s representative prior to initiation
of the study. The consent document contains a full explanation of the possible risks, advantages,
and alternate treatment options, and availability of treatment in the case of injury, in accordance
with the United States Code of Federal Regulation, Title 21 
 Part 50 (21CFR 50). The consent
document indicates that by signature, the subject permits witnessing of applicable study
procedures by the sponsor’s representative, as well as access to relevant medical records by the
sponsor’s representative and by representatives of the FDA. The sponsor’s representative will
submit a copy of the initial IRB and sponsor’s representative-approved consent form to the FDA
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and will maintain copies of revised consent documents that have been reviewed and approved by
US Investigational Review Board and ORP.
A written informed consent document, in compliance with 21CFR Part 50, 32 CFR Part 219,
and the Belmont Principles and HIPAA Authorization will be signed by the subject before any
study-related procedures are initiated for that subject. This consent document must be retained by
the investigator as part of the study records. Each subject will receive a copy of the signed
informed consent document. The investigators or their designees will present the protocol in lay
terms to individual subjects. Questions on the purpose of the protocol, protocol procedures, and
risks to the subjects will then be solicited. Any question that cannot be answered will be referred
to the PI. No subject should grant consent until questions have been answered to his/her
satisfaction. The subject should understand that the study product is an investigational drug and
is not licensed by the FDA for commercial use, but is permitted to be used in this clinical
research. Informed consent includes the principle that it is critical the subject be informed about
the principal potential risks and benefits. This information will allow the subject to make a
personal risk versus benefit decision and understand the following:
• Participation is entirely voluntary,
• Subjects may withdraw from participation at any time,
• Refusal to participate involves no penalty, and
• The individual is free to ask any questions that will allow him/her to understand the
nature of the protocol.  /-  
04
• A description ofthis clinical trial will be available on ,
http://www.ClinicalTrials.gov, as required by US law.
Should the protocol be modified, the subject consent document must be revised to reflect the
changes to the protocol. If a previously enrolled subject is directly affected by the change, the
subject will receive a copy of the revised informed consent document. The approved revision
.l . 
1. 
1 
111.
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16 Data Handling and Recordkeeping 
~
The primary source document for this study will be the subject's medical record. If separate
research records are maintained by the investigator, the medical record and the research records
will be considered the source documents for the purposes of auditing the study. The source
documents will be retained at the site.
For this study, an EDC database system will be used for the collection of the study data in an
electronic format. The EDC database system will be designed based on the protocol
requirements, the approved eCRF layouts and specifications, and in accordance with 21CFR
Part 11. The eCRF layouts and specifications define and identify the applicable source data that
will be collected and captured into the EDC database system. The applicable source data will be
electronically transcribed by the site designee onto the eCRF (data entry screens) in the EDC
database system .  The investigator is ultimately responsible for the accuracy ofthe data 
-
transcribed on the eCRF. Data monitoring will be performed in the EDC database system by the
study monitor and the designated Data Management group .  
,
A detailed data management plan will be written and approved by the study team and the
Principal Investigator prior to study start, with approval by the sponsor’s data manager in the
USAMMDA CSSD. All updates to the data management plan must be approved before study
close-out and database lock.
16. 1  Inspection of Records f~IA
The sponsor’s representative or designee will be allowed to conduct site visits at the
investigation facility for the purpose of monitoring any aspect of the study. The investigator
agrees to allow the monitor to inspect the drug storage area, investigational product stocks, drug
accountability records, subject charts, study source documents, and other records relative to
study conduct.  
.. 
'.
Subjects’ health information is used to report results of research to the sponsor’s representative
and Federal regulators and may be reviewed during study audits for compliance with study plans,
regulations, and research policies. The informed consent document indicates that by signature,
the subject permits access to relevant medical records by the sponsor and its representatives, U.S.
Investigatonal Review Board and by representatives of the FDA in order to audit or monitor the
study data.
Upon a subject’s termination from the trial, completed eCRFs will be ready and available for on-
site review by the sponsor’s representative or the designated representative within 14 days after
receipt of the subject’s data. ~~
16.2 Retention of Records 1  
The Principal Investigator must maintain all documentation relating to the study for a period of
2 years after the last marketing application approval, or if not approved for 2 years following the
discontinuance of the investigational product for investigation. If it becomes necessary for the
sponsor’s representative or designee or the FDA to reviewany documentation relating to the
study, the investigator must permit access to such records.
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Completed, monitored eCRFs will be stored in a secure location by the sponsor’s representative
or designee. A copy of each completed eCRF will be retained by the investigator.
The Principal Investigator will be responsible for retaining sufficient information about each
subject, ie, name, address, telephone number, driver’s license number and subject identifier in
the study, so that the sponsor’s representative, the IRB of record, the FDA, employees of
USAMRMC, or other regulatory authorities may have access to this information should the need
arise .  
.
It is the policy of the USAMRMC that data sheets are to be completed for all subjects
participating in research (Form 60-R, Volunteer Registry Data Sheet). The data sheets will be
entered into this Command’s Volunteer Registry Database. The information to be entered into
this confidential data base includes the subject’s name, address, and Social Security Number;
study title; and dates of participation. The intent of this data base is twofold: first, to readily
answer questions concerning an individual’s participation in research sponsored by USAMRMC;
and second, to ensure that USAMRMC can exercise its obligation to ensure research subjects are
adequately warned (duty to warn) of risks and to provide new information as it becomes
available. The information will be stored at USAMRMC for a minimum of 75 years. The
Volunteer Registry Database is a separate entity and is not linked to the study database.
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17 Publication Policy 
4
All data collected during this study will be used to support this IND. All data may be published
in the open medical or military literature with the identity of the subjects protected. Anyone
desiring to publish or present data obtained during the conduct of the study will conform to Salus
Research policies and then forward the publication for review to the Commander, USAMMDA
or designee and usarmy.detrick.medcom-usamrmc.list.clearances@mail.mil prior to submission.
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18 List of References 
~
Allen FE and Smith BE. Impact of dental sick call on combat effectiveness: The dental fitness
class 3 soldier. Mil Med. 1992;157(4):200-3.
Bateman A, Singh A, Shustik C, Mars WM, and Solomon S. The isolation and identification of
multiple forms of the neutrophil granule peptides from human leukemic cells. J Biol Chem.
1991;266(12):7524-30.
Bengoechea JA and Skurnik M. Temperature-regulated efflux pump/potassium antiporter system
mediates resistance to cationic antimicrobial peptides in yersinia .  Mol.  Microbiol. 
2000;37(1):67-80.
Boman HG. Gene-encoded peptide antibiotics and the concept of innate immunity: An update
review. Scand J Immunol. 1998;48(1):15-25.
Chaffin J, King JE, and Fretwell LD. U.S. Army dental emergency rates in bosnia. Milit. Med.
2001;166:1074-78. 
Clinical Study Report Anti-Plaque Chewing Gum (APCG) Sponsor Study # S-11-14 Site Study
Number 12-D-212 Clinical Study Report “A Double-Blind, Randomized, Controlled, Dose
Escalation Clinical Trial of an Antiplaque Chewing Gum – Phase 1 Safety and Tolerability and
Phase 2a Safety, Tolerability and Proof of Concept in a Gingivitis Population May 27, 2016
Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science.
1994;264(5157):375-82 .  
,
Deutsch WM and Simecek JW. Dental emergencies among marines ashore in operations desert
shield/storm. Mil Med. 1996;1611(110):620-3.
Dorrer E and Teuber M .  Induction ofpolymyxin resistance in pseudomonas fluorescens by
phosphate limitation. Arch. Microbiol. 1977;114(1):87-89.
Dunn WJ, Langsten RE, Flores S, and Fandell JE. Dental emergency rates at two expeditionary
medical support facilities supporting operations enduring and iraqi freedom. Mil Med.
2004;169(7):510-4.
Elsbach P. What is the real role of antimicrobial polypeptides that can mediate several other
inflammatory responses? J. Clin. Invest. 2003;111(  1):1643-45.
Faraj J, Dorati R, Worthen D, Selmin F, Capan Y, Leung K-P, et al. The development of a
peptide-containing chewing gum as a sustained release antiplaque antimicrobial delivery system.
AAPS PharmSciTech. 2007;8(1):26.
“Fort Wayne, IN Metropolitan Statistical Area.” Wikipedia.org. Available from
https://en.wikipedia.org/wiki/Fort_Wayne,_IN_Metropolitan_Statistical_Area (accessed June 20,
2016).
Friedrich C, Scott MG, Karunaratne N, Yan H, and Hancock RE. Salt-resistant alpha-helical
cationic antimicrobial peptides. Antimicrob. Agents Chemother. 1999;43(7):1542-48.
Gilmore K, Chen P, and Leung KP. Antimicrobial peptides for plaque control. Advances in
Dental Research. 2009;37(11):779-88.
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Guina T, Yi EC, Wang H, Hackett M, and Miller SI. A phop-regulated outer membrane protease
of salmonella enterica serovar typhimurium promotes resistance to alpha-helical antimicrobial
peptides. J. Bacteriol. 2000;182(14):4077-86.
Hancock RE. Peptide antibiotics. Lancet. 1997;349(9049):418-22. ~
Hancock RE and Chapple DS. Peptide antibiotics. Antimicrob. Agents Chemother.
1999;43(6):1317-23. 
Hancock  RE, Falla T, and Brown M. Cationic bactericidal peptides. Adv. Microb. Physiol.
1995 ;37 : 135-75 .  
-».
Hancock RE and Lehrer R. Cationic peptides: A new source of antibiotics. Trends Biotechnol.
1998; 16(2):82-88 .  
.
Hancock REW and Sahl HG .  Antimicrobial and host-defense peptides as new anti-infective P  
therapeutic strategies.  Nat.  Biotechnol.  2006;24(12):1551 
-57 . 1 
*
Haps S, Slot DE, Berchier CE, and Vander-Weijden GA. The effect of cetylpyridinium chloride-
containing mouth rinses as adjuncts to toothbrushing on plaque and parameters of gingival
inflammation: A systematic review. Int J Dent Hyg. 2008;6(4):290-303.
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The effects of histatin-derived basic antimicrobial peptides on oral biofilms. J Dent Res.
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<
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KSL-W Investigator’s Brochure, version #2, Date June 2016
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Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389-95.
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,-, - - r~ / - /,-, I ./. -/
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Appe ndices 
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Appendix A. 
Study Personnel Roles and Responsibilities – Salus Research 
Study Staff
Jeffery L. Milleman, DDS, MPA
Kimberly R. Milleman, RDH, MS
Kirstin K. Battershell, RN, MBA
Responsibility 
Principal Investigator; Examiner
Sub-Investigator; Examiner D  <
Senior Clinical Coordinator; Vital Signs; Urine
Drug Screen, Urine Pregnancy Test
Julie E. Wygant 
Front Desk; Recruiting
Brian T. Marks 
Kara K. Wygant
Study Product Preparation
Kaylie S .  Wills 
- Randomization
Abigale L. Yoder 
Informed Consent; Medical History &
Demographics Collection
Jack L. Lowe 
A' 
Recorder 
.-/
Justin M. Bute ~ 
Product Distribution; Product Use Instructions;
Supervised Use; Evaluate Compliance
Holly M .  Scott, RDH, BS 4 
Dental Polishing ( Supervised Dental
Hygienist)
Dental Hygienist * 
.- 
Dental Polishing (Independent Contractors)
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j 
.
plague
An index for the entire mouth is determined by dividing the total score by the number surfaces (
a maximum of 2 x 2 x 14 = 56 surfaces) examined.
CALCULATION EXAMPLE: 
Assuming nonrestored upper jaw and lower jaw surfaces are examined and the scores are stored
in the following two tables:
Upper Buccal surface Lingual 
jaw 
score 
surface score 
25 
2 
2
22 
1  
3
21 
3 
2
11 
0 
1  
12 
0 
0
13 
1  
2
14 
1  
3
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15 
2 
2
17 
5 
3
Total 
15 
18
Lower Buccal surface Lingual 
jaw 
score 
surface score 
47 
4 
5
44 
3 
5
- 
J
43  
2 /<~  /
v
3 '~  
42 
2
3 /
41  
~2 \, 4
32  .,..... 0  
2  
33
0
2
0
-
34
0 
Total 
0
15 
27
.
Index =I[ Total score / The number surfaces examined 
~~((15+ 18)+ (15+ 27))/ 36= 2.1~
The index for the entire mouth is 2.1.
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Appendix C. 
Guidance for Industry - Toxicity Grading Scale for Healthy Adult and
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform 
ation/Guidances/Vaccines/ucm091977.pdf 
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Appendix D. 
ePRO Electronic Diary 
formation 
Information 
b
Each subject will record the start and stop times for chewing gum on the ePRO Electronic Diary
Information System. This data will be collected via the internet. The subject will receive three
emails per day containing a link to the respective ePRO form. Each form will be identified by
“Day” and “Time of Chew”. For example, for Day 1the forms will be identified as: Day 1-
Chew 1 (morning), Day 1 – Chew 2 (afternoon), Day 1Chew 3 (evening). Over the course of the
study there will be a total of12forms (one for each chew) to be completed .  ,
The subject will open the email and click the link to the ePRO form. On the form, the subject
will enter the start and stop times for each chew and “submit” this information in real time.
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SAP_001.pdf: 
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