Clinical trial NCT03508700
Conditions: PTSD
Keywords: TNX-102 SL Bedtime Sublingual Safety PTSD
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2018-04-19; Completion date: 2019-09-30
Enrollment: 93 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluate the long-term safety of TNX-102 SL 5.6 mg taken daily at bedtime over an additional 40 weeks in patients with PTSD who have participated in a double-blind lead-in study and completed an initial 12-week open-label extension study (TNX-CY-P303).

Detailed description:
This is an open-label, extension trial designed to evaluate safety over 40 additional weeks of TNX-102 SL therapy taken daily at bedtime for the treatment of PTSD.

The study will consist of 5 in-clinic study visits, including Baseline Visit 1 (Day 0, which is anticipated to be the same visit as the last visit of the 12-week open-label extension study TNX-CY-P303), followed by in-clinic visits after 7, 16, 28 and 40 weeks of open-label treatment.

Arms: arm 1: 2 tablets of TNX-102 SL 2.8 mg taken simultaneously and sublingually (under the tongue) each day at bedtime starting on Day 0 for 40 weeks
Interventions: intervention 1: TNX-102 SL 5.6 mg
Intervention descriptions: intervention 1: cyclobenzaprine HCl sublingual tablets

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
I have read the TNX-CY-P306 protocol and agree to conduct the study as outlined.  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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PROCEDURES IN CASE OF EMERGENCY 
Table 1: Emergency Contact Information 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Tonix Pharmaceuticals, Inc. 
Name of Investigational Product: 
Tonmya®/TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets) 
Name of Active Ingredient: 
Cyclobenzaprine HCl 
Title of Study: 
A 40 to 52-Week Open-Label Extension Study to Evaluate TNX-102 SL Taken Daily at Bedtime 
in Patients with PTSD 
Study period (months): 18 
Estimated date first patient enrolled:  April 2018 
Estimated date last patient completed: September 2019 
Phase of development: 3 
 
Objectives 
Primary: 
The primary objective of the study is to evaluate the long-term safety of TNX-102 SL 5.6 mg taken 
daily at bedtime over an additional 40 to 52 weeks in patients with PTSD who have participated in a 
double-blind lead-in P301 or HONOR study.  Some patients will have also participated in an initial 
12-week open-label extension study (TNX-CY-P303).  This will provide at least 52 weeks of TNX-
102 SL 5.6 mg exposure data for at least 50 patients.   
Methodology:  
This is an open-label, extension trial designed to evaluate safety of additional 40 to 52 weeks of TNX-
102 SL 5.6 mg taken daily at bedtime for the treatment of PTSD. There are two possible “tracks” 
patients can use to enroll into this study: 
Track A:  patients that complete the double-blind lead-in HONOR study and complete or are 
active (at the time of study discontinuation) in the 12-week open-label extension study, P303, 
and received active drug in the 12-week double-blind lead-in study, P301/HONOR. 
Track B:  patients that are currently enrolled in the double-blind lead-in P301/HONOR study that 
has been discontinued due to results of an interim analysis or are active (at the time of study 
discontinuation) in the 12-week open-label extension study, P303, and received placebo in the 
12-week double-blind lead-in study, P301/HONOR. 
The study will consist of 5 or 6 in-clinic study visits, including Baseline Visit 1 (Day 0, which is 
anticipated to be the same visit as the last visit of the 12-week open-label extension study P303 for 
Track A patients), followed by in-clinic visits after 7, 16, 28 and 40 weeks of open-label treatment.  
Patients who are active in the 12-week double-blind lead-in study (P301/HONOR) at the time of 
enrollment to P306 will also have a 2-week phone check-in visit. All Track B patients will have 52 
weeks of open-label treatment and a Visit 7.  For patients enrolled from the discontinued double-blind 
lead-in study, P301/HONOR, the P306 Baseline Visit will occur in lieu of an early termination visit.   
Patient safety parameters recorded at the final visit in the double-blind lead-in HONOR study (which 
is the baseline visit in the 12-week open-label extension study P303) can also be used as the baseline 
safety values for the P306 extension study for Track A patients.  Patients will attend clinic visits at 7-, 
9-, and 12-week intervals as indicated in the study visit schedule.  Eligible patients who provide 
written informed consent will be provided with a supply of TNX-102 SL 2.8 mg tablets sufficient for 


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dosing until their next scheduled in-clinic study visit. At each clinic visit, patients will return their 
TNX-102 SL medication and will receive sufficient supplies to last them until the next scheduled 
visit.  Patients will also have the option to have blood drawn for pharmacogenomic testing.   
Number of patients (planned):  
The study will enroll up to 200 patients. 
Inclusion/Exclusion Criteria: 
Inclusion criteria: 
1. The patient has either a) completed a double-blind lead-in HONOR study and completed or is 
active (at the time of study discontinuation) in the 12-week open-label extension study, P303, 
or b) is currently enrolled in the double-blind lead-in HONOR study that has been 
discontinued due to results of an interim analysis, and is judged by the investigator as 
reasonably compliant, with at least 60% compliance with study medication usage (based on 
drug accountability). 
2. The patient has provided written informed consent to participate in this extension study.  
Note: Separate written, signed informed consent will be required if the patient is to participate 
in the optional pharmacogenomic assessment.  A decision not to participate in the optional 
pharmacogenomic testing will not affect the patient’s eligibility for the main study. 
3. The patient met all prior inclusion and exclusion requirements for the double-blind lead-in 
HONOR study, or the site received medical monitor approval for the patient to remain in the 
lead-in study after the retrospective discovery of an entry violation that did not pose any 
threat to the patient’s safety or well-being.  
4. During the course of the lead-in HONOR study or 12-week open-label extension P303 study, 
the patient has had no intervening medical conditions including pregnancy, clinically 
significant increase in suicidal ideation (plan or intent) or significant worsening of 
depression, newly arising clinically significant abnormal laboratory tests, or any clinically 
significant, uncontrolled, or unstable medical or surgical condition that could affect the 
patient’s ability to participate in the study or potentially compromise the patient’s well-being 
during the study. 
5. The patient does not require treatment with a potent (strong) cytochrome P450 subtype 3A4 
(CYP3A4) inhibitor, or St. John’s wort. 
6. The patient is willing to refrain from use of all other formulations of cyclobenzaprine for the 
duration of the study. 
7. The patient is willing to refrain from use of monoamine oxidase inhibitors for the duration of 
the study. 
8. Female patients of childbearing potential continue to agree to practice one of the medically 
acceptable methods of birth control detailed in the lead-in study. 
 
Exclusion Criteria:  
There are no exclusion criteria for this study. 
 
Investigational product, dosage and mode of administration: 


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Name: Tonmya®1/TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 
Dose, route, frequency: 2 tablets of TNX-102 SL 2.8 mg taken simultaneously and sublingually 
(under the tongue) each day at bedtime starting on Day 0 for 40 to 52 weeks. 
Duration of treatment: 
40 to 52 weeks 
Reference therapy, dosage and mode of administration: None 
Criteria for evaluation: 
The primary objective of the study is to evaluate the safety of bedtime treatment with TNX-102 SL 
5.6 mg for an additional 40 to 52 weeks in patients with PTSD who have either completed the double-
blind lead-in HONOR study and completed or are active (at the time of study discontinuation) in the 
12-week open-label extension study, P303, or were enrolled in the double-blind lead-in HONOR 
study that has been discontinued due to results of an interim analysis.  Safety will be assessed by the 
monitoring and recording of AEs, clinical laboratory tests, vital signs, the monitoring of suicidality 
using the Columbia Suicide Rating Scale (C-SSRS) scale, and the monitoring of depressive 
symptoms using the Beck Depression Inventory (BDI-II). Safety as well as durability of response will 
also be assessed by the monitoring of PTSD symptoms using the PTSD Checklist-Specific Version 
(PCL-S) at Visit 5 (Week 28) and Visit 6 (Week 40) in order to monitor for any potential worsening 
of PTSD symptoms or its symptoms clusters during the final 12-weeks of the study. Patients enrolled 
under Track B will also have an additional PCL-S evaluated for safety at their Visit 7 (Week 52). 
Limited efficacy assessments consisting of the CGI-I, SDS, PROMIS Sleep Disturbance and the BDI-
II will be collected at each visit. The PCL-S will be used for efficacy assessments at Visits 5 and 6 
only. 
Statistics 
Analysis Population:  
The Safety Population will comprise all patients who have been exposed to TNX-102 SL. 
 
Safety Analyses:   
Safety data will be summarized as a single treatment group receiving 1 or more doses of TNX-102 SL 
5.6 mg.  Adverse events will be coded using the same version of the Medical Dictionary for 
Regulatory Activities (MedDRA) as used for the lead-in HONOR study and will be summarized 
overall and by preferred term and system organ class (SOC).  Adverse events will also be summarized 
by severity and relationship to study drug.  Serious AEs and AEs leading to discontinuation of study 
drug will also be summarized. Adverse events that are ongoing in the 12-week open-label extension 
study P303 or the lead-in double blind HONOR study will be transcribed into the eCRF.  All other 
adverse events that are reported after starting TNX-102 SL in this extension study, or that worsen 
after entry into this extension study, will be considered newly emergent AEs (NEAEs), even if the 
type of event was previously reported (and resolved) during either the HONOR study or the 12-week 
open-label extension study. 
Actual values and change from baseline for clinical laboratory test results, vital sign measurements, 
depression status via the BDI-II and PTSD symptom status via the PCL-S, will be summarized at 
endpoint using descriptive statistics (n, mean, SD, median, minimum, and maximum).  The number of 
                                                 
1 Tonmya is the FDA conditionally accepted proposed proprietary name for TNX-102 SL for the treatment of 
PTSD. 


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patients with baseline and treatment-emergent suicidal ideation and/or suicidal behavior or self-
injurious behavior, based on the C-SSRS, will be summarized by treatment group. 
 
Efficacy Analyses: 
Descriptive statistics by study visit will be displayed for: 
▪ 
Proportion of patients with a CGI-I score of “very much improved” or “much improved” 
from baseline 
▪ 
Change from baseline in the SDS 
▪ 
Change from baseline in patients’ quality of sleep score using the PROMIS Sleep 
Disturbance scale  
▪ 
Change from baseline in BDI-II total score 
▪ 
Change from Visit 5 to Visit 6 in PCL-S total score 
 
Pharmacogenomic Analyses: 
Potential genetic determinants of treatment response will be examined by the assessment of genetic 
variants in relation to treatment outcome. A blood sample will be obtained from patients who have 
signed a separate informed consent form for the pharmacogenomic analyses.  The blood sample can 
be obtained as soon as the patient has agreed to be tested and has signed the separate informed 
consent form; i.e., the blood draw is not tied to any specific study visit, hence it can be obtained at 
any time.   
 
The first step of the pharmacogenomic analyses will involve exome sequencing and analysis for 
allelic polymorphisms related to treatment response to TNX-102 SL. It is presumed that unused 
sample will be stored up to fifteen years, and potentially utilized to develop a pharmacogenomic test 
for determining likelihood of treatment response to TNX-102 SL.   


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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 .................8 
4. 
INTRODUCTION ......................................................................................................14 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................15 
5.1. 
Primary Objective .......................................................................................................15 
5.2. 
Secondary Objectives .................................................................................................15 
6. 
INVESTIGATIONAL PLAN .....................................................................................16 
6.1. 
Overall Study Design ..................................................................................................16 
6.2. 
Number of Patients and Treatment Assignment .........................................................16 
6.3. 
Study Endpoints ..........................................................................................................17 
6.3.1. 
Safety ..........................................................................................................................17 
6.3.2. 
Efficacy .......................................................................................................................17 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................17 
7.1. 
Informed Consent .......................................................................................................17 
7.2. 
Inclusion Criteria ........................................................................................................18 
7.3. 
Patient Exclusion Criteria ...........................................................................................18 
7.4. 
Withdrawal Criteria ....................................................................................................19 
8. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................20 
8.1. 
Study Drug Packaging, and Labeling and Storage .....................................................20 
8.2. 
Dosing Instructions .....................................................................................................20 
8.3. 
Dispensing Instructions ..............................................................................................21 
8.4. 
Release of Clinical Study Supplies to the Investigator ...............................................21 
8.5. 
Concomitant Medications ...........................................................................................21 
8.6. 
Study Drug Accountability and Reconciliation ..........................................................22 
9. 
STUDY VISITS AND PROCEDURES .....................................................................23 
9.1. 
Visit 1 – Screening/Baseline (Week 0, Day 1) ...........................................................23 
9.1.1. 
Informed Consent .......................................................................................................23 
9.1.2. 
Screening Overview ....................................................................................................23 


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9.1.3. 
Patient Numbering ......................................................................................................23 
9.1.4. 
Pharmacogenomic Assessment ...................................................................................24 
9.1.5. 
Visit 1 Baseline Assessments/Procedures (Week 0) ..................................................24 
9.2. 
Visit 2 (Telephone Visit: Week 2) ..............................................................................25 
9.3. 
Visits 3, 4, and 5 (Weeks 7, 16, and 28) .....................................................................25 
9.4. 
Visit 6 (Week 40) ........................................................................................................26 
9.5. 
Early Termination (ET) ..............................................................................................27 
9.6. 
Unscheduled Visits .....................................................................................................28 
10. 
STUDY ASSESSMENTS ..........................................................................................29 
10.1. 
Screening Assessments ...............................................................................................29 
10.2. 
Efficacy Assessments .................................................................................................29 
10.2.1. 
Clinical Global Impression of Improvement (CGI-I) .................................................29 
10.2.2. 
Sheehan Disability Scale (SDS) .................................................................................29 
10.2.3. 
PROMIS Sleep Disturbance Scale ..............................................................................29 
10.2.4. 
Beck Depression Index (BDI-II) ................................................................................30 
10.2.5. 
PTSD Checklist-Specific Version (PCL-S) ................................................................30 
10.3. 
Pharmacogenomics Testing ........................................................................................30 
10.4. 
Safety Parameters .......................................................................................................30 
10.4.1. 
Adverse Events (AEs) .................................................................................................31 
10.4.1.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................31 
10.4.1.2. 
Safety Planning Intervention (SPI) .............................................................................31 
10.4.1.3. 
Visual Examination of Oral Cavity ............................................................................32 
10.4.1.4. 
Vital Signs ..................................................................................................................32 
10.4.1.5. 
Clinical Laboratory Assessments ...............................................................................32 
11. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS AND PREGNANCY ..................................................................................33 
11.1. 
Definition of Adverse Events .....................................................................................33 
11.2. 
Adverse Event Recording ...........................................................................................34 
11.2.1. 
Coding the Adverse Event ..........................................................................................34 
11.2.2. 
Severity of Adverse Event ..........................................................................................34 
11.2.3. 
Relationship of Adverse Events to Study Drug ..........................................................34 
11.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................35 
11.4. 
Pregnancy ...................................................................................................................37 


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12. 
STATISTICS ..............................................................................................................38 
12.1. 
Evaluation of Safety ...................................................................................................38 
12.2. 
Evaluation of Efficacy ................................................................................................38 
12.3. 
Estimate of Sample Size .............................................................................................38 
12.4. 
Assessment of Demographic and Baseline Characteristics and Patient 
Disposition ..................................................................................................................39 
13. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................40 
13.1. 
Protocol Modifications and Deviations ......................................................................40 
13.2. 
Study Termination ......................................................................................................40 
14. 
ETHICAL CONSIDERATIONS................................................................................41 
14.1. 
Ethical Conduct of the Study ......................................................................................41 
14.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................41 
14.3. 
Written Informed Consent ..........................................................................................41 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................43 
15.1. 
Maintaining Privacy and Confidentiality....................................................................43 
15.2. 
Maintaining Essential Clinical Documents ................................................................43 
15.3. 
Data Handling .............................................................................................................44 
15.4. 
Case Report Forms (CRFs) .........................................................................................44 
15.5. 
Screening Records ......................................................................................................44 
15.6. 
Clinical Laboratory Certification ................................................................................44 
15.7. 
Site Monitoring and Tonix’s Right to Review Records .............................................45 
15.8. 
Audits and Inspections ................................................................................................45 
16. 
CONFIDENTIALITY ................................................................................................46 
16.1. 
Protection of Patient Anonymity ................................................................................46 
16.2. 
Confidentiality of Study Information .........................................................................46 
16.3. 
Publication of Data and Protection of Trade Secrets ..................................................46 
17. 
LIST OF REFERENCES ............................................................................................48 
18. 
APPENDICES ............................................................................................................49 
APPENDIX 1. STUDY DESIGN AND SCHEDULE OF ASSESSMENTS .............................49 
APPENDIX 2. LIST OF CYP3A INHIBITORS ........................................................................51 
APPENDIX 3. AMRIX® PACKAGE INSERT (DATED MAY 2018) .....................................52 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Clinical Laboratory Assessments ...............................................................................32 
Table 3: 
Medical Monitoring Contact Information ..................................................................36 


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 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BDI-II 
Beck Depression Inventory–II 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression- Improvement from Initiation of Treatment 
CK 
Creatinine Kinase 
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP3A4 
Cytochrome P450 subtype 3A4 
e.g. 
Exempli gratia (for example) 
EC 
Ethics Committee 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCl 
Hydrochloride 
HIPAA 
Health Insurance Portability and Accountability Act 
i.e. 
id est (that is) 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MCH 
Mean corpuscular hemoglobin 


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Abbreviation or 
Specialist Term 
Explanation 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram(s) 
N, n 
Number (of patients) 
NA 
Not applicable 
NEAE 
Newly Emergent Adverse Event 
PCL-S 
PTSD Checklist-Specific Version 
PROMIS 
Patient-Reported Outcome Measurement Information System 
PTSD 
Posttraumatic Stress Disorder 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 
SL 
Sublingual 
SNRIs 
Serotonin–norepinephrine reuptake inhibitors 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SPI 
Safety Planning Intervention 
SSRIs 
Selective serotonin reuptake inhibitors 
TNX-102 SL 
Cyclobenzaprine HCl sublingual tablets 
Tonmya 
FDA conditionally accepted proposed proprietary name for TNX-102 SL for the 
treatment of PTSD 
US 
United States 
VA 
Veteran’s Administration 
WBC 
White blood cell 
WHO 
World Health Organization 


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4. 
INTRODUCTION 
The background information provided in the lead-in study protocol and the most current TNX-
102 SL Investigator’s Brochure is relevant to this extension study.  
 
 
 
 
 
 
 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety of TNX-102 SL taken daily 
at bedtime over an additional 40 to 52 weeks in patients with PTSD who have participated in a 
double-blind lead-in HONOR study and possibly a 12-week open-label extension study P303. 
5.2. 
Secondary Objectives 
The secondary objective of the study is to evaluate the long-term effect of TNX-102 SL taken 
daily at bedtime over an additional 40 to 52 weeks in patients with PTSD who have participated 
in a double-blind lead-in HONOR study and possibly a 12-week open-label extension study 
P303. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a 40 to 52-week, multicenter, open-label extension study designed to establish long-term 
safety exposure and to examine the long-term effect with daily bedtime dosing of TNX-102 SL 
5.6 mg (2 x 2.8mg tablets) in patients with PTSD.  This study will be conducted at approximately 
35 sites in the United States (US).  
Patients who have either: (a) completed the double-blind lead-in study and complete, or are 
active (at the time of study discontinuation) in the 12-week open-label extension study, P303; or 
(b) are currently enrolled in the double-blind lead-in study (HONOR study) that has been 
discontinued due to results of an interim analysis , will be eligible.  For Track A patients, this 
extension study consists of 5 in-clinic visits, including the Screening/Baseline visit and visits 
after 7, 16, 28 and 40 weeks of treatment (Visits 3-6).  There will also be a telephone visit after 
two weeks of treatment (Visit 2) for patients enrolling from the double-blind lead-in study, 
P301/HONOR.  The total treatment duration of this study will be 40 weeks for patients enrolled 
under Track A criteria, and 52 weeks for patients enrolled under Track B criteria.  Therefore, the 
maximum total duration of continuous treatment with TNX-102 SL could be approximately 64 
weeks for those patients assigned to TNX-102 SL in the lead-in HONOR study who then also 
completed the 12-week open-label extension study P303.  
For patients enrolling from the open-label extension study, P303, there is no need to repeat 
assessments at Visit 1 for this study, if the patient enrolls and initiates study treatment within 
fourteen days of completing the 12-week open-label extension study P303.  For patients who are 
active in the double-blind lead-in study, P301/HONOR, all Baseline procedures and assessments 
will be completed at Visit 1. 
After the patient has participated in the lead-in HONOR study or the open-label extension study, 
P303, and has consented to participate in this open-label extension study, patients will be 
dispensed a 7-week supply of open-label TNX-102 SL tablets (3 bottles) and will be instructed to 
take 2 tablets of study drug sublingually daily at bedtime, starting on the evening of Visit 1.  A 
phone visit will be completed after 2 weeks of treatment for patients enrolling from the double-
blind lead-in study, P301/HONOR.  All patients will return to the study center for safety and 
efficacy assessments at Weeks 7, 16, 28, and 40 (or early termination). Patients enrolled under 
Track B criteria will continue to dose for an additional 12 weeks and have the last study visit at 
Week 52.  Patients will return their TNX-102 SL medication (including empty bottles) at these 
visits.  Patients will also receive a 9-week supply of TNX-102 SL (4 bottles) at the Week 7 visit, 
and a 12-week supply (5 bottles) at the Week 16, 28 and 40 (Week 40 for Track B patients only) 
visits.  Patients will be allowed to take other medications deemed appropriate by their health care 
providers to manage their PTSD and other conditions, including currently approved PTSD 
therapies.  See Section 8.5 for a discussion of allowed concomitant treatments.  
The study timeline and events schedule is provided in Appendix 1. 
6.2. 
Number of Patients and Treatment Assignment 
Up to 200 patients will enroll into this study.  Eligible patients will either have completed a 
double-blind lead-in HONOR study and participated in a 12-week open-label study P303 or will 


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have been currently enrolled in a double-blind lead-in HONOR study when that study was 
discontinued due to results of an interim analysis. 
All patients will be assigned to TNX-102 SL, 5.6 mg regardless of which treatment arm they 
were randomized to in the lead-in HONOR study.   
6.3. 
Study Endpoints 
6.3.1. 
 Safety 
Safety will be assessed by: 
▪ Adverse events (AEs) and serious AEs (SAEs) throughout the entire duration of the 
study, including assessment of AEs involving the oral cavity 
▪ Change from baseline in clinical laboratory test results 
▪ Changes from baseline indicative of increased suicidal ideation or behavior as assessed 
by the Columbia Suicide Severity Rating Scale (C-SSRS) 
▪ Change from baseline in Beck Depression Inventory-II (BDI-II) 
▪ Changes from baseline in vital signs and weight 
▪ Track A patients only: Change from Visit 5 to Visit 6 in PTSD Checklist-Specific 
Version (PCL-S) 
▪ Track B patients only: Change from Visit 5 to Visit 7 in PTSD Checklist-Specific 
Version (PCL-S) 
6.3.2. 
Efficacy  
Descriptive statistics by treatment and study visit will be displayed for a number of efficacy 
endpoints including: 
▪ Proportion of patients with a Clinical Global Impression-Improvement from Initiation of 
Treatment (CGI-I) score of “very much improved” or “much improved” from baseline 
▪ Change from baseline in the Sheehan Disability Scale (SDS)  
▪ Change from baseline in patients’ quality of sleep using the Patient-Reported Outcome 
Measurement Information System (PROMIS) Sleep Disturbance scale  
▪ Change from baseline in BDI-II score 
▪ Change from Visit 5 to Visit 6 in PTSD Checklist-Specific Version (PCL-S) 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1. 
Informed Consent 
A potential patient may be screened for eligibility only after the nature of the study, its purpose, 
and any other information relevant to the patient’s decision to participate have been explained to 
him or her and the patient has voluntarily confirmed his or her willingness to participate.  The 
investigator will determine the potential patient’s suitability for the study by interviewing the 


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patient and by reviewing the patient’s experience in the double-blind lead-in HONOR study 
and/or 12-week open-label extension study P303.  
Informed consent is documented by means of a written, signed, and dated informed consent form 
(ICF).  Separate written, signed informed consent must be obtained if the patient is to participate 
in the optional pharmacogenomic assessment.  Additional information is provided in 
Section 14.3. 
7.2. 
Inclusion Criteria 
1. The patient has either a) completed the double-blind lead-in study and completed or is 
active (at the time of study discontinuation) in the 12-week open-label extension study 
(P303), or b) is currently enrolled in the double-blind lead-in study that was discontinued 
due to results of an interim analysis, and is judged by the investigator as reasonably 
compliant, with at least 60% compliance with study medication usage (based on drug 
accountability). 
2. The patient has provided written informed consent to participate in this extension study.  
Note: Separate written, signed informed consent will be required if the patient is to 
participate in the optional pharmacogenomic assessment.  A decision not to participate in 
the optional pharmacogenomic testing will not affect the patient’s eligibility for the main 
study. 
3. The patient met all prior inclusion and exclusion requirements for the double-blind lead-
in study, or the site received medical monitor approval for the patient to remain in the 
lead-in study after the retrospective discovery of an entry violation that did not pose any 
threat to the patient’s safety or well-being.  
4. During the course of the lead-in study or 12-week open-label extension study, the patient 
has had no intervening medical conditions including pregnancy, clinically significant 
increase in suicidal ideation (plan or intent) or significant worsening of depression, newly 
arising clinically significant abnormal laboratory tests, or any clinically significant, 
uncontrolled, or unstable medical or surgical condition that could affect the patient’s 
ability to participate in the study or potentially compromise the patient’s well-being 
during the study. 
5. The patient does not require treatment with a potent (strong) cytochrome P450 subtype 
3A4 (CYP3A4) inhibitor, or St. John’s wort. 
6. The patient is willing to refrain from use of all other formulations of cyclobenzaprine for 
the duration of the study. 
7. The patient is willing to refrain from use of monoamine oxidase inhibitors for the 
duration of the study. 
8. Female patients of childbearing potential continue to agree to practice one of the 
medically acceptable methods of birth control detailed in the lead-in study. 
7.3. 
Patient Exclusion Criteria  
There are no exclusion criteria for this study. 


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7.4. 
Withdrawal Criteria 
There are no pre-specified withdrawal criteria for this study.  In accordance with the Declaration 
of Helsinki, human patients have the right to withdraw from the study at any time for any reason.  
The investigator and Tonix also have the right to remove patients from the study.  Additional 
information regarding withdrawal or discontinuation of patients is described in detail in 
Section 9.6. 


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8. 
STUDY DRUG MATERIALS AND MANAGEMENT 
8.1. 
Study Drug Packaging, and Labeling and Storage 
The study medication bottles will be labeled minimally with the following information:  study 
number TNX-CY-P306 (P306), sponsor name and address, bottle number, drug name, quantity, 
storage conditions, usage instructions, and caution statements for investigational new drug, i.e., 
Caution: New Drug Limited by United States Law to Investigational Use, and Keep Out of 
Reach of Children and Pets. 
Each study medication bottle will contain 40 tablets.  Since the patient will dose with two tablets 
sublingually each night, three bottles will be dispensed to each patient at Visit 1/Baseline.  Four 
bottles will be dispensed at Week 7 and five bottles at Weeks 16, 28 and 40 (Week 40 for Track 
B patients only); this will provide the patient with enough study drug between visits, plus 
additional tablets to cover loss and/or visit window variability.  The patient should be instructed 
to take all the tablets in one bottle before opening another bottle.  The patient should be 
instructed to keep this study medication in a safe location out of extreme environmental 
conditions and out of the reach of children and pets, and that this medication is not to be taken by 
any individual other than the study patient.  Each patient will also be instructed that they will be 
expected to return all bottles and all unused study medication at each clinic visit; unused 
medication will be counted to assess compliance with study drug treatment. 
Storage of the study drug at the investigational site should be under locked and secure conditions 
with limited staff access.  Study drug should be stored at 20-25°C/68-77°F in a temperature/ 
humidity-monitored room; however, brief excursion (15-30°C/59-86°F) as defined in the Study’s 
Reference Manual (IP Receipt and Storage) is permitted without sponsor’s approval. 
8.2. 
Dosing Instructions 
Patients will be instructed to take two (2) TNX-102 SL 2.8 mg tablets sublingually, placed 
simultaneously under the tongue, each evening at bedtime starting on evening of Day 0 and 
continuing without interruption for 40 to 52 weeks.  The study drug should be taken at bedtime 
after teeth brushing and other oral care has been completed.  The mouth/sublingual area should 
be moist at the time of dosing, so the patient should drink a few sips of water prior to dosing, 
especially if prone to dry mouth.  Patients will be instructed to place the two TNX-102 SL 2.8 
mg tablets under their tongue and keep them there until they have dissolved.  They should not 
swallow, crush or chew the tablets.  Patients should not eat or drink (or chew gum) for at least 15 
minutes after dosing, and preferably not until morning.  Patients will be reminded that only two 
(2) tablets are allowed per day. Note: In the event that the patient misses a dose, instruct the 
patient to continue dosing with two (2) tablets the next evening; i.e., they should not take more to 
make up for the missed dose. 
Patients should also be reminded to keep the desiccant in the bottle after opening and to screw 
the cap on tightly after dosing. 
 


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8.3. 
Dispensing Instructions 
Each enrolled patient will be assigned 3, 4 or 5 bottles of TNX-102 SL at each dispensing visit.  
Bottles of TNX-102 SL tablets are numbered and will be supplied to sites as open stock.  Patients 
are reminded to open and use one bottle of TNX-102 SL tablets at a time. 
8.4. 
Release of Clinical Study Supplies to the Investigator 
Tonix or Tonix’s designee’s standard operating procedures (SOP) for releasing clinical trial 
supplies to the site will be followed. 
8.5. 
Concomitant Medications  
Many of the restrictions in the lead-in study related to concomitant medications and trauma-
focused psychotherapy will be relaxed.  Therefore, patients may utilize antidepressants, mood 
stabilizers, anticonvulsants, benzodiazepines, stimulants, and opioids, if needed, unless 
specifically excluded as outlined below.  Patients may take medications to help them sleep, per 
the judgment of the investigator.  
Any concomitant medications or other treatments, including dietary supplements, must be 
recorded in the patient’s medical record and case report form along with the indication, dose and 
dates of treatment.  
The following medications are specifically excluded during the study and patients must agree to 
refrain from use of these medications during the study:   
• Any other forms of cyclobenzaprine (FLEXERIL®, AMRIX®, FEXMID®, or generic 
equivalents) continue to be specifically excluded during the study and patients must 
agree to refrain from use of these medications during the study.  
• Monoamine oxidase inhibitors (tranylcypromine, phenelzine, isocarboxazid, and 
selegiline)   
• Cytochrome P450 3A4 inhibitors (strong ones only) (refer to Appendix 2 for a list).  
• St. John’s wort  
NOTE: Patients initiating treatment with antidepressants, tramadol or other opioids, triptans, or 
any other serotonergic medication should be cautioned about the possibility of serotonin 
syndrome which has been reported in patients receiving cyclobenzaprine with selective serotonin 
reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and other 
serotoninergic agents. (See Appendix 3, AMRIX® Package Insert, Warnings Section).  The 
patient should be instructed to call the clinic immediately in the event of any of the warning 
signs or symptoms of serotonin syndrome, as outlined in the informed consent.  The investigator 
should carefully review the patient’s complete list of medications when considering new 
treatments and the site should ask the patient to call the site (or return for an unscheduled clinic 
visit) within one week after adding a new serotonergic therapy (or increasing the dose of a prior 
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8.6. 
Study Drug Accountability and Reconciliation 
All patients will be expected to bring their bottles of study medication with them to study visits.  
The site staff will inspect the medication bottles and perform a count of the tablets remaining in 
the bottles and the number of tablets that the patient should have returned (based on the number 
of days since the previous visit).  The number of tablets dispensed, the number returned, and the 
number expected to be returned will be recorded in the patient’s record.  An assessment of 
medication adherence should be done by the study staff to ensure that the patient understands all 
dosing instructions and is taking the medication as prescribed.  If it is found that the patient is not 
taking the study medication as prescribed, the patient will be re-counseled on correct 
administration, and this should be noted in the patients’ record, and discussed with the medical 
monitor, if necessary.  
If the patient fails to return all unused study drug as expected, the patient should be questioned 
regarding the reason for the lower than expected tablet number and about potential misuse, abuse 
or diversion.  In situations where more than 2 tablets per week cannot be accounted for, the 
investigator will be asked to evaluate the situation, and a written summary should be added to the 
source and entered onto the case report form (CRF).  In addition, the medical monitor should be 
contacted any time a patient requests replacement medication for any reason (e.g., loss of bottles 
or damage to study drug).  Situations where replacement drug is requested, or when more than 2 
tablets per week cannot be accounted for, should be recorded as deviations.   
All study medication, including partial and empty bottles, must be maintained at the study site 
until Tonix or its designee verifies drug accountability and provides instruction for the 
destruction or the return of the investigational product to the Sponsor’s drug distribution depot.  
Tonix or their designee will perform drug accountability which entails reconciliation between the 
amount of drug shipped to the study site, study drug assigned and dispensed to the patient 
(including returned unused assigned study drug), and study supplies that were never dispensed 
and/or assigned to patients.  
 


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9. 
STUDY VISITS AND PROCEDURES 
The overall and detailed schedule for study procedures and visits is provided in Appendix 1. 
9.1. 
Visit 1 – Screening/Baseline (Week 0, Day 1) 
9.1.1. 
Informed Consent 
Before the potential patient has undergone any study-related screening procedures, the nature of 
the study and the potential risks associated with it will be explained to the patient, and the patient 
will be given an opportunity to ask questions to his or her satisfaction.  After all questions are 
answered, but before proceeding further, the patient must read and sign a written informed 
consent form.  This signed informed consent form will be retained in the Investigator’s study 
file, and the date the patient signed the form will be entered into the CRF.  The patient will be 
provided with a copy of his or her signed and dated informed consent form.  The patient will be 
required to sign all updated informed consents. 
Separate written, signed informed consent must be obtained if the patient is to participate in the 
optional pharmacogenomic assessment.   
 
9.1.2. 
Screening Overview 
The first study visit, Visit 1, will be where the study is explained to the prospective study patient, 
where written informed consent will be obtained and documented, and where protocol-specified 
study procedures and assessments will be completed.   
For patients enrolling into this study from the 12-week open label extension study, P303, the 
P306 Baseline Visit (Visit 1) date is intended to be the same date as the final visit of the 12-week 
open label extension study, P303.  However, if there are extenuating circumstances, Visit 1 of 
P306 may occur within fourteen days of their final visit in P303 without repeating baseline 
assessments.   If more than fourteen days elapse between the final visit of P303 and start of the 
P306 study, medical monitor approval will be required and baseline assessments will need to be 
repeated.   
For patients enrolling directly from the double-blind lead-in study, P301, all Visit 1 assessments 
will be performed.  These patients are also expected to enter the P306 study at the same time as 
their final P301 visit; however, if there are extenuating circumstances, then Visit 1 of P306 may 
occur within fourteen days of their final P301 visit.    
Once the patient has provided written informed consent to participate and has met all relevant 
inclusion criteria, this patient is eligible to begin the open-label treatment period, starting at 
bedtime on the day of enrollment.  The patient should be dispensed three bottles of TNX-102 SL 
tablets, along with dosing and storage instructions.  The end-of-study information collected at the 
final visit of the 12-week open label extension study P303, or the Visit 1 assessments completed 
as part of this protocol, will be considered the baseline values for Study P306. 
9.1.3. 
Patient Numbering 
All patients who participated in the double-blind lead-in HONOR study will retain their original 
concatenated 6-digit site-patient number, i.e., all patients entering P306.   


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9.1.4. 
Pharmacogenomic Assessment  
Patients should be offered the opportunity to participate in the pharmacogenomic assessment as 
soon as Protocol Amendment 01 has been approved and implemented at the clinical site.  The 
blood draw for this assessment is not tied to any specific visit; instead, it should be obtained after 
the patient has reviewed and signed the separate pharmacogenomic testing informed consent 
form, irrespective of the visit at which the consent is signed.    
9.1.5. 
Visit 1 Baseline Assessments/Procedures (Week 0) 
 
The following assessments/procedures will be completed at Visit 1.   
 
For all patients: 
▪ Obtain written informed consent to participate 
▪ Inclusion criteria 
▪ Review and transcribe new concomitant medications as well as those which are to be 
continued from the double-blind lead-in HONOR study or the 12-week open-label 
extension study P303 
▪ Review and transcribe new AEs as well as those which are ongoing from the double-
blind lead-in HONOR study or the 12-week open-label extension study P303 
 
For patients enrolling from the double-blind lead-in study, P301/HONOR only (or  patients 
rolling over to study P306 more than 14 days after the final visit of the 12-week open-label 
extension study P303): 
▪ Obtain vital signs, including weight. The height collected at baseline from the lead-in 
study will be utilized for body mass index (BMI) calculations in this study. 
▪ Perform a visual exam of the oral cavity  
▪ Have the patient complete the PROMIS-Sleep Disturbance scale and the SDS.  
Review each scale for completeness once done.  
▪ Have the patient complete the BDI-II  
▪ Conduct the C-SSRS after reviewing the results of the BDI-II 
▪ Draw blood for clinical laboratory testing  
▪ Review patient’s lifetime psychiatric treatment history, demographic information and 
medical history to ensure the information recorded during the double-blind lead-in 
study is accurate and complete, as it will also be included in the extension study’s 
database.   
Only those patients meeting all of the inclusion criteria will be eligible to continue.   
 
For all patients: 
 
After all study requirements for Visit 1 of P306 have been fulfilled, the patient will:  


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▪ Be dispensed 3 bottles of TNX-102 SL tablets and be instructed to begin dosing with 
study medication at bedtime, starting the evening of Visit 1;  
▪ Receive instruction regarding proper sublingual dosing technique and the time of 
expected dosing; and  
▪ Schedule the telephone Visit 2 (for patients enrolled from the double-blind lead-in 
study, P301/HONOR, only) and receive an appointment to return to the clinic for 
Visit 3. 
9.2. 
Visit 2 (Telephone Visit: Week 2) 
For patients enrolled from the double-blind lead-in study, P301/HONOR only:  Visit 2 will be 
done as a telephone call to the patient and should be conducted after 2 weeks of treatment, on 
Day 14 ± 3 days. 
The following steps should be completed: 
▪ Assess changes in concomitant medications 
▪ Assess study drug compliance based on patient verbal report 
▪ Assess occurrence of AEs, including any oral AEs and whether an unscheduled visit 
is indicated for an examination of the oral cavity 
▪ Review patient instructions regarding drug dosing and storage  
▪ Administer the ‘Since Last Visit’ C-SSRS telephonically 
9.3. 
Visits 3, 4, and 5 (Weeks 7, 16, and 28) 
These visits are conducted after 7, 16, and 28 weeks (± 7 days) of treatment respectively.  The 
following assessments and procedures are to be conducted at each of these visits in the following 
general order:  
▪ Collect returned study medication from patient and perform drug accountability 
▪ Assess study drug compliance  
▪ Assess for changes in concomitant medications 
▪ Assess for occurrence of AEs  
if any oral AEs have been reported (other than numbness, tingling or bitter taste), 
perform and document an examination of the oral cavity  
▪ Have the patient complete the “baseline” PCL-S (Visit 5 only) 
▪ Have the patient complete the PROMIS-Sleep Disturbance Scale and the SDS.  
Review each scale for completeness once done. 
▪ Have the patient complete the BDI-II 
▪ Conduct the C-SSRS after reviewing the results of the BDI-II  
▪ Vital signs and weight 


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▪ Draw blood for clinical laboratory tests (Visit 5 only) 
▪ Urine pregnancy test (for women of child-bearing potential) 
▪ Inspect the oral cavity and document findings, if any (Visit 5 only) 
▪ Conduct the CGI-I, using the P306 baseline visit as comparison  
▪ Dispense 4 new bottles of TNX-102 SL tablets at Week 7 (Visit 3).  At Weeks 16 
(Visit 4) and 28 (Visit 5), dispense 5 new bottles. 
 
Review patient instructions regarding drug dosing and storage, and schedule appointment for 
next clinic visit.  
 
9.4. 
Visit 6 (Week 40) 
 
Visit 6 is to be conducted after 40 weeks (±7 days) of treatment in the extension study. At this 
visit, the patient (Track A only) will return all remaining study drug and the following 
assessments and procedures are to be completed in the following general order:  
▪ Collect returned study medication from patient and perform drug accountability 
▪ Assess study drug compliance  
▪ Assess for occurrence of AEs  
▪ Assess for changes in concomitant medications  
▪ Obtain vital signs including weight 
▪ Track A patients only: Draw blood for clinical laboratory tests 
▪ For women of child-bearing potential, conduct urine pregnancy test 
▪ Track A patients only: Inspect the oral cavity and document findings, if any 
▪ Have the patient complete the PCL-S 
▪ Have the patient complete the PROMIS-Sleep Disturbance Scale and SDS 
▪ Have the patient complete the BDI-II 
▪ Conduct the C-SSRS after reviewing the results of the BDI-II 
▪ Conduct CGI-I comparing to the P306 baseline 
▪ Track B patients only: Dispense 5 new bottles of TNX-102 SL tablets  
 
9.5. 
Visit 7 (Week 52) 
 
Track B patients only: Visit 7 is to be conducted after 52 weeks (±7 days) of treatment in the 
extension study. At this visit, the patient will return all remaining study drug and the following 
assessments and procedures are to be completed in the following general order:  
▪ Collect returned study medication from patient and perform drug accountability 


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▪ Assess study drug compliance  
▪ Assess for occurrence of AEs  
▪ Assess for changes in concomitant medications  
▪ Obtain vital signs including weight 
▪ Draw blood for clinical laboratory tests 
▪ For women of child-bearing potential, conduct urine pregnancy test 
▪ Inspect the oral cavity and document findings, if any 
▪ Have the patient complete the PCL-S 
▪ Have the patient complete the PROMIS-Sleep Disturbance Scale and SDS 
▪ Have the patient complete the BDI-II 
▪ Conduct the C-SSRS after reviewing the results of the BDI-II 
▪ Conduct CGI-I comparing to the P306 baseline 
 
9.6. 
Early Termination (ET) 
In accordance with the Declaration of Helsinki, patients have the right to withdraw from the 
study at any time for any reason, and they will be advised of this right.  The investigator and 
Tonix also have the right to remove patients from the study.  Specific reasons for removal of a 
patient from the study could include, but are not limited to: 
▪ An AE 
▪ An illness that, in the judgment of the investigator or Tonix, might invalidate the 
study results or place the patient at risk 
▪ The request of the patient, investigator, or Tonix, whether for administrative or other 
reasons 
▪ Pregnancy 
Patients who wish to terminate their participation in the study should be instructed to come to the 
clinic for an Early Termination Visit.  The purpose of the Early Termination visit is to obtain 
critical information about the patient’s participation, and should be scheduled preferably before 
there has been a substantial lapse in study medication usage.  However, even if there has been a 
medication lapse, the patient should be encouraged to return to the clinic for this visit, and should 
be instructed to return all remaining study medication.  
The following assessments and procedures are completed at this visit in the following general 
order:  
▪ Collect returned study medication from patient and perform drug accountability 
▪ Assess study drug compliance  
▪ Assess for occurrence of AEs  


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▪ Assess for changes in concomitant medications  
▪ Obtain vital signs including weight 
▪ Draw blood for clinical laboratory tests 
▪ For women of child-bearing potential, conduct urine pregnancy test 
▪ Inspect the oral cavity and document findings, if any 
▪ Have the patient complete the PROMIS-Sleep Disturbance Scale and SDS 
▪ Have the patient complete the BDI-II 
▪ Conduct the C-SSRS after reviewing the results of the BDI-II 
▪ Conduct CGI-I comparing to the P306 baseline 
Once these assessments have been completed, the patient may be discharged from the study, 
provided there is no need for additional follow-up to continue to monitor an AE or other 
condition. 
9.7. 
Unscheduled Visits 
Patients may need to be seen at other times than the scheduled study visits for additional safety 
assessments or to follow-up, as medically necessary, on clinical laboratory, physical 
examination, or other findings.  In addition, if a patient calls between scheduled visits to report a 
visible lesion in the oral cavity or other concerning oral cavity AE, the patient should be asked to 
return to the clinic as soon as possible for an unscheduled oral cavity examination.  Unscheduled 
examinations are NOT required for reports of oral numbness, tingling, bitter taste, or for other 
mild or transient AEs that are not concerning to the patient.  If an additional study visit occurs, 
the date and nature of the visit will be documented in the CRF and in the source documents.  The 
patient should be advised to bring study medication with them to the unscheduled visit. 


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10. 
STUDY ASSESSMENTS 
10.1. 
Screening Assessments 
The results of the screening assessments should be reviewed to ensure that the patient continues 
to satisfy all entry criteria and otherwise remains a satisfactory patient for the extension study.  
Laboratory assessments obtained at the final visit of the double-blind lead-in HONOR study or 
the 12-week open-label extension study P303 will not be available prior to the patient’s entry 
into the extension study, but should be reviewed within 7 days when they become available, to 
ensure the patient’s ongoing well-being. 
10.2. 
Efficacy Assessments 
A secondary objective of this study is to evaluate the long-term effect of TNX-102 SL and these 
endpoints are derived from both clinician-administered and subjective patient-completed 
assessments.  The clinician-administered assessments must be administered by qualified and 
trained individuals at each clinical site.  Study specific training will be required before new staff 
that were not trained for the lead-in study are allowed to administer these scales.  In an attempt to 
minimize variability in responses of a given patient over time, it is important that the same rater 
administer the scales to a given patient throughout the study as much as possible.  It is also 
important that the assessments, including those that are patient-completed, be conducted in the 
specified order, according to specific instructions, and in a setting where the patient has minimal 
distractions and sufficient time to complete them.  After completion of these assessments, the 
study coordinator should review the responses for completeness with the patient.  
10.2.1. 
Clinical Global Impression of Improvement (CGI-I) 
The CGI-I is a commonly used clinician-rated scale designed to assess overall clinical 
improvement (change) since baseline.  The CGI-I will be completed at each in-clinic visit after 
baseline.  It will be the responsibility of the Principal Investigator or his qualified designee to 
assess change in the subject’s overall status. 
10.2.2. 
Sheehan Disability Scale (SDS) 
The SDS scale is a self-report questionnaire that was designed to assess the subject’s view of the 
degree to which symptoms have disrupted work, social life/ leisure activities, and family life/ 
home responsibilities during the past week.  In addition, the SDS asks the subject to provide the 
number of days or work lost as well as unproductive days.  The SDS will be administered at each 
in-clinic visit. 
10.2.3. 
PROMIS Sleep Disturbance Scale  
PROMIS refers to the Patient-Reported Outcome Measurement Information System 
(www.nihpromis.org), an NIH-funded initiative to develop instruments to be used across chronic 
conditions.  The PROMIS scale for sleep disturbance (form 8a) will be administered at all in-
clinic visits. 


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10.2.4. 
Beck Depression Index (BDI-II) 
BDI-II refers to the patient-rated assessments of depressive symptomology.  The BDI-II will be 
administered at all in-clinic visits.  Each patient’s response to the BDI suicidality question (item 
9) should be reviewed and compared to the C-SSRS responses to ensure careful assessment of 
any suicidal ideation and resolution of any discrepancies between the self-reported BDI-II and 
the C-SSRS interview. 
10.2.5. 
PTSD Checklist-Specific Version (PCL-S) 
Developed by the National Center for Posttraumatic Stress Disorder, the PCL-S is a 17-item self-
report measure reflecting DSM-IV symptoms of PTSD. The PCL-S aims to link symptom 
endorsements to a specified event or stressful experience, which for P306 has been identified by 
the subject as their Index Trauma during the lead-in double blind study (TNX-CY-P301). 
Respondents rate each item from 1 ("not at all") to 5 ("extremely") to indicate the degree to 
which they have been bothered by that particular symptom over the past month.  
In addition, the long-term safety of TNX-102 SL on PTSD based on PCL-S completed by 
patients in Visit 5 (Week 28) and Visit 6 (Week 40) and Visit 7 (Week 52 for patients enrolled 
under Track B), is assessed with this scale. The mean change in PCL-S total score and PCL-S 
clusters scores from Visit 5 (Week 28) to Visit 6 (Week 40), or to Visit 7 for Track B patients 
will detect any potential worsening in total PTSD score or symptoms clusters in the final 12-
weeks, or 24-weeks for Track B patients, of the study.  Since PCL-S is added to the study when a 
significant number of patients have passed the Visit 4 (Week 16 time point, Visit 5 (Week 28) is 
chosen as the “baseline” for PCL-S in order to capture the vast majority of the patients who 
enrolled in the study from its beginning. 
10.3. 
Pharmacogenomics Testing 
For pharmacogenomic analysis, a single blood draw collected in two PAXgene DNA tubes will 
be obtained from each patient after they have provided separate written, signed informed consent 
for pharmacogenomic analysis.  The purpose of this testing is to allow exome sequencing and 
analysis for genetic variants related to treatment response to TNX-102 SL. It is presumed that 
unused sample will be stored up to fifteen years, and potentially utilized to develop a 
pharmacogenomic test for determining likelihood of treatment response to TNX-102 SL.  A 
decision not to participate in optional pharmacogenomic testing will not affect the patient’s 
eligibility for the main study. Patients have the right to stop participating at any time during the 
study or during the time of sample storage, and, if a patient decides to withdraw from the 
pharmacogenomics portion of this study, any remaining sample will be destroyed and not used 
for further research.  Data collected before a patient’s withdrawal from the pharmacogenomics 
portion of this study will remain in the research database. 
10.4. 
Safety Parameters  
Safety will be assessed by evaluation of adverse events, responses on the C-SSRS, clinical 
laboratory tests, examinations of the oral cavity, vital signs, weight, patient-rated assessments of 
depressive symptomology (BDI-II) and PTSD symptomology (PCL-S).  


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10.4.1. 
Adverse Events (AEs)  
Patients will be monitored for AEs throughout the study, from the time the patient signs an 
informed consent onward.  AEs that are spontaneously reported, elicited or observed are to be 
recorded on the CRF with the date, time of onset, date and time of resolution, severity, 
seriousness, causality (relationship to study medication), actions required, and outcome.  
To elicit AEs, non-leading, simple questions with minimal connotations should be used as the 
initial questions at all evaluation points during the study.  Examples of these questions can be:  
▪ How have you felt since your last visit?  
▪ Have you had any health problems since your last visit?  
If an AE occurs, the investigator will institute support and/or treatment as deemed appropriate.  
If a non-serious AE is unresolved on the last day of the study, an effort should be made to follow 
up until the AE is resolved or stabilized, the patient is lost to follow-up, or there is some other 
resolution of the event.  
There are many symptoms associated with PTSD that can vary in intensity and frequency over 
time.  Only symptoms that significantly worsen or become more frequent, and in the opinion of 
the patient are outside of their normal experience, should be reported as adverse events.  
If a patient reports an oral adverse event other than numbness, tingling or bitter taste, the 
Investigator should examine the oral cavity to confirm presence or absence of any lesion or other 
abnormality, and document the exam.  Additional details related to onset, duration, severity and 
reversibility of the oral event will also be documented.  
10.4.1.1. Columbia-Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS is a clinician-administered interview developed by researchers at Columbia 
University to assess suicide risk and to track suicidal ideation and behavior during clinical trials.  
This scale is intended to be administered by individuals who have received training in its 
administration.  The questions contained in the Columbia-Suicide Severity Rating Scale are 
suggested probes.  Ultimately, the determination of the presence of suicidal ideation or behavior 
depends on the judgment of the individual administering the scale.  
The “since last visit” version of the C-SSRS will be completed at all study visits.  Note that if 
there has been a significant change in responses to this scale indicative of increased suicide risk, 
appropriate intervention should be prescribed Section 10.4.1.2 and an AE should be recorded.   
The patient’s response to BDI-II item 9 (suicidal ideation) should be reviewed prior to 
conducting the C-SSRS at the in-clinic visits to ensure the patient’s responses are consistent 
between the BDI and the C-SSRS (and/or the reason for any inconsistency documented in the 
patient’s chart).        
10.4.1.2. Safety Planning Intervention (SPI)  
The C-SSRS is completed at every visit in order to assess for changes in suicidality during the 
study.  If a patient scores a 4 or 5 on the Suicidal Ideation section of the C-SSRS at a clinic visit 
following enrollment, the patient should be withdrawn from the study and referred for 
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If a patient scores a 2 or 3 on the Suicidal Ideation section of the C-SSRS at any visit, the 
investigator should consider the implementation of a Safety Planning Intervention (SPI).  The 
recommended SPI for this study is the plan developed by Barbara Stanley, PhD and Gregory 
Brown, PhD which has been adopted by the US Veteran’s Administration (VA) (Stanley & 
Brown, 2012).  The VA SPI is a brief clinical intervention aimed at mitigating suicide risk.  It 
consists of a written, prioritized list of coping strategies and sources of support that patients can 
use to alleviate a suicidal crisis.  Sites may use an internally-developed SPI if similar in scope 
and purpose to the VA SPI.  
10.4.1.3. Visual Examination of Oral Cavity  
A visual examination of the oral cavity should be done at Baseline/Visit 1 (or the Week 12 Visit 
of the 12-week open label study) and after 28 weeks (Visit 5) and 40 weeks (Visit 6) for Track A 
patients, or after 52 weeks of treatment (Visit 7) for Track B patients, and/or at ET.  In addition 
to these regularly scheduled examinations, a visual inspection of the oral cavity (including the 
sublingual area) should be done any time a patient reports a lesion or other finding in the oral 
cavity other than numbness, tingling or bitter taste, in order to document the presence or absence 
of any visible abnormalities.  Additional details related to onset, duration, severity and 
reversibility of oral events will also be documented in the CRF.  
10.4.1.4. Vital Signs  
Vital signs (sitting blood pressure and heart rate, respiratory rate, oral temperature, and weight) 
will be assessed at Visits 1, 3, 4, 5, 6 and 7 (Visit 7 for Track B patients only).  Height will be 
transferred from the lead-in study database for BMI calculations (done at Baseline and Visit 6 for 
Track A patients or Visit 7 for Track B patients).  
10.4.1.5. Clinical Laboratory Assessments  
The clinical laboratory evaluations to be performed in this study are listed in Table 2.  All tests 
will be performed at Baseline/Visit 1 (or the Week 12 Visit of the 12-week open label HONOR 
study), after 28 weeks (Visit 5) and after 40 weeks of treatment (Visit 6) for Track A patients, or 
after 52 weeks of treatment (Visit 7) for Track B patients, or ET.  
With the exception of the urine pregnancy tests, all clinical laboratory evaluations will be 
analyzed via a central clinical laboratory, and information regarding appropriate sample volume, 
collection tubes, sample labeling and handling, and shipment will be provided in a study manual. 
Each clinically significant abnormal laboratory value or other clinically meaningful abnormality 
should be followed until the abnormality resolves or until a decision is made that it is not likely 
to resolve.  If such abnormalities do not return to normal within a reasonable period, their 
etiology should be identified and Tonix or designee should be notified.  Treatment-emergent 
clinically significant abnormalities in laboratory values will be recorded as AEs.  
 
Table 2:  
Clinical Laboratory Assessments  
Clinical chemistry 
Hematology  
Alanine aminotransferase (ALT)  
Hematocrit  


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Alkaline phosphatase  
Hemoglobin  
Aspartate aminotransferase (AST)   
MCH concentration (MCHC)  
Bilirubin (total)  
Mean corpuscular hemoglobin (MCH)  
Blood urea nitrogen (BUN)  
Mean corpuscular volume (MCV)  
Calcium  
Platelet count  
Chloride  
Red blood cell (RBC) count  
Cholesterol (total)  
White blood cell (WBC) count differential  
Creatinine kinase (CK)  
      Neutrophil count (absolute and %)  
Creatinine  
      Lymphocyte count (absolute and %)  
Glucose  
      Monocyte count (absolute and %)  
Phosphorus  
      Eosinophil count (absolute and %)  
Potassium  
      Basophil count (absolute and %)  
Protein (albumin and total)  
WBC count  
Sodium  
  
Urine Pregnancy Test (qualitative 
dipstick)a  
   
Pharmacogenomic testing (optional; 
can be obtained at any visit, including 
an early termination visit) 
 
a Pregnancy testing for females of child-bearing potential only.  A positive pregnancy test mandates withdrawal 
from the study (all visits). 
11. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS AND PREGNANCY 
11.1. 
Definition of Adverse Events 
According to International Council on Harmonisation (ICH) guidance E2A, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, an AE is any untoward 
medical occurrence in a patient or clinical investigation patient administered a pharmaceutical 
product and which is not necessarily required to have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
A newly-emergent adverse event (NEAE) is defined as any new AE that starts after the patient’s 
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week open-label extension study and which then exhibits an increase in severity, frequency or 
relationship after the patient’s participation in P306 has begun.  NEAEs and “All AEs” will be 
tallied by System Organ Class (SOC) and preferred terms.  AEs that are ongoing at the time of 
the patient’s baseline visit for P306 but which resolve, or persist without change in severity, 
frequency or relationship to study drug during the extension study, will be included in the tally of 
all AEs.   
11.2. 
Adverse Event Recording 
11.2.1. 
Coding the Adverse Event 
Standard medical terminology should be used in describing AEs.  Medical Dictionary for 
Regulatory Activities (MedDRA)® will be used as the standard coding dictionary for AEs and in 
describing the patient’s medical history, and the World Health Organization (WHO) Drug 
Dictionary will be used to code concomitant medications.  Informal descriptions should be 
avoided. 
11.2.2. 
Severity of Adverse Event 
AEs should be graded as mild, moderate, or severe using the following definitions. 
• Mild: Awareness of signs or symptoms, but easily tolerated and of minor irritant type 
causing no loss of time from normal activities.  Symptoms do not require therapy or a 
medical evaluation; signs and symptoms are transient. 
• Moderate: Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe: Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
“serious “and “severe,” which are not synonymous, the following note of clarification is 
provided.  The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, maybe of 
relatively minor medical significance (such as severe headache).  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.  Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations. 
11.2.3. 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the following 
descriptions. 
• Not Related: This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt.  That is, another cause of 
the event is most plausible; and/or a clinically plausible temporal sequence is 


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inconsistent with the onset of the event and the administration of study drug and/or a 
causal relationship is considered biologically implausible. 
• Unlikely Related: This category applies to an AE that could reasonably be considered 
caused by something else, and where there is no known or expected response pattern 
to the suspected study drug. 
• Possibly Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been 
produced by a number of other factors. 
11.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions 
Any SAE that occurs at any time during the study, or within 28 days after the patient’s last 
exposure to study drug, including a clinically significantly abnormal laboratory test result that is 
considered serious, must be reported to Tonix or its designee(s) so that Tonix may comply with 
regulatory obligations.  If the SAE is life-threatening or fatal, it must be reported to Tonix or its 
designee(s) immediately, by email or telephone.  For these and all other SAEs, an SAE report 
form must be completed and sent by facsimile or email to Tonix or its designee(s) within 24 
hours of the site’s initial awareness of the event.  These requirements apply equally to all 
patients, regardless of the study phase or the at-risk patient’s treatment assignment. 
A serious adverse event (experience) or reaction is any untoward medical occurrence that, at any 
dose: 
• Results in death, 
• Is life-threatening, 
• Requires in-patient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
A death occurring during the study or reported to the Investigator after study participation (no 
required post-study time limit) must be reported to Tonix or its designee(s) immediately, whether 
or not it is considered treatment-related.  Initial SAE reports must be followed by detailed 


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descriptions.  These should include copies of hospital case records and other documents when 
requested.  The Contract Research Organization (CRO) will confirm via email or facsimile when 
it has received SAE documentation.  If such confirmation is not received at the site in a timely 
manner, it is then the responsibility of the site to contact the CRO to ensure that the SAE 
documentation was indeed received by the CRO.   
The Investigator or other study personnel must immediately inform one of the Tonix Medical 
Monitors by phone or email of any AE considered serious or otherwise significant, as described 
above.  In addition, a completed SAE report form must be submitted to
 
 within 24 hours of the site’s initial awareness of the event. 
 
Contact information for the Medical Monitors is provided below: 
 
 
For questions pertaining to the reporting of SAEs or the completion of SAE documentation, 
site personnel should call the 
 
The investigator, or the sponsor or designee in the case of a central Institutional Review Board 
(IRB), also must notify the Ethics Committee (EC)/IRB of the occurrence of the SAE, in writing, 
as soon as is practicable and in accordance with local law.  A copy of this notification must be 
provided to Tonix or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an Investigational New 
Drug (IND) Safety Report will be prepared for submission to the FDA. 


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11.4. 
Pregnancy 
The active pharmaceutical ingredient in TNX-102 SL 2.8 mg tablets is cyclobenzaprine HCl, 
which is in Pregnancy Category B (See Appendix 3 for AMRIX® Package Insert).  All 
pregnancies occurring during the study (after exposure to study drug) or within 30 days after 
discontinuation of study drug must be followed until resolution (i.e., birth or voluntary or 
spontaneous termination of the pregnancy).  Any patient found to be pregnant at any time during 
the study will be withdrawn from the study immediately.  Any pregnancy outcome that meets the 
criteria for an SAE will be reported as an SAE. 


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12. 
STATISTICS 
A description of any statistical analyses to be performed will be provided in a statistical analysis 
plan (SAP), which will be finalized prior to database lock.    
12.1. 
Evaluation of Safety  
Safety data will be summarized as a single treatment group receiving 1 or more doses of TNX-
102 SL (patients that have taken only 1 tablet of TNX-102 SL will be included).   
Safety will be assessed by the monitoring and recording of AEs, clinical laboratory tests, vital 
signs, visual examination of the oral cavity findings, the monitoring of suicidality using the 
Columbia C-SSRS scale, and patient-rated assessments of depressive symptomology (BDI-II) 
and PTSD symptomology (PCL-S). 
AEs will be coded using the MedDRA and will be summarized overall and by preferred term and 
SOC. AEs will also be summarized by severity and relationship to study drug. SAEs and AEs 
leading to discontinuation of study drug will also be summarized.  
Actual values and changes from the extension study baseline values for clinical laboratory test 
results and vital sign measurements will be summarized at endpoint using descriptive statistics 
(n, mean, standard deviation (SD), median, minimum, and maximum).  Laboratory values will be 
displayed in the data listings along with corresponding normal ranges, and those that are outside 
the normal range will be flagged.   
Based on the C-SSRS results, the frequency and severity of suicidal ideation and behavior will 
be tabulated at each time point.  The number of patients with baseline and treatment-emergent 
suicidal ideation and/or suicidal behavior or self-injurious behavior, based on the C-SSRS, will 
be summarized by treatment group. 
All data gathered will be listed by patient and parameter, and clinically significant abnormalities 
should be recorded as AEs. AEs of special interest indicating potential abuse and dependency 
will be evaluated and summarized as described in the Statistical Analysis Plan. 
12.2. 
Evaluation of Efficacy  
As this is a long-term safety study, minimal conclusions will be available concerning long-term 
efficacy. The efficacy analyses will focus on durability of the response achieved prior to entry into 
this extension study, based on the CGI-I for patients in Track A and for patients on active drug in 
the lead-in HONOR study or the P303-early-terminated patients (due to IA results) who were on 
placebo in P301 in Track B. In addition, durability of response for both Track A and B patients 
will be assessed by measuring the change in PCL-S scores from Visit 5 (Week 28) to Visit 6 (Week 
40) in order to detect any potential worsening in PTSD symptoms as a result of longer term use of 
TNX-102 SL 5.6 mg. For Track B patients, an additional Visit 7 (Week 52) PCL-S assessment 
with be available for subset analysis of durability of response. 
12.3. Estimate of Sample Size  
No sample size calculations were made for this study as it is a follow-on, open-label study.  The 
sample size for this study will depend upon the number of patients who participate in the lead-in 


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HONOR study, remain eligible for entry, and indicate willingness to participate in this extension 
study.  
12.4. 
Assessment of Demographic and Baseline Characteristics and 
Patient Disposition 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (n, mean, median, SD, minimum, and maximum).  
Demographic and baseline characteristic variables will be summarized based on the data 
obtained at the screening visit from the lead-in HONOR study. The number of patients who 
enroll in the study and the number and percentage of patients in each analysis population who 
complete the treatment period will be presented. The frequency and percentage of patients who 
withdraw from the study, along with the reason for withdrawal or discontinuation, will also be 
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13. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
13.1. 
Protocol Modifications and Deviations 
The investigator will make all reasonable efforts to comply with the written protocol and 
protocol amendments.  All protocol modifications must be reviewed and approved by the 
appropriate EC/IRB before the revised protocol can be implemented.  Emergency revisions that 
eliminate an apparent hazard to patients do not require preapproval by the EC/IRB.  However, 
the EC/IRB must be notified, in writing, as soon as possible after the modification has been 
made.  A copy of this communication must be forwarded to Tonix. 
13.2. 
Study Termination 
The study may be prematurely terminated at any time at the discretion of Tonix, its designee, or 
the principal investigator.  Should premature termination be considered necessary, written 
notification documenting the reason for study termination will be provided, and specific 
procedures for termination will be arranged.  Circumstances that may warrant premature study 
termination include, but are not limited to, the following. 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to the requirements of the protocol 
• Insufficient provision of complete and evaluable data 
• Plans to modify, suspend, or discontinue development of the study drug 
In the event that the study is terminated prematurely, all study materials must be returned to 
Tonix or its designee. 


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14. 
ETHICAL CONSIDERATIONS 
14.1. 
Ethical Conduct of the Study 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964CI) and amendments and clarifications adopted by 
subsequent General Assemblies.  The investigator will make sure that the study described in this 
protocol is conducted in full conformance with those principles, the protocol, current FDA 
regulations, ICH GCP guidelines, Good Laboratory Practices (GLP) guidelines, local ethical and 
regulatory requirements, including the Federal Food, Drug and Cosmetic Act, US applicable 
Code of Federal Regulations (CFR) (title 21), any EC requirements relative to clinical studies.  
As required by the US FDA, the study drug may not be shipped to any participating investigator 
until the requisite study documentation has been submitted to the IND. 
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual patient.  The investigator will also make sure he or she is 
thoroughly familiar with the appropriate administration and potential risks of administration of 
the study drug, as described in this protocol and the Investigator’s Brochure, prior to the 
initiation of the study. 
14.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review 
The EC/IRB must be a properly constituted board or committee operating in accordance with 21 
CFR Part 56, “Institutional Review Boards.”  This protocol, any protocol amendments, the 
associated informed consent forms, and the informed consent procedures must be submitted to 
the EC/IRB for review and approved before the enrollment of any patient into the trial. 
All types of patient recruitment or advertising information must be submitted to Tonix or its 
designee and to the EC/IRB for review and approval prior to implementation.  EC/IRB approval 
of any protocol amendments must be received before any of the changes outlined in the 
amendments are put into effect, except when the amendment has been enacted to eliminate a 
potential hazard to study patients.  In such cases, the chair of the EC/IRB should be notified 
immediately and the amendment forwarded to the EC/IRB for review and approval. 
14.3. 
Written Informed Consent 
It is the responsibility of the investigator to obtain signed written informed consent from each 
potential study patient prior to the conduct of any screening or other study procedures.  This 
written informed consent will be obtained after the methods, objectives, and potential risks of the 
study have been fully explained to the potential patient.  The investigator must explain to each 
patient that he or she is completely free to refuse to enter the study or to withdraw from it at any 
time.  NOTE:  Patients on antidepressant therapy should be warned of a potential serious drug 
interaction and should be advised to contact their study site immediately if they experience any 
symptoms that might represent possible serotonin syndrome, including fever, confusion or 
agitation, hallucinations, sweating, high or low blood pressure, rapid heart rate, tremor, muscle 
rigidity or nausea, vomiting or diarrhea. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human 


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Patients,” the HIPAA regulations, and all other applicable regulatory requirements.  A properly 
executed written ICF shall be read, signed, and dated by each patient prior to entering the trial or 
prior to performing any study procedure.  The original signed and dated ICF will be kept on file 
at the study site.  Patients will be given a copy of the signed ICF and will be informed of any 
new developments during the course of the study that might influence their continued 
participation in the study. 
The investigator or a qualified designee will be available to answer each patient’s questions 
throughout the study, and all questions must be answered to the patient’s satisfaction.  If the 
protocol is amended and a revised ICF is introduced during the study, each patient’s further 
consent must be obtained.  The new version of the ICF must be approved by the EC, prior to 
subsequently obtaining each patient’s consent. 
Receipt of written informed consent will be documented in each patient’s or potential patient’s 
CRF.  The signed ICF must remain in each patient’s study file and must be available for 
verification by study monitors at all times. 
Separate written, signed informed consent must be obtained if the patient is to participate in the 
optional pharmacogenomic assessment. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Maintaining Privacy and Confidentiality 
In order to maintain patient privacy, all CRFs, study drug accountability records, and other 
documents, including communications between the study site and Tonix, will identify patients 
only by their initials or their assigned study identification numbers.  If required, the investigator 
will grant monitors and auditors from Tonix or its designee and/or regulatory authority’s access 
to patients’ original medical records for verification of the data gathered on the CRFs and to 
audit the data collection process.  Patients’ confidentiality will be maintained and will not be 
made publicly available. 
Special Provisions for Confidentiality:  A Certificate of Confidentiality (CoC) has been 
obtained from the FDA for the investigators to protect patients enrolled in the study.  
Investigators may use the Certificate to avoid being compelled to make "involuntary disclosure" 
(e.g., subpoenas, insurers, employers, or other third parties) of names and other identifying 
information about any individual who participates as a research patient (i.e., about whom the 
investigator maintains identifying information) during any time the Certificate is in effect. 
15.2. 
Maintaining Essential Clinical Documents 
Study site files for the retention of regulatory documents will be established at the beginning of 
the study, maintained for the duration of the study, and retained according to FDA and ICH/GCP 
guidelines and applicable regulatory requirements.  The records maintained must be adequate to 
fully document appropriate protection of study patients/patients, the validity of the study, the 
integrity of the data, and the manner in which the study was conducted. 
The investigator’s site file, copies of protocols, CRFs, originals of test result reports, drug 
disposition logs, correspondence, records of written informed consent, and other documents 
pertaining to the conduct of the study must be kept on file by the investigator and in readily 
accessible order for at least 2 years after the last approval of a marketing application, until at 
least 2 years have elapsed after formal discontinuation of the clinical development of the 
investigational product, or according to local regulatory requirements.  No study document may 
be destroyed without prior written consent from Tonix or its designee.  Should the investigator 
wish to withdraw from the responsibility of keeping the study records, custody must be 
transferred to a person willing to accept the responsibility.  Tonix must be notified in writing in 
advance if a custodial change is to occur.  It is important that the investigator remain ready to 
provide background information from the archived study records on request. 
The sponsor or designee will maintain adequate study records for at least 2 years after the last 
approval of a marketing application or for at least 2 years after clinical development of the study 
drug for the indication being studied has been discontinued.  After that period, the sponsor will 
be contacted to determine whether the study records will be forwarded to the sponsor, destroyed, 
or kept at the location of the designee or another facility for a longer period of time. 


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15.3. 
Data Handling 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as per 
the SOPs of the CRO.  The investigator will assume the responsibility of ensuring the 
completeness and accuracy of the clinical data.   
All laboratory results will be analyzed by an accredited and licensed clinical laboratory facility.  
Clinical laboratory data will be transferred from the central laboratory to the clinical database 
maintained by the CRO using systems which are validated and Part 11-compliant. 
The responsible clinical study monitor(s) will check data at the monitoring visits to the clinical 
study site.  The investigator will ensure that the data collected are accurate, complete, and 
legible.  Any changes made to the clinical data will be documented with a full audit trail. 
Aspects of the clinical and statistical phases of the study, including all associated documentation 
may be reviewed by the Quality Assurance Unit of the contract research organization using a 
risk-assessment approach.  The final clinical and statistical report will be audited to ensure that, 
as far as can be reasonably established, the methods described and the results reported accurately 
reflect the raw data generated during the study. 
15.4. 
Case Report Forms (CRFs) 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study patient.  
Data must be recorded on CRFs approved by Tonix or its designee.  Data (including AEs) will be 
recorded on raw data sheets and/or electronic or paper source documents. 
If selected data is collected via paper (patient questionnaires, etc.), the data must be entered into 
the eCRF and verified that it has been transcribed correctly. 
15.5. 
Screening Records 
A record must be kept of all patients considered for the study who sign informed consent and 
who began any screening procedures.  The information should include the patient’ initials, 
unique patient identification numbers, whether they passed or failed screening, and, if they 
failed, the reason for screen failure. 
15.6. 
Clinical Laboratory Certification 
A central clinical laboratory will be used to analyze all samples in this study, with the exception 
of the urine pregnancy test and ad hoc urine drug screens.  The investigator must maintain, on 
file, written evidence that the central clinical laboratory to be used is certified under the Clinical 
Laboratory Improvement Act or equivalent certification (depending on local regulations).  
Further, the investigator will maintain a copy of the certification, the range of normal values, the 
effective dates for the ranges, and the units of measurement for all laboratory tests requested in 
the protocol.  If any of the laboratory measurements will be transformed and/or categorized in 
any way, a description of the procedures(s) used should be included.  The investigator is 
expected to receive these documents before the shipment of clinical supplies. 


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15.7. 
Site Monitoring and Tonix’s Right to Review Records 
Monitoring and auditing procedures developed by Tonix and/or its designee will be implemented 
to ensure compliance with FDA and ICH GCP and GLP guidelines. 
Tonix’s designated representative (the monitor or auditor) will contact the investigator and 
conduct regular visits to the clinical site.  The monitor will be expected and allowed to verify the 
investigator’s qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of EC/IRB review, with the stipulation that patient confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements.  
The monitor will also be responsible for confirming adherence to the study protocol, inspecting 
CRFs and source documents, and ensuring the integrity of the data.  CRFs will be checked for 
accuracy, completeness, and clarity and will be cross-checked for consistency with source 
documents, including laboratory test reports and other patient records.  Instances of missing or 
uninterpretable data will be resolved in coordination with the investigator. 
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications with the study site by e-
mail, telephone, facsimile, and mail.  The investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve any and 
all questions raised and difficulties detected by the monitor. 
15.8. 
Audits and Inspections 
The investigator understands that regulatory authorities, the EC/IRB, and/or Tonix or their 
designees have the right to access all CRFs, source documents, and other study documentation 
for on-site audit or inspection and will retain this right from the start of the study to at least 2 
years after the last approval of a marketing application or for at least 2 years after clinical 
development of the study drug for the indication being studied has been discontinued.  The 
investigator is required to guarantee access to these documents and to cooperate with and support 
such audits and inspections. 


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16. 
CONFIDENTIALITY 
16.1. 
Protection of Patient Anonymity 
The investigator must make sure that each patient’s anonymity is maintained.  On CRFs or other 
documents submitted to Tonix or its agent, patient should not be identified by their names, but 
rather by their initials and the assigned study identification numbers.  The investigator should 
keep a separate record of the patient initials, randomization codes, patient names, address, and 
contact information.  Documents that contain the names associated with these initials and codes 
are not for submission to Tonix or its agents (e.g., written informed consent forms).  These 
records should be maintained by the investigator in strict confidence except to the extent 
necessary to allow auditing by regulatory authorities, Tonix, or its agents.  These records should 
be kept in compliance with HIPAA regulations. 
Special Provisions for Confidentiality:  In addition, a Certificate of Confidentiality (CoC) has 
been obtained from the FDA for the investigators to protect patients enrolled in the study.  
Investigators can use the Certificate to avoid being compelled to make "involuntary disclosure" 
(e.g., subpoenas, insurers, employers, or other third parties) of names and other identifying 
information about any individual who participates as a research patient (i.e., about whom the 
investigator maintains identifying information) during any time the Certificate is in effect. 
16.2. 
Confidentiality of Study Information 
All information relevant to this study, whether supplied by Tonix or its agents to the investigator 
or collected by the investigator in support of this study, is privileged and confidential.  The 
investigator agrees to use this information to carry out the study and will not use it for other 
purposes without written consent from Tonix.  It is understood that the investigator is under 
obligation to provide Tonix with all data obtained during the study.  The information obtained 
from this study will be used by Tonix towards the clinical development of the indicated 
investigational drug and may be disclosed by Tonix to regulatory authorities, other investigators, 
corporate partners, or consultants as required. 
16.3. 
Publication of Data and Protection of Trade Secrets 
No presentations, abstracts (including meeting abstracts), or other publications based on the 
conduct or results of this study will be permitted without the express written permission of Tonix 
or its designated agent.  All such presentations or publications will proceed only as 
collaborations between Tonix and the investigators. 
If the investigator wishes to publish the results of this study, a copy of the proposed manuscript 
or abstract (including meeting abstracts) will be provided to Tonix or its designee for review, 
revision, and approval at least sixty (60) days before the expected date of submission for 
publication, unless otherwise arranged with Tonix in writing.  This will enable Tonix to protect 
its proprietary information and augment the publication with insights or information of which the 
investigator may not be aware. 
Patient names and other identifiers, such as photographs or audio or video recordings, may not 
be disclosed in any publication or public forum without prior written authorization from the 


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patients involved or their legal guardians.  Tonix retains authority to delete any of its confidential 
information from such disclosures. 


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17. 
LIST OF REFERENCES 
Stanley B and Brown GK.  Safety planning intervention: A brief intervention to mitigate suicide 
risk.  Cognitive and Behavioral Practice 2012; 19:256-264. 


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18. 
APPENDICES 
APPENDIX 1. STUDY DESIGN AND SCHEDULE OF ASSESSMENTS 
Period 
Baseline 
Phonef 
Clinic Visits 
Visit 
1 
2 
3 
4 
5 
6 
7j 
Study Week 
0 
2 
7 
16 
28 
40 
52 
Study Day 
0 
14 ± 3 
49 ± 7 
112 ± 7 
196 ± 7 
280 ± 7 
365 ± 7 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion Criteria  
X 
 
 
 
 
 
 
Concomitant Medicationsb 
X 
Xf 
X 
X 
X 
X 
X 
Vital Signs and weight  
Xa 
 
X 
X 
X 
X 
X 
Inspection of oral cavityc 
Xa 
 
 
 
X 
X i 
X 
Pregnancy Testd 
Xa 
 
X 
X 
X 
X 
X 
Clinical Laboratory Assessments 
Xa 
 
 
 
X 
X i 
X 
BDI-II 
Xa 
 
X 
X 
X 
X 
X 
C-SSRS 
Xa 
Xf 
X 
X 
X 
X 
X 
CGI-I (compared to P306 baseline only)e 
 
 
X 
X 
X 
X 
X 
PROMIS-Sleep (short form) 
Xa 
 
X 
X 
X 
X 
X 
SDS 
Xa 
 
X 
X 
X 
X 
X 
PCL-S 
 
 
 
 
Xh 
Xh 
X 
Pharmacogenomic blood draw 
(optional)g 
* 
* 
* 
* 
* 
* 
* 
Adverse Events 
X 
Xf 
X 
X 
X 
X 
X 
Telephone Visit 
 
Xf 
 
 
 
 
 
Dispense Study Drug 
X 
 
X 
X 
X 
Xj 
 
Collect/ Count Study Drug Returned 
 
 
X 
X 
X 
X 
X 
 
Abbreviations:  BDI-II = Beck Depression Inventory-II; C-SSRS = Columbia-Suicide Severity Rating Scales; CGI-I 
(Clinician Global Impression of Improvement); PROMIS = Patient Reported Outcomes Measurement Information 
System; SDS = Sheehan Disability Scale; PCL-S = PTSD Checklist-Specific Version  
 
a These assessments are only to be conducted for patients entering the study from Track B, or Track A patients that 
roll over into P306 greater than 14 days after the final visit of the previous study. 
b Medications that are ongoing at the end of the previous study will be recorded as such in this study. 
c In addition to the regularly scheduled examination, a visual examination of the oral cavity should be done at any 
visit in which an oral adverse event has been reported. 
d Women of child-bearing potential only. 
e The CGI-I will be done only in comparison to the baseline visit of P306.   
f Patients enrolled from the double-blind lead-in study, P301/HONOR, only will have the phone check-in. 


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*/gThe blood draw for the pharmacogenomic assessment can be obtained at any study visit (including an early 
termination visit).  It should only be obtained one time during the study.  Separate written, signed informed consent 
will be required if the patient is to participate in the optional pharmacogenomic assessment.  
h Visit 5(Week 28) will be the “baseline” for PCL-S because it will capture the vast majority of the patients who 
have enrolled from the start of P306. The mean change in PCL-S total score and PCL-S clusters scores from Visit 5 
(Week 28) to Visit 6 (Week 40), and to Visit 7 for Track B patients, will detect any potential worsening in total 
PTSD score or symptoms clusters due to long-term treatment of TNX-102 SL in the final 12-weeks, and 24-weeks 
for Track B patients, of the study.  
i Track A patients only. 
j Track B patients only. 
 
 


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APPENDIX 2. LIST OF CYP3A INHIBITORS 
Taken from Table 3, FDA Draft Guidance for Industry:  Drug Interaction Studies—Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations; Feb 2012; 
updated Sept. 26, 2016).  Excluded strong CYP3A4 inhibitors are listed in the far left column of 
the table. 
 
Strong Inhibitors 
 
≥ 5-fold increase in AUC  
Or, > 80% decrease in CL 
Moderate Inhibitors  
 
≥ 2 but < 5-fold increase in AUC  
Or 50-80% decrease in CL 
Weak Inhibitors 
 
≥ 1.25 but < 2-fold increase 
in AUC  
Or, 20-50% decrease in CL 
CYP3A4 
Boceprevir 
clarithromycin  
cobicistat 
conivaptan 
danoprevir 
elvitegravir 
grapefruit juice  
indinavir  
itraconazole 
ketoconazole  
lopinavir   
mibefradil 
nefazodone 
nelfinavir 
paritaprevir 
posaconazole 
ritonavir  
saquinavir  
telaprevir 
telithromycin 
tipranavir 
troleandomycin 
voriconazole 
 
amprenavir 
aprepitant 
atazanavir 
cimetidine 
ciprofloxacin 
clotrimazole 
crizotinib 
cyclosporine 
darunavir/ritonavir 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fluvoxamine 
fosamprenavir 
imatinib 
tofisopam 
verapamil 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
chlorzoxazone 
cilostazol 
fosaprepitant 
fluoxetine 
gingko 
goldenseal  
isoniazid 
istradefylline 
ivacaftor 
lapatinib 
lomitapide 
nilotinib 
oral contraceptives 
pazopanib 
ranitidine 
ranolazine 
tacrolimus 
tipranavir/ritonavir 
ticagrelor 
zileuton 
Source:  Table 3-2,  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 


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APPENDIX 3. AMRIX® PACKAGE INSERT (DATED MAY 2018) 
 


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SAP_001.pdf: 


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Final v1.0 
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15APR2024 
DOCUMENT HISTORY
 


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15APR2024
SIGNATURE PAGE AND APPROVALS


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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................2
TABLE OF CONTENTS ..................................................................................................4
ABBREVIATIONS ............................................................................................................6
1.
OVERVIEW ...........................................................................................................8
2.
STUDY OBJECTIVES AND ENDPOINTS ........................................................8
2.1
Study Objectives ..........................................................................................8
2.1.1
Primary Objective ............................................................................8
2.1.2
Secondary Objectives .......................................................................9
2.2
Study Endpoints ...........................................................................................9
2.2.1
Efficacy Endpoints ...........................................................................9
2.2.2
Safety Endpoints ..............................................................................9
3.
OVERALL STUDY DESIGN AND PLAN .......................................................10
3.1
Selection of Study Population ....................................................................10
3.2
Method of Treatment Assignment and Randomization .............................11
4.
ANALYSIS AND REPORTING ........................................................................11
4.1
Final Analysis ............................................................................................11
5.
SAMPLE SIZE DETERMINATION .................................................................12
6.
ANALYSIS POPULATIONS .............................................................................13
7.
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................14
7.1
General Statistical Methodology................................................................14
7.1.1
Adjustments for Multiplicity and Other Alpha Control .................14
7.1.2
Data Handling for Participants Who Discontinue Study Drug or 
Withdraw from the Study...............................................................14
7.2
Efficacy Assessments .................................................................................15
7.2.1
Clinician Global Impression of Improvement (CGI-I) ..................15
7.2.2
Sheehan Disability Scale (SDS) .....................................................15
7.2.3
Other Efficacy Outcomes ...............................................................15
7.3
Safety Assessments ....................................................................................16
7.3.1
Adverse Event and Prior/Concomitant Medication handling 
conventions ....................................................................................16
8.
STUDY PARTICIPANTS AND DEMOGRAPHICS .......................................17
8.1
Disposition of Participants and Withdrawals .............................................17
8.2
Protocol Deviations ....................................................................................17


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8.3
Demographics and Other Baseline Characteristics ....................................18
9.
EFFICACY ANALYSES ....................................................................................19
9.1
Continuous Outcomes................................................................................19
9.1.1
Efficacy Analysis Model................................................................19
9.1.2
Categorical outcomes .....................................................................20
10.
SAFETY AND TOLERABILITY ANALYSIS .................................................20
10.1
Adverse Events ..........................................................................................20
10.1.1 Adverse Events Leading to Discontinuation of Study Drug ..........21
10.1.2 Serious Adverse Events .................................................................21
10.1.3 Deaths ............................................................................................21
10.2
Clinical Laboratory Evaluations ................................................................22
10.3
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................22
10.4
Vital Signs ..................................................................................................23
10.5
Visual Examination of Oral Cavity............................................................23
11.
MEDICATIONS ..................................................................................................23
11.1
Concomitant Medication ............................................................................23
11.2
Exposure and Compliance .........................................................................24
12.
LONG-TERM SAFETY ANALYSES ...............................................................24
12.1
Long-Term Disposition ..............................................................................25
12.2
Long-Term Adverse Events Analyses .......................................................25
12.3
Long-Term Vital Signs Analyses ...............................................................26
12.4
Long-Term Clinical Laboratory Evaluations .............................................27
12.5
Long-Term Exposure .................................................................................29
13.
CHANGES FROM PLANNED ANALYSIS .....................................................29
14.
REFERENCES .....................................................................................................30
15.
APPENDICES ......................................................................................................31
15.1
Appendix 1 .................................................................................................31
15.1.1 General Reporting Conventions .....................................................31
15.1.2 Population Summary Conventions ................................................32
15.2
Appendix 2: PROMIS T-score Conversions..............................................33
15.3
Appendix 3:  Abuse Terms ........................................................................34


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ABBREVIATIONS
ABBREVIATION
DEFINITION OR DESCRIPTION
AE
Adverse Event
ADaM
Analysis Data Model
BDI-II
Beck Depression Inventory II
BMI
Body Mass Index
CA-AF
Criterion A  Assessment Form
CAPS-5 
Clinician Administered PTSD Scale (for DSM-5)
CGI-I 
Clinical Global Impression- Improvement from Initiation of Treatment
CI 
Confidence Interval
CMH
Cochran Mantel Haenszel
CRF
Case Report Form
CRO
Contract Research Organization  
CSR
Clinical Study Report
C-SSRS 
Columbia-Suicide Severity Rating Scale
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders (Version 4)
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (Version 5)
ECG 
Electrocardiogram 
EDC
Electronic Data Capture
e.g. 
Exempli gratia (for example)
EMA
European Medicines Agency
ET
Early Termination
FDA
Food and Drug Administration 
HCl
Hydrochloride
ICH 
International Council for Harmonization 
IDMC
Independent Data Monitoring Committee 
i.e.
id est (that is) 
IWRS
Interactive Web Response System 
LS
Least Squares
MAR
Missing at Random
MDE
Major Depressive Episode
MedDRA
Medical Dictionary for Regulatory Activities
Military-Related 
Related to service in any branch of the armed services (active or veteran), 
or as a military contractor
MINI 
Mini International Neuropsychiatric Interview
MMRM 
Mixed Model Repeated Measures
N, n
Number (of participants)
NEAE 
Newly-Emergent Adverse Event
NIH
National Institutes of Health
PGIC
Patient Global Impression of Change Scale
PROMIS
Patient-Reported Outcome Measurement Information System
PTSD
Posttraumatic Stress Disorder
REML
Restricted Maximum Likelihood 
SAE
Serious Adverse Event 


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SAP 
Statistical Analysis Plan
SAS®
Statistical Analysis System 
SD 
Standard deviation
SDS 
Sheehan Disability Scale
SDTM
Study Data Tabulation Model
SE 
Standard Error
SL
Sublingual
SOC
System Organ Class 
TEAE
Treatment Emergent Adverse Event
TNX-102 SL
Cyclobenzaprine HCl sublingual tablets
WHO-DD
World Health Organization Drug Dictionary 


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1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
protocol TNX-CY-P306: A 40 to 52-Week Open-Label Extension Study to Evaluate 
TNX-102 SL Taken Daily at Bedtime in Patients with PTSD; Amendment 4, Dated 
05JUN2019. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by FDA, European Medicines Agency (EMA), and International Council for 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use: Guidance on Statistical Principles in Clinical Trials.  All work planned and 
reported for this SAP will follow internationally accepted guidelines, published by the 
American Statistical Association and the Royal Statistical Society, for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports 
(CSRs), regulatory submissions, or future manuscripts.  Also, post-hoc exploratory 
analyses not necessarily identified in this SAP may be performed to further examine 
study data.  Any post-hoc, or unplanned exploratory analysis performed will be clearly 
identified as such in the final CSR. 
 
 
 
 
 
 
 
 
 
 
 
 
The reader of this SAP is encouraged to also read the clinical protocol, and other 
identified documents, for details on the planned conduct of this study.  Operational 
aspects related to collection and timing of planned clinical assessments are not repeated 
in this SAP unless relevant to the planned analysis. 
For purposes of clarity, all analyses in this SAP refer to data collected in study TNX-CY-
P306, except to the extent that some baseline measures may have been collected in a prior 
study (Section 7.1) and except for the analyses set forth in Section 12.   
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to evaluate the long-term safety of TNX-102 SL 
taken daily at bedtime over an additional 40 to 52 weeks in patients with PTSD who have 
participated in a double-blind lead-in HONOR study (TNX-CY-P301) and possibly a 12-
week open-label extension study TNX-CY-P303. 


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2.1.2 Secondary Objectives 
The secondary objective of the study is to evaluate the long-term effect of TNX-102 SL 
taken daily at bedtime over an additional 40 to 52 weeks in patients with PTSD who have 
participated in a double-blind lead-in HONOR study (TNX-CY-P301) and possibly a 
12-week open-label extension study TNX-CY-P303. 
2.2 Study Endpoints 
2.2.1 Efficacy Endpoints  
Comparisons will be made at each study week of data collection to the baseline of this 
study. 
Efficacy endpoints include:  
 Average CGI-I score (scored 1-7) 
 Proportion of patients with a CGI-
  
 Change from baseline in the SDS total score 
 Change from baseline in the individual items assessed using the SDS 
 
 
Disturbance scale 
 Change from baseline in BDI-II score 
 Change from week 28 to week 40 in PCL-S 
 Change from week 28 to week 52 in PCL-S (Track B subjects only) 
 Change from week 40 to week 52 in PCL-S (Track B subjects only) 
2.2.2 Safety Endpoints 
Safety will be assessed by: 
 Adverse events (AE) and serious AEs (SAEs) throughout the entire duration 
of the study, including detailed assessment of AEs involving the oral cavity. 
 Changes from baseline in clinical laboratory test results. 
 Changes from baseline in vital signs and weight. 
 Change from baseline in BDI-II. 
 Suicidal ideation or behavior as reported on the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
 
 


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3. OVERALL STUDY DESIGN AND PLAN 
This is a 40 to 52-week, multicenter, open-label extension study designed to establish 
long-term safety exposure and to examine the long-term effect with daily bedtime dosing 
of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) in patients with PTSD. This study will be 
conducted at approximately 35 sites in the United States (US). 
Patients who have either: (a) completed the double-blind lead-in study (P301/HONOR 
study), and completed or are active (at the time of study discontinuation) in the 12-week 
open-label extension study, P303; or (b) are enrolled in the double-blind lead-in study 
(P301/HONOR study) that has been discontinued due to results of an interim analysis, 
will be eligible. For Track A patients, this extension study consists of 5 in-clinic visits, 
including the Screening/Baseline visit and visits after 7, 16, 28, and 40 weeks of 
treatment (Visits 3-6). There will also be a telephone visit after 2 weeks of treatment 
(Visit 2) for patients enrolling from the double-blind lead-in study, P301/HONOR. The 
total treatment duration of this study will be 40 weeks for patients enrolled under Track A 
criteria, and 52 weeks for patients enrolled under Track B criteria. Therefore, the 
maximum total duration of continuous treatment with TNX-102 SL could be 
approximately 64 weeks for those patients assigned to TNX-102 SL in the lead-in 
HONOR study who then also completed the 12-week open-label extension study P303. 
For patients enrolling from the open-label extension study, P303 (Track A), there is no 
need to repeat assessments at Visit 1 for this study, if the patient enrolls and initiates 
study treatment within fourteen days of completing the 12-week open-label extension 
study P303. For patients who are active in the double-blind lead-in study, P301/HONOR 
(Track B), all Baseline procedures and assessments will be completed at Visit 1. 
After the patient has participated in the lead-in HONOR study or the open-label extension 
study, P303, and has consented to participate in this open-label extension study, patients 
will be dispensed a 7-week supply of open-label TNX-102 SL tablets (3 bottles) and will 
be instructed to take 2 tablets of study drug sublingually daily at bedtime, starting on the 
evening of Visit 1. A phone visit will be completed after 2 weeks of treatment for patients 
enrolling from the double blind lead-in study, P301/HONOR. All patients will return to 
the study center for safety and efficacy assessments at Weeks 7, 16, 28, and 40 (or early 
termination). Patients enrolled under Track B criteria will continue to dose for an 
additional 12 weeks and have the last study visit at Week 52. Patients will return their 
TNX-102 SL medication (including empty bottles) at these visits. Patients will also 
receive a 9-week supply of TNX-102 SL (4 bottles) at the Week 7 visit, and a 12-week 
supply (5 bottles) at the Week 16, 28 and 40 (Week 40 for Track B patients only) visits. 
Patients will be allowed to take other medications deemed appropriate by their health 
care providers to manage their PTSD and other conditions, including currently approved 
PTSD therapies. 
3.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to the protocol. 


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3.2 Method of Treatment Assignment and Randomization 
All patients will be assigned to TNX-102 SL, 5.6 mg regardless of which treatment arm 
they were randomized to in the lead-in study. No patients or site personnel will know 
what the prior treatment was in the double-blind lead-in study. 
Throughout this document, when describing analyses performed by treatment group, this 
will refer to the treatment that the subject was randomized to in the double-blind lead-in 
study. 
4. ANALYSIS AND REPORTING 
4.1 Final Analysis 
All final, planned analyses will be performed after the last participant has completed all 
study assessments, all relevant study data have been processed and integrated into the 
analysis database, and the database has been locked.  
 


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5. SAMPLE SIZE DETERMINATION 
No sample size calculations were made for this study as it is a follow-on, open-label 
study. The sample size for this study will depend upon the number of patients who 
complete the lead-in study, remain eligible for entry, and indicate willingness to 
participate in this extension study. 
 


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6. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study:  
 Safety Population (SAFETY): All participants who receive at least 1 dose of 
study drug in Study TNX-CY-P306. Participants who are issued study drug, but 
return 100% of it (i.e., none consumed) will be excluded from the Safety 
Population; likewise, participants that have no follow up following receipt of 
study drug to indicate they took drug are excluded.  All analyses will be 
performed using this population, unless otherwise specified in this SAP.  
 
 


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7. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
7.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and 
secondary variables.  In general, tables will summarize data by treatment group as 
defined in Section 3.2 and visit. 
All tables will be completed for the Safety Population unless otherwise specified.  
Continuous, quantitative, variable summaries will include the number of participants (N) 
with non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum.  
Categorical, qualitative, variable summaries will include the frequency and percentage of 
participants who are in the particular category.  In general, the denominator for the 
percentage calculation will be based upon the total number of participants in the study 
population for the treatment group unless otherwise specified.  
Unless otherwise noted, baseline values are defined as the last non-missing measurement 
prior to the first dose of open-label study drug in Study TNX-CY-P306.  Change from 
baseline will be defined as the post-baseline visit value minus the baseline value. 
ET participants will only be followed if required to monitor an on-going adverse event or 
other condition. 
Participants are not supposed to change study sites; however, should this be necessary to 
allow a participant to continue in the study, participants will be analyzed under the site 
where they were initially enrolled. 
Study day after first dose is defined as assessment date  first dose date +1.  Dates prior 
to first dose are defined as assessment date  first dose date.  Note that the protocol refers 
 
All analyses will be performed using Statistical Analysis System (SAS®) Software 
version 9.4 or later.  
Unless otherwise noted, 95% confidence intervals will be presented for statistical tests. 
7.1.1 Adjustments for Multiplicity and Other Alpha Control 
7.1.1.1 Multiplicity 
No adjustments will be made from multiplicity and all p-values will be nominal.   
7.1.2 Data Handling for Participants Who Discontinue Study Drug or Withdraw 
from the Study 
Participants who withdraw/drop out from the study will have their ET visit data collected 
and included in the analysis based on the closest visit window (Week 7, 16, 28, 40, or 
52).  Visit windows will be assigned by splitting the periods between visits at the 
midpoint between the visits.  If more than one record falls within the window, the one 
closest to the target date will be used in the analysis, with preference given to the 
scheduled visits in the case of equidistant visits.   


Protocol: TNX-CY-P306                                                                                 Page 15 of 36 
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7.2 Efficacy Assessments 
There is no formal testing order to the efficacy assessments in this protocol; however, 
they are described below in approximate order of importance. 
7.2.1 Clinician Global Impression of Improvement (CGI-I) 
The CGI-I will be completed by an Investigator to evaluate the participant
status since 
the start of the current study (P306).  The CGI-I will be completed at each in-clinic visit 
after baseline. It will be the responsibility of the Principal Investigator or his qualified 
 and answer the following 
question:  
Since the initiation of treatment in P306, the participant is:  
1 = Very much improved  
2 = Much improved  
3 = Minimally improved  
4 = No change  
5 = Minimally worse  
6 = Much worse  
7 = Very much worse 
The primary analysis of CGI will treat it as a continuous variable (scored 1-7 as above).   
There will be an additional outcome presented where a responder on the CGI-I is defined 
a participant 
 and compared 
between the study arms. 
7.2.2 Sheehan Disability Scale (SDS) 
The SDS scale is a self-report questionnaire that was designed to assess the participant
view of the degree to which symptoms have disrupted work/school, social life/leisure 
activities, and family life/home responsibilities during the previous 2 weeks (Sheehan & 
Sheehan, 2008). In addition, the SDS asks the participant to provide the number of days 
of work/school lost as well as unproductive days in the past two weeks.  The SDS scale 
will be completed by the participant at Baseline and after 7, 16, 27, and 40 weeks, plus 52 
weeks for Track B participants. A total score will be calculated summing the three 
individual 11-point (0-10) scales.  For participants that do not respond to the work/school 
disruption because the participant checked the box indicating he/she has not worked or 
attended school for reasons unrelated to the disorder (PTSD), the total score will sum the 
other 2 domain questions and multiply by 1.5 (rounding up to the nearest whole number) 
to maintain the scale of 0-30 for the total score.  Participants with missing values on the 
other items will be missing for the total. 
7.2.3 Other Efficacy Outcomes 
7.2.3.1 PROMIS Sleep Disturbance Instrument  
 
PROMIS refers to the Patient-Reported Outcome Measurement Information System 
(www.nihpromis.org), a National Institutes of Health (NIH)-funded initiative to develop 
instruments to be used across chronic conditions.  


Protocol: TNX-CY-P306                                                                                 Page 16 of 36 
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The PROMIS sleep disturbance scale (short form 8a) will be assessed at Baseline and 
after 7, 16, 27, and 40 weeks, plus 52 weeks for Track B participants. 
The sleep disturbance scale will be calculated summing the individual item scores of the 
8 items.   These summed scores will be transformed to T-scores using the published 
conversions (see Section 15.2). 
7.2.3.2 BDI-II 
The Beck Depression Inventory (BDI-II) is a 21-item measure of the severity of current 
depressive symptoms, extensively validated for use in both medical and mental health 
populations.  While this instrument does not provide a psychiatric diagnosis of depression 
and has considerable overlap with PTSD associated symptoms, it does provide a 
continuous scale for measuring changes in the severity of symptomatology.  The BDI-II 
will be completed by the participant at all in-clinic visits. 
7.3 Safety Assessments 
Safety will be assessed by: 
 AE and SAEs throughout the entire duration of the study, including detailed 
assessment of AEs involving the oral cavity. 
 Changes from baseline in clinical laboratory test results. 
 Changes from baseline in vital signs and weight. 
 Change from baseline in BDI-II (see Section 7.2.3). 
 Suicidal ideation or behavior as assessed by the C-SSRS. 
7.3.1 Adverse Event and Prior/Concomitant Medication handling conventions 
To handle missing or partial prior/concomitant medication dates, the following rules will 
be applied. 
For partial start dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then: 
a. If the year matches the year of the first dose date, then impute the month 
and day of the first dose date. 
b. Otherwise, assign January.  
3. If the day is unknown, then: 
a. If the month and year match the month and year of the first dose date, then 
impute the day of the first dose date. 
b. Otherwise, assign 01.  


Protocol: TNX-CY-P306                                                                                 Page 17 of 36 
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For partial end dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then assign December.  
3. If the day is unknown, then assign the last day of the month. 
After implementing the rules above, to determine whether medications with missing start 
or stop dates are prior or concomitant medications, the following strategy will be used: 
1. If the start date and stop date are both missing, then the most conservative 
approach is taken and the medication is considered to be a concomitant 
medication. 
2. If the start date is missing but the stop date is not missing and is after the day of 
first study dose administration, then the most conservative approach is taken and 
the medication is considered to be concomitant. 
3. If the start date is missing but the stop date is not missing and is on or before the 
day of first study dose and after the date of signed informed consent, then the 
medication is considered to be a prior medication. 
4. If the start date is not missing but the stop date is missing, then the most 
conservative approach is taken and medication is considered to be concomitant. 
possibly 
  
8. STUDY PARTICIPANTS AND DEMOGRAPHICS 
8.1 Disposition of Participants and Withdrawals 
The numbers and percentage of participants entering, completing the study, and 
withdrawing from the study, along with reasons for withdrawal, will be tabulated overall 
and by treatment group.  This summary will be based on all participants who have data 
entered into the database.  
8.2 Protocol Deviations 
Protocol deviations will be checked on complete data for all participants, determined 
during a data review meeting before database lock and the final analysis. 
Protocol deviations will be summarized by type and by treatment group for the Safety 
population
deviation is identified either as 
upon the integrity of the study data or the participant
-being. 
Individual participants with protocol deviations will be listed. 


Protocol: TNX-CY-P306                                                                                 Page 18 of 36 
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8.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
completed for all participants in the safety population by treatment groups, unless 
otherwise specified. 
Descriptive summaries of demographic and other baseline conditions will include: 
 Demographics (age, gender, race/ethnicity, height, weight, body mass index 
(BMI), family status, education, presence of current MDE, current nicotine, 
alcohol and THC usage, and employment status).   
 CAPS-5 Assessment (Diagnostic version)  
-up 
measures. 
Medical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 and summarized by System Organ Class (SOC) and Preferred 
Term using frequency counts by treatment group.  Note that the medical history, 
demographics, and baseline characteristic data are collected in the lead-in study; this 
analysis displays that information for the population of subjects that entered this study. 
 


Protocol: TNX-CY-P306                                                                                 Page 19 of 36 
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9. EFFICACY ANALYSES 
9.1 Continuous Outcomes 
The mean change from baseline in the continuous outcome of interest will be analyzed 
using a restricted maximum likelihood (REML) based repeated measures approach, 
without imputation. The model will include all participants in the safety population. The 
dependent variable will be the observed change from baseline with respect to each 
outcome at each post-randomization visit.  
9.1.1 Efficacy Analysis Model 
A Mixed Model Repeated Measures (MMRM) analysis will be performed for the change 
from baseline in separate, independent models for each endpoint. The model will include 
all participants in the safety population, and the dependent variable will be the observed 
change from baseline the outcome of interest at each post-randomization visit. Covariates 
in the model will include the fixed categorical effects of treatment group exposure, site, 
sex, visit and treatment group by visit interaction, as well as the continuous fixed 
covariates of baseline score and baseline score by visit interaction. An unstructured 
covariance matrix will be used to model the within-subject variance-covariance errors. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom.  Should the unstructured model fail to converge, an autoregressive AR(1) 
covariance structure will be attempted, then finally compound symmetric should AR(1) 
not converge. 
The least squares means and 95% confidence intervals (CIs) will be calculated for the 
treatment difference between the subjects that received TNX-102 SL in a prior study and 
those that did not. 
These endpoints to be analyzed with this model will include: 
 CGI-I score. 
 Change from baseline in SDS total.  
 Change from baseline in participants
Sleep Disturbance scale.  
 Change from baseline in the disruption of work/school activities assessed 
using the SDS.  
 Change from baseline in disruption of social life/ leisure activities assessed 
using the SDS. 
 Change from baseline in the disruption of family life/home responsibilities 
assessed using the SDS. 
 Change from baseline in BDI-II score. 
The model will be changed to include the corresponding baseline value of each the 
endpoints. To estimate the difference between the treatment arms in CGI-I score (which 
does not have baseline assessments), the same method will be used, however, with the 
observed baseline response and associated interactions removed from the list of 
covariates. All visits will be included in the analysis. P-values from these comparisons 
will be considered nominal. 


Protocol: TNX-CY-P306                                                                                 Page 20 of 36 
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For each outcome, descriptive statistics (mean, SD, median, minimum and maximum) 
will be reported as well as LS means, standard error (SE) and p-values comparing the 
arms at each visit.  In addition, for the SDS, the frequency of participants not working or 
attending school due to reasons unrelated to PTSD will be reported overall and within 
each visit. 
9.1.2 Categorical outcomes 
The proportion of responders (participants with a CGI-
) over time will be reported with the number and percentage of 
participants in each group (participants that received TNX-102 SL in a prior study and 
those that did not). Participants with missing data will be analyzed as though they are 
non-responders. A difference in proportions Z-test and the corresponding two-sided 95% 
CIs will also be reported.  Two-sided p-values for the test of no difference between the 
groups will be provided. 
10. SAFETY AND TOLERABILITY ANALYSIS 
The safety analysis will be run on the Safety Population.  The analysis of safety 
assessments in this study will include summaries of the following safety and tolerability 
data collected for each participant: 
 Adverse Events 
 Clinical Laboratory Investigations  
 C-SSRS 
 Vital Signs  
 Visual Examinations of Oral Cavity 
 BDI-II 
Summaries of continuous parameters will include raw values and change from baseline, 
as appropriate. Listings of safety data will also be presented. 
Analyses in this Section 10 will be based on data collected in Study TNX-CY-P306.  
Long-term safety analyses that span subject data from TNX-CY-P301, TNX-CY-P303, 
and TNX-CY-P306 are addressed in Section 12. 
10.1 Adverse Events 
All AEs will be coded using MedDRA, version 19.0. 
Newly emergent adverse events (NEAEs) are defined as any new AE that started after the 
 study drug in Study TNX-CY-P306, or any unresolved AE first 
reported in Study TNX-CY-P301 or Study TNX-CY-P303 that exhibited an increase in 
Study TNX-CY-P306 
had begun. For clarity, adverse events are classified as NEAEs based on a negative response 
to the 
.  
An AE summary table will be presented for the following: 
 NEAEs by severity 


Protocol: TNX-CY-P306                                                                                 Page 21 of 36 
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 NEAEs leading to study drug discontinuation  
 NEAEs by relationship 
 SAEs 
 Oral Cavity NEAEs 
Summaries of incidence rates (frequencies and percentages) of individual AEs by 
MedDRA SOC and preferred term will be prepared.  Such summaries will be displayed 
for all NEAEs, NEAEs by maximum severity, NEAEs by strongest relationship to study 
drug, and oral cavity NEAEs.  Incidence of oral cavity NEAEs will be presented by 
category and preferred term, rather than SOC and preferred term. 
Each participant will be counted only once within each summation level (SOC; preferred 
term). If a participant experiences more than one NEAE within each summation level 
only, the NEAE with the strongest relationship or the maximum severity, as appropriate, 
will be included in the summaries of relationship and severity. 
Oral cavity adverse events will be defined by a custom MedDRA query (CMQ). These 
events will be further divided into 4 categories, as follows: 1) Sensory 2) Discomfort 3) 
Irritation/inflammation and 4) Lesions. Each category will be defined by a CMQ.   
Additionally, a summary of the Oral Cavity AE characteristics will be presented; this 
includes information such as temporal proximity to the dose, duration and whether the 
AE was present the following morning.  For purposes of this summary, only oral cavity 
NEAEs with the  
CRF 
 will be 
included.   
NEAEs pertaining to abuse potential will be reported by SOC and preferred term, and 
displayed in tabular format. Terms to be included may be found in Appendix 3. 
In the AE data listings, all AEs collected in study TNX-CY-P306 will be displayed.  AEs 
that are newly-emergent will be flagged. 
10.1.1 Adverse Events Leading to Discontinuation of Study Drug  
A summary of incidence rates (frequencies and percentages) of NEAEs leading to 
discontinuation of study drug by SOC and preferred term will be prepared for the Safety 
population.  
A data listing of AEs leading to discontinuation of study drug will also be provided, 
displaying details of the event(s) captured on the CRF. 
10.1.2 Serious Adverse Events 
A summary of incidence rates (frequencies and percentages) of newly-emergent SAEs by 
SOC and preferred term will be prepared for the Safety Population.  A data listing of all 
SAEs will also be provided, displaying details of the event(s) captured on the CRF. 
10.1.3 Deaths 
A listing of deaths will also be provided for the Safety Population. 


Protocol: TNX-CY-P306                                                                                 Page 22 of 36 
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10.2 Clinical Laboratory Evaluations 
Laboratory data include analyses for Chemistry and Hematology and will be summarized 
by visit for the Safety Population.  Descriptive summaries of actual values and change 
from baseline will be presented by study visit. 95% confidence intervals will be presented 
for change from baseline for each visit. ET data will be analyzed with the closest visit 
that does not have a valid assessment value. 
Laboratory values will be displayed in the data listings and those that are outside the 
normal range 
will be flagged, along with corresponding normal ranges.  
Values pre-defined as potentially clinically significant 
flagged.  For each laboratory analysis, shifts in assessments of abnormality from baseline 
to each scheduled time point will be presented in shift tables.   
A by-participant listing of all clinical laboratory data will also be provided. 
10.3 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument that measures suicidal ideation and behavior.  Items 
measuring suicidal ideation and suicidal behavior are displayed in the table below.  
Frequency counts of yes/no responses to items below and whether any suicidal ideation 
or behavior is present will be summarized as described below.  
The overall number of participants with any suicidal ideation or behavior (by type and in 
total) or self-injurious behavior while on-treatment will be provided by treatment group.  
For ideation, participants will only be counted once at each visit and/or time frame at the 
worst-case response for ideation type (1-5), where 1 is the least severe and 5 is the most 
severe type of ideation.      
Category
Items 
A) Suicidal 
Ideation 
(1) Type 1:  Wish to be dead
(2) Type 2:  Non-specific active suicidal thoughts
(3) Type 3:  Active suicidal ideation with any methods (not plan) 
without intent to act
(4) Type 4:  Active suicidal ideation with any some intent to act, 
without specific plan 
(5) Type 5:  Active suicidal ideation with specific plan and intent 
 
B) Suicidal 
Behavior 
(1) Preparatory acts or behavior 
(2) Aborted attempt 
(3) Interrupted attempt
(4) Actual attempt
(5) Completed suicide
Suicidal Behavior present (composite of items 1-5) 
Non-Suicidal Self-Injurious Behavior 
Suicidal intensity of ideation will be calculated by tallying up the five intensity items to 
create a total score ranging 0-25.  If a participant does not have any suicidal ideation, a 
score of 0 will be given.  Separate tables will be created for the entire Safety Population 


Protocol: TNX-CY-P306                                                                                 Page 23 of 36 
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as well as the population comprising only participants exhibiting any suicidal ideation.  
Suicidal intensity of ideation total score will be summarized using descriptive statistics 
by treatment group. 
A data listing of C-SSRS results will include only participants with suicidal ideation, 
suicidal behavior, or self-injurious behavior without suicidal intent.  For participants with 
suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent at 
any time, data from all visits are displayed. 
10.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values 
and change from baseline at each assessment time point and last on-treatment assessment 
will be calculated for vital signs including weight, BMI, body temperature, pulse rate, 
systolic blood pressure and diastolic blood pressure. 95% confidence intervals will be 
presented for change from baseline. 
These summaries will be presented by assessment time for the Safety Population.  ET 
data will be analyzed with the closest visit that does not have a valid assessment value. 
10.5 Visual Examination of Oral Cavity 
A visual examination of the oral cavity will be assessed at Baseline and Week 12.  A 
visual examination is to be done any time a participant spontaneously reports an oral 
adverse event (aside from AEs known to be sensory-only, such as numbness, tingling or 
bitter taste) to confirm presence or absence of any signs of irritation or other visible 
abnormalities.  A data listing of the visual examination results performed at each 
scheduled visit and at the time of an adverse event will be presented. 
11. MEDICATIONS 
11.1 Concomitant Medication 
All medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) Version September 2016.  Prior and concomitant medications will be 
summarized by treatment group and by the number and percentage of participants taking 
each medication, classified by using WHO-DD Anatomical Therapeutic Chemical 
Level 3 and preferred term.  
Prior medications are defined as medications or therapies initiated prior to the start of the 
study drug and terminating prior to the start of study drug in protocol P301.  Hence, these 
medications or therapies will have end dates prior to the first dose date of study drug.  
Concomitant medications are defined as any medications other than the study drug that a 
participant receives concurrently with the study drug.  These medications will have end 
dates on or after the first dose date of the study drug until ten days after last dose date.   
There should be no new prior medications recorded in protocol P306 as these should be 
captured entirely in P301.  Concomitant medications will be summarized ATC Level 3 
and preferred name.  All medications will be presented in a listing.  
Please refer to Section 7.3 for the conventions used to impute partial start dates and end 
dates of concomitant medications.  


Protocol: TNX-CY-P306                                                                                 Page 24 of 36 
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11.2 Exposure and Compliance 
The treatment duration will be calculated as (number of days=last dose date 
 first dose 
date+1) and summarized.  Participants that are lost to follow up or have a missing last dose 
date will be assigned a last dose date of the day before the last attended clinic visit for 
analysis purposes.    
All pill count shortage (negative pill count) of greater than 4 doses (8 tablets) per 4-week 
assessment period and/or any between-visit compliance <70% will be considered protocol 
deviations, and the reason for the pill count discrepancy will be discussed with the 
participant and documented in the CRF to ensure that any cases of potential abuse or misuse 
are identified.  Participants with more than one significant incidence of negative pill count 
discrepancy during the double-blind phase of the study will be closely monitored by the 
investigator.  
Exposure in P306 will be measured using the last date of treatment and first date of 
treatment.  Total exposure will be defined as the last date of treatment minus the first date 
of treatment plus one.  The number of participants with total exposure by visit weeks (eg, 
0 -12 weeks, >=12  24 weeks, >=24  36 weeks, >=36  48 weeks, and >=48 weeks) will 
be presented.  Additionally, exposure days, defined as the total number of tablets taken 
divided by 2 (and rounded up to the nearest whole number), will be summarized.   
Compliance will similarly be summarized across all study visits for each treatment arm.  
Study drug compliance as a percentage will be defined as the number of pills taken by the 
participant divided by the total number of pills that the participant was assigned to take 
multiplied by 100.   
For calculating the compliance and exposure days, the following convention will be 
applied:  for periods where drug is issued, but the participant does not return any bottles 
or tablets, or the participant misses the visit entirely, that period will not contribute to the 
compliance or exposure calculation unless the bottles are returned at a later visit. 
Compliance will be summarized with descriptive statistics by treatment arm.  The 
number and percentages of participants within certain categories of compliance e.g. 
<50%, 50% to <70%, 70% to 100%, >100% will be presented. Compliance between 
70% to 114% will not be considered a protocol deviation.  Tablet counts, calculation of 
compliance overall and by visit, and participant-reported reasons for all tablet 
discrepancies at all visits will be presented in a listing.  
In addition, participants with significant over-usage or otherwise unaccounted-for 
missing tablets resulting in >114% compliance for any visit (e.g., failure to return 
>8 tablets per 4 week interval) will be summarized by visit and overall. These listings 
will include both the participant-reported reason for the discrepancy plus the 
Clinically significant 
drug accountability discrepancies associated with missing medication, loss of drug, or 
cases in which the PI confirms concern over drug abuse, misuse or diversion, will be 
examined and discussed in the CSR.   
12. LONG-TERM SAFETY ANALYSES 


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Select safety analyses will be conducted on the data collected across Studies 
TNX-CY-P301, TNX-CY-P303, and TNX-CY-P306 
-
.  
For purposes of clarity, only subjects in the TNX-CY-P306 Safety Population are 
included in these analyses, except where specified in Section 12.1. The purpose of this set 
of analyses is to support the long-term safety profile of TNX-102 SL 5.6 mg per day.  
Certain definitions and analyses in this Section 12 may differ from that of other sections 
in this SAP. 
All analyses will be summarized for the TNX-102 SL group only, except where specified 
in Section 12.1.  For subjects who were treated with placebo in Study TNX-CY-P301, 
analyses will exclude the subject data from Study TNX-CY-P301 (except to the extent 
the baseline record may come from Study TNX-CY-P301, as applicable). For purposes of 
Sections 12.3 and 12.4, baseline is the last assessment prior to dosing with TNX-102 SL 
for the first time. 
12.1 Long-Term Disposition 
The numbers and percentage of subjects who received study drug in each study, 
completed each study, and withdrew from each study will be tabulated, by treatment 
sequence and overall.  The number and percentage of subjects in each unique study 
sequence will also be tabulated.  This summary will be created once for the 
TNX-CY-P301 Safety Population (ie, any subject who dosed in TNX-CY-P301) and 
repeated for the TNX-CY-P306 Safety Population (ie, any subject who dosed in TNX-
CY-P306).  
12.2 Long-Term Adverse Events Analyses 
For purposes of the long-term AE analyses, treatment-emergent AEs (TEAEs) are any 
AE with an onset at the time of or following the start of treatment in any of the 3 studies 
(TNX-CY-P301, TNX-CY-P303, and TNX-CY-P306).  To align with the study-level 
CSR, any AE identified as a TEAE in the study-level CSR for study TNX-CY-P301 will 
be deemed a TEAE.   
Analyses of TEAEs will be presented only for the TNX-102 SL group.  Specifically, for 
subjects who were actually treated with placebo in Study TNX-CY-P301, any TEAEs 
collected in Study TNX-CY-P301 would be disregarded; only TEAEs that are 
newly-emergent in Studies TNX-CY-P303 or TNX-CY-P306 would be included.  For 
subjects treated with TNX-102 SL in Study TNX-CY-P301, any AE identified in either 
the TNX-CY-P303 or TNX-CY-P306 database will be deemed treatment-emergent and 
eligible for inclusion in analyses, unless the start date is collected and is prior to the 
treatment start date in TNX-CY-P301. 
An overall summary of AEs will summarize the number and percentage of subjects with 
any TEAE, nonfatal serious TEAE, TEAE leading to death, TEAE by maximum severity, 
TEAE by maximum relationship, TEAE leading to dose interruption, TEAE leading to 
dose reduction, TEAE leading to study drug discontinuation, or oral cavity TEAE (see 
definition below in this section) by category, in the long-term analysis period.  
The following analyses of TEAEs will be completed: 
 Overall summary of TEAEs 






Protocol: TNX-CY-P306                                                                                 Page 28 of 36 
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peak AST vs. peak total bilirubin, as well as for the greater of peak AST and peak ALT 
vs. peak total bilirubin.  


Protocol: TNX-CY-P306                                                                                 Page 29 of 36 
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12.5 Long-Term Exposure 
Summary statistics will be presented for duration of exposure (days and weeks) in the 
long-term analysis period, defined as the [last dose date of TNX-102 SL  first dose date 
of TNX-102 SL + 1], for TNX-102 SL.  Duration of treatment (weeks) will also be 
summarized as categorical measures (eg, 0 -12 weeks, >=12  24 weeks, >=24  36 
weeks, >=36  48 weeks, and >=48 weeks).  
13. CHANGES FROM PLANNED ANALYSIS 
Study day as it appears in data listings and the Study Data Tabulation Model (SDTM) 
and Analysis Data Model (ADaM) datasets will differ from the protocol:  The protocol 
 
 


Protocol: TNX-CY-P306                                                                                 Page 30 of 36 
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14. REFERENCES 
Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics, U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), February 2010. 
January 2017 Assessment of Abuse Potential for Drugs  Guidance for Industry 
TNX-CY-P303: A 12-Week Open-Label Extension Study to Evaluate TNX-102 SL 
Taken Daily at Bedtime in Patients with PTSD (17MAR2017); Amendment 1, Dated 
31MAR2017. 
Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ. Venlafaxine 
extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled 
study. J Clin Psychopharmacol. 2006;26(3):259-67. 
Galati, S. (2023
 
Krystal JH, Rosenheck RA, Cramer JA, Vessicchio JC, Jones KM, Vertrees JE, Horney 
RA, Huang GD, Stock C; Veterans Affairs Cooperative Study No. 504 Group. 
Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic 
military service-related PTSD: a randomized trial. JAMA. 2011;306(5):493-502. 
Sheehan KH & Sheehan DV. Assessing treatment effects in clinical trials with the Discan 
metric of the Sheehan Disability Scale. Int Clin Psychopharmacol 2008:23:70-83.  
Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using Controlled Clinical 
Trials to Learn More About Drug-Induced Liver Injury. Hepatology. 2008, 48:1680-
1689. 
Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx, et al. The Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5). 2013: Instrument available from the 
National Center for PTSD at www.ptsd.va.gov.  


Protocol: TNX-CY-P306                                                                                 Page 31 of 36 
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15. APPENDICES 
15.1 Appendix 1 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation 
with common notations. 
15.1.1 General Reporting Conventions 
 All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a clinical study report (CSR). 
 Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR. 
 Legends will be used for all figures with more than one variable or item 
displayed. 
 Figures will be in black and white, unless color figures have been identified as 
useful for discriminating presentation in the figure.  Lines in figures should be 
wide enough to view the line after being photocopied.  
 Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
 Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing. 
Hexadecimal character representations are allowed (e.g., , , ). 
 All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, listings, and graphs (TLGs). 
 All footnotes will be left justified at the bottom of a page.  Footnotes must be 
present on the page where they are first referenced.  Footnotes should be used 
sparingly and must add value to the TLG.  If more than four footnote lines are 
planned then a cover page may be used to display footnotes. 
 Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
 All date values will be presented as YYYY-MM-DD (e.g., 2001-10-17) 
format.  A four-digit year is preferred for all dates. 
 All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study.  
 Time durations will be reported in mixed HHhr MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 


Protocol: TNX-CY-P306                                                                                 Page 32 of 36 
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durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
 All TLGs will have the name of the program, location, programmer, and a 
date stamp on the bottom of each output.  
 All analysis programs developed for a TLG display will be self-contained to 
facilitate transfer of programs to multiple computing environments and 
transfer to a regulatory agency (if requested).  
15.1.2 Population Summary Conventions 
 Population(s) represented on the tables or data listings will be clearly 
identical in name to that identified in the protocol or SAP. 
 Consistent terminology will be used to define and identify a population.  
Common nomenclature may include (a) All Participants, (b) ITT, (c) Safety, 
and (d) PP. 
 Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., MITT >60 years of 
age) used for analysis in a table or figure. 
 Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
 Population sizes shown with summary statistics are the samples sizes (n) of 
Participants with non-missing values.  
 All population summaries for categorical variables will include all categories 
that were planned and for which the Participants may have had a response.  
Percentages corresponding to null categories (cells) will be suppressed. 
 All population summaries for continuous variables will include: n, mean, SD, 
minimum, and maximum.  Other summaries (e.g. number missing, median, 
quartiles, 95% confidence intervals, CV or %CV) may be used as appropriate. 
 All percentages are rounded and reported to a single decimal point (xx.x%).  
A percentage of 100% will be reported as 100%.  A percentage of zero will be 
reported as 0. 
 Population summaries that include P values will report the P value to 
three decimal places with a leading zero (0.001).  All P values reported on 
default output from statistical software (i.e., SAS® Software) may be reported 
at the default level of precision. P values <0.001 should be reported as <0.001 
not 0.000. 
 


Protocol: TNX-CY-P306                                                                                 Page 33 of 36 
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15.2 Appendix 2: PROMIS T-score Conversions 
 
 


Protocol: TNX-CY-P306                                                                                 Page 34 of 36 
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15.3 Appendix 3:  Abuse Terms   
The following preferred terms will be used to identify AEs potentially related to abuse. 
Category 
MedDRA Preferred Term  
Central nervous system depression 
terms 
 
Bradyphrenia 
Depression 
Dysphoria 
Hypersomnia 
Hypersomnia related to another mental condition 
Infant sedation 
Neonatal oversedation 
Post-injection delirium sedation syndrome 
Sedation* 
Sedation complication 
Sedative therapy 
Somnolence* 
Somnolence neonatal 
Stupor 
Central nervous system stimulation 
terms 
 
Affect lability 
Aggression 
Agitation 
Anxiety 
Disinhibition 
Energy increased 
Feeling jittery 
Flight of ideas 
Hypervigilance 
Irritability 
Psychomotor hyperactivity 
Restlessness 
Dissociative/psychotic-related terms 
 
Abnormal behaviour 
Acute psychosis 
Amnesia 
Delirium 
Delusion 
Delusion of grandeur 
Delusional perception 
Depersonalisation 
Depersonalisation/derealisation disorder 
Derealisation 
Disturbance in attention 


Protocol: TNX-CY-P306                                                                                 Page 35 of 36 
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Hallucination
Hallucination, auditory 
Hallucination, gustatory 
Hallucination, olfactory
Hallucination, synaesthetic 
Hallucination, tactile 
Hallucination, visual 
Hallucinations, mixed 
Hypnagogic hallucination 
Hypnopompic hallucination 
Mixed delusion 
Psychotic disorder 
Sensory disturbance 
Substance-induced psychotic disorder 
Thinking abnormal 
Transient psychosis 
Euphoria-related terms 
Elevated mood 
Euphoric mood 
Feeling drunk 
Feeling of relaxation 
General terms  
Dependence 
Drug abuse 
Drug abuser 
Drug dependence 
Drug dependence, antepartum 
Drug dependence, postpartum 
Drug diversion 
Drug use disorder 
Drug use disorder, antepartum 
Drug use disorder, postpartum 
Drug withdrawal convulsions 
Drug withdrawal headache 
Drug withdrawal maintenance therapy 
Drug withdrawal syndrome 
Drug withdrawal syndrome neonatal 
Substance abuse 
Substance abuser 
Substance dependence 
Substance use disorder 
Withdrawal arrhythmia 
Withdrawal catatonia 
Withdrawal hypertension 


Protocol: TNX-CY-P306                                                                                 Page 36 of 36 
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Withdrawal syndrome
Terms not captured elsewhere 
Confusional state 
Disorientation 
Emotional disorder
Feeling abnormal 
Homicidal ideation 
Inappropriate affect 
Intentional misuse of drug delivery system 
Intentional product misuse 
Logorrhoea 
Mania 
Memory impairment 
Mental disorder 
Mood altered 
Mood disorder due to a general medical condition 
Mood swings 
Overdose 
Prescription form tampering 
Product tampering 
Substance-induced mood disorder 
Suicidal ideation 
Suspected product tampering 
*Anticipated drug effects 
Note: Terms are 
2023.)