Clinical trial NCT02761993
Conditions: Periodontal Disease
Sponsor: Noveome Biotherapeutics, formerly Stemnion
Start date: 2016-04-01; Completion date: 2017-10-01
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether ST266 will reduce pocket depth (PD) as an adjunctive to scaling and root planing (SRP) in subjects with moderate to severe periodontal disease.

Detailed description:
The study is a 9-month, randomized, double-blind, parallel-design study of subjects with existing moderate to severe periodontal disease randomly assigned to one of three groups. The primary endpoint of PD change will be evaluated following 9 months of treatment. Subjects will be followed for 9 months for safety and radiographic evaluations.

Subjects who meet inclusion criteria will be randomized to one of three treatment groups.

Randomization will be stratified by site and smoker status (never smoked or quit smoking more than two years ago vs. has smoked within the last two years). Randomization will be blocked such that assignment to treatment groups both within sites and within smoker status will be approximately even (1:1:1). Treatment will be initiated after SRP.

All subjects will be evaluated at baseline and Days 1, 15, 30, 60, 90, 180, and 270.

Arms: arm 1: Group 1 received ST266 treatment daily on Days 1 through 5, 8 through 12, 22, and 30, and then monthly for 7 months (Days 60, 90, 120, 150, 180, 210, and 240). arm 2: Group 2 received ST266 treatment 2x/week (with at least 1 day between treatments) for the first 3 months, and then monthly for 5 months (Days 120, 150, 180, 210, and 240). arm 3: Group 3 received commercially available sterile saline (0.9% sodium chloride) according to the same schedule as Group 1.
Interventions: intervention 1: ST266 intervention 2: Saline (0.9% NaCl)
Intervention descriptions: intervention 1: 1X ST266 applied in a dose of 20 microliters per tooth. Total daily dose will be less than 1 milliliter. ST266 will be applied directly to the marginal gingiva around each tooth (buccal and lingual). intervention 2: Saline applied in a dose of 20 microliters per tooth. Total daily dose will be less than 1 milliliter. Saline will be applied directly to the marginal gingiva around each tooth (buccal and lingual).

Protocol documents:
Prot_000.pdf: 
ST266-PERIO-201 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED STUDY TO EVALUATE THE SAFETY, 
EFFICACY, AND TREATMENT REGIMEN OF ST266 IN 
SUBJECTS WITH MODERATE TO SEVERE 
PERIODONTITIS 
NCT2761993 


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1. 
+TITLE PAGE 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY, 
EFFICACY, AND TREATMENT REGIMEN OF ST266 IN 
SUBJECTS WITH MODERATE TO SEVERE 
PERIODONTITIS 
 
Name of Investigational Compound:  
ST266 
IND:  
 
 
 
 
 
 
 
 
 
15,825 
Investigational Phase: 
 
 
 
 
 
Phase 2a 
Study Number:  
 
 
 
 
 
 
ST266-PERIO-201 
 
Sponsor:  
 
 
 
 
 
 
 
 
Stemnion, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
100 Technology Drive, Suite 200 
 
 
 
 
 
 
 
 
 
 
 
 
Pittsburgh, PA 15219 
 
 
Date: 08 September 2017 
 
 
 
 
 
Confidentiality Statement 
This document contains information from Stemnion, Inc. and is of confidential, trade secret, 
and/or proprietary nature and may not be disclosed unless such disclosure is required by federal 
or state law or regulation. It is loaned to you for your confidential review on behalf of Stemnion 
Inc. only and is not to be photocopied, disclosed, or transmitted to any other person or party 
without the advance written approval of Stemnion, Inc. You are responsible for the safekeeping 
and return of this document to Stemnion, Inc. upon its request. You will be provided with 
updated information and amendments as they are available. 
 
 


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APPROVAL SIGNATURE PAGE 
/ 
-!ah Lessem, MD, PhD 
Medical Monitor, Consultant 
Date 
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INVESTIGATOR’S AGREEMENT 
 
I have read the protocol ST266-PERIO-201 and agree to conduct the study as outlined and in 
accordance with Good Clinical Practice (GCP) Guidelines. I agree to maintain the confidentiality 
of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Stemnion, Inc. 
Name of Investigational Product: 
ST266 [Amnion-derived Cellular Cytokine Solution (ACCS)] 
Name of Active Ingredient: 
ST266 (ACCS) is a novel secretome derived from proprietary cells. ST266 is composed of a complex 
mixture of cytokines, growth factors, nucleic acids, and undefined cellular components produced by 
cultured amnion-derived multi-potent progenitor (AMP) Cells in Iscove’s Modified Dulbecco’s 
Medium (IMDM). It contains at least 75 cytokines and growth factors in physiological concentrations 
and 2 proteins (0.5% human serum albumin and epidermal growth factor) that are added to support the 
growth of the cells. 
Title of Study:  
A randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, and treatment 
regimen of ST266 in subjects with moderate to severe periodontitis. 
Study Center(s): Multi-center (approximately 5 to 7 clinical sites in the United States) 
Phase of Development: Phase 2a 
Objectives:  
Primary: 
To determine the efficacy of ST266 to reduce pocket depth (PD) adjunctive to scaling and root planing 
(SRP). 
Secondary: 
To determine safety and changes in: 
• 
Clinical attachment level (CAL) 
• 
Bleeding on probing (BOP) 
Study Design: 
The study is a 9-month, randomized, double-blind, parallel-design study of subjects with existing 
moderate to severe periodontal disease randomly assigned to one of three groups. The primary endpoint 
of PD change will be evaluated following 9 months of treatment. Subjects will be followed for 
9 months for safety and radiographic evaluations. 
Subjects who meet inclusion criteria will be randomized to one of three treatment groups. 
Randomization will be stratified by site and smoker status (never smoked or quit smoking more than 
two years ago vs. has smoked within the last two years). Randomization will be blocked such that 
assignment to treatment groups both within sites and within smoker status will be approximately even 
(1:1:1). Treatment will be initiated after SRP. 
All subjects will be evaluated at baseline and Days 1, 15, 30, 60, 90, 180, and 270. 
Number of Subjects (Planned): A total of 150 subjects will be enrolled in the study, 50 per group. 
Study Duration per Subject: Each subject will be enrolled in the study for 9 months. 
 
 


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Diagnosis and Main Criteria for Inclusion:  
Moderate to severe periodontal disease according to American Academy of Periodontists (AAP) 
definition (at least 6 teeth with 6mm or greater PD and 3 mm or greater CAL at baseline). 
 
Inclusion Criteria: 
1. Provision of signed, written informed consent prior to participation in any study-related procedures. 
2. Good general health as evidenced by medical history. 
3. Between 18 and 85 years of age at time of informed consent signature. 
4. Male or female. 
5. Minimum of 18 teeth, excluding third molars. 
6. Having moderate to severe periodontal disease according to AAP definition (at least 6 teeth ≥6 mm 
PD and ≥3 mm CAL at baseline). 
7. Having >30 percent bleeding sites upon probing. 
8. Willing to abstain from chewing gums and other mouth rinses for the study duration. 
9. Ability and willingness to attend all study visits and comply with all study visits and comply with 
all study procedures and requirements. 
10. Willingness to abstain from routine dental care. 
11. For women with reproductive potential, willingness to use highly effective contraception (e.g. 
licensed hormonal contraception, intrauterine device, abstinence, or vasectomy in partner). 
 
Exclusion Criteria: 
1. Presence of orthodontic appliances. 
2. A soft or hard tissue tumor of the oral cavity. 
3. Any dental condition that requires immediate treatment, such as carious lesions. 
4. Participation in any other clinical study within 30 days of screening or during the study. 
5. Pregnancy or lactation. If a subject meets this criterion, she may be rescreened for study 
participation when she no longer meets this criterion. 
6. Antibiotic therapy within the last 30 days. 
7. Chronic use (≥3 times/week) of anti-inflammatory medications (e.g., non-steroidal 
anti-inflammatory drugs, steroids). Low-dose aspirin (less than 325 mg daily) is allowed. 
8. Immunocompromised subjects. 
9. Subjects with cancer or a history of cancer within the last 5 years of screening. 
10. Any medical history or any concomitant medication that might affect the assessment of the study 
treatment or periodontal tissues, such as diabetes, nifedipine, phenytoin (Dilantin), or anticoagulant 
medications (e.g., warfarin [Coumadin] etc.). 
11. Involvement in the planning or conduct of the study. 
12. History of any clinically significant disease or disorder which, in the opinion of the investigator, 
may either put the subject at risk because of participation in the study, or interfere with 
interpretation of the subject’s study results. 
13. Previous randomization for treatment in the present study. 
 
 


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Investigational product, dosage and mode of administration: 1X ST266 applied in a dose of 
20 microliters per tooth. Total daily dose will be less than 1 milliliter. ST266 will be applied directly to 
the marginal gingiva around each tooth (buccal and lingual) using sterile packaged pipette tips 
compatible with the Eppendorf Repeater M4 device. 
Duration of Treatment:  
Group 1: ST266 dosed daily on Days 1-5, 8-12, 22, and 30, and then monthly for 7 months (Days 60, 
90, 120, 150, 180, 210, and 240). 
Group 2: ST266 dosed 2x/week (with at least one day between treatments) for the first 3 months and 
monthly for 5 months thereafter (Days 120, 150, 180, 210, and 240). 
Group 3: Placebo dosed at the same frequency as Group 1. 
Placebo, Dosage, and Mode of Administration: Sterile saline (0.9% NaCl) will be applied in the 
same manner and in the same volume as the investigational product, ST266. 
Criteria for Evaluation: 
Efficacy: The primary efficacy endpoint of this study is the average change in each patient between the 
PD at baseline and the PD at 9 months (Day 270) for those pockets ≥6 mm at baseline. 
Secondary efficacy endpoints of this study are: (1) change from baseline in CAL at 9 months (Day 
270); (2) change from baseline in BOP at 9 months (Day 270); and (3) change from baseline in PD at 9 
months (Day 270) using all tooth-sites. 
Exploratory endpoints of this study are: (1) Pro-inflammatory mediators, enzymes, and bone markers 
will be measured in gingival crevicular fluid (GCF) and serum at the baseline, Days 15, 90, 180, and 
270; (2) microbial analysis of periodontal flora will be performed at baseline and at Days 15, 90, 180, 
and 270; and (3) change from baseline in radiographic bone levels (RBL) at Days 90 and 270; (4) 
FMPI analyzed at Days 90, 180 and 270; and (5) change from baseline in PD, CAL and BOP will be 
analyzed on Days 90 and 180. 
Safety: The safety endpoints are frequency and pattern of adverse events (AEs) and serious adverse 
events (SAEs). 
Planned Sample Size: The sample size for the study is based on the sample size required to reject the 
null hypothesis for the primary efficacy endpoint. 
The number of subjects was estimated based on 2 meta-analysis studies that reviewed 50 and 
72 articles respectively (Bonito, 2005) to reach a significant difference in PD reduction at 9 months 
compared with placebo. 
Using the normal approximation for sample size determination for 2 independent samples, t-tests, and 
assuming a PD reduction of 0.5 mm on average (difference in means) with a standard deviation of 
0.7 mm, alpha=0.05 (0.025 per comparison), and 85% power, a sample size of 44 per group will be 
required. The expected dropout rate is 20% based on previous experiments; hence 50 subjects will be 
enrolled per group.  Generalized estimating equations (GEE) analyses will be performed and therefore, 
the actual power will be between 85 and 90%. 
Statistical methods: Analysis of the clinical efficacy data will consist of modeling endpoints, 
including change from baseline in PD, CAL, BOP, and FMPI, with treatment group as a main effect 
and adjusting for baseline values of a given endpoint. Post-baseline treatment comparisons will be 
modeled through a GEE method (with a linear link and exchangeable covariance matrix), adjusting for 
the baseline value. Methods of analysis for periodontal flora, inflammatory cytokine levels in GCF and 
in serum, and RBL will be described in separate statistical analysis plans. Results will be considered 
significant if p<0.05. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................7 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................11 
5. 
INTRODUCTION ......................................................................................................12 
5.1. 
Trial Rationale ............................................................................................................12 
5.2. 
Experience with ST266 ...............................................................................................12 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................14 
6.1. 
Primary Objective .......................................................................................................14 
6.2. 
Secondary Objectives .................................................................................................14 
7. 
INVESTIGATIONAL PLAN .....................................................................................15 
7.1. 
Overall Study Design ..................................................................................................15 
7.2. 
Number of Subjects ....................................................................................................16 
7.3. 
Treatment Assignment ................................................................................................16 
7.4. 
Rescue Therapy ..........................................................................................................16 
7.5. 
Criteria for Study Termination ...................................................................................17 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................20 
8.1. 
Subject Inclusion Criteria ...........................................................................................20 
8.2. 
Subject Exclusion Criteria ..........................................................................................20 
8.3. 
Re-screening of Subjects ............................................................................................21 
8.4. 
Subject Withdrawal Criteria .......................................................................................21 
9. 
TREATMENT OF SUBJECTS ..................................................................................22 
9.1. 
Description of Study Drug ..........................................................................................22 
9.2. 
Concomitant Medications ...........................................................................................22 
9.3. 
Treatment Compliance ................................................................................................22 
9.4. 
Randomization and Blinding ......................................................................................23 
9.5. 
Treatment Visits ..........................................................................................................23 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................24 


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10.1. 
Study Drug ..................................................................................................................24 
10.2. 
Study Drug Packaging and Labeling ..........................................................................24 
10.3. 
Study Drug Storage .....................................................................................................24 
10.4. 
Study Drug Preparation ..............................................................................................24 
10.5. 
Administration ............................................................................................................24 
10.6. 
Study Drug Accountability .........................................................................................24 
10.7. 
Study Drug Handling and Disposal ............................................................................25 
10.8. 
Placebo ........................................................................................................................25 
11. 
ASSESSMENT OF EFFICACY ................................................................................26 
11.1. 
Criteria for Primary and Secondary Efficacy Endpoint Evaluations: .........................26 
11.2. 
Exploratory Evaluations .............................................................................................26 
11.3. 
Standardization and Calibration of Procedures ..........................................................27 
12. 
ASSESSMENT OF SAFETY .....................................................................................28 
12.1. 
Safety Parameters .......................................................................................................28 
12.1.1. 
Demographic/Medical History ...................................................................................28 
12.1.2. 
Vital Signs ..................................................................................................................28 
12.1.3. 
Weight and Height ......................................................................................................28 
12.1.4. 
General Assessments ..................................................................................................28 
12.1.5. 
Laboratory Assessments .............................................................................................28 
12.1.6. 
Hematology .................................................................................................................28 
12.1.6.1. 
Blood Chemistry .........................................................................................................29 
12.1.6.2. 
Urinalysis ....................................................................................................................29 
12.1.6.3. 
Pregnancy Screen ........................................................................................................29 
12.2. 
Adverse and Serious Adverse Events .........................................................................29 
12.2.1. 
Introduction .................................................................................................................29 
12.2.2. 
Adverse Event (AE) ....................................................................................................29 
12.2.3. 
Serious Adverse Event (SAE) ....................................................................................29 
12.2.4. 
Severity of AEs/SAEs .................................................................................................30 
12.3. 
Relationship to Study Drug and Expectedness ...........................................................31 
12.4. 
Collection and Recording Adverse Events .................................................................31 
12.4.1. 
Period of Collection ....................................................................................................31 
12.4.1.1. 
Methods of Collection ................................................................................................31 


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12.4.2. 
Recording Method ......................................................................................................32 
12.4.2.1. 
Adverse Events ...........................................................................................................32 
12.4.2.2. 
Serious Adverse Events ..............................................................................................32 
12.5. 
Recording and Reporting Adverse Events ..................................................................32 
12.5.1. 
Reporting SAEs to the Sponsor ..................................................................................32 
12.5.2. 
Reporting SAEs to Health Authorities .......................................................................33 
12.5.3. 
Reporting SAEs to IRB(s) or Ethics Committee(s) ....................................................33 
12.5.4. 
Reporting Pregnancy ..................................................................................................34 
13. 
STATISTICS ..............................................................................................................35 
13.1. 
Analysis Populations ..................................................................................................35 
13.2. 
Prevention and Treatment of Missing Data ................................................................35 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................36 
14.1. 
Study Monitoring ........................................................................................................36 
14.2. 
Audits and Inspections ................................................................................................36 
14.3. 
Institutional Review Board (IRB) ...............................................................................37 
14.4. 
Access to Protected Health Information (PHI) ...........................................................37 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................38 
16. 
ETHICS ......................................................................................................................39 
16.1. 
Ethics Review .............................................................................................................39 
16.2. 
Ethical Conduct of the Study ......................................................................................39 
16.3. 
Written Informed Consent ..........................................................................................39 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................40 
17.1. 
Inspection of Records .................................................................................................40 
17.2. 
Retention of Records ..................................................................................................40 
18. 
PUBLICATION POLICY ..........................................................................................41 
19. 
REFERENCES ...........................................................................................................42 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................11 
Table 2: 
ST-04-13 Efficacy Outcomes .....................................................................................13 
Table 3: 
Study Design and Schedule of Assessments ..............................................................18 
Table 4: 
Investigational Product ...............................................................................................22 
Table 5: 
Treatment Windows by Group (+/- Days) ..................................................................22 
Table 6: 
Attribution of Adverse Events ....................................................................................31 
 
LIST OF FIGURES 
Figure 1: 
Dosing Schedules ........................................................................................................19 
 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AAP 
American Academy of Periodontists 
AE 
Adverse event 
AMP 
Amnion-derived multi-potent progenitor cells 
BOP 
Bleeding on probing 
CAL 
Clinical attachment level 
CEJ 
Cemento-enamel junction 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FMPI 
Full-mouth plaque index 
GCF 
Gingival crevicular fluid 
GCP 
Good Clinical Practice 
GEE 
Generalized estimating equation 
HbA1c 
Glycated hemoglobin 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IL 
Interleukin 
IMDM 
Iscove’s Modified Dulbecco’s Medium 
IND 
Investigational New Drug Application 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
MMP 
Matrix metalloproteinase 
PD 
Pocket depth 
PGE2 
Prostaglandin E2 
RBL 
Radiographic bone level 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SRP 
Scaling and root planing 
ST266 
Study drug: amnion-derived cellular cytokine solution 


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5. 
INTRODUCTION 
Periodontal disease is a problem affecting millions of Americans and one for which adequate 
therapy is lacking. In periodontitis, an acute inflammatory reaction occurs and, if unresolved 
with failure of return of tissue to homeostasis, there is neutrophil-mediated tissue destruction, 
and inflammation becomes chronic. Although infection by Gram-negative bacteria such as 
Porphyromonas gingivalis is considered to be the primary etiologic factor in periodontal disease, 
the cause-and-effect relationship between the pathogen and disease is not clear. What is clear, 
however, is that a biofilm develops and left unchecked, tissue and bone of the periodontium are 
destroyed. To reduce the inflammatory response in tissues, drugs such as non-steroidal 
anti-inflammatory agents have been used with limited long-term success. Antibiotic therapy may 
provide a short-term benefit without a long-term solution. ST266 offers a novel alternative 
mechanism for treatment of periodontal disease. 
5.1. 
Trial Rationale 
Resolution of inflammation may reduce injury, promote healing, and return tissue homeostasis. 
Rapid elimination of the invading leukocytes from a lesion is the desired outcome following an 
inflammatory event. This task becomes more formidable when the acute inflammatory response 
progresses to chronic inflammation with destruction of the cellular matrix, scarring, and fibrosis. 
Thus, an essential goal for intervention in inflammatory disease is the return of tissue 
homeostasis (Serhan, 2011). Interventions in the management of periodontitis such as root 
planing offer some benefit in removing etiologic agents associated with inflammation and 
thereby arrest to some degree the periodontal disease; however, such procedures do not resolve 
the inflammation and restore tissue homeostasis. Without restoration of tissue homeostasis, 
inflammatory cells having pro-inflammatory products, such as prostaglandin E2 (PGE2), persist 
causing swelling, irritation, pain, collagen destruction, and ultimately bone resorption (Kantarci, 
2006). Agents that stimulate the resolution of inflammation may offer some therapeutic 
advantage in the treatment of periodontitis compared with more traditional pharmacologic 
interventions. 
5.2. 
Experience with ST266 
ST266, in some ways, may be ideally suited for treating periodontitis. ST266 has been shown in 
in vitro experiments to reduce the amount of inflammatory cytokines, specifically PGE2. In 
in vivo experimental models of periodontitis in rabbits, employed to evaluate the effect of ST266 
on periodontal disease, there was a marked reduction in the inflammation with the use of ST266. 
Furthermore, there was restoration of lost bone with histological evidence of resolution of the 
inflammatory infiltrates. 
In a phase 1 study of gingivitis, a related disease, 54 subjects (18 per arm) were treated. Subjects 
had a modified gingival index score of 2.0 or greater and >40% bleeding sites at initial 
presentation. Three (3) cohorts were tested: Two (2) different ST266 concentrations (1X and 
0.3X ST266) were compared with the saline placebo control cohort. Subjects received daily 
20 µL topical treatments per tooth for 10 days administered over 2 weeks (560 μL maximum 
dose). A follow-up visit was conducted at Day 42 for clinical measurements and safety analysis. 


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Efficacy results of the phase 1 study are summarized in Table 2. Statistically significant changes 
in clinical attachment level (CAL) and pocket depth (PD) were observed relative to placebo for 
both the 0.3X and 1X ST266 treatment groups at Day 42 (p <0.05). Furthermore, 
pro-inflammatory cytokine biomarkers, interleukin (IL)-1ß and IL-6, were significantly 
decreased in both the 0.3X and 1X ST266 treatment groups relative to placebo at Day 12 
(p <0.05). These findings suggest that ST266 has a beneficial effect in subjects with gingivitis 
and supports prior studies demonstrating anti-inflammatory properties of ST266 mediated via 
modulation of pro-inflammatory cytokines. 
Table 2: 
ST-04-13 Efficacy Outcomes 
 
No significant safety issues were identified in the phase 1 study. Safety parameters were 
compared for both ST266 treatment groups (1X and 0.3X) relative to placebo using appropriate 
statistical methods. This included adverse events (AEs), vital signs, and oral cavity examination 
results. One serious adverse event (SAE; assault-fractured cheek bone, laceration) occurred 
during this study that was clearly not related to the study protocol or study product. There were 
125 AEs/oral cavity exam findings reported during the entire study, all of which were 
categorized as mild. Out of 125 events, 3 (2.5%) were categorized as related, 5 (4%) were 
categorized as possibly related, and 5 (4%) were categorized as unlikely related. All related and 
possibly related events were reported by the same two subjects, both of whom were assigned to 
placebo. These results suggest that ST266 was safe and was well tolerated by subjects with 
gingivitis when administered at the 0.3X and 1X concentrations for at least 10 days of treatment.  
Periodontitis with severe bony destruction remains the primary cause of tooth loss. ST266 has 
been shown to be profoundly anti-inflammatory in both in vitro and in vivo preclinical 
experiments including an accepted rabbit model of periodontitis. These findings, coupled with 
the excellent safety profile for ST266 in both animal testing and a phase 1 clinical trial as well as 
use of ST266 in topical dermal and topical ocular trials in more than 90 subjects, support the 
proposed clinical investigation of ST266 in the treatment of periodontal disease. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective is to determine the efficacy of ST266 to reduce pocket depth (PD) as an 
adjunctive to scaling and root planing (SRP). 
6.2. 
Secondary Objectives 
The secondary objectives of this study are to determine: (1) safety as established by assessment 
of AEs and SAEs, and (2) changes in the following clinical parameters: 
• Clinical attachment level (CAL) 
• Bleeding on probing (BOP) 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
The study is a 9-month, randomized, double-blind, placebo-controlled, parallel-design study of 
subjects with existing moderate to severe periodontal disease. The study design and duration is 
similar to the study design with previous compounds, e.g. Minocycline Microspheres, 
chlorhexidine chip, and others.  Subjects will be recruited at multiple treatment sites. All subjects 
will be treated by a dental professional at the study site. The dental professional will be a 
qualified and trained licensed periodontist, dentist, or dental hygienist skilled in periodontal 
clinical research. All investigators will be trained in grading clinical parameters in the same 
manner for consistency. After signing informed consent, subjects will be screened with a medical 
and dental history and full mouth dental examination. Clinical parameters will be recorded 
including PD, CAL, and BOP. Subjects will have urinalysis in addition to blood tests including 
hematology and chemistry (liver and kidney function) panels. Women of child-bearing potential 
will be administered a pregnancy test. 
If inclusion/exclusion criteria are met, subjects will undergo a baseline visit with measurements 
of FMPI, collection of gingival crevicular fluid (GCF), and blood samples. Subgingival plaque 
samples will be collected for microbial analysis. Vertical bitewing X-rays will be collected to 
assess RBL. Subjects will undergo SRP procedure(s) prior to being randomly assigned to 1 of 
3 treatment groups indicated in Section 7.3. Local anesthesia must be used for SRP. All 
treatments of ST266 or placebo will be administered in office by a dental professional.  
All subjects will be evaluated at screening, baseline, and Days 1, 15, 30, 60, 90, 180, and 270. 
Evaluations will be performed by a blinded dental professional to mask the group as all groups 
do not have the same study schedule. The blinded examiners will be independent from the dental 
professionals who apply the study drug to the subjects, thereby ensuring that the treatment 
assignment cannot be inferred based on the treatment schedule. 
At each evaluation, medical and dental history will be updated, an oral exam will be performed, 
and AEs and SAEs will be assessed and recorded. PD, CAL, and BOP will be evaluated at 
screening and on Days 15, 30, 60, 90, 180, and 270. Subjects will have urinalysis in addition to 
blood tests including hematology and chemistry (liver and kidney function) panels done at 
screening and repeated at Days 90 and 270. FMPI will be recorded at baseline and on Days 15, 
30, 60, 90, 180, and 270. Inflammatory cytokines in serum will be measured at baseline and on 
Days 15, 90, 180, and 270. GCF will be collected and analyzed at baseline and on Days 15, 90, 
180, and 270. Microbial analysis of periodontal flora will be performed at baseline and on 
Days 15, 90, 180, and 270. 
At each treatment visit, in addition to administration of ST266 or placebo, medical and dental 
history will be updated, AEs and SAEs will be assessed and recorded, concomitant medications 
will be recorded, and oral hygiene instruction will be provided. 
Randomization will be stratified by site and smoker status (never smoked or quit smoking more 
than two years ago vs. has smoked within the last two years). Randomization will be blocked 
such that assignment to treatment groups both within sites and within smoker status will be 


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approximately even (1:1:1). ST266 will be supplied to the study site and prepared for use by 
trained clinical staff, who will not be the same as the dental professionals evaluating the subjects. 
Primary Endpoint: The primary effectiveness endpoint of this study is the average change in 
PD from baseline to 9 months (Day 270) in tooth-sites with baseline PD ≥ 6mm.  This endpoint 
will be analyzed at the patient level similar to other studies. 
Secondary Endpoints: Secondary efficacy endpoints of this study are: (1) change from baseline 
in CAL at 9 months (Day 270) with baseline PD ≥ 6mm; (2) change from baseline in BOP at 9 
months (Day 270) using whole-mouth average, and (3) change from baseline in PD at 9 months 
(Day 270) using all tooth-sites.  
Baseline refers to the initial measurement of the endpoint, which may occur at the screening or 
baseline visit according to the schedule of assessments. 
Safety Endpoints: The safety endpoints are frequency and pattern of AEs and SAEs. 
Exploratory Endpoints: Pro-inflammatory mediators, enzymes, and bone markers will be 
measured in GCF and serum at baseline and on Days 15, 90, 180, and 270. Microbial analysis of 
periodontal flora will be performed at baseline and on Days 15, 90, 180, and 270.  Change from 
baseline in RBL will be measured at Days 90 and 270. All x-rays for RBL will be read at a 
central location using predefined criteria.  PD, CAL and BOP will also be analyzed at Days 90 
and 180. FMPI will also be analyzed at Days 90, 180 and 270. 
7.2. 
Number of Subjects 
One hundred and fifty (150) subjects will be enrolled. The sample size for the study is based on 
the sample size required to reject the null hypothesis for the primary efficacy endpoint which 
contains two comparisons. Using the normal approximation for sample size determination for 
two independent samples, t-tests, and assuming a PD reduction of 0.5 mm on average (difference 
in means) with a standard deviation of 0.7 mm, alpha=0.05 (Bonferroni corrected, alpha 0.025 
per comparison), and 85% power, a sample size of 44 per group will be required. The expected 
dropout rate is 20% based on previous experiments and current enrollment trends hence 50 
subjects will be enrolled per group.  GEE analyses will be performed and therefore, the actual 
power will be between 85 and 90%.   
7.3. 
Treatment Assignment 
Group 1: ST266 dosed daily on Days 1-5, 8-12, 22, and 30 and then monthly for 7 months 
(Days 60, 90, 120, 150, 180, 210, and 240). 
Group 2: ST266 dosed 2x/week (with at least one day between treatments) for the first 3 months 
and monthly for 5 months thereafter (Days 120, 150, 180, 210, and 240). 
Group 3: Placebo dosed at the same frequency as Group 1. 
7.4. 
Rescue Therapy 
If at Day 90 or later a subject experiences progression of periodontitis in any tooth, rescue 
therapy will be provided. Progression of periodontitis is defined as an increase of 2 mm or more 
in PD or CAL from the baseline measurement (Goodson, 1982). Rescue therapy will consist of 


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the standard of care therapy at the tooth site where progression of periodontal disease occurred. 
Rescue therapy at the tooth site may occur immediately at the scheduled visit, or as soon as the 
investigator determines is reasonable to ensure the subject receives standard of care therapy. 
Subjects that receive rescue therapy will continue to participate in all remaining study visits 
through study completion. 
7.5. 
Criteria for Study Termination 
Safety assessments will be performed throughout the course of the study. Any potential safety 
issues that arise will be reviewed by the sponsor’s Medical Monitor in consultation with the 
study investigators to identify the appropriate course of action. If the sponsor elects to terminate 
the study for any reason, the investigator will be responsible for notification of the institutional 
review board (IRB) and will withhold further treatment of study participants. 


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Table 3: 
Study Design and Schedule of Assessments 
Evaluation 
 
 
 
 
Treatment and Follow-up Period 
Visit 1 
Visit 2 
Visit 3/3b 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10/EOS 
Screening 
Baseline 
(≤30 days from 
screening) 
SRP 
(≤10 days from 
baseline) 
Day 1a 
(≤3 days from SRP) 
Day 15 
(±1 day) 
Day 30 
(±3 days) 
Day 60 
(±3 days) 
Day 90 
(±5 days) 
Day 180 
(±7 days) 
Day 270 
(±7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (female subjects) 
X 
 
 
 
 
 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Dental History 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
Xb 
 
 
 
 
 
 
 
 
X 
Medical/Dental History Updateg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
Xc 
 
 
 
 
 
 
 
SRPd 
 
 
X 
 
 
 
 
 
 
 
Full Mouth Plaque Index 
(FMPI) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Clinical Measurements 
(PD, CAL, BOP) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
GCF Sampling 
 
X 
 
 
X 
 
 
Xe 
Xe 
X 
Serum Sampling 
 
X 
 
 
X 
 
 
X 
X 
X 
Microbial Sampling 
 
X 
 
 
X 
 
 
X 
X 
X 
Radiographs 
 
X 
 
 
 
 
 
X 
 
X 
General Labs 
Xf 
 
 
 
 
 
 
X 
 
X 
Administration of Test Article 
 
 
 
In-office treatments as scheduled in Figure 1 
 
Oral Hygiene Instructiong 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BOP=bleeding on probing; CAL=clinical attachment level; EOS=end of study; FMPI=full-mouth plaque index; GCF=gingival crevicular fluid; HbA1c=glycated hemoglobin; 
IWRS=interactive web response system; PD=pocket depth; SRP=scaling and root planing. 
a The first in-office treatment may be performed on the same day as the last SRP visit. The last SRP may occur on Visit 3/3b, or as an Unscheduled Visit. The Unscheduled Visit may be 
combined with Visit 4. Product administration must occur within 3 days of the last SRP visit.  
b Height is measured only at screening. 
c Randomization occurs by IWRS after SRP has been completed. 
d SRP may be initiated on the same day as the Baseline visit and may require more than one visit. Subjects with moderate to heavy deposits will typically have no more than two 
quadrants treated in a single SRP visit. Local anesthesia must be used for SRP. 
e Sample is collected before treatment is applied. 
f HbA1c is measured at screening only. 
g Performed at each treatment visit, as well as at each evaluation visit. 


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Figure 1: Dosing Schedules 
 
 
Treatment Windows by Group (+/- Days) 
 
Visit Day 
Groups 1, 3 
≤12 
22 
30 
60 
90 
120 
150 
180 
210 
240 
N/A 
3 
3 
3 
5 
7 
7 
7 
7 
7 
 
Group 2 
≤ 90 
120 
150 
180 
210 
240 
N/A 
7 
7 
7 
7 
7 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Provision of signed, written informed consent prior to participation in any study-related 
procedures. 
2. Good general health as evidenced by the medical history. 
3. Between 18 and 85 years of age at the time of informed consent signature. 
4. Male or female. 
5. Minimum of 18 teeth, excluding third molars. 
6. Having moderate to severe periodontal disease according to American Academy of 
Periodontists (AAP) definition (at least 6 teeth with ≥6 mm PD and ≥3 mm CAL at 
baseline). 
7. Having >30 percent bleeding sites upon probing. 
8. Willing to abstain from chewing gums and other mouth rinses for the study duration. 
9. Ability and willingness to attend all study visits and comply with all study procedures 
and requirements. 
10. Willingness to abstain from routine dental care. 
11. For women with reproductive potential, willingness to use highly effective contraception 
(e.g., licensed hormonal contraception, intrauterine device, abstinence, or vasectomy in 
partner). 
8.2. 
Subject Exclusion Criteria 
1. Presence of orthodontic appliances. 
2. A soft or hard tissue tumor of the oral cavity. 
3. Any dental condition that requires immediate treatment, such as carious lesions. 
4. Participation in any other clinical study within 30 days of screening or during the study. 
5. Pregnancy or lactation. If a subject meets this criterion, she may be rescreened for study 
participation when she no longer meets this criterion. 
6. Antibiotic therapy within the last 30 days. 
7. Chronic use (≥3 times/week) of anti-inflammatory medications (e.g., non-steroidal 
anti-inflammatory drugs, steroids). Low-dose aspirin (less than 325 mg daily) is allowed. 
8. Immunocompromised subjects. 
9. Subjects with cancer or a history of cancer within the last 5 years of screening. 


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10. Any medical history or any concomitant medication that might affect the assessment of 
the study treatment or periodontal tissues, such as diabetes1, nifedipine, phenytoin 
(Dilantin), or anticoagulant medications (e.g., warfarin [Coumadin] etc.). 
11. Involvement in the planning or conduct of the study. 
12. History of any clinically significant disease or disorder which, in the opinion of the 
investigator, may either put the subject at risk because of participation in the study, or 
interfere with interpretation of the subject’s study results. 
13. Previous randomization for treatment in the present study. 
8.3. 
Re-screening of Subjects 
Subjects may be re-screened provided that they do not fail inclusion criterion 6 (having moderate 
to severe periodontal disease according to the AAP definition [at least 6 teeth with ≥6 mm PD 
and ≥3 mm CAL at baseline]). 
8.4. 
Subject Withdrawal Criteria 
Subjects may voluntarily withdraw from the study, or be removed from the study at the 
discretion of the investigator or sponsor at any time. If such withdrawal occurs, or if the subject 
fails to return for visits, the investigator should determine the primary reason for a subject’s 
premature withdrawal from the study and record the reason in the subject’s study records. 
All subjects prematurely discontinuing from the trial, regardless of cause, should be scheduled as 
soon as possible for a follow-up safety visit, which will include all assessments planned for 
Day 270 (end of study). 
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
document all steps taken to contact the subject, e.g., dates of telephone calls, registered letters, 
etc. 
Subjects who are withdrawn from the study after beginning treatment will not be replaced. 
 
 
 
 
 
_________________________ 
1 For the purposes of subject exclusion, diabetes is defined as any subject with (i) a history of 
type 1 or type 2 diabetes, (ii) prior or concomitant prescription of diabetes medications, or (iii) a 
laboratory test for glycated hemoglobin ≥6.5. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name: 
ST266 [Amnion-derived Cellular Cytokine Solution (ACCS)] 
Dosage Form: 
Liquid to be applied by pipette 
Unit Dose 
20 μL/tooth 
Route of Administration 
Topical application directly to the marginal gingiva 
Physical Description 
Clear to slightly yellow liquid that is free of particulates 
Manufacturer 
Stemnion, Inc. 
9.2. 
Concomitant Medications 
Use of concomitant treatment must be recorded in the subject’s medical record and the electronic 
case report form (eCRF), including treatment/drug name, dose, indication, and start/stop dates. In 
addition, no homeopathic remedies (such as treatment with coconut oil) may be used during the 
study. 
9.3. 
Treatment Compliance 
Every treatment application of study drug will be performed in the dental clinic by the 
clinician/investigator (dental professional); therefore, non-compliance can be assessed easily by 
the investigator. 
Treatments that are missed may be completed if done within the number of days indicated in 
Table 5 from the original scheduled date. 
Subjects who miss 20% or more of their prescribed treatments will be considered non-compliant 
and excluded from the per-protocol statistical analysis. 
Table 5: 
Treatment Windows by Group (+/- Days) 
 
Visit Day 
Groups 1, 3 
≤12 
22 
30 
60 
90 
120 
150 
180 
210 
240 
N/A 
3 
3 
3 
5 
7 
7 
7 
7 
7 
 
Group 2 
≤ 90 
120 
150 
180 
210 
240 
N/A 
7 
7 
7 
7 
7 
 


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9.4. 
Randomization and Blinding 
A randomization scheme will be generated via interactive web response system (IWRS). 
Subjects will be randomized at the site after SRP is complete. Randomization will be stratified 
by site and smoker status (never smoked or quit smoking more than two years ago vs. has 
smoked within the last two years). Randomization will be blocked such that assignment to 
treatment groups both within sites and within smoker status will be approximately even (1:1:1). 
Any subjects that are discontinued after randomization and prior to treatment may be replaced. 
Examiners will be blinded to the treatment assignment. 
A list of all subjects who have been treated will be maintained at the trial site, including each 
subject’s identity, date of enrollment, and corresponding subject ID, so that any subject may be 
identified if required for any reason. The list is kept by the clinical site and must not be available 
to the sponsor. The electronic data collection system (EDC) will assign a screening ID number 
when a subject’s data is entered at the screening visit. The subject will be identified only by that 
number until he/she is either randomized or withdrawn from the study. Upon randomization, the 
subject’s screening ID number will be converted to a randomization ID number. Subjects will be 
identified only by either the screening ID number or the randomization number. 
Treatment assignments will be blinded to the examiner, treatment administrator, and the subjects. 
Only in case of medical emergency or occurrence of AEs that warrant unblinding in the opinion 
of the Medical Monitor, will the treatment assignment be unblinded and made available to the 
investigator and the Medical Monitor. In the event of study unblinding, a non-study statistician 
will be assigned as the “unblinded statistician” to assist in unblinding and any safety review. 
If the investigator feels it is necessary to unblind a subject’s treatment assignment after an 
emergency situation, the investigator should contact the Medical Monitor or designee. Only after 
consultation with the Medical Monitor will a decision be made as to whether the treatment for 
the subject should be unblinded. The treatment assignment will be revealed on a subject-by-
subject basis, thus leaving the blinding on the remaining subjects intact. 
9.5. 
Treatment Visits 
Treatment visits will consist of a review of the subject’s medical and dental history, including 
recording concomitant medications. Additionally, the study medication will be applied to the 
buccal and lingual surfaces of the teeth.  Following the application of the study medication an 
assessment of AEs will be performed.  Subjects will be given oral hygiene instructions prior to 
the end of the visit. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
ST266 (ACCS) is a novel secretome derived from proprietary cells. ST266 is composed of a 
complex mixture of cytokines, growth factors, nucleic acids, and undefined cellular components 
produced by cultured amnion-derived multi-potent progenitor (AMP) Cells in Iscove’s Modified 
Dulbecco’s Medium (IMDM). It contains at least 75 cytokines and growth factors in very low or 
physiological concentrations and 2 proteins (0.5% human serum albumin and epidermal growth 
factor) that are added to support the growth of the cells. 
10.2. 
Study Drug Packaging and Labeling 
ST266 will be provided to the clinical site in two container types: frozen in sterile, single-use 
glass vials and in refrigerated liquid form provided in single-use plastic ampoules. Eppendorf 
pipettes and sterile pipette tips to be used for topical application of ST266 will also be provided 
to the site. The dispensing vials and pipette tips are single-use and will not be re-used. 
10.3. 
Study Drug Storage 
ST266 must be stored per container type.  
• ST266 in single-use glass vials must be stored frozen (-20±5°C) until the day of use. 
• ST266 in single-use plastic ampoules must be stored refrigerated (2-8°C) until the 
day of use. 
10.4. 
Study Drug Preparation 
The study staff assigned and trained for “product handling” will transfer ST266 to a 5 mL tube 
(RNase, DNase and pyrogen free) that is then provided to the dental clinic.  
• ST266 in single-use glass vials must be thawed prior to dispensing 1.5 mL of ST266 
to a 5 mL tube. 
• ST266 contained in a single-use plastic ampoule is ready to use. Approximately, 
1.3±0.2 mL of ST266 is transferred to a 5 mL tube. 
10.5. 
Administration 
In the dental clinic, the Eppendorf pipette with the sterile tip supplied by the sponsor will be 
filled with 1 mL of ST266. Twenty (20) microliters (10 μL to buccal surfaces and 10 μL to 
lingual surfaces) of ST266 will be applied directly to each tooth at the gingival margin by the 
study clinician at each treatment visit. The total daily dose will be less than 1 mL. 
10.6. 
Study Drug Accountability 
Used and unopened containers of study drug will be retained in the study pharmacy for drug 
reconciliation by study staff trained in product handling and accountability. 


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10.7. 
Study Drug Handling and Disposal 
Study drug must be handled with protective gloves and mask. Opened containers of study drug 
from the clinic will be disposed of onsite using the standard handling protocol for the clinic after 
drug accountability has been performed by the sponsor or its agents. Unopened containers of 
study drug will be returned to Stemnion after accountability is performed at the end of the study 
for each site. 
10.8. 
Placebo 
Commercially available sterile saline (0.9% NaCl) will be supplied to the clinical site by the 
sponsor for use as the placebo (treatment for Group 3) for the study. Sterile saline is stored at 
room temperature as indicated by the packaging and is ready for use. Sterile saline will be 
applied in the same manner and in the same volume as the investigational product, ST266. 
Accountability, handling, and disposal procedures are the same as for the study drug. 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Criteria for Primary and Secondary Efficacy Endpoint Evaluations: 
a. Pocket Depth (PD): Periodontal pocket depth will be determined with a UNC-15 
periodontal probe at 6 sites per tooth, and rounded to the next lower whole millimeter. 
b. Clinical Attachment Level (CAL): The measurement of the position of the soft tissue 
in relation to the cemento-enamel junction (CEJ) that is a fixed point, using probing 
depth and the distance from the gingival margin to the CEJ. 
c. Bleeding On Probing (BOP): Dichotomous score of 0 or 1 indicating whether the site 
bleeds upon probing is performed independently of the gingival index measurement. 
Bleeding on probing will be measured from the 6 sites of the tooth as a secondary 
periodontitis variable: 
0 = No bleeding 
1 = Bleeding within 15 seconds following probing 
11.2. 
Exploratory Evaluations 
a. Cytokine/Chemokine Analysis: In order to detect the changes in local (GCF) and 
systemic (blood serum) levels of pro-inflammatory mediators, enzymes, and bone 
markers that are known to play a role in the tissue destruction and bone 
resorption/formation, analysis will be analyzed in the of GCF and serum specimens. 
For this purpose, pro-inflammatory mediators including, cytokines/chemokines 
(IL-1b, IL-6, IL-8, IL-17A), matrix metalloproteinases (MMPs) including MMP-1, 
MMP-8, and MMP-9, and bone markers (RANKL, Osteoprotegrin) will be analyzed. 
Crevicular fluid samples will be obtained from up to 4 teeth before the first dose of 
ST266, and before dosing on Days 15, 90, 180, and 270, if applicable. Cytokine 
analysis will also be obtained from serum samples collected at baseline and on 
Days 15, 90, 180, and 270. 
b. Microbial Analysis: To detect subgingival microflora, subgingival plaque samples 
from the 2 teeth with the deepest PD will be collected at baseline and on Days 15, 90, 
180, and 270, and analyzed using a DNA-DNA hybridization technique to provide a 
qualitative and semi-quantitative assessment of oral bacteria including: Treponema 
denticola, Tannerella forsythia, Porphyromonas gingivalis, Centruroides gracilis, 
Campylobacter rectus, Campylobacter showae, Eubacterium nodatum, 
Fusobacterium periodonticum, Fusobacterium nucleatum polymorph, Fusobacterium 
nucleatum nucleatum, Fusobacterium nucleatum vincenti, Prevotella intermedia, 
Parvimonas micra, Prevotella nigrescens, Streptococcus constellatus, Streptococcus 
gordonii, Streptococcus intermedia, Streptococcus mitis, Streptococcus oralis, 
Streptococcus sanguinis, Aggregatibacter actinomycetemcomitans, Capnocytophaga 
gingivalis, Capnocytophaga ochracea, Capnocytophaga sputigena, Eikenella 
corrodens, Actinomyces odontolyticus, Veillonella parvula, Actinomyces 
gerencseriae, Actinomyces israelli, Actinomyces naeslundii, Actinomyces viscosus, 
Eubacterium saburreum, Gemella morbillorum, Leptotrichia bucallis, Neisseria 


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mucosa, Propionibacterium acnes, Prevotella melaninogenica, Streptococcus 
anginosus, Selenomonas noxia, and Treponema socranskii. Results will be compared 
with known probe standards and scored on an ordinal scale of 0 to 5 as follows: 
0 = No signal detected 
1 = <105 bacteria 
2 = ~105 bacteria 
3 = >105 bacteria 
4 = ~106 bacteria 
5 = >106 bacteria 
c. Radiographic Bone Level (RBL): Up to four vertical bitewing x-ray radiographs will 
be obtained at baseline and Days 90 and 270. For each time point, a total of two (2) 
radiographs will be taken from each side of the mouth. Crestal bone levels will be 
measured in mm relative to the CEJ, and changes in bone levels at Days 90 and 270 
will be calculated relative to the baseline measurement. This procedure will be 
standardized for all sites, and radiographs will be interpreted by a central reading 
center. 
d. Full-mouth Plaque Index (FMPI, Turesky modification of Quigley-Hein): Disclosing 
solution will be applied to the teeth and then plaque will be measured at 6 sites of 
each tooth.  
0 = No plaque 
1 = Separate flecks of plaque at the cervical margin of the tooth. 
2 = A thin continuous band of plaque (up to 1 mm) at the cervical margin of the tooth. 
3 = A band of plaque wider than 1 mm but covering less than one-third of the crown 
of the tooth. 
4 = Plaque covering at least one-third but less than two-thirds of the crown of the 
tooth. 
5 = Plaque covering two-thirds or more of the crown of the tooth. 
11.3. 
Standardization and Calibration of Procedures 
Clinical assessments of PD, CAL, and BOP will be used to assess the efficacy of the therapy. 
Radiographic procedures, GCF, FMPI, and microbial sampling will also be performed.  All of 
these procedures are prone to technique-sensitive sources of variability and require 
standardization and/or calibration exercises to minimize measurement variability. Such training 
exercises at each site will occur prior to the start of screening at each respective site. A dedicated 
oral examiner at the primary clinical center will serve as the “gold standard” examiner for 
calibration sessions. Details of the training protocols are provided in the Clinical Procedures 
Manual. 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The scope of safety monitoring is to assess the potential risks to the participants and ensure the 
safety of the participants during this trial. In order to monitor the data and safety, all necessary 
data including AE/SAE reports, safety reports (from Stemnion), subjects’ medical/medication 
history, concomitant medication reports, review of subject conduct/compliance, soft and hard 
tissue evaluations at every visit, and dropout rates will be used and reviewed throughout the 
study. Serum chemistry including liver and kidney function, complete blood count, and 
urinalysis will be done at screening, Day 90, and Day 270. In women of child-bearing potential, 
a pregnancy test will be performed prior to enrollment and again at the last study visit (Day 270). 
12.1.1. 
Demographic/Medical History 
Complete medical history will be taken at screening. Interim history will be taken at each 
treatment and follow-up visit. 
12.1.2. 
Vital Signs 
Blood pressure, heart rate, temperature, and respiratory rate will be recorded at screening, 
baseline, and at each evaluation visit. 
12.1.3. 
Weight and Height 
Height and weight will be recorded at screening and weight will be recorded at Day 270. 
12.1.4. 
General Assessments 
A general assessment looking for allergic and potential toxic reactions will be made at each visit 
prior to treatment with study drug. The oral mucosa will be examined at each visit. 
12.1.5. 
Laboratory Assessments 
Blood (10 to 15 mL) and urine samples (3 to 5 mL) will be sent to a certified laboratory for 
hematology, blood chemistry, and urine tests at screening and at Days 90 and 270. If a subject 
has any laboratory value that was normal upon entry into the trial and becomes abnormal, the 
sponsor’s Medical Monitor will review the data with the investigator to assess whether the 
laboratory value represents a safety concern. 
12.1.6. 
Hematology 
Complete blood count will be performed at screening and at Days 90 and 270. If a subject 
develops hemoglobin, hematocrit, or white blood cell count outside the normal range (as per the 
laboratory normal range values), that case will be reviewed by the sponsor’s Medical Monitor. 
The Medical Monitor may determine that the subject will receive no further study drug 
treatment. 


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12.1.6.1. Blood Chemistry 
Serum glucose, C-reactive protein, blood urea nitrogen, creatinine, electrolytes, HbA1c (at 
screening only), and liver function including bilirubin and hepatic enzymes will be measured at 
screening and at Days 90 and 270.  
12.1.6.2. Urinalysis 
Urinalysis will be performed at screening and at Days 90 and 270. If a subject develops 
hematuria or proteinuria after treatment is initiated, that case will be reviewed by the sponsor’s 
Medical Monitor, who may determine that the subject will receive no further study drug 
treatment. 
12.1.6.3. Pregnancy Screen 
Urine pregnancy testing will be performed at screening and at the final visit (Day 270) on 
females of child-bearing potential using commercially available pregnancy tests. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Introduction 
This section defines the types of AEs and outlines the procedures for appropriately collecting, 
grading, recording, and reporting them. Information in this section complies with Title 21 Code 
of Federal Regulations (CFR) Part 312, International Conference on Harmonisation (ICH) 
Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, and ICH Guideline E6: Good Clinical Practice: Consolidated Guidance. 
The investigator is responsible for the detection and documentation of AEs regardless of 
treatment group or suspected causal relationship to the investigational product. For all AEs, the 
investigator must pursue and obtain information adequate to determine the outcome of the AE 
and to assess whether it meets the criteria for classification as a SAE requiring immediate 
notification to the sponsor or its designated representative. 
12.2.2. 
Adverse Event (AE) 
An AE is defined as any untoward or unfavorable medical occurrence associated with the 
subject’s participation in the research, whether or not considered related to the subject’s 
participation in the research. Any medical condition that is present at the time that the subject is 
screened will be considered as medical history and not recorded as an AE; however, if the 
condition worsens at any time during the study, it will be recorded and reported as an AE. 
All AEs that occur after any subject signed consent, before treatment, during treatment, or within 
30 days following the last final dose of treatment, whether or not they are related to the study, 
must be recorded. 
12.2.3. 
Serious Adverse Event (SAE) 
An AE is considered “serious” if, in the view of either the investigator or the sponsor, it results in 
any of the following outcomes (21 CFR 312.32(a)): 


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• Death: A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported to the 
Sponsor whether it is considered treatment related or not. 
• Is life-threatening: An AE or suspected adverse reaction (SAR) is considered 
“life-threatening” if, in the view of either the investigator or the sponsor, its 
occurrence places the participant at immediate risk of death. It does not include an 
AE or SAR that, had it occurred in a more severe form, might have caused death. 
• In-patient hospitalization or prolongation of existing hospitalization. Planned 
hospitalization or planned prolonged hospitalization do not fulfill the criteria for 
being an SAE, but should be documented in the subject’s medical record. Additional 
details further defining hospitalization criteria can be found in the Clinical Procedures 
Manual. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly or birth defect. 
Or 
• Is a medically important condition, i.e., events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition 
above. Examples are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, and convulsions that do not result in 
hospitalization, development of drug dependency, or drug abuse. 
All SAEs that occur after any subject has signed consent, before treatment, during treatment, or 
within 30 days following the final dose of treatment, whether or not they are related to the study, 
must be recorded. 
If an event meets any of the above definitions, regardless of the severity or relationship of the 
event to the study product, the event must be reported to the sponsor as described in 
Section 12.5.1. 
12.2.4. 
Severity of AEs/SAEs 
The study site will grade the severity of AEs experienced by study participants according to the 
following criteria: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
• Life-threatening 
Note: The terms serious and severe are not synonymous. Serious criteria as defined in 
Section 12.2.3 above serve as a guide for defining regulatory reporting obligations. The term 
severe is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 


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or severe headache); the event itself, however, may be of relatively minor medical significance. 
This is not the same as serious, which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or functioning. Therefore, an AE of 
severe headache might not be considered serious, but a moderate infection for which a subject is 
hospitalized should be reported as an SAE. 
12.3. 
Relationship to Study Drug and Expectedness 
An investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (not related, possibly related, or definitely related). The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “not related.” If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possibly” or “definitely,” the event will be considered to be related to the investigational 
product for the purposes of expedited regulatory reporting. 
The sponsor’s determination of attribution will be used for reporting to the appropriate health 
authorities. The relation of an AE to study participation will be determined using the descriptors 
and definitions provided in Table 6. Additionally, in this study there are no suspected SAEs and 
all SAEs will be considered suspected unexpected serious adverse reactions (SUSARs). 
Table 6: 
Attribution of Adverse Events 
Not related 
The AE is clearly not related.  
Possibly 
related 
The AE has a reasonable possibility to be related; there is evidence to suggest a 
causal relationship.  
Definitely 
related 
The AE is clearly related. 
12.4. 
Collection and Recording Adverse Events 
12.4.1. 
Period of Collection 
All AEs and SAEs will be collected from the time the informed consent is signed until the end of 
the study. All AEs and SAEs that occur after any subject has signed consent, before treatment, 
during treatment, or within 30 days following the final dose of treatment, whether or not they are 
related to the study, must be recorded. 
12.4.1.1. Methods of Collection 
Adverse events may be collected as follows: 
• Observing the participant 


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• Questioning the participant in an unbiased and non-leading manner 
• Receiving an unsolicited complaint from the participant 
An abnormal value or result from a clinical or laboratory evaluation can also indicate an AE if it 
is determined by the investigator to be clinically significant. If this is the case, it must be 
recorded in the source document and as an AE on the appropriate AE form(s). The evaluation 
that produced the value or result should be repeated until that value or result returns to normal or 
is stable, establishing a new baseline and the participant’s safety is not at risk. 
An abnormal laboratory value recorded at screening is not considered an AE, but is treated as a 
preexisting condition and should be recorded in the subject’s medical history. 
12.4.2. 
Recording Method 
12.4.2.1. Adverse Events 
Throughout the study, the investigator will record AEs on the appropriate eCRF regardless of 
their severity or relation to the study product. The investigator will treat participants 
experiencing AEs appropriately and observe them at suitable intervals until their symptoms 
resolve or their status stabilizes.  
Once recorded, an AE will be followed until it either; resolves with or without sequelae, the 
subject ends study participation, 30 days after the final dose of study treatment, or 30 days after 
the subject prematurely withdraws (without withdrawing consent) or is withdrawn from the 
study, whichever occurs first. 
12.4.2.2. Serious Adverse Events 
Serious adverse events will be recorded on the AE eCRF and on the SAE eCRF, and health 
authorities will be notified as outlined in Section 12.5.2. 
12.5. 
Recording and Reporting Adverse Events 
After learning that a participant has experienced an AE, the investigator or designee is 
responsible for recording the AE in the eCRF, regardless of relationship or expectedness. If the 
AE is determined to be serious, expedited reporting is required per Section 12.5.1. 
12.5.1. 
Reporting SAEs to the Sponsor 
The following process for reporting an SAE ensures compliance with 21 CFR 312 and ICH 
guidelines. After learning that a participant has experienced an SAE, the investigator or designee 
is responsible for reporting the SAE, regardless of relationship or expectedness, within 
1 business day of becoming aware of the event. The initial SAE report should include as much 
information as possible, but at a minimum must include the following: 
• Reporter 
• Subject ID 
• Serious AE term 
• Relationship to study medication(s) 


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• Reason why the event is serious 
Supplemental eCRF pages should be current at the time of SAE reporting: medical history, 
concomitant medications, demographics, and death as applicable. If an SAE is related or possibly 
related, unblinding may occur per Section 9.4. 
Unavailable details of the event should not delay submission of the known information. As 
additional details become available, the SAE eCRF should be updated and re-submitted via the 
EDC system. Every time the SAE eCRF is submitted, it should be signed by the investigator or 
sub-investigator.  
For additional information regarding SAE reporting, contact Rho Product Safety: 
Rho Product Safety  
6330 Quadrangle Drive, Suite 500 
Chapel Hill, NC  27517 
Toll-free: 1-888-746-7231 
SAE Fax Line: 1-888-746-3293 
 
Email: rho_productsafety@rhoworld.com 
12.5.2. 
Reporting SAEs to Health Authorities 
The Sponsor will report Investigational New Drug (IND) Safety Reports to the Food and Drug 
Administration (FDA) and investigators in accordance with the FDA regulations detailed in 
21 CFR 312.32. 
The sponsor shall promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from any source, foreign or domestic. The sponsor shall notify 
the FDA and all participating investigators in a written IND safety report of any adverse 
experience associated with use of the drug that is both serious and unexpected.  
These events, which require unblinding, must be reported by the sponsor to the appropriate 
health authorities within 15 calendar days; fatal or life-threatening events must be reported 
within 7 calendar days. 
12.5.3. 
Reporting SAEs to IRB(s) or Ethics Committee(s) 
It is the responsibility of the investigators to promptly notify their respective IRB(s) or 
independent ethics committee(s) (IECs) of IND Safety reports or other matters involving risk to 
patients as mandated by the IRBs/IECs. 
SUSARs are to be reported to the investigators and to the IRBs/IECs when the following 
conditions occur: 
• The event must be an SAE. 
• There must be a certain degree of probability that the event is an adverse reaction 
from the administered drug. 
• The adverse reaction must be unexpected, that is to say, not foreseen in the 
Investigator’s Brochure. 


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12.5.4. 
Reporting Pregnancy 
During the study, all subjects should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period). If pregnancy is confirmed, 
the subject will be withdrawn from the study and followed until the pregnancy comes to term. 
The investigator is responsible for reporting all available pregnancy information within 
1 business day of becoming aware of the event. Study treatment must be discontinued 
immediately in the event of a pregnancy. Monitoring of the participant should continue until the 
conclusion of the pregnancy. Follow-up information detailing the outcome of the pregnancy 
should be reported as it becomes available even if the subject was discontinued from the study. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
Any pregnancy complication or premature terminations including miscarriage, spontaneous 
abortion, or elective termination of a pregnancy for medical reasons will be reported as an SAE, 
as described in Section 12.4.2.2. Elective abortions for no medical reason and without 
complications should not be handled as AEs. Should the pregnancy result in a congenital 
abnormality or birth defect, a separate SAE report must be submitted. Furthermore, all neonatal 
deaths that occur within 30 days of the birth should be reported as SAEs, without regard to 
causality. In addition, any infant death that occurs after the 30-day reporting period that the 
investigator suspects is related to the in utero exposure to the study treatment should also be 
reported. 


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13. 
STATISTICS 
Analysis of the clinical efficacy data will consist of modeling endpoints, including PD, CAL, 
BOP, and FMPI, with treatment group as the main effect and adjusted for baseline.  Post-baseline 
treatment comparisons will be modeled through a generalized estimating equations (GEE) 
method (with a linear link and exchangeable covariance matrix), adjusting for the baseline value. 
Methods of analysis for periodontal microbial flora profiles, inflammatory cytokine levels in 
GCF and in serum and RBL will be described in separate statistical analyses plans. Results will 
be considered significant if p <0.05. 
13.1. 
Analysis Populations 
Statistical analyses will be based on the analysis populations as defined below: 
• Safety population: All randomized subjects who use at least one dose of study drug, 
regardless of whether or not they undergo any study assessments. 
• Intention-to-Treat (ITT) population: All randomized subjects. 
• Per Protocol (PP) population: All subjects who use at least one dose of study drug and 
do not deviate from the protocol as per the statistical analysis plan.  
Further details regarding the specific analyses associated with each study population are 
provided in the statistical analysis plan. 
13.2. 
Prevention and Treatment of Missing Data 
Efforts will be made by the sponsor and investigators to maximize subject compliance with the 
study protocol. Previous studies of adjunctive treatments for periodontitis reported subject 
completion rates >90% (Paquette, 2004). Because this study requires a significant number of 
in-office treatments, a more conservative estimate of a 20% dropout rate has been made, which is 
reflected in the sample size calculation (Section 7.2). 
Missing data in this study will be treated according to standard practices based on published 
recommendations of the National Research Council Panel on Handling Missing Data in Clinical 
Trials (National Research Council, 2010). Methods for imputation of missing data are provided 
in the statistical analysis plan. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative for the sponsor 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Stemnion or its representatives. This will 
be documented in a Clinical Study Agreement between Stemnion and the investigator. 
During the study, a monitor or representative for the sponsor will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the subject’s medical records at the clinical site, and other records relevant to 
the study. This will require direct access to all original records for each subject (e.g., 
clinic charts). 
• Record and report any protocol deviations not previously sent to the sponsor. 
• Confirm AEs and SAEs have been properly documented on case report forms, any SAEs 
have been forwarded to Stemnion and SAEs that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Quality control and quality assurance may be performed before, during, and after the study by 
the sponsor or authorized personnel. Regulatory authorities in certain countries reserve the right 
to audit study sites following submission of data in regulatory applications. The investigator may 
be given due notice of any intended audit by a regulatory body. By signing this protocol and the 
FDA Form 1572, the investigator acknowledges that these inspection procedures may take place 
and agrees to provide access to the required subject records and other study documentation. 
Furthermore, the investigator agrees to inform the sponsor immediately of any known or 
suspected inspection by authorities. If the investigator does not comply with the protocol, GCP, 
or regulations, Stemnion, Inc. reserves the right to disqualify the investigator and/or site from the 
current or future protocols. 


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14.3. 
Institutional Review Board (IRB) 
This study is being conducted under a United States IND application. All clinical study sites 
involved in this study must follow FDA and ICH GCP guidelines. United States federal 
regulations require that all investigational drug studies be conducted under the auspices of an 
IRB/IEC, as defined in 21 CFR 56, and in accordance with the Declaration of Helsinki (1989). 
This committee, the makeup of which must conform to federal, state, and local guidelines 
regarding such, will approve all aspects of the study, including the protocol and informed 
consent to be used and any modifications made to the protocol or informed consent, prior to 
study initiation. The investigator will provide the sponsor with a copy of the communication 
from the IRB/IEC to the investigator indicating approval of the protocol and consent form. All 
changes to the protocol or consent form must be reviewed and approved prior to implementation 
except where necessary to eliminate apparent immediate hazards to human subjects. 
The investigator will be responsible for obtaining an annual IRB/IEC re-approval throughout the 
duration of the study. Copies of the investigator’s annual report to the IRB/IEC and copies of the 
IRB/IEC’s continuance of approval must be retained in the site study files and furnished to the 
sponsor. 
14.4. 
Access to Protected Health Information (PHI) 
Study personnel will have access to a subject’s protected health information (PHI). This 
information may be obtained by the sponsor, which includes any persons or companies that are 
working with, working for, or owned by the sponsor. PHI may be given to the U.S. Food and 
Drug Administration (FDA), Department of Health and Human Services (DHHS) agencies, other 
governmental agencies in the U.S., governmental agencies in other countries, and governmental 
agencies to which certain diseases (reportable diseases) must be reported. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Stemnion, Inc. may 
conduct a quality assurance audit. Refer to Section 14.2 for details regarding the audit process. 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
investigator must submit written approval to the sponsor before he or she can enroll any subject 
into the study. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product. 
Stemnion will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The investigator will ensure that this study is conducted in full conformance with the principles 
of the Declaration of Helsinki or with the laws and regulations of the country in which the 
research is conducted, whichever affords greater protection to the individual. The study must 
fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite 
Guideline or with local law if it affords greater protection to the subject. 
16.3. 
Written Informed Consent 
The investigator will be responsible for obtaining an Informed Consent signed by each subject or 
his/her legally authorized representative, prior to his/her participation in the study, in accordance 
with 21 CFR Part 50.20. Informed Consent will be obtained from a subject or his/her legally 
authorized representative after a full explanation of the purpose of the study, the risks and 
discomforts involved, potential benefits, etc., have been provided by the investigator or designee, 
both verbally and in writing. The original or a copy of the signed copy of the Informed Consent 
must be maintained in the institution’s records, and is subject to inspection by a representative of 
Stemnion, Inc. or regulatory agencies. The subject or his/her legally authorized representative 
will also be given a copy of the signed consent form. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Stemnion, Inc. will be allowed to conduct site visits to the investigation facilities for the purpose 
of monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. Regulatory agencies and other 
government agencies may inspect study records. 
17.2. 
Retention of Records 
It is the responsibility of the investigator and study staff to maintain a comprehensive and 
centralized filing system of all study-related documentation, which is suitable for inspection at 
any time by the sponsor, its designees, and regulatory agencies. These should minimally include: 
− Subject files including the completed eCRF, supporting source documentation, 
and the Informed Consent. 
− Study files (Regulatory Binder) including the protocol with all amendments, the 
Investigators’ Brochure, copies of all regulatory documentation and all 
correspondence with the IRB/IEC, regulatory authority (if applicable), and 
Stemnion, Inc. 
− Pharmacy files including all drug shipment, receipt, dispensing, destruction and 
accountability records, and pharmacy-related correspondence. 
The FDA requires that an investigator retain records for a period of 2 years following the date a 
New Drug Application (NDA) or Biologics License Application (BLA) is approved for the 
indication for which the drug is being investigated. If the application or license is not approved 
for such indication, the investigator will retain records until 2 years after the investigation is 
discontinued. In the event that storage of records becomes a problem or the investigator moves, 
the investigator will contact the sponsor immediately so provisions can be made. 
Upon completion of the study, and at yearly intervals during the study, the investigator is 
required to submit a summary report to the IRB. These reports may be prepared by Stemnion, 
Inc. in collaboration with the investigator. 


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18. 
PUBLICATION POLICY 
Information concerning ST266 and patent application processes, scientific data, or other 
pertinent information is confidential and remains the property of Stemnion, Inc. The investigator 
may use this information for the purposes of the study only. It is understood by the investigator 
that Stemnion, Inc. will use information developed in this clinical study in connection with the 
development of ST266 and, therefore, may disclose it as required to other participating clinical 
investigators and to regulatory agencies. In order to allow the use of the information derived 
from this clinical study, the investigator understands that he/she has an obligation to provide 
complete test results and all data developed during this study to the sponsor, Stemnion, Inc. 


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19. 
REFERENCES 
Bonito AJ, Lux L, Lohr KN. Impact of local adjuncts to scaling and root planing in periodontal 
disease therapy: a systematic review. J Periodontol. 2005;76(8):1227-36. 
Goodson JM, Tanner AC, Haffajee AD, Sornberger GC, Socransky SS. Patterns of progression 
and regression of advanced destructive periodontal disease. J Clin Periodontol. 1982;9(6):472-
81. 
Kantarci A, Hasturk H, Van Dyke T. Host-mediated resolution of inflammation in periodontal 
diseases. Periodontol 2000. 2006;40(1):144-63. 
National Research Council. The prevention and treatment of missing data in clinical trials. 
Washington, DC: The National Academies Press; 2010 
Paquette DW, Hanlon A, Lessem J, Williams RC. Clinical relevance of adjunctive minocycline 
microspheres in patients with chronic periodontitis: secondary analysis of a phase 3 trial. J 
Periodontol. 2004;75(4):531-6. 
Serhan CN. The resolution of inflammation: the devil in the flask and in the details. FASEB J. 
2011;25(5):1441-8. 
 

SAP_001.pdf: 
ST266-PERIO-201 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED STUDY TO EVALUATE THE SAFETY, 
EFFICACY, AND TREATMENT REGIMEN OF ST266 IN 
SUBJECTS WITH MODERATE TO SEVERE 
PERIODONTITIS 
NCT2761993 


Stemnion, Inc.  
CONFIDENTIAL 
                 Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
                                 02 October 2017 
 
 
STATISTICAL ANALYSIS PLAN 
02 October 2017 
VERSION 4.0 
 
 
 
 
 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY, 
EFFICACY, AND TREATMENT REGIMEN OF ST266 IN 
SUBJECTS WITH MODERATE TO SEVERE 
PERIODONTITIS 
 
 
 
 
PROTOCOL NUMBER ST266-PERIO-201 
 
 
 
 
 
 
 
SPONSORED BY 
 
Noveome Biotherapeutics, Inc 
100 Technology Dr. Ste 200 
Pittsburgh, PA 15219 
 
 
 
 
 
 
PREPARED BY 
 
Rho, Inc. 
6330 Quadrangle Drive, Suite 500 
Chapel Hill, NC  27517 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
 
 
 
 
Version:  ST266-Perio-201_SAP_v4.0 
 
Page 1 of 35 
 


Stemnion, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
This document is confidential and proprietary to Stemnion, Inc.  Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Stemnion, Inc, except that this 
document may be disclosed to appropriate Institutional Review Boards under the condition that they keep 
the information confidential. 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
0.1 
08 August  2016 
Original Version 
0.2 
08 November 2016 
Updated per sponsor comments 
0.3 
26 December 2016 
Updated per sponsor comments 
0.4 
09 January 2016 
Updated per sponsor comments.  Includes 
options for managing the analysis of rescue 
therapy. 
0.5 
31 January 2017 
Updated per teleconference with team on 
26Jan17 
0.6 
10 February 2017 
Updated per teleconference with team on 
03Feb17 and continuing discussion among 
statisticians from Forsyth and Rho and the 
team at Stemnion/Noveome 
1.0 
20 March  2017 
Finalize per phone call on 2/28/2017 
2.0 
05 April 2017 
Updated primary endpoint analysis to be 
only on tooth-sites with baseline PD 
>=6mm. 
Re-organization of endpoints into secondary 
versus exploratory analyses 
3.0 
10 April 2017 
Updated missing data imputation section for 
clarity and method 
3.1 
14 September 2017 
Updated the SAP to fully characterize the 
statistical model.  Added site and smoker 
status as covariates in the primary analysis. 
Changed the Primary Endpoint from change 
from baseline PD at 90 days to the change 
from baseline PD at 270 days. 
Removed Amended Per Protocol (APP) 
population 
3.2 
29 September 2017 
Added smoking status and treatment group 
in model as an interaction term. 
Added exploratory endpoints % of patients 
Version:  ST266-Perio-201_SAP_v4.0 
 
Page 2 of 35 


Stemnion, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
with pockets a) < 5mm, b) decreasing by 2 
mm or more that at baseline were ≥5mm, 
and c) 75% of pockets < 5 mm that at 
baseline were ≥5mm 
4.0 
02 October 2017 
Final 
 
 
Version:  ST266-Perio-201_SAP_v4.0 
 
Page 3 of 35 




Stemnion, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
APPROVALS 
Approved: 
 
Date: 
 
 
Jan Lessem, MD, PhD 
On behalf of Noveome 
 
 
 
 
Date: 
 
 
John Hall 
Director, Clinical Operations, Stemnion 
 
 
 
 
Date: 
 
 
Marcus Herman-Giddens 
Biostatistician, Rho, Inc. 
 
 
Version:  ST266-Perio-201_SAP_v4.0 
 
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Stemnion, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 7 
LIST OF IN-TEXT TABLES ............................................................................................. 8 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 9 
2. 
PROTOCOL SUMMARY ........................................................................................ 10 
2.1 
Study Objectives ......................................................................................... 13 
2.2 
Overall Study Design and Plan ................................................................... 13 
2.3 
Study Population ......................................................................................... 15 
2.4 
Treatment Regimens................................................................................... 15 
2.5 
Treatment Group Assignments or Randomization ....................................... 15 
2.6 
Sample Size Determination ......................................................................... 16 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 17 
4. 
ANALYSIS POPULATIONS ................................................................................... 18 
5. 
STUDY SUBJECTS ............................................................................................... 19 
5.1 
Disposition of Subjects ................................................................................ 19 
5.2 
Protocol Deviations ..................................................................................... 19 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 20 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 21 
8. 
EFFICACY EVALUATION ..................................................................................... 22 
8.1 
Overview of Efficacy Analysis Issues .......................................................... 22 
8.1.1 
Handling of Dropouts or Missing Data ................................................ 22 
8.1.2 
Rescue Therapy ................................................................................ 22 
8.1.2.1 
Amendment to Protocol Rescue Criteria ............................... 22 
8.1.3 
Multicenter Studies ............................................................................ 22 
8.1.4 
Assessment Time Windows ............................................................... 23 
8.2 
Efficacy Variables ....................................................................................... 23 
8.3 
Analysis Methods ........................................................................................ 23 
8.3.1 
Primary Efficacy Analyses ................................................................. 23 
8.3.2 
Secondary Efficacy Analyses ............................................................. 24 
8.3.3 
Efficacy Analyses at Other Time Points ............................................. 25 
8.3.4 
Exploratory Efficacy Analyses ............................................................ 25 
8.4 
Examination of Subgroups .......................................................................... 26 
8.5 
Exploratory Categorical Analysis of PD ....................................................... 26 
8.6 
Pooled comparisons ................................................................................... 27 
9. 
SAFETY EVALUATION ......................................................................................... 28 
9.1 
Overview of Safety Analysis Methods ......................................................... 28 
9.2 
Extent of Exposure ...................................................................................... 28 
9.3 
Adverse Events ........................................................................................... 28 
9.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 29 
9.5 
Clinical Laboratory Evaluation ..................................................................... 29 
9.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 29 
9.6.1 
Vital Signs .......................................................................................... 29 
9.6.2 
Physical Examinations ....................................................................... 30 
9.6.3 
Other Safety Measures ...................................................................... 30 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
10. TIMING OF DATA COLLECTION AND ANALYSES ............................................. 31 
11. REFERENCES ....................................................................................................... 32 
12. APPENDICES ........................................................................................................ 33 
12.1 
Study Flow Chart ........................................................................................ 33 
12.2 
Schedule of Events ..................................................................................... 34 
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Stemnion, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
AAP 
American Academy of Periodontists 
AE 
Adverse event 
AMP 
Amnion-derived multi-potent progenitor cells 
BOP 
Bleeding on probing 
CAL 
Clinical attachment level 
CEJ 
Cemento-enamel junction 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FMPI 
Full-mouth plaque index 
GCF 
Gingival crevicular fluid 
GCP 
Good Clinical Practice 
GEE 
Generalized estimating equation 
HbA1c 
Glycated hemoglobin 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IL 
Interleukin 
IMDM 
Iscove’s Modified Dulbecco’s Medium 
IND 
Investigational New Drug Application 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
MMP 
Matrix metalloproteinase 
PD 
Pocket depth 
PGE2 
Prostaglandin E2 
RBL 
Radiographic bone level 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SRP 
Scaling and root planing 
ST266 
Study drug: amnion-derived cellular cytokine solution 
 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
LIST OF IN-TEXT TABLES 
Table 8-1 
Efficacy Variables and Analysis Methods ...................................... 23 
 
 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
1. 
PURPOSE OF THE ANALYSES 
This study is a randomized, double-blind, placebo-controlled study to evaluate the safety, 
efficacy, and treatment regimen of ST266 in subjects with moderate to severe 
periodontitis.  The purpose of the analysis is to estimate both the safety and efficacy of 
two regimens of ST266 at 270 days following scaling and root planing.  Analysis of the 
primary and secondary endpoints will be conducted after all subjects have completed the 
Day 270 visit (“Primary Completion Date”).  
The statistical analysis plan (SAP) for protocol ST266-PERIO-201 is being developed 
before database lock and any analyses of the primary endpoint.  The SAP contains 
detailed information of the planned statistical analyses and reporting of the study data for 
use in the final clinical study report (CSR).  It is written with due consideration of the 
recommendations outlined in the most recent International Conference on Harmonization 
(ICH) E9 Guideline entitled Guidance for Industry: Statistical Principles for Clinical 
Trials [1] and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports [2]. 
Separate statistical analysis plans are being developed for exploratory endpoints: 
cytokines in gingival crevicular fluid (GCF) and serum, periodontal microbial flora as 
determined from microbial analyses, and radiographic bone level (RBL). These analyses 
will be appended to this SAP upon completion. 
The SAP describes the populations that will be analyzed and the efficacy and safety 
assessments that will be evaluated.  It also provides details of the specific statistical 
methods that will be used.  If additional analyses are required to supplement the planned 
analyses described in this SAP, they will be identified as post-hoc analyses in the CSR. 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
2. 
PROTOCOL SUMMARY 
Name of Sponsor/Company: 
Stemnion, Inc. 
Name of Investigational Product: 
ST266 [Amnion-derived Cellular Cytokine Solution (ACCS)] 
Title of Study:  
A randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, and 
treatment regimen of ST266 in subjects with moderate to severe periodontitis. 
Study Center(s): Multi-center (6 clinical sites in the United States) 
Phase of Development: Phase 2a 
Objectives:  
Primary: 
To determine the efficacy of ST266 to reduce pocket depth (PD) adjunctive to scaling and root 
planing 270 days after initiation of treatment. 
Secondary: 
To determine safety and changes in: 
• 
Clinical attachment level (CAL) 
• 
Bleeding on probing (BOP) 
Study Design: 
The study is a 9-month, randomized, double-blind, parallel-design study of subjects with 
existing moderate to severe periodontal disease randomly assigned to one of three groups. The 
primary endpoint of PD change will be evaluated following 270 days on study.  Subjects will be 
followed for 9 months for safety and radiographic evaluations. 
Subjects who meet inclusion and exclusion criteria will be randomized to one of three treatment 
groups. Randomization will be stratified by site and smoker status (never smoked or quit 
smoking more than two years ago vs. has smoked within the last two years). Randomization will 
be blocked such that assignment to treatment groups both within sites and within smoker status 
will be approximately even (1:1:1). Treatment will be initiated after scaling and root planing 
(SRP). 
All subjects will be evaluated at baseline and Days 1, 15, 30, 60, 90, 180, and 270. 
Number of Subjects (Planned): A total of 150 subjects will be enrolled in the study, 50 per 
group. 
Study Duration per Subject: Each subject will be enrolled in the study for 9 months. 
Diagnosis and main criteria for inclusion:  
Moderate to severe periodontal disease according to American Academy of Periodontists (AAP) 
definition (at least 6 teeth with 6mm or greater pocket depth and 3 mm or greater CAL at 
baseline). 
 
Inclusion Criteria: 
1. Provision of signed, written informed consent prior to participation in any study-related 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
procedures. 
2. Good general health as evidenced by medical history. 
3. Between 18 and 85 years of age at time of informed consent signature. 
4. Male or female. 
5. Minimum of 18 teeth, excluding third molars. 
6. Having moderate to severe periodontal disease according to AAP definition (at least 6 
teeth ≥6 mm PD and ≥3 mm CAL at baseline). 
7. Having >30 percent bleeding sites upon probing. 
8. Willing to abstain from chewing gums and other mouth rinses for the study duration. 
9. Ability and willingness to attend all study visits and comply with all study visits and 
comply with all study procedures and requirements. 
10. Willingness to abstain from routine dental care. 
11. For women with reproductive potential, willingness to use highly effective 
contraception (e.g. licensed hormonal contraception, intrauterine device, abstinence, or 
vasectomy in partner). 
 
Exclusion Criteria: 
1. Presence of orthodontic appliances. 
2. A soft or hard tissue tumor of the oral cavity. 
3. Carious lesions requiring immediate treatment. 
4. Participation in any other clinical study within 30 days of screening or during the study. 
5. Pregnancy or lactation. If a subject meets this criterion, she may be rescreened for study 
participation when she no longer meets this criterion. 
6. Antibiotic therapy within the last 30 days. 
7. Chronic use (≥3 times/week) of anti-inflammatory medications (e.g., non-steroidal 
anti-inflammatory drugs, steroids). Low-dose aspirin (less than 325 mg daily) is 
allowed. 
8. Immunocompromised subjects. 
9. Subjects with cancer or a history of cancer within the last 5 years of screening. 
10. Any medical history or any concomitant medication that might affect the assessment of 
the study treatment or periodontal tissues, such as diabetes, nifedipine, phenytoin 
(Dilantin), or anticoagulant medications (e.g., warfarin [Coumadin] etc.). 
11. Involvement in the planning or conduct of the study. 
12. History of any clinically significant disease or disorder which, in the opinion of the 
investigator, may either put the subject at risk because of participation in the study, or 
interfere with interpretation of the subject’s study results. 
13. Previous randomization for treatment in the present study. 
Investigational product, dosage and mode of administration: 1X ST266 applied in a dose of 
20 microliters per tooth. Total daily dose will be less than 1 milliliter. ST266 will be applied 
directly to the marginal gingiva around each tooth (buccal and lingual) using sterile packaged 
pipette tips compatible with the Eppendorf Repeater M4 device. 
 
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Statistical Analysis Plan 
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02 October 2017 
Duration of Treatment:  
Group 1: ST266 dosed daily on Days 1-5, 8-12, 22, and 30, and then monthly for 7 months 
(Days 60, 90, 120, 150, 180, 210, and 240). 
Group 2: ST266 dosed 2x/week (with at least one day between treatments) for the first 3 
months and monthly for 5 months thereafter (Days 120, 150, 180, 210, and 240). 
Group 3: Placebo dosed at the same frequency as Group 1. 
Placebo, Dosage, and Mode of Administration: Sterile saline (0.9% NaCl) will be applied in 
the same manner and in the same volume as the investigational product, ST266. 
Criteria for Evaluation: 
Efficacy:  
The primary efficacy endpoint of this study is the change from baseline in the PD for each 
patient at 9 months (Day 270) for those pockets ≥6mm at baseline. 
Secondary efficacy endpoints of this study are: 
 (1) Change from baseline in CAL at 9 months and (2) change from baseline in BOP at 9 months 
for those pockets ≥6mm at baseline. 
Exploratory endpoints of this study are:  
(1) Pro-inflammatory mediators, enzymes and bone markers will be measured in gingival 
crevicular fluid (GCF) and serum at the baseline, Days 15, 90, 180, and 270; 
 (2) Microbial analysis of periodontal flora will be performed at baseline and at Days 15, 90, 
180, and 270; and  
(3) Change from baseline in radiographic bone levels (RBL) at Days 90 and 270.  PD, CAL, 
BOP, and FMPI will also be summarized at Days 90, 180 and 270. 
(4) Smoker/treatment interaction will be summarized for PD and CAL at Days 90, 180, and 270.  
(5) Percent of patients with all pockets < 5mm will be summarized at Days 90, 180 and 270. 
(6) Percent of patients with pockets decreasing by 2mm or more that at baseline were ≥5mm will 
be summarized at Days 90, 180 and 270.  
(7) Percent of patients with 75% of pockets < 5mm that at baseline were ≥5mm will be  
summarized at Days 90, 180 and 270. 
Safety: The safety endpoints are frequency and pattern of adverse events (AEs) and serious 
adverse events (SAEs). 
Planned Sample Size: 
The sample size for the study is based on the sample size required to compare treatment with 
ST266 versus placebo for the primary efficacy endpoint. 
The number of subjects was estimated based on two meta-analysis studies that reviewed 50 and 
72 articles respectively (Bonito, 2005). 
Using the normal approximation for sample size determination for an independent sample t-test, 
and assuming a PD reduction of 0.5 mm on average (difference in means) with a standard 
deviation of 0.7 mm, alpha=0.05 (0.025 per comparison, Bonferroni correction), and 85% 
power, a sample size of 44 per group will be required. The expected dropout rate is 
approximately 10% based on previous experiments; hence 50 subjects will be enrolled per 
group.   
Statistical methods: 
Analysis of the clinical efficacy data will consist of modeling endpoints, including change from 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
baseline in PD, CAL, BOP, and FMPI, with treatment group, smoking status, and investigational 
site as main effects and the interaction of smoking status and treatment group.  Post-baseline 
treatment comparisons will be modeled through a GEE method (with a linear link and within-
patient exchangeable covariance matrix), adjusting for the baseline value. Methods of analysis 
for periodontal flora, inflammatory cytokine levels in GCF and in serum, and RBL will be 
described in separate statistical analysis plans. 
 
2.1 
Study Objectives 
The primary objective is to estimate the efficacy of ST266 to reduce pocket depth (PD) as 
an adjunctive to scaling and root planing (SRP). 
The secondary objectives of this study are to determine: (1) safety as established by 
assessment of AEs and SAEs, and (2) changes in the following clinical parameters: 
• Clinical attachment level (CAL) 
• Bleeding on probing (BOP) 
Additional exploratory objectives are to compare the effects of the treatments and dosing 
schedules in the following: 
• Proinflammatory mediators, enzymes, and bone markers in gingival crevicular 
fluid (GCF) and serum 
• Periodontal flora as determined from microbial analyses  
• Radiographic bone level (RBL) 
• Full-mouth plaque index (FMPI)   
• Percent of patients with all pockets < 5mm  
• Percent of patients with pockets decreasing by 2mm or more that at baseline 
were ≥5mm 
• Percent of patients with 75% of pockets < 5mm that at baseline were ≥5mm 
2.2 
Overall Study Design and Plan 
The study is a 9-month, randomized, double-blind, placebo controlled, parallel design 
study of subjects with existing moderate to severe periodontal disease. All subjects will 
be treated by a dental professional at the study site. The dental professional will be a 
qualified and trained licensed periodontist, dentist, or dental hygienist skilled in 
periodontal clinical research. All investigators will be trained in grading clinical 
parameters in the same manner for consistency. Subjects will be recruited at multiple 
treatment sites. After signing informed consent, subjects will be screened with a medical 
and dental history and full mouth dental examination. Clinical parameters will be 
recorded including PD, CAL, and BOP. Subjects will have urinalysis in addition to blood 
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Statistical Analysis Plan 
Protocol No. ST266-PERIO-201 
 
02 October 2017 
tests including hematology and chemistry (liver and kidney function) panels. Women of 
child-bearing potential will be administered a pregnancy test. 
If inclusion/exclusion criteria are met, subjects will undergo a baseline visit with 
measurements of FMPI, collection of gingival crevicular fluid (GCF) and blood samples. 
Subgingival plaque samples will be collected for microbial analysis. Vertical bitewing X-
rays will be collected to assess RBL. Subjects will undergo SRP procedure(s) prior to 
being randomly assigned to one of three treatment groups as described in section 2.5.  
Local anesthesia must be used for SRP.  All treatments of ST266 or placebo will be 
administered in office by a dental professional.  
All subjects will be evaluated at screening, baseline, and Days 1, 15, 30, 60, 90, 180, and 
270. Evaluations will be performed by a blinded dental professional to mask the group as 
all groups do not have the same study schedule. The blinded examiners will be 
independent from the dental professionals who apply the study drug to the subjects, 
thereby ensuring that the treatment assignment cannot be inferred based on the treatment 
schedule. 
At each evaluation, medical and dental history will be updated, an oral exam will be 
performed, and AEs and SAEs will be assessed and recorded. PD, CAL, and BOP will be 
evaluated at screening and on Days 15, 30, 60, 90, 180, and 270. Subjects will have 
urinalysis in addition to blood tests including hematology and chemistry (liver and kidney 
function) panels done at screening and repeated at Days 90 and 270. FMPI will be 
recorded at baseline and on Days 15, 30, 60, 90, 180, and 270. Inflammatory cytokines in 
serum will be measured at baseline and on Days 15, 90, 180, and 270. GCF will be 
collected and analyzed at baseline and on Days 15, 90, 180, and 270. Microbial analysis 
of periodontal flora will be performed at baseline and on Days 15, 90, 180, and 270. 
At each treatment visit, in addition to administration of ST266 or placebo, medical and 
dental history will be updated, AEs and SAEs will be assessed and recorded, concomitant 
medications will be recorded, and oral hygiene instruction will be provided. 
Randomization will be stratified by site and smoker status (never smoked or quit smoking 
more than two years ago vs. has smoked within the last two years). Randomization will 
be blocked such that assignment to treatment groups both within sites and within smoker 
status will be approximately even (1:1:1). ST266 will be supplied to the study site and 
prepared for use by trained clinical staff, who will not be the same as the dental 
professionals evaluating the subjects. 
Primary Endpoint: The primary endpoint of this study is the average change from 
baseline in tooth site PD for each patient at 9 months (Day 270) in tooth sites with 
baseline PD ≥ 6mm.  The change in pocket depth at each tooth site will be the dependent 
variable with the average over all tooth-sites for each patient being estimated by the 
statistical model.   
 
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02 October 2017 
Secondary Endpoints: The secondary endpoints of this study are:  
• change from baseline in CAL at 270 days in tooth sites with baseline PD ≥ 
6mm 
• change from baseline in BOP for each patient at 270 days.  BOP for each 
patient is calculated as the percent of tooth sites in the whole mouth with 
bleeding on probing. 
Baseline refers to the initial measurement of the endpoint, which may occur at the 
screening or baseline visit according to the schedule of assessments. 
 
Safety Endpoints: The safety endpoints are the frequency and pattern of AEs and SAEs. 
Exploratory Endpoints: Pro-inflammatory mediators, enzymes, and bone markers will 
be measured in GCF and serum at baseline and Days 15, 90, 180, and 270. Microbial 
analysis of periodontal flora will be performed at baseline and at Days 15, 90, 180, and 
270.  Change from baseline in RBL will be measured at Days 90 and 270.  PD, CAL, 
BOP, will also be analyzed at Days 180 and 270.  FMPI will also be analyzed at Days 90, 
180 and 270. Percent of patients with all pockets < 5mm, percent of patients with pockets 
decreasing by 2mm or more that at baseline were ≥5mm, and percent of patients with 
75% of pockets < 5mm that at baseline were ≥5mm will be shown at Days 90, 180 and 
270.  
2.3 
Study Population 
The population of this study comprises adults with moderate to severe periodontitis who 
meet the inclusion/exclusion criteria as described in the protocol synopsis in Section 2 of 
the SAP. Approximately 150 subjects will be enrolled with 50 subjects per treatment 
group.  Subjects may be re-screened if they do not fail inclusion criteria #6 (having 
moderate to severe periodontal disease according to the AAP definition [at least 6 teeth 
with ≥6 mm PD and ≥3 mm CAL at baseline). 
2.4 
Treatment Regimens 
Group 1: ST266 dosed daily on Days 1-5, 8-12, 22, and 30 and then monthly for 7 
months (Days 60, 90, 120, 150, 180, 210, and 240). 
Group 2: ST266 dosed 2x/week (with at least one day between treatments) for the first 3 
months and monthly for 5 months thereafter (Days 120, 150, 180, 210, and 
240). 
Group 3: Placebo dosed at the same frequency as Group 1. 
2.5 
Treatment Group Assignments or Randomization 
Randomization will be stratified by site and smoker status (never smoked or quit smoking 
more than two years ago versus has smoked within the last two years). Randomization 
will be blocked such that assignment to treatment groups both within sites and within 
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Statistical Analysis Plan 
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smoker status will be approximately even (1:1:1). ST266 will be supplied to the study site 
and prepared for use by trained clinical staff, who will not be the same as the dental 
professionals evaluating the subjects. 
At the 90-Day analysis, one statistician and one programmer will be unblinded in order to 
generate the unblinded 90-day analysis.  Another team of statisticians and programmers 
will remain blinded until the 270-day analysis at the end of the study. 
2.6 
Sample Size Determination 
One hundred and fifty (150) subjects will be enrolled.  The sample size for the study is 
based on the sample size required to compare treatment with ST266 versus placebo for 
the primary efficacy endpoint. 
The number of subjects was estimated based on two meta-analysis studies that reviewed 
50 and 72 articles respectively (Bonito, 2005). 
Using the normal approximation for sample size determination for an independent sample 
t-test, and assuming a PD reduction of 0.5 mm on average (difference in means) with a 
standard deviation of 0.7 mm, alpha=0.05 (0.025 per comparison, Bonferroni correction), 
and 85% power, a sample size of 44 per group will be required. The expected dropout 
rate is approximately 10% based on previous experiments; hence 50 subjects will be 
enrolled per group.   
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02 October 2017 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
For continuous endpoints, the summary statistics will generally include number of 
subjects with data (n), mean, standard deviation, median, minimum and maximum. No 
preliminary rounding will be performed; rounding will only occur after analysis.  To 
round, the digit to right of last significant digit will be considered:  if < 5 then round 
down, if ≥ 5 then round up.  Means and medians will be presented with one more decimal 
place than the precision of the data.  Standard deviations will be presented with two more 
decimal places than the precision of the data.  Percentages will be presented with one 
decimal place.  Minimums and maximums will be presented with the same precision as 
the original data. 
 For categorical endpoints, the summary statistics will generally include:  number of 
subjects randomized and/or dosed, number of subjects with data, and the percentage of 
those with data in each category.  Frequency distributions will be presented as 
appropriate.  
Analysis of the clinical efficacy data will consist of modeling endpoints, including 
change from baseline in PD, CAL, BOP, and FMPI, with treatment group, patients, 
smoking status, and investigational site as  main effects and adjusting for baseline values 
of a given endpoint. Post-baseline treatment comparisons will be modeled through a GEE 
method (with a linear link and exchangeable covariance matrix), adjusting for the 
baseline value. Methods of analysis for periodontal flora, inflammatory cytokine levels in 
GCF and in serum, and RBL will be described in separate statistical analysis plans. 
Hypothesis testing, unless otherwise indicated, will be two-sided.  When confidence 
intervals are presented, they will be two-sided with a confidence coefficient of 95%.   
Actual P-values will be reported to 3 decimal places if greater than 0.001.  If less than 
0.001, the value ‘<0.001’ will be reported.  
The statistical software, SAS® version 9.3 or above, will be used for all summaries and 
statistical analyses. 
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4. 
ANALYSIS POPULATIONS 
Statistical analyses will be based on the analysis populations as defined below: 
• Safety population: All randomized subjects who use at least one dose of study 
drug, regardless of whether or not they undergo any study assessments. 
• Intention-to-Treat (ITT) population: All randomized subjects. 
• Per Protocol (PP) population: All subjects who use at least one dose of study 
drug and do not have major protocol deviations as defined in § 5.2.  
 
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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Subject disposition will be summarized in tables and listings: overall, by treatment, by 
smoking status at baseline, and by site.   
• The number of subjects screened (overall) 
• The number of subjects enrolled and randomized 
• The number of subjects treated 
• The number of subjects who have completed each visit 
• The number of subjects who discontinued study treatment; overall and by 
discontinuation reason: 
• Adverse Event 
• Death 
• Lack of Efficacy 
• Lost to Follow-up 
• Non-Compliance with Study Duration 
• Physician Decision 
• Pregnancy 
• Progressive Disease 
• Protocol Violation 
• Recovery 
• Screen Failure 
• Study Terminated by Sponsor 
• Technical Problems 
• Withdrawal by Subject 
• Other 
5.2 
Protocol Deviations 
Major protocol deviation information will be maintained separately from the electronic 
CRF, and exports of these data will be delivered separately from the clinical datasets.  A 
major deviation is one that may affect the outcome, analysis, or interpretation of the 
study.  These deviations may include, but are not limited to, the following: 
Inclusion/exclusion criteria deviations, randomization deviations, and terminations for 
lack of compliance. Major protocol deviations will be identified by an expert committee 
prior to unblinding the study.  Protocol deviations can be self-reported, recorded 
following interim monitoring visits, or following remote monitoring.  For the per protocol 
analysis all subjects with minor deviations will be included.  All subjects with major 
deviations will be reviewed as described above and will not be included in the per 
protocol analysis. 
Subjects who miss 20% or more of their prescribed treatments will be considered non-
compliant and will be excluded from the per-protocol statistical analysis. 
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Statistical Analysis Plan 
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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Baseline data (demography, medical history, dental history, and baseline disease 
characteristics) will be summarized. 
Demography includes age, sex, race, and ethnicity. Sex, race, and ethnicity will be 
tabulated in frequencies and continuous summary statistics will be presented for age at 
screening.  Data will also be presented in a listing. 
The number and percentage of subjects with each medical history event will be presented 
by body system and event term.  A listing will also be created which will include the 
body system, event term, whether the medical history event is ongoing and controlled, as 
well as the start and end dates of the event and any associated comments.  
The number and percentage of subjects who have been diagnosed with periodontitis, 
abscesses, or who have had any oral surgeries or root canals, or are currently 
experiencing dental pain will be presented.  A listing will also be created which will 
include the above events as well as their associated dates, the date the subject last visited 
a dentist or hygienist, frequency of flossing and mouth rinse, and interdental irrigation 
devices. 
Results of the baseline oral exam will be listing by area examined and will denote an 
abnormal or normal result; and, if abnormal, the associated description of the abnormality 
will be listed.  The presence of periodontal abscess or endodontic abscess will also be 
presented. 
Tooth status at baseline will be presented in a listing by subject and tooth, and will denote 
whether the tooth is missing, sound, decayed, filled, fractured, has a crown, and/or is an 
implanted tooth. 
Quadrants completed during the scaling the root planing procedure at visit 3 will be 
presented in a listing. 
Demographic and baseline disease characteristics will be presented for the safety 
population. 
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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Every treatment application of study drug will be performed in the dental clinic by the 
clinician/investigator (dental professional); therefore, the investigator can assess non-
compliance based on subject attendance of scheduled treatments. 
Missed treatments may be completed if done within the treatment windows described in 
the protocol. 
Subjects who miss 20% or more of their prescribed treatments will be considered non-
compliant and excluded from the per-protocol statistical analysis. 
Treatment compliance will be calculated as: 
[(# doses completed within X days (with “X” as defined above) from original 
scheduled dose date)/ (# planned doses)]*100 
Treatment compliance will be presented by group at each visit and overall using both 
continuous summary statistics and the following frequency cut-offs: <50%, 50 - 80%, 
>80% for the ITT population.   
Treatment compliance will also be presented in a listing presenting subject, dosing 
schedule/treatment group, planned dosing day, whether the subject was dosed within “X” 
days (with “X” as defined above”), actual dosing day, and treatment compliance. 
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8. 
EFFICACY EVALUATION 
8.1 
Overview of Efficacy Analysis Issues 
8.1.1 
Handling of Dropouts or Missing Data 
All reasonable efforts will be made to minimize missing data.  However, there are two 
possibilities for data being missing.  In one case, the measurement associated with an 
individual pocket may be missing at an evaluation.  In this case, the worst previous value 
for this variable will be imputed for that tooth/pocket.  Furthermore, the data from an 
entire patient may be missing because they withdrew before completing the study.   For 
this imputation, an approach similar to that for each site will be employed.  For visits that 
would follow a patient’s premature discontinuation from the study, the worst observation 
associated with each individual pocket will be imputed for all subsequent visits for that 
patient and will thus also be carried forward for the 270-day evaluation.  Subjects who 
drop out of the study will not be replaced. 
8.1.2 
Rescue Therapy 
The need for rescue therapy including the site requiring therapy, the date and study day, 
the pocket depth (PD), whether SRP was performed, the protocol version under which the 
subject was enrolled, and any associated comments will be presented in a listing. 
Additionally, a table will be created to summarize and compare the need for and timing 
of rescue therapy across the three treatment groups. 
Further ad-hoc exploratory analyses to examine the characteristics of subjects receiving 
rescue therapy and the circumstances surrounding the need for rescue therapy may be 
conducted. 
8.1.2.1 
Amendment to Protocol Rescue Criteria 
In this study, rescue therapy was intended to occur only after the Day 90 evaluation. 
However, under early versions of the protocol, the timing of rescue therapy was not 
explicitly stated, and rescue therapy was permitted at any time after the initial SRP 
treatment if indicated by clinical parameters (PD or CAL). A subsequent amendment to 
the protocol (Amendment 2) was made to correct this issue, but some subjects enrolled 
under the earlier versions of the protocol received “premature” rescue therapy prior to 
Day 90.  
Pockets/teeth that are “rescued” should be considered treatment failures after rescue.  For 
this reason, rescued teeth/pockets will be assigned a value equal to the worst score 
observed at any previous visit for that pocket/tooth in the primary and secondary 
analyses..  
8.1.3 
Multicenter Studies 
This is a multi-center study and randomization has been stratified by site.   
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8.1.4 
Assessment Time Windows 
See Section 15.2 for the Schedule of Assessments.  Assessments within the stated visit 
windows will be considered for analysis of the given time point.  If multiple assessments 
occur within a visit window, the assessment occurring closest to the target day for the 
assessment will be used in the analysis. In the case of a tie, the worst record will be used. 
8.2 
Efficacy Variables 
Table 8-1 
Efficacy Variables and Analysis Methods 
Efficacy Variables 
Method 1 a 
Primary 
 
Pocket Depth 
Δ from baseline at Day 270 in tooth-sites with 
baseline PD ≥6mm a 
Secondary 
 
Clinical Attachment Level 
Δ from baseline at Day 270 in tooth-sites with 
baseline PD ≥6mm a 
Bleeding on Probing 
Δ from baseline at Day 270 using whole mouth 
average percentage of site with bleeding on probing b 
 
 
a Generalized Estimating Equations will be used as the primary analytical method.  The dependent variable will be 
change from baseline to Day 270 and the model will include treatment group, patients, smoking status, and 
investigational site for a given endpoint.  A linear link and exchangeable covariance matrix will be employed. Only 
treatment comparisons at Day 270 will report a p-value.  Comparisons at other time points will only present the point 
estimate and 95% confidence interval.  The analyses will incorporate all data from individual tooth sites within         
each subject.  
b ANCOVA will be used for the analysis of this variable.  The dependent variable will be change from baseline to Day 
270 and the model will include treatment group, patients, smoking status, and investigational site for this endpoint.  
Only treatment comparisons at Day 270 will report a p-value.  Comparisons at other time points will only present the 
point estimate and 95% confidence interval.   
8.3 
Analysis Methods 
The Day 270 analyses will be independent of the Day 90 analyses.  All primary and 
secondary efficacy analyses unless otherwise stated will be performed on the ITT 
population.  Unblinding will be performed for the Primary and secondary analyses at Day 
270. 
8.3.1 
Primary Efficacy Analyses 
The generalized estimating equations (GEE) method with a linear link and exchangeable 
covariance matrix (within subject correlation structure) will be used to estimate the 
treatment group effects with respect to change from baseline PD at 270 days, adjusted for 
baseline PD in tooth-sites with baseline PD ≥6 mm.  The two primary hypotheses to be 
tested are:  
1) The change in PD from baseline (PD ≥6 mm) (Screening Visit) at the 270 Day 
Visit differs between the Group 1 (see section 2.4) and Group 3 (placebo) 
treatments. Point estimates and 95% confidence intervals will be presented for the 
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treatment group differences in PD change from baseline at Day 270 by baseline 
smoker status.;   
2) The change in PD from baseline (PD ≥6 mm) (Screening Visit) at the 270 Day 
Visit differs between the Group 2 (see section 2.4) and Group 3 (placebo) 
treatments. Point estimates and 95% confidence intervals will be presented for the 
treatment group differences in PD change from baseline at Day 270 by baseline 
smoker status.    
SAS code for the GEE model is as follows: 
 
proc gee data=Day270dataset   
   where (base>=6 and ITT Set=’Y’  and paramcd='PDEPTH'); 
   class subjid trt01a site smoker_status; 
   model chg = trt01a base site smoker_status smoker_status*trt01a; 
   repeated  sub=subjid /type=exch; 
   lsmeans trt01a/pdiff; 
run; 
 
Where: 
1) The Day270dataset only includes records for Day 270visit) 
2) chg = change from baseline of each individual toot site 
3) (base>=6 and ittfl='Y' and paramcd='PDEPTH'):  subsets the dataset to include only 
PD outcomes, the ITT population, and tooth sites with baseline PD greater or equal 
to 6mm.    
4) chg= change in PD from baseline 
5) trt01a = treatment group 
6) site=investigator institution rather than tooth site 
7) base = baseline PD 
The 15-, 30-, and 60-Day visits were not included in the primary statistical model since 
the tooth-sites at the earlier visits may still be healing from the effects of the SRP 
procedure with possible SRP-related gingival swelling affecting the PD measures.  
Since there are two primary hypotheses, Bonferroni corrections will control for 
multiplicity with p<0.025 considered significant.  Point estimates and 95% confidence 
intervals will be presented for the treatment group differences in change from baseline at 
each assessment time point.  These analyses will be performed once all the subjects 
(excluding those withdrawn) have been unblinded and completed their 270-Day Visit.  
8.3.2 
Secondary Efficacy Analyses 
Additional secondary efficacy analyses will be performed  to test the effects of treatment 
group and their interactions on the secondary endpoints of the change from baseline in 
CAL and BOP at Day 270.  For the CAL analysis, the GEE analyses will be performed 
with the same statistical model as described in the primary PD  efficacy analysis  but with 
the change from baseline in CAL of tooth-sites with baseline PD ≥6 mm as the dependent 
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variable.  Separate hypotheses will be performed for testing the treatment effects of group 
1 versus group 3 (placebo) and group 2 versus group 3 (placebo).  As described above, 
this model will include the baseline smoker status (smoker or non-smoker) by treatment 
group interaction.   For the secondary efficacy analyses of the BOP change from baseline, 
ANCOVA will be performed with treatment group as the main effect, and covariates for 
baseline PD, site, patients, smoker status, and the baseline smoker status (smoker or non-
smoker) by treatment group interaction .   Point estimates and 95% confidence intervals 
will be presented for the treatment group differences in CAL and BOP change from 
baseline at Day 270 and by baseline smoker status.    
The CAL and BOP secondary analyses described above will be tested hierarchically in 
the order of: CAL change from baseline at Day 270, and BOP (presented as a whole 
mouth average percentage) change from baseline at Day 270.  The treatment effects for 
the CAL or BOP change from baseline at the Day 270 Visit will be compared between 
Treatment Group 1 and Placebo, and between Treatment Group 2 and Placebo.  The 
alpha will be set at 0.025 to allow for the Bonferroni correction for 2 multiple 
comparisons for secondary endpoints.  Since the smoker status by treatment group 
interaction is acting as a gatekeeper for further inference testing by smoker status, no 
additional corrections will be made for multiplicity for any additional analyses of the 
effects of treatment on CAL and BOP by smoker status. These analyses will be 
performed once all the subjects (excluding those withdrawn) completed their 270-Day 
Visit. 
All primary and secondary analyses performed on the ITT population will be repeated 
using the per protocol population. 
8.3.3 
Efficacy Analyses at Other Time Points 
The same technique used for the primary and secondary endpoints will be used for the 
other assessed time points.  Point estimates and 95% confidence intervals will be 
presented for change from baseline at each assessment time point.  The p-values will not 
be presented for these analyses. Actual value and change from baseline will be presented 
for each scheduled collection visit for the summarized endpoint.  Please refer to Section 
15.2 for the schedule of assessments. 
8.3.4 
Exploratory Efficacy Analyses  
FMPI will be analyzed using the GEE method described in section 8.3.1 at days 90, 180, 
and 270.  Additionally, CAL change from baseline at days 180 and 270 using all tooth-
sites will be analyzed using GEE.  PD change from baseline at days 90, 180, and 270 
using a whole-mouth average will be analyzed using ANCOVA with the model described 
previously. 
Analysis methods for the exploratory efficacy outcomes, (1) inflammatory cytokines in 
GCF and serum, (2) microbial periodontal flora and (3) RBL will be described in a 
separate statistical analysis plan. 
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8.4 
Examination of Subgroups 
To explore the potential effect of age and gender on response,  and to further explore the 
effect of smoking, PD and CAL in tooth-sites with baseline PD ≥ 6mm will also 
investigated with exploratory analyses using the following categories: 
• Age (< median age; ≥ median age) 
• Gender (male, female) 
• Current disease smoking status (smoker – has smoked within the past two years, 
non-smoker – has never smoked or quit > 2 years ago). 
The model used for the original analyses of these variables will form the basis for 
separate analyses for each of these factors.  However, in addition to the factors in the 
original model, an additional main effect (e.g. gender) and interaction term (e.g. gender 
by treatment) will be included in the model. 
8.5 
Exploratory Categorical Analysis of PD  
In addition to analyzing PD as continuous variable, it is often useful to analyze PD 
categorically. The following may also be summarized descriptively:   
• Percent of subjects in each group with a mean PD change from baseline <-4mm, 
<-3mm, <-2mm, <-1mm, -1mm to 1mm, >1mm, >2mm, >3mm, >4mm at 90, 180 
and 270 days 
• Percent of subjects with pockets decreasing by 2mm or more that at baseline were 
< 5mm at 90, 180, and 270 days. 
• Percent of tooth sites in each group with a mean PD change from baseline            
<-4mm, <-3mm, <-2mm, <-1mm, -1mm to 1mm, >1mm, >2mm, >3mm, >4mm at 
90, 180 and 270 days 
• Percent of subjects in each group with a mean PD <5mm, <6mm and < 7mm at 
90, 180 and 270 days 
• Percent of subjects in each group with all PD <5mm, <6mm and < 7mm at 90, 
180 and 270 days 
• Percent of subjects with 75% of pockets < 5mm that at baseline were < 5mm  at 
90, 180, and 270 days. 
• Percent of tooth sites in each group with a mean PD <5mm, <6mm and < 7mm at 
90, 180 and 270 days 
• Percent of subjects in each group with PD <5mm at day 90 by baseline PD 
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8.6 
Pooled comparisons 
In addition to the above analyses that compare results between each active treatment 
group (N=50/group) and the placebo group (N=50), “pooled” analyses will be performed 
that combine the data from both active treatment groups (N=100) for comparison to the 
placebo group (N=50).  Point estimates and 95% confidence intervals will be presented 
for change from baseline at each assessment time point.  The p-values will not be 
presented for these analyses.    
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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
Safety analyses will be presented descriptively on the safety population.  No statistical 
testing will be performed.  
9.2 
Extent of Exposure 
Treatment compliance will be presented at each visit and overall by group using both 
continuous summary statistics and the following frequency cut-offs: <50%, 50 - 80%, 80 
- 90%%, >90%. 
Treatment compliance will be calculated as: 
[(# doses completed within X days (within 3 days in the first 60 days; within 5 days at 
Day 90; within 7 days at Day 180) from original scheduled dose date)/(# planned 
doses)]*100 
Duration of therapy will be summarized by treatment group using continuous summary 
statistics.  Duration of therapy in months will be calculated as: 
(last dose date – first dose date + 1)/30.4375. 
Number of doses received will be summarized by treatment group using continuous 
summary statistics.   
Information regarding the extent of exposure will also be presented in a listing presenting 
subject, dosing schedule/treatment group, planned dosing day, whether the subject was 
dose within X days (within 3 days in the first 60 days; within 5 days at Day 90; within 7 
days at Day 180), actual dosing day, treatment compliance, duration of therapy, and 
number of doses received. 
9.3 
Adverse Events 
The most recently available MedDRA dictionary version will be used for the 
classification of adverse events. 
On-study AEs are those with a start date on or after the first treatment dose date and prior 
to the last treatment dose date + 30 Days. 
On-study adverse events will be summarized overall by treatment group and by worst 
severity.  Drug-related adverse events will also be tabulated.   
All adverse events will be presented in a listing which includes first treatment dose date, 
onset and resolution date/day (or whether it is ongoing), system organ class and preferred 
term, investigator term, whether the event is serious, whether the adverse event involves 
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hematuria or proteinuria, severity grade, relationship to study drug, action taken, 
sequelae, and outcome. 
9.4 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
The number of deaths will be presented along with the corresponding reason for death. 
On study serious adverse events will be classified by system organ class and preferred 
term.  They will be presented overall by treatment group and by worst severity.  Drug-
related serious adverse events will also be tabulated.   
On study adverse events leading to discontinuation will be classified by system organ 
class and preferred term.  They will be presented overall by treatment group and by worst 
severity.  Drug-related adverse events leading to discontinuation will also be tabulated.   
9.5 
Clinical Laboratory Evaluation 
Blood is to be drawn and urine collected for laboratory analysis at Screening, and on 
Days 90 and 270.  The following clinical laboratory parameters are to be assessed:  
• Hematology: Complete blood count 
• Blood chemistry: serum glucose, C-reactive protein, blood urea nitrogen, 
creatinine, electrolytes, HbA1c (at screening only), and liver function including 
bilirubin and hepatic enzymes 
• Urinalysis: hematuria, proteinuria, pregnancy test (at screening and final visit 
only) 
Tables will present continuous summary statistics for each lab parameter collected by 
visit and treatment group. 
Laboratory values outside the normal range will be flagged as “high” or “low”.  
Percentage of subjects with values falling in high, normal, and low ranges will be 
summarized by lab parameter and visit, by treatment group. 
9.6 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.6.1 
Vital Signs 
Systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and 
temperature will be collected at screening, baseline, SRP visit, day 1, day 15, day 30, day 
60, Day 90, Day 180 and Day 270 (or end of study).  Height and weight will be collected 
at screening and Day 270 (or end of study). 
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Summaries of actual values and change from baseline at each visit will be presented in a 
table.  A listing will also be provided with vital sign value at each visit as well as an 
indicator of the clinical significance of the finding, if any. 
9.6.2 
Physical Examinations 
An oral exam will also take place at each visit.  Results will be presented in a listing 
similar to that described in Section 6 of the SAP but will also include the visit associated 
with the exam results. 
9.6.3 
Other Safety Measures 
Medical and dental history will be updated at each visit.  Medical history events and 
dental history events since baseline will be presented in a listing similar to that described 
in Section 6 of the SAP but will also include the visit associated with the exam results.  
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10. 
TIMING OF DATA COLLECTION AND ANALYSES 
In this study, subjects will be followed for a total duration of 9 months.  After all subjects 
have completed their Day 270 visit, the database will be locked and Day 270 analysis will 
be performed. Results will be presented as described above with the additional data from 
Days 180 and 270. 
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11. 
REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance 
for Industry: Statistical Principles for Clinical Trials. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, 
September 16, 1998, page 49583. 
2. US Federal Register. (1996) International Conference on Harmonization; Guidance 
for Industry: Structure and Content of Clinical Study Reports. Department of Health 
and Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 
17, 1996, page 37320. 
3. Yuan YC.  Multiple imputation for missing data: Concepts and new development.  
SAS Institute, Inc. 2000. 
4. Rubin DB. Inference and missing data. Biometrika 1976;63(3):581–90. 
5. Schafer JL. Analysis of incomplete multivariate data. London: Chapman & Hall; 
1997. 
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12. 
APPENDICES 
12.1 
Study Flow Chart 
 
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12.2 
Schedule of Events 
 
 
 
 
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